WO2015140717A1 - Novel 3-indol substituted derivatives, pharmaceutical compositions and methods for use - Google Patents

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

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WO2015140717A1
WO2015140717A1 PCT/IB2015/051957 IB2015051957W WO2015140717A1 WO 2015140717 A1 WO2015140717 A1 WO 2015140717A1 IB 2015051957 W IB2015051957 W IB 2015051957W WO 2015140717 A1 WO2015140717 A1 WO 2015140717A1
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Prior art keywords
fluoro
indol
benzo
alkyl
mmol
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PCT/IB2015/051957
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French (fr)
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WO2015140717A9 (en
Inventor
Sandra CAUWENBERGHS
Stefano Crosignani
Gregory DRIESSENS
Frederik Deroose
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Iteos Therapeutics
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Priority claimed from BE2014/0776A external-priority patent/BE1021253B1/en
Application filed by Iteos Therapeutics filed Critical Iteos Therapeutics
Priority to CA2942761A priority Critical patent/CA2942761A1/en
Priority to JP2016557605A priority patent/JP2017507983A/en
Priority to EP15714653.1A priority patent/EP3119763A1/en
Publication of WO2015140717A1 publication Critical patent/WO2015140717A1/en
Priority to BR112017019699-9A priority patent/BR112017019699A2/en
Priority to CA2979616A priority patent/CA2979616C/en
Priority to CN201680028408.7A priority patent/CN107635990A/en
Priority to US15/072,534 priority patent/US9873690B2/en
Priority to PCT/IB2016/051509 priority patent/WO2016147144A1/en
Priority to KR1020177029203A priority patent/KR102013512B1/en
Priority to JP2017548261A priority patent/JP6775516B2/en
Priority to MX2017011951A priority patent/MX2017011951A/en
Priority to RU2017130845A priority patent/RU2672252C1/en
Priority to EP16711022.0A priority patent/EP3271354A1/en
Priority to AU2016231832A priority patent/AU2016231832B2/en
Priority to SG11201706992TA priority patent/SG11201706992TA/en
Publication of WO2015140717A9 publication Critical patent/WO2015140717A9/en
Priority to IL254124A priority patent/IL254124A0/en
Priority to HK18103418.8A priority patent/HK1243999A1/en

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Definitions

  • the present invention relates to novel 3-(indol-3-yl)-pyridine derivatives, including pharmaceutically acceptable enantiomers, salts and solvates thereof.
  • Compounds of the invention are inhibitors of TDO2 (tryptophan 2,3-dioxygenase) and are useful as therapeutic compounds, particularly in the treatment and/or prevention of cancers.
  • 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).
  • cancer cells 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).
  • epithelial cells e.g., syncytiotrophoblasts in the placenta
  • tryptophan 2,3-dioxygenase which is considered responsible for regulating systemic tryptophan levels in the liver
  • TDO2 tryptophan 2,3-dioxygenase
  • 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
  • pancreatic carcinoma Pancreatic carcinoma
  • TDO2 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, 201 1 , 478(7368), 197-203).
  • the first evidence for this was provided through inhibition of TDO2 by a small molecule which inhibited tumor growth in a P815 mastocytoma tumor model with a prophylactic vaccination approach (Pilotte L et al., Proc Natl Acad Sci U S A, 2012, 109(7), 2497- 502).
  • P815mTDO2 expressing tumors were rejected less in comparison to P815 tumors transfected with an empty vector, clearly demonstrating a growth benefit for TDO2 expressing tumors.
  • TDO2 inhibitor Inhibition with a TDO2 inhibitor strongly decreased tumor growth in P815mTDO2 implanted tumors. Anti-tumor activity with the TDO2 inhibitor was equally observed in the P815 control implanted tumors negative for TDO2, thus providing evidence for an effect of TDO2 expressed in the immune system of the animal.
  • TDO2 In line with its expression profile in liver, TDO2 was found predominantly in
  • HCC hepatocellular carcinoma
  • RNA expression is a good indication for therapeutic evaluation of TDO2 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 TDO2 activity modulation in the control of liver tumor development.
  • TDO2 is expressed in neurons, microglia and astrocytes and the potential benefit of TDO2 inhibition in the context of glioma was shown in another animal model.
  • Platten and collaborators demonstrated that the 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, 201 1 , 478(7368), 197-203).
  • the TDO-AHR pathway is active in human brain tumors and is associated with malignant progression and poor survival.
  • TDO2 imRNA tumor types in which TDO2 imRNA 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 TDO2 targeting beyond HCC and glioma (Pilotte L et 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 TDO2 targeting in those cancers Sperner-Schweger B et al, Immunology, 201 1 , 216 (3); 296-301 ).
  • IDO1 indoleamine 2,3-dioxygenase
  • 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.
  • IFN- gamma inflammatory mediators
  • 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 (Dolusic E and Frederick R., Expert Opin Ther Pat., 2013, 23(10), 1367-81 ).
  • TDO2 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): 121 1 -27; Wu et al, 2013, Plos One, 8(4):e59749; Fuvesi et al, 2012, J Neural Transm, 1 19(2):225-34; Widner et al, 2002, J Neural Transm, 109(2):181 -9; Comings et al, 1996, Pharmacogenetics,
  • TDO2 inhibitors were proposed in WO2010/008427 and by Dolusic, E. et al.
  • the present invention provides new TDO2 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 TDO2, 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.
  • a compound of Formula I is provided or a pharmaceutically acceptable salt, solvent or solvate thereof, where A1 , A2, A3, Y1 , Y2, Y4, R1 , R2, R3, X1 and X3 are as defined herein.
  • a first one of A 1 , A 2 and A 3 is N, a second one of A 1 , A 2 and A 3 is C and the third one of A 1 , A 2 and A 3 is N or O.
  • a 2 is N and one of A 1 and A 3 is N or S and the other is C.
  • a 1 or A 3 is S, A 1 -Y 1 or A 3 -Y 3 is SO 2 .
  • a 2 is C and one of A 1 and A 3 is N and the other is N or O.
  • a 1 or A 3 is O, and C is substituted with CR 6 R 7 R 8 as defined herein and one of R 6 , R 7 , R 8 is a 1 .
  • A1 or A3 is O, and C is substituted with CR 6 R 7 R 8 and R 6 , R 7 or R 8 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, COCH 3 , COOH, or SO 2 CH 3 .
  • one of A 1 , A 2 or A 3 is S or A 1 -Y 1 , A 2 -Y 2 , or A 3 -Y 3 is SO 2 ; one of A 1 , A 2 or A 3 is N or C and one of A 1 , A 2 and A 3 is C.
  • X 1 and X 2 are independently H or F.
  • R 1 , R 2 and R 3 represent each independently H, halogen or methyl, or may each be H.
  • a pharmaceutical composition 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.
  • a medicament which comprises a compound according to Formula I, or a pharmaceutically acceptable enantiomer, salt or solvate thereof.
  • 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 TDO2 inhibitor.
  • a method of treating and/or preventing of cancer 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 TDO2 inhibitor.
  • the method comprises administering a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • a process for manufacturing a compound of Formula I or a pharmaceutically acceptable enantiomer, salt or solvate thereof comprises:
  • X 1 and X 2 represent each independently H, halogen, alkyl, haloalkyl
  • Z 1 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)
  • R 1 , R 2 , R 3 , A 1 , A 2 , A 3 , Y 1 , Y 2 and Y 3 are as defined herein; and Z 2 and Z 3 represent H or alkyl groups, with the possibility for Z 2 and Z 3 to form a ring; so as to obtain a compound of Formula (iii),
  • X 1 and X 2 represent each independently H, halogen, alkyl, or haloalkyl
  • R 1 , R 2 and R 3 represent each independently H, halogen, C1 -C6 alkyl, alkoxy, or haloalkyl, optionally substituted by one or more substituents selected from halogen, hydroxyl, OR 4 , COOR 4 , CONR 4 R 5 , NR 4 COR 5 , NR 4 R 5 , SO 2 R 4 , SO 2 NR 4 R 5 , NR 4 SO 2 R 5 , SO 2 R 4 , aryl, CO-alkyl, or C1 -C6 alkyl which is optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 4 and R 5 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino;
  • a 1 , A 2 and A 3 represent each independently C, N, S or O, wherein when A 1 , A 2 or A 3 is S, A 1 -Y 1 , A 2 -Y 2 or A 3 -Y 3 is optionally SO 2 ; each of Y 1 , Y 2 and Y 3 is either absent or represent independently
  • R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6.
  • R 11 represents a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyi, alkylaryl, heteroaryl, heteroarylalkyi, alkylheteroaryl, hydroxyl, or amino; v) C1 -C10 alkyl, linear or branched; optionally substituted with up to three substituents selected from halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SOR 9 , aryl, or CO-alkyl, wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyi, alkylaryl, heteroaryl, heteroarylalkyi, alkylhetero
  • heterocyclyl substituted, selected from C1 -C6 alkyl, heterocyclyl, aryl, arylalkyi, alkylaryl, heteroaryl, heteroarylalkyi, alkylheteroaryl, or amino; vi) heterocyclyl or C1 -C2 alkyl - heterocyclyl; wherein the heterocyclyl is optionally substituted with up to three substituents halogen, hydroxyl, oxo, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO-alkyl, or alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1
  • X 1 and X 2 represent each independently H, halogen, alkyl, haloalkyi, preferably H or F;
  • R 1 , R 2 and R 3 represent each independently H, halogen, C1 -C6 alkyl, alkoxy, haloalkyi, optionally substituted by one or more substituents selected from the group comprising halogen, hydroxyl, OR 4 , COOR 4 , CONR 4 R 5 , NR 4 COR 5 , NR 4 R 5 , SO 2 R 4 , SO 2 NR 4 R 5 , NR 4 SO 2 R 5 , SO 2 R 4 , aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 4 and R 5 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
  • R 1 , R 2 and R 3 represent each independently H, halogen or alkyl, preferably R 1 , R 2 and R 3 represent each independently H, halogen or methyl, preferably R 1 , R 2 and R 3 represent each H; A 1 , A 2 and A 3 represent each independently C, N or O; each of Y 1 , Y 2 and Y 3 is either absent or represent independently
  • R 6 , R 7 and R 8 represent each independently:
  • R 9 and R 10 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, SO 2 R 11 , wherein R 11 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
  • NR 9 COR 10 NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SOR 9 , aryl, CO- alkyl
  • R 9 and R 10 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, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO- alkyl,
  • R 11 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, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SOR 9 , aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl
  • ring being preferably selected from: cycloalkyl, optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; hetero
  • R 12 and R 13 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 A 1 , A 2 and A 3 are not all C; provided that when one of A 1 , A 2 and A 3 is N, the two others are not both C; provided that compound of Formula I is not 3-(benzofuran-5-yl)-6-chloro-1 /-/-indole or 3- (benzo[d][1 ,3]dioxol-5-yl)-1 H-indole.
  • 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.
  • X 1 and X 2 represent each independently H or halogen, preferably H or F. According to a specific embodiment, X 1 represents H and X 2 represents F. According to a preferred embodiment, in Formula I, R 1 , R 2 and R 3 represent each H.
  • X 1 and X 2 represent each independently H or halogen and R 1 , R 2 and R 3 represent each H; preferably X 1 represents H and X 2 represents F and R 1 , R 2 and R 3 represent each H
  • a first one of A 1 , A 2 and A 3 is N
  • a second one of A 1 , A 2 and A 3 is C
  • the third one of A 1 , A 2 and A 3 is N or O.
  • a 2 is N and one of A 1 and A 3 is N or S r and the other is C. According to one embodiment, in Formula I, A 2 is C and one of A 1 and A 3 is N and the other is N or O.
  • a 1 or A 3 is O, and C is substituted with CR 6 R 7 R 8 and R 6 , R 7 or R 8 is heterocyclyl or C1 -heterocycyl
  • the heterocyclyl is piperidine, pyrrolidine, piperazine, morpholine, or2,6-diazaspiro[3.3]heptane, any of which may be optionally substituted with one or more of C1 -C3 alkyl, amino, hydroxyl, halogen, COCH 3 , COOH, or SO 2 CH 3 .
  • a 1 or A 3 is S, A 1 -Y 1 or A 3 -Y 3 is SO 2 .
  • one of A 1 , A 2 or A 3 is S or A 1 -Y 1 , A 2 -Y 2 , or A 3 -Y 3 is SO 2 ; one of A 1 , A 2 or A 3 is N or C and one of A 1 , A 2 and A 3 is C.
  • preferred com ounds of Formula I are those of Formula 11-1
  • a 1 and A 3 are not both C.
  • one of A 1 and A 1 is S and the other is C, A 1 -Y 1 or A 3 -Y 3 is optionally SO 2 , and the C is optionally substituted with oxo.
  • preferred com ounds of Formula I are those of Formula II-2
  • ⁇ A 1 , A 3 ⁇ are not ⁇ C, N ⁇ , ⁇ N, C ⁇ or ⁇ C, C ⁇ .
  • preferred compounds of Formula I are those of Formula 11-1 a
  • preferred com ounds of Formula I are those of Formula 11-1 b
  • preferred compounds of Formula I are those of Formula ll-2a
  • a 1 is not C.
  • preferred compounds of Formula I are those of Formula ll-2b
  • a 3 is not C.
  • preferred compounds of Formula I are those of Formula 11-1 a1
  • Y 1 represents H and Y 3 is as defined in Formula I, preferably, Y 3 represents:
  • R 6 , R 7 and R 8 represent each independently:
  • NR 9 COR 10 NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SOR 9 , aryl, CO-alkyl, wherein R 9 and R 10 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, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO- alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; • -CO-R 11 wherein R 11 represents a group selected from amine, alkyl
  • NR 9 SO 2 R 10 SOR 9 , aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
  • preferred compounds of Formula I are those of Formula 11-1 a2
  • R 6 , R 7 and R 8 represent each independently:
  • NR 9 COR 10 NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SOR 9 , aryl, CO-alkyl, wherein R 9 and R 10 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, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO- alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
  • amine alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 ,
  • NR 9 SO 2 R 10 SOR 9 , aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH;
  • R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; • R 6 , R 7 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, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10
  • preferred compounds of Formula I are those of Formula 11-1 b1
  • Il-1 b1 and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X 1 , X 2 , R 1 , R 2 , R 3 , Y 1 and Y 3 are as defined in Formula I.
  • Y 3 represents H and Y 1 is as defined in Formula I, preferably, Y 1 represents:
  • R 6 , R 7 and R 8 represent each independently:
  • NR 9 COR 10 NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SOR 9 , aryl, CO-alkyl, wherein R 9 and R 10 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, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO- alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
  • R 11 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, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 ,
  • NR 9 SO 2 R 10 SOR 9 , aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
  • N-1 b2 and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X 1 , X 2 , R 1 , R 2 , R 3 , Y 2 and Y 3 are as defined in Formula I.
  • Y 3 represents H and Y 2 is as defined in Formula I, preferably, Y 2 represents:
  • R 6 , R 7 and R 8 represent each independently:
  • NR 9 COR 10 NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SOR 9 , aryl, CO-alkyl, wherein R 9 and R 10 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, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO- alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; • -CO-R 11 or -SO 2 R 11 wherein R 11 represents a group compris
  • NR 9 SO 2 R 10 SOR 9 , aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
  • preferred compounds of Formula I are those of Formula Il-2a1
  • Il-2a1 and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X 1 , X 2 , R 1 , R 2 , R 3 , Y 1 and Y 2 are as defined in Formula I.
  • Y 1 represents H and Y 2 is as defined in Formula I, preferably, Y 2 represents:
  • R 6 , R 7 and R 8 represent each
  • R 11 represents a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino, CO-alkyl, SO 2 R 11 , wherein R 11 represents a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
  • NR 9 COR 10 NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SOR 9 , aryl, CO-alkyl, wherein R 9 and R 10 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, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO- alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
  • amine, alkyl, heterocyclyl preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide
  • preferred compounds of Formula I are those of Formula Il-2a2 2
  • Il-2a2 and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X 1 , X 2 , R 1 , R 2 , R 3 and Y 2 are as defined in Formula I.
  • Y 2 represents:
  • R 6 , R 7 and R 8 represent each
  • amine alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 ,
  • NR 9 SO 2 R 10 SOR 9 , aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.
  • preferred compounds of Formula I are those of Formula Il-2b1
  • Il-2b1 and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X 1 , X 2 , R 1 , R 2 , R 3 , Y 2 and Y 3 are as defined in Formula I.
  • Y 3 represents H and Y 2 is as defined in Formula I, preferably, Y 2 represents:
  • R 6 , R 7 and R 8 represent each independently:
  • R 11 represents a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino, CO-alkyl, SO 2 R 11 , wherein R 11 represents a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
  • R 9 and R 10 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, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO- alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and
  • R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.
  • preferred compounds of Formula I are those of Formula Il-2b2
  • Il-2b2 and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X 1 , X 2 , R 1 , R 2 , R 3 and Y 2 are as defined in Formula I, wherein the dotted line is an absent or a bond.
  • R 6 , R 7 and R 8 represent each independently:
  • heterocyclyl or C1 -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, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO- alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroary
  • R 11 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, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SOR 9 , aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalky
  • 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 CH 3 , or COOH.
  • preferred com ounds of Formula I are those of Formula Il-2b3
  • Il-2b3 and pharmaceutically acceptable enantiomers, salts and solvates thereof wherein X 1 , X 2 , R 1 , R 2 , R 3 , Y 1 , and Y 2 and Y 3 are as defined in Formula I.
  • R 1 , R 2 or R 3 are each independently H, halogen, or C1 -C6 alkyl, preferably, C1 alkyl.
  • X 1 and X 2 are independently H or halogen.
  • the compounds of Table 1 were named using ChemBioDraw ® Ultra version 12.0 (PerkinElmer).
  • the compounds of Formula I 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.
  • 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 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, laurate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate,
  • methylnitrate calcium edetate, mucate, napsylate, chloride, clavulanate, N oleate, edetate, estolate, pantothenate, polygalacuronate, salicylate, glutamate,
  • naphthylate 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, 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, 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
  • hydrochloride/chloride hydrobromide/bromide, bisulphate/sulphate, nitrate, citrate, and acetate.
  • the compounds of the invention may also form internal salts, and such compounds are within the scope of the invention.
  • 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.
  • compositions of Formula I may be prepared by one or more of these methods:
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the invention further relates to a first process for manufacturing of compounds of Formula I
  • X 1 and X 2 are as defined in Formula I;
  • Z 1 represents H or an amino protecting group such as for example an arylsulphonyl, a te/t-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)
  • R 1 , R 2 , R 3 , A 1 , A 2 , A 3 , Y 1 , Y 2 and Y 3 are as defined in Formula I;
  • Z 2 and Z 3 represent H or alkyl groups, with the possibility for Z 2 and Z 3 to form a ring; so as to obtain a compound of Formula (iii),
  • step (a1 ) of the process of the invention may be performed with or without a catalyst such as but not limited to Pd 2 (dba) 3 , Pd(PPh 3 ) 4 , dichlorobis(triphenylphosphine)palladium(ll) or 1 ,1 '-bis(diphenylphosphino)ferrocene- dichloro palladium(ll), 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(oTol) 3 , PPh 3 , BINAP, P(iBu) 3 or any other suitable phosphine ligand known to those skilled in the art.
  • a catalyst such as but not limited to Pd 2 (dba) 3 , Pd(PPh 3 ) 4 , dichlorobis(triphenylphosphine)palladium(ll) or 1 ,1 '-bis(dipheny
  • step (a1 ) of the process of the invention may be performed in the presence of bases such as but not limited to K 3 PO 4 , K 2 CO 3 , Na 2 CO 3 .
  • step (a1 ) 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.
  • step (a1 ) 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.
  • the deprotection (b1 ) may be performed, depending on the nature of the group Z 1 , by treatment with bases, such as but not limited to sodium hydroxide, potassium hydroxide, potassium carbonate.
  • the deprotection may be performed in the presence or absence of a suitable solvent such as but not limited to methanol, ethanol, isopropanol, terf-butanol, THF, DMF, Dioxane, water or a mixture thereof.
  • a suitable solvent such as but not limited to methanol, ethanol, isopropanol, terf-butanol, THF, DMF, Dioxane, water or a mixture thereof.
  • 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.
  • the deprotection (b1 ) may be performed, depending on the nature of the group Z 1 in the presence of strong acids, such as but not limited to HCI, TFA, HF, HBr.
  • the deprotection may be performed in the presence or absence of a suitable solvent such as methanol, ethanol, isopropanol, te/t-butanol, THF, DMF, Dioxane, water or a mixture thereof.
  • the deprotection may be performed at a temperature between about 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
  • Y 1 , Y 2 and Y 3 represent respectively Y 1 , Y 2 and Y 3 as defined in Formula I with the condition that at least one of Y 1 , Y 2 and Y 3 is H;
  • Z 1 represents H or an amino protecting group such as for example an arylsulphonyl, a te/t-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)
  • alkylation step (a2) is performed in presence of a compound of Formula (vi) Y 4 -X
  • Y 4 represent Y 1 , Y 2 or ⁇ 3 , as defined in Formula I, with the condition that Y 4 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.
  • halogen preferably iodine, bromine or chlorine
  • alkylsulfonyloxy having 1 -6 carbon atoms preferably methylsulfonyloxy or trifluoro- methylsulfonyloxy
  • arylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy), or any other leaving group known to those skilled in the art.
  • 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 te/t-butoxide, potassium te/t-butoxide, sodium hydride, lithium diisopropyl amide, buthyl lithium.
  • bases such as but not limited to potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, sodium te/t-butoxide, potassium te/t-butoxide, sodium hydride, lithium diisopropyl amide, buthyl lithium.
  • 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, te/t-butanol, THF, dioxane, dichloromethane, water.
  • a suitable solvent such as but not limited to DMF, methanol, ethanol, isopropanol, te/t-butanol, THF, dioxane, dichloromethane, water.
  • 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.
  • 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.
  • 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.
  • 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 Il-2a1 wherein Y 1 is H:
  • Z 1 represents H or an amino protecting group such as for example an arylsulphonyl, a te/t-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 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) 2
  • 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.
  • 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.
  • step (a3) of the process of the invention may be performed in the presence of bases such as but not limited to triethylamine,
  • step (a3) of the process of the invention may be performed in the presence of a suitable solvent such as but not limited to
  • step (a3) further comprises adding a suitable acid, such as but not limited to acetic acid, wherever necessary to complete cyclization.
  • 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.
  • step (a3) 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.
  • 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 Formula I
  • Z 1 represents H or an amino protecting group such as for example an arylsulphonyl, a te/t-butoxy carbonyl, a methoxymethyl, a para-methoxy benzyl, a benzyl or any other suitable protecting group known to those skilled in the art
  • Z 2 and Z 3 represent H or alkyl groups, with the possibility for Z 2 and Z 3 to form a ring;
  • R 1 , R 2 , R 3 , A 1 , A 2 , A 3 , Y 1 , Y 2 and Y 3 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
  • halogen preferably iodine, bromine or chlorine
  • alkylsulfonyloxy having 1 -6 carbon atoms preferably methylsulfonyloxy or trifluoromethylsulfonyloxy
  • arylsulfonyloxy having 6-10 carbon atoms
  • step (b4) of the process of the invention may be performed with or without a catalyst such as but not limited to Pd2(dba)3, Pd(PPh 3 ) 4 , dichlorobis(triphenylphosphine)palladium(ll) or 1 ,1 '-bis(diphenylphosphino)ferrocene- dichloro palladium(ll), 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(oTol) 3 , PPh 3 , BINAP, P(iBu) 3 or any other suitable phosphine ligand known to those skilled in the art.
  • a catalyst such as but not limited to Pd2(dba)3, Pd(PPh 3 ) 4 , dichlorobis(triphenylphosphine)palladium(ll) or 1 ,1 '-bis(diphenylphosphin
  • step (a4) of the process of the invention may be performed in the presence of bases such as but not limited to K 3 PO 4 , K 2 CO 3 , Na 2 CO 3 .
  • 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.
  • 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.
  • 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.
  • the deprotection step (b4) may be performed in conditions described above for deprotection (b1 ).
  • 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.
  • 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.
  • acyl group is to be understood in the broadest sense in connection with the present process.
  • acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and, in particular, alkoxy-icarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups.
  • 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 (terf-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-iimore CBZ, Fmoc, benzyl and acetyl.
  • 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.
  • hydroxyl- protecting groups are, inter alia, benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p- toluenesulfonyl, terf-butyl and acetyl, where benzyl and terf-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.
  • 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.
  • 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 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 as carbon).
  • a catalyst for example a noble-metal catalyst, such as palladium, advantageously on a support, such as carbon.
  • Suitable solvents 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 ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30°C.
  • 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
  • amides such as acetamide, dimethylacetamide, A/-methylpyrrolidone (NMP) or dimethyhformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); 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.
  • NMP NMP
  • DMF dimethyhformamide
  • nitriles such as acetonitrile
  • sulfoxides such as dimethyl sulfoxide (DMSO)
  • carbon disulfide such as 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 solvent
  • Esters can be hydrolysed, for example, using HCI, H 2 SO 4 , or using LiOH, NaOH or KOH in water, water/THF, water/THF/ethanol or water/dioxane, at temperatures between 0 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 -60°C and +30°C.
  • an inert solvent such as dichloromethane or THF
  • a base such as triethylamine or pyridine
  • the invention is further directed to the use of the compounds of the invention or pharmaceutically acceptable enantiomers, salts and solvates thereof as TDO2 inhibitors.
  • 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 TDO2 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 TDO2 inhibitors.
  • 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.
  • 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.
  • the cancer may be metastatic or non-metastatic.
  • the cancer may be may be familial or sporadic.
  • 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.
  • 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
  • non-solid tumours include but are not limited to hematological neoplasms.
  • 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.
  • 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.
  • 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.
  • a method for modulating TDO2 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
  • 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.
  • 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.
  • a compound of Formula I or a pharmaceutically acceptable enantiomer, salt and solvate thereof for the manufacture of a medicament for modulating TDO2 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.
  • 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.
  • 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.
  • parenteral administration such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion
  • topical administration including ocular
  • 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;
  • 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
  • compositions 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.
  • 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, polyvinylpyrrol
  • 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, 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, 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.
  • the active compound of the invention may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion.
  • groups may be substituted, such groups may be substituted with one or more 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.
  • halogen means fluoro (F), chloro (CI), bromo (Br), or iodo (I).
  • alkyl by itself or as part of another substituent refers to a hydrocarbyl radical of Formula CnH 2 n + i wherein n is a number greater than or equal to 1 .
  • Alkyl groups may contain 1 to 10 carbons (inclusive), i.e., C1 , C2, C3, C4, C5, C6, C7, C8, C9 or C10, i.e., C1 -C10 alkyl.
  • alkyl groups of this invention comprise from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, more preferably from 1 to 3 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).
  • haloalkyi 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 haloalkyi radicals include fluoromethyl, difluoromethyl, trifluoro methyl and the like.
  • the haloalkyi is a C1 to C6 alkyl group substituted with at least one halogen.
  • the haloalkyi is a C1 to C4 alkyl group substituted with at least one halogen. Each halogen substitution may be independently selected.
  • cycloalkyi is a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated hydrocarbyl group having 1 or 2 cyclic structures.
  • Cycloalkyi includes monocyclic or bicyclic hydrocarbyl groups. Cycloalkyi 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 cycloalkyi groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, with cyclopropyl being particularly preferred.
  • heteroatom referns to a sulfur, nitrogen or oxygen atom.
  • heterocyclyl where at least one carbon atom in a cycloalkyi group is replaced with a heteroatom, the resultant ring is referred to herein as "heterocyclyl".
  • 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 1 1 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,
  • heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows.
  • 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.
  • aryl 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.
  • heteroaryl 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, quin
  • arylalkyl refers to any group -alkyl-aryl.
  • alkylaryl refers to any group -aryl-alkyl.
  • heteroarylalkyl refers to any group -alkyl-heteroaryl.
  • alkylheteroaryl refers to any group -heteroaryl-alkyl.
  • alkoxy refers to any group O-alkyl.
  • haloalkoxy refers to any group O-haloalkyl.
  • 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.
  • groups derived from -NH2 are "alkylamino" groups, i.e. N-alkyl groups, comprising monoalkylamino and dialkylamino.
  • alkylamino i.e. N-alkyl groups, comprising monoalkylamino and dialkylamino.
  • amino include NH2, NHMe or NMe2.
  • 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, te/t-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.
  • 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.
  • 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.
  • solvent molecule e.g., ethanol.
  • solvate 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.
  • solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid.
  • solvate encompasses both solution-phase and isolatable solvates.
  • Solvate may encompass solvates of salts of the compounds of Formula I.
  • hydrate refers to when the solvent molecule is water and may be an inorganic salt containing nH 2 O, wherein n is the number of water molecules per formula unit of the salt. N may be 1 ⁇ 2, 1 1 ⁇ 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.
  • 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.
  • predrug 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.
  • 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.
  • human refers to a subject of both genders and at any stage of development (i.e. neonate, infant, juvenile, adolescent, adult).
  • treat are meant to include alleviating, attenuating or abrogating a condition or disease and/or its attendant symptoms.
  • prevent refers to a method of 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.
  • therapeutically effective amount means the amount of active agent or active ingredient that is sufficient to achieve the desired therapeutic or prophylactic effect in the patient to which/whom it is administered.
  • administration 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 treated or prevented.
  • pharmaceutically acceptable is meant that the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the patient thereof.
  • pharmaceutical vehicle means a carrier or inert medium used as solvent or diluent in which the pharmaceutically active agent is formulated and/or 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.
  • the term “about” means a variability of 10 % from the reference given, unless otherwise specified.
  • MS mass spectrometry
  • 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 ⁇ , unless otherwise reported. All HPLC purifications were performed with a gradient of CH 3 CN /H 2 O/NH 4 HCO 3 (5 imM), CH 3 CN /H 2 O/TFA (0.1 %), or CH 3 CN /H 2 O/NH 3 H 2 O (0.1 %).
  • 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.
  • reaction mixture was stirred for 1 hour and quenched with saturated aqueous NaHCO 3 (30 mL).
  • the aqueous layer was extracted with DCM (70 mLx2).
  • the combined organic layers were washed with brine (20 mL), dried over anhydrous

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-(indol-3-yl)-pyridine derivatives, including pharmaceutically acceptable enantiomers, salts and solvates thereof. Compounds of the invention are inhibitors of TDO2 (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 , 1 191 - 1 193), 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 (TDO2), 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 S A, 2012, 109(7), 2497-502). TDO2 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, 201 1 , 478(7368), 197-203). The first evidence for this was provided through inhibition of TDO2 by a small molecule which inhibited tumor growth in a P815 mastocytoma tumor model with a prophylactic vaccination approach (Pilotte L et al., Proc Natl Acad Sci U S A, 2012, 109(7), 2497- 502). P815mTDO2 expressing tumors were rejected less in comparison to P815 tumors transfected with an empty vector, clearly demonstrating a growth benefit for TDO2 expressing tumors. Inhibition with a TDO2 inhibitor strongly decreased tumor growth in P815mTDO2 implanted tumors. Anti-tumor activity with the TDO2 inhibitor was equally observed in the P815 control implanted tumors negative for TDO2, thus providing evidence for an effect of TDO2 expressed in the immune system of the animal. These experiments for the first time provided clear evidence for a role of TDO2 in regulating tumor growth through expression in the cancer cell as well as immune compartment.
In line with its expression profile in liver, TDO2 was found predominantly in
hepatocellular carcinoma (HCC) (Pilotte L et 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, 201 1 , 10(9), 4120-33). In the context of liver carcinoma itself, very high RNA expression is a good indication for therapeutic evaluation of TDO2 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 TDO2 activity modulation in the control of liver tumor development.
In addition to expression in liver, TDO2 is expressed in neurons, microglia and astrocytes and the potential benefit of TDO2 inhibition in the context of glioma was shown in another animal model. Platten and collaborators demonstrated that the 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, 201 1 , 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(1 1 ), 3225-34). Here tryptophan catabolism was shown to occur in microglia cells as well. The above data thus provides evidence for TDO2 targeting in glioma with brain-penetrant small molecules.
Other tumor types in which TDO2 imRNA 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 TDO2 targeting beyond HCC and glioma (Pilotte L et 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 TDO2 targeting in those cancers (Sperner-Unterweger B et al, Immunology, 201 1 , 216 (3); 296-301 ).
The tryptophan catabolism in some cancers might be also increased by the expression of indoleamine 2,3-dioxygenase (IDO1 ) 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 (Dolusic 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 checkpoints (Holmgaard RB et al., J Exp Med., 2013, 210(7), 1389-402) or therapeutic vaccines.
In the context of neurological brain disorders, TDO2 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): 121 1 -27; Wu et al, 2013, Plos One, 8(4):e59749; Fuvesi et al, 2012, J Neural Transm, 1 19(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, 1 12(1 ):1 12-22).
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 TDO2 inhibitors were proposed in WO2010/008427 and by Dolusic, E. et al.
(Dolusic et al., J. Med. Chem., 201 1 , 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 TDO2 inhibitors with improved efficacy for cancer treatment and/or prevention.
SUMMARY OF THE INVENTION
The present invention provides new TDO2 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 TDO2, 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 A1 , A2, A3, Y1 , Y2, Y4, R1 , R2, R3, X1 and X3 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 O. 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 O. In yet a further embodiment, A1 or A3 is O, and C is substituted with CR6R7R8 as defined herein and one of R6, R7, R8 is a 1 . wherein A1 or A3 is O, and C is substituted with CR6R7R8 and 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. 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 TDO2 inhibitor. 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:
(a1 ) reacting a compound of Formula (i)
Figure imgf000007_0001
0)
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)
Figure imgf000007_0002
(")
wherein
R1, R2, R3, A1, A2, A3, Y1, Y2 and Y3 are as defined herein; 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),
Figure imgf000008_0001
(III) wherein Z x X2, R1 , R2, R3, A1 , A2, A3, Y1 , Y2 and Y3 are defined herein; and
(b1 ) in the case wherein Z1 is not H, deprotecting the indole amine of compound of Formula (iii), to afford compound of Formula I.
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
Figure imgf000009_0001
I
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, SO2R4, SO2NR4R5, NR4SO2R5, SO2R4, 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
a) a hydrogen atom;
b) oxo;
c) SH
d) 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, arylalkyi, alkylaryl, heteroaryl, heteroarylalkyi, alkylheteroaryl, amino, CO-alkyl, or SO2R11 , wherein R11 represents a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyi, alkylaryl, heteroaryl, heteroarylalkyi, 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, arylalkyi, alkylaryl, heteroaryl, heteroarylalkyi, alkylheteroaryl, or amino; vi) heterocyclyl or C1 -C2 alkyl - heterocyclyl; wherein the heterocyclyl is 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, arylalkyi, alkylaryl, heteroaryl, heteroarylalkyi, 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, arylalkyi, alkylaryl, heteroaryl, heteroarylalkyi, 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, arylalkyi, alkylaryl, heteroaryl, heteroarylalkyi, 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, arylalkyi, alkylaryl, heteroaryl, heteroarylalkyi, 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, arylalkyi, alkylaryl, heteroaryl, heteroarylalkyi, alkylheteroaryl, or amino; and wherein R11 represents a hydrogen atom or an optionally substituted group selected from aryl, arylalkyi, alkylaryl, heteroaryl, heteroarylalkyi, 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 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-yl)-6-chloro-1 /-/-indole or 3- (benzo[d][1 ,3]dioxol-5-yl)-1 H-indole.
In another embodiment, in Formula I:
X1 and X2 represent each independently H, halogen, alkyl, haloalkyi, preferably H or F;
R1, R2 and R3 represent each independently H, halogen, C1 -C6 alkyl, alkoxy, haloalkyi, optionally substituted by one or more substituents selected from the group comprising halogen, hydroxyl, OR4, COOR4, CONR4R5, NR4COR5, NR4R5, SO2R4, SO2NR4R5, NR4SO2R5, SO2R4, 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 O; each of Y1 , Y2 and Y3 is either absent or represent independently
- a hydrogen atom;
- oxo ;
- CR6R7R8, NR6R7 and OR6 wherein R6, R7 and R8 represent each independently:
• a hydrogen atom; halogen, preferably F, CI or I, more preferably F;
hydroxyl;
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, SO2R11, 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, CONR9R10,
NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SOR9, aryl, 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, 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, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, 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 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-R11 or -SO2R11 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, SO2R9, SO2NR9R10, NR9SO2R10, 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 R10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 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, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, 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 R10 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, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, 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 R10 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, SO2R9, SO2NR9R10, NR9SO2R11, SO2R9, 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 R10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, 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 R11 represents an alkyl group optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR12,
COOR12, CONR12R13, NR12COR13, NR12R13, SO2R12, SO2NR12R13, NR12SO2R13, 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-yl)-6-chloro-1 /-/-indole or 3- (benzo[d][1 ,3]dioxol-5-yl)-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 O.
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 I, A2 is C and one of A1 and A3 is N and the other is N or O. In one embodiment, wherein A1 or A3 is O, and C is substituted with CR6R7R8 and R6, R7 or R8 is heterocyclyl or C1 -heterocycyl, the heterocyclyl is piperidine, pyrrolidine, piperazine, morpholine, or2,6-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.
According to another embodiment, in Formula I, A1 or A3 is S, A1-Y1 or A3-Y3 is SO2. Optionally, 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.
In one embodiment, preferred com ounds of Formula I are those of Formula 11-1
Figure imgf000016_0001
11-1 and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, X2, R1 , R2, R3, A1 , A3, Y1 , Y2 and Y3 are as defined in Formula I.
According to one embodiment, in Formula 11-1 , A1 and A3 are not both C. According to antoher embodiment, one of A1 and A1 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 com ounds of Formula I are those of Formula II-2
Figure imgf000016_0002
II-2 and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, X2, R1 , R2, R3, A1 , A3, Y1 , Y2 and Y3 are as defined in Formula I.
According to one embodiment, in Formula 11-1 , {A1, 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
Figure imgf000017_0001
11-1 a and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, X2, R1 , R2, R3, A1 , Y1, Y2 and Y3 are as defined in Formula I.
In one embodiment, preferred com ounds of Formula I are those of Formula 11-1 b
Figure imgf000017_0002
and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, X2, R1 , R2, R3, A3, Y1, Y2 and Y3 are as defined in Formula I.
In one embodiment, preferred compounds of Formula I are those of Formula ll-2a
Figure imgf000018_0001
11 -2a and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, X2, R1 , R2, R3, A1 , Y1, Y2 and Y3 are as defined in Formula I.
According to one embodiment, in Formula ll-2a, A1 is not C. In one embodiment, preferred compounds of Formula I are those of Formula ll-2b
Figure imgf000018_0002
l l-2b and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, X2, R1 , R2, R3, A3, Y1, Y2 and Y3 are as defined in Formula I.
According to one embodiment, in Formula ll-2b, A3 is not C.
In one embodiment, preferred compounds of Formula I are those of Formula 11-1 a1
Figure imgf000019_0001
l l-i ai 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 11-1 a1 , Y1 represents H and Y3 is as defined in Formula I, preferably, Y3 represents:
- a hydrogen atom;
- CR6R7R8 wherein R6, R7 and R8 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, CONR9R10,
NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SOR9, aryl, 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, 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, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, 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 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-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, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10,
NR9SO2R10, 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 R10 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, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, 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 R10 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 11-1 a2
Figure imgf000020_0001
11-1 a2 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 11-1 a2, Y1 represents H and Y2 is as defined in Formula I, preferably, Y2 represents:
- a hydrogen atom;
- CR6R7R8 wherein R6, R7 and R8 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, CONR9R10,
NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SOR9, aryl, 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, 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, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, 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 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-R11 or -SO2R11 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, SO2R9, SO2NR9R10,
NR9SO2R10, 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 R10 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, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, 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 R10 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 11-1 b1
Figure imgf000022_0001
Il-1 b1 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 11-1 b1 , Y3 represents H and Y1 is as defined in Formula I, preferably, Y1 represents:
- a hydrogen atom;
- CR6R7R8 wherein R6, R7 and R8 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, CONR9R10,
NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SOR9, aryl, 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, 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, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, 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 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-R11 or -SO2R11 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, SO2R9, SO2NR9R10,
NR9SO2R10, 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 R10 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, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, 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 R10 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 11-1 b2
Figure imgf000024_0001
N-1 b2 and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, X2, R1 , R2, R3, Y2 and Y3 are as defined in Formula I.
According to a preferred embodiment, in Formula 11-1 b2, Y3 represents H and Y2 is as defined in Formula I, preferably, Y2 represents:
- a hydrogen atom;
- CR6R7R8 wherein R6, R7 and R8 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, CONR9R10,
NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SOR9, aryl, 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, 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, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, 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 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-R11 or -SO2R11 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, SO2R9, SO2NR9R10,
NR9SO2R10, 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 R10 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, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, 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 R10 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 Il-2a1
Figure imgf000025_0001
Il-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 Il-2a1 , Y1 represents H and Y2 is as defined in Formula I, preferably, Y2 represents:
- a hydrogen atom;
- CR6R7R8, NR6R7 and OR6 wherein R6, R7 and R8 represent each
independently:
• a hydrogen atom;
• 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, SO2R11 , 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, CONR9R10,
NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SOR9, aryl, 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, 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, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, 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 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-R11 or -SO2R11 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, SO2R9, SO2NR9R10, NR9SO2R10, 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 R10 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, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, 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 R10 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 Il-2a2 2
Figure imgf000027_0001
Il-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 Il-2a2, Y2 represents:
- a hydrogen atom;
- CR6R7R8, NR6R7 and OR6 wherein R6, R7 and R8 represent each
independently:
• a hydrogen atom; • 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, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, 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 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-R11 or -SO2R11 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, SO2R9, SO2NR9R10,
NR9SO2R10, 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 R10 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 Il-2b1
Figure imgf000028_0001
Il-2b1 and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, X2, R1 , R2, R3, Y2 and Y3 are as defined in Formula I. According to a preferred embodiment, in Formula Il-2b1 , Y3 represents H and Y2 is as defined in Formula I, preferably, Y2 represents:
- a hydrogen atom;
- CR6R7R8 wherein R6, R7 and R8 represent each independently:
· a hydrogen atom;
• 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, SO2R11 , 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, CONR9R10,
NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SOR9, aryl,
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, 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, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, 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
R10 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 Il-2b2
Figure imgf000030_0001
Il-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 Il-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 R8 represent each independently:
• a hydrogen atom;
• heterocyclyl or C1 -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, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, 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 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-R11 or -SO2R11 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, SO2R9, SO2NR9R10, NR9SO2R10, 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 R10 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, 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.
In one embodiment, preferred com ounds of Formula I are those of Formula Il-2b3
Figure imgf000031_0001
Il-2b3 and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, X2, R1 , R2, R3, Y1, and Y2 and Y3 are as defined in Formula I.
In one embodiment of Formula Il-2b3, R1 , R2 or R3 are each independently H, halogen, or C1 -C6 alkyl, preferably, C1 alkyl. In a further embodiment of Formula Il-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.
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Cpd n° Structure Chemical name
5-(6-fluoro-1 H-indol-3-
47
yl)benzo[d]oxazole
5-(6-fluoro-1 H-indol-3-yl)-2-
48
methylbenzo[d]oxazole
5-(6-fluoro-1 H-indol-3-yl)-2-
49
(piperidin-4-yl)benzo[d]oxazole
1 -(4-(5-(6-fluoro-1 H-indol-3-
50 yl)benzo[d]oxazol-2- yl)piperidin-1 -yl)ethanone
A/-(5-(6-fluoro-1 H-indol-3-
51 yl)benzo[d]oxazol-2- yl)acetamide
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Cpd n° Structure Chemical name
5-(1 H-indol-3-
1 18
yl)benzo[d]oxazole
H
6-(6-fluoro-1 H-indol-3-yl)-2-
((1 -(methylsulfonyl)piperidin-4-
1 19
yl)methyl)benzo[d]oxazole
0
6-(6-fluoro-1 H-indol-3-yl)-2-(2- (4-(methylsulfonyl)piperazin-1 -
120
yl)ethyl)benzo[d]oxazole
H
5-(5-chloro-1 H-indol-3-
121
yl)benzo[d]oxazole
H
A/-((6-(6-fluoro-1 H-indol-3- yl)benzo[d]oxazol-2-yl)methyl)-
122 2-(4-methylpiperazin-1 - yl)ethanesulfonamide
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
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 I 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 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, laurate, 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,
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, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, 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, 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
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 I with the desired acid;
(ii) by reacting the compound of Formula I with the desired base;
(iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of Formula I 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 I to 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 I throughout this specification, includes all of ts subformulae, Formula II (including 11-1 , 11-1 a, Il-1 a1 , Il-1 a2, ll-1 b, Il-1 b1 , 11-1 b2, II-2, II- 2a, Il-2a1 , Il-2a2, ll-2b, Il-2b1 , Il-2b2, Il-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
Figure imgf000063_0001
and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1 , X2, R1 , R2, R3, A1, A2, A3, Y1 , Y2 and Y3 are as defined in Formula I;
comprising: ) reacting a compound of Formula (i)
Figure imgf000064_0001
(')
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 te/t-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)
Figure imgf000064_0002
(")
wherein
R1, R2, R3, A1, A2, A3, Y1, Y2 and Y3 are as defined in Formula I;
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),
Figure imgf000065_0001
(iii) wherein Z x X2, R1 , R2, R3, A1 , A2, A3, Y1 , Y2 and Y3 are as defined 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 I.
According to one embodiment, step (a1 ) 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(ll) or 1 ,1 '-bis(diphenylphosphino)ferrocene- dichloro palladium(ll), 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(oTol)3, PPh3, BINAP, P(iBu)3 or any other suitable phosphine ligand known to those skilled in the art.
According to one embodiment, step (a1 ) 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 (a1 ) 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 (a1 ) 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 such as but not limited to methanol, ethanol, isopropanol, terf-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, 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, te/t-butanol, THF, DMF, Dioxane, water or a mixture thereof. According to one embodiment, the deprotection may be performed at a temperature between about 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
Figure imgf000066_0001
and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1 , X2, R1 , R2, R3, A1, A2, A3, Y1 , Y2 and Y3 are as defined in Formula I;
with the condition that at least one of Y1 , Y2 and Y3 is not H or absent; comprising:
(a2) alkylating a compound of Formula (iv)
Figure imgf000067_0001
wherein X1, X2, R1, R2, R3, A1, A2, A3, are as defined in Formula I,
Y1 , Y2 and Y3 represent respectively Y1 , 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 te/t-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)
Figure imgf000067_0002
(v) wherein X1, X2, R1, R2, R3, A1 , A2, A3, Y1, Y2, Y3 and Z1 are defined as above with the condition that at least one of Y1 , 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 Y1 , Y2 or Υ3, as defined in Formula I, 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 te/t-butoxide, potassium te/t-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, te/t-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 Il-2a1 wherein Y1 is H:
Figure imgf000069_0001
and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, X2, R1, R2, R3, and Y2 are as defined in Formula I; comprising:
(a3) reacting a compound of Formula (vii)
Figure imgf000069_0002
(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 te/t-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)
Figure imgf000069_0003
(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) 2
Figure imgf000070_0001
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 Il-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 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 Formula I
Figure imgf000071_0001
and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, X2, R1, R2, R3, A1, A2, A3, Y1, Y2 and Y3 are as defined in Formula I;
comprising:
(a4) reacting a compound of Formula (x)
Figure imgf000071_0002
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 te/t-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 to form a ring;
with a compound of Formula (xi)
Figure imgf000072_0001
wherein
R1, R2, R3, A1, A2, A3, Y1, 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
Figure imgf000072_0002
(Xii) wherein Z1 , X1, X2, R1 , R2, R3, A1 , A2, A3, Y1 , 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(ll) or 1 ,1 '-bis(diphenylphosphino)ferrocene- dichloro palladium(ll), 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(oTol)3, PPh3, BINAP, P(iBu)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 (terf-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-iimore 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, terf-butyl and acetyl, where benzyl and terf-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 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 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- butanol or terf-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, A/-methylpyrrolidone (NMP) or dimethyhformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); 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, H2SO4, or using LiOH, NaOH or KOH in water, water/THF, water/THF/ethanol or water/dioxane, at temperatures between 0 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 -60°C 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 TDO2 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 TDO2 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 TDO2 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 TDO2 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 TDO2 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, 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, 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, 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 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 (CI), bromo (Br), or iodo (I).
The following definitions are used in connection with the compounds described herein. 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 CnH2n+i wherein n is a number greater than or equal to 1 . Alkyl groups may contain 1 to 10 carbons (inclusive), i.e., C1 , 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 3 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 "haloalkyi" 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 haloalkyi radicals include fluoromethyl, difluoromethyl, trifluoro methyl and the like. In one example, the haloalkyi is a C1 to C6 alkyl group substituted with at least one halogen. In another example, the haloalkyi is a C1 to C4 alkyl group substituted with at least one halogen. Each halogen substitution may be independently selected.
The term "cycloalkyi" 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. Cycloalkyi includes monocyclic or bicyclic hydrocarbyl groups. Cycloalkyi 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 cycloalkyi 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 cycloalkyi 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 1 1 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 O-alkyl. The term"haloalkoxy" refers to any group O-haloalkyl.
The term "oxo" refers to a =O 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, te/t-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 nH2O, wherein n is the number of water molecules per formula unit of the salt. N may be ½, 1 ½ , 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 (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 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 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 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 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 61 10 (Electron Spray Ionization, ESI) or a Waters Acquity SQD (ESI) The NMR data provided in the examples described below were obtained as followed: Bruker Ultrashield™ 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 Xbridge™ Prep C18 OBD column 19x150 mm 5 μιη, unless otherwise reported. All HPLC purifications were performed with a gradient of CH3CN /H2O/NH4HCO3 (5 imM), CH3CN /H2O/TFA (0.1 %), or CH3CN /H2O/NH3 H2O (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 Ν,Ν-dimethylformamide; dppf is 1 ,1 '- bis(diphenylphosphino)ferrocene; EtOH is ethanol; HATU is 2-(1 H-7-azabenzotriazol- 1 -yl)-1 ,1 ,3,3-tetramethyl uronium hexafluorophosphate methanaminium; Hz is hertz; KOAc is potassium acetate; MeOH is methanol; MHz is megahertz; imM 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; PPh3 is
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 -(phenylsulfonyl)-1 /-/-indole
Figure imgf000088_0001
The title compound was prepared using the same procedure as reported
(WO2010/136491 A1 ).
Intermediate 2:
tert-butyl 6-fluoro-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indole-1 carboxylate
Figure imgf000088_0002
The title compound was prepared using the same procedure as reported
(US2014/256706 A1 ).
Intermediate 3: 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indazole
Figure imgf000089_0001
A mixture of 6-bromo-1 /-/-indazole (700 mg; 3.55 mmol), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(1 ,3,2-dioxaborolane) (1 .50 g; 5.91 mmol), Pd(dppf)CI2- 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 EtOAc (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
Ci3H17BN2O2+H+ [M+H]+: calcd. 245.1 ; found: 245.0.
Intermediate 4: 6-(6-fluoro-1 -(phenylsulfonyl)-l - -indol-3-yl)-1 /-/-indazole
Figure imgf000089_0002
To a mixture of 6-fluoro-3-iodo-1 -(phenylsulfonyl)-l /-/-indole (Intermediate 1 ; 400 mg; 1 .00 mmol), 6-(4,4,5,5-tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-1 /-/-indazole (Intermediate 3; 366 mg; 1 .50 mmol) and Cs2CO3 (978 mg; 3.00 mmol) in DME (9 mL) and water (3 mL) was added Pd(dppf)CI2- DCM (82 mg; 0.1 mmol) under nitrogen. The mixture was heated at 150°C for 1 hour in a microwave reactor. The mixture was filtered through Celite and diluted with EtOAc (100 mL) and water (100 mL). The aqueous layer was extracted with EtOAc (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/EtOAc = 5/1 - 2/1 ) to afford 390 mg (100%) of the title compound as a yellow solid. LC-MS for C2iH14FN3O2S+H+ [M+H]+: calcd. 392.1 ; found: 391 .8. 1 H NMR (300 MHz, DMSO-afe) δ [ppm]: 13.13 (s, 1 H), 8.20 - 8.1 1 (m, 4H), 7.93 - 7.78 (m, 4H), 7.77 - 7.70 (m, 1 H), 7.65 - 7.60 (m, 2H), 7.44 (dd, J = 9.3, 2.1 Hz, 1 H), 7.26 (ddd, J = 9.3, 9.0, 2.1 Hz, 1 H). Intermediate 5: terf-butyl 4-((6-(6-fluoro-1 -(phenylsulfonyl)-1 - -indol-3-yl)-1 /-/-indazol-1 - yl)methyl)piperidine-1 -carboxylate and te/t-butyl 4-((6-(6-fluoro-1 -(phenylsulfonyl)-1 /-/- indol-3-yl)-2 -/-indazol-2-yl)methyl)piperidine-1 -carboxylate
B
Figure imgf000090_0001
A mixture of 6-fluoro-3-iodo-1 -(phenylsulfonyl)-l /-/-indole (Intermediate 1 ; 1 .00 g; 2.55 mmol), te/t-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 EtOAc (100 imL), filtered, concentrated, and purified by a silica gel chromatography (petroleum ether/EtOAc = 6/1 - 2/1 ) to afford 1 .1 1 g (74%) of a mixture of the title compounds as a yellow solid. LC-MS for C32H33FN4O4S+H+ [M+H]+: calcd. 589.2; found: 588.9.
Intermediate 6: 6-(6-fluoro-1 -(phenylsulfonyl)-l /-/-indol-3-yl)-1 -(piperidin-4-ylmethyl)-1 H- indazole hydrochloride and 6-(6-fluoro-1 -(phenylsulfonyl)-1 /-/-indol-3-yl)-2-(piperidin-4- ylmethyl)-2/-/-indazole hydrochloride
Figure imgf000090_0002
To a solution of te/t-butyl 4-((6-(6-fluoro-1 -(phenylsulfonyl)-1 /-/-indol-3-yl)-1 /-/-indazol-1 - yl)methyl)piperidine-1 -carboxylate and te/t-butyl 4-((6-(6-fluoro-1 -(phenylsulfonyl)-1 /-/- indol-3-yl)-2/-/-indazol-2-yl)methyl)piperidine-1 -carboxylate (Intermediate 5; 1 .06 g; 1 .80 mmol) in MeOH (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 C27H25FN4O2S+H+ [M+H]+: calcd. 489.2; found: 488.9. Intermediate 7: 1 -(4-((6-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-1 H-indazol-1 - yl)methyl)piperidin-1 -yl)ethanone
Figure imgf000091_0001
To a solution of 6-(6-fluoro-1 -(phenylsulfonyl)-l - -indol-3-yl)-1 -(piperidin-4-ylmethyl)-1 H- indazole hydrochloride and 6-(6-fluoro-1 -(phenylsulfonyl)-1 H-indol-3-yl)-2-(piperidin-4- 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 (1 16.6 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
Na2SO4, filtered, concentrated, and purified by preparative TLC (EtOAc) to afford 267 mg (40%) of the title compound as a yellow solid. LC-MS for C29H27FN4O3S+H+ [M+H]+: calcd. 531 .2; found: 530.9.
3-(6-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-1 H-indazol-1
Figure imgf000092_0001
A mixture of 6-(6-fluoro-1 -(phenylsulfonyl)-1 - -indol-3-yl)-1 H-indazole (Intermediate 4; 200 mg; 0.51 mmol), 3-bromopropanamide (389 mg; 2.56 mmol), K2CO3 (21 1 mg; 1 .53 mmol) and Kl (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 H2O (20 mL) and the aqueous layer was extracted with EtOAc (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/EtOAc = 2/1 - 0/1 ) to afford 95 mg (40%) of the title compound as a yellow solid. LC-MS for C24H 9FN4O3S+H+ [M+H]+: calcd. 463.1 ; found: 462.8.
Intermediate 9: terf-butyl 4-(6-(6-fluoro-1 -(phenylsulfonyl)-1 - -indol-3-yl)-1 /-/-indazol-1 - yl)piperidine-1 -carboxylate and te/t-butyl 4-(6-(6-fluoro-1 -(phenylsulfonyl)-1 /-/-indol-3-yl)- 2 -/-indazol-2-yl)piperidine-1 -carboxylate
Figure imgf000092_0002
A mixture of 6-fluoro-3-iodo-1 -(phenylsulfonyl)-1 /-/-indole (Intermediate 1 ; 560 mg; 1 .43 mmol), terf-butyl 4-((methylsulfonyl)oxy)piperidine-1 -carboxylate (0.60 g; 2.15 mmol) and Cs2CO3 (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 EtOAc (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 C3i H3i FN4O4S+H+ [M+H]+: calcd. 575.2; found: 574.8.
Intermediate 10: 6-(6-fluoro-1 -(phenylsulfonyl)-l - -indol-3-yl)-1 -(piperidin-4-yl)-1 H- indazole hydrochloride and 6-(6-fluoro-1 -(phenylsulfonyl)-1 H-indol-3-yl)-2-(piperidin-4- yl)-2 - -indazole hydrochloride
Figure imgf000093_0001
Following the general method as outlined in Intermediate 6, starting from terf-butyl 4-(6- (6-fluoro-1 -(phenylsulfonyl)-l -/-indol-3-yl)-1 -/-indazol-1 -yl)piperidine-1 -carboxylate and te/t-butyl 4-(6-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-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 C26H23FN4O2S+H+ [M+H]+: calcd. 475.2; found: 474.8.
Intermediate 1 1 : 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indazole
Figure imgf000093_0002
A mixture of 5-bromo-1 H-indazole (500 mg; 2.54 mmol), 4,4,4',4', 5,5,5', 5'-octamethyl- 2,2'-bi(1 ,3,2-dioxaborolane) (1 .29 g; 5.08 mmol), Pd(dppf)CI2- 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 EtOAc (100 mL), washed with H2O (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 Ci3Hi7BN2O2+H+ [M+H]+: calcd. 245.1 ; found: 245.2.
Intermediate 12: 5-(6-fluoro-1 -(phenylsulfonyl)-l - -indol-3-yl)-1 /-/-indazole
Figure imgf000094_0001
To a mixture of 6-fluoro-3-iodo-1 -(phenylsulfonyl)-l /-/-indole (Intermediate 1 ; 200 mg; 0.50 mmol), 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-indazole (Intermediate 1 1 ; 345 mg crude; 0.74 mmol) and Cs2CO3 (488 mg; 1 .50 mmol) in DME (6 imL) and water (2 imL) was added Pd(dppf)CI2- 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 EtOAc (100 imL) and water (100 imL). The aqueous layer was extracted with EtOAc (50 imL). 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 C2i H14FN3O2S+H+ [M+H]+: calcd. 392.1 ; found: 392.0.
Intermediate 13: 2-(5-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-1 H-indazol-1 - yl)acetamide and 2-(5-(6-fluoro-1 -(phenylsulfonyl)-1 /-/-indol-3-yl)-2/-/-indazol-2- yl)acetamide
Figure imgf000094_0002
A mixture of 5-(6-fluoro-1 -(phenylsulfonyl)-1 - -indol-3-yl)-1 H-indazole (Intermediate 12; 500 mg; 1 .28 mmol), 2-bromoacetamide (900 mg; 6.52 mmol), K2CO3 (540 mg; 3.91 mmol) and Kl (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 H2O (10 mL) and extracted with EtOAc (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 C23Hi7FN4O3S+H+ [M+H]+: calcd. 449.1 ; found: 448.8.
Intermediate 14: terf-butyl 4-((5-(6-fluoro-1 -(phenylsulfonyl)-1 - -indol-3-yl)-1 - -indazol-1 - yl)methyl)piperidine-1 -carboxylate and te/t-butyl 4-((5-(6-fluoro-1 -(phenylsulfonyl)-l H- indol-3-yl)-2 -/-indazol-2-yl)methyl)piperidine-1 -carboxylate
Figure imgf000095_0001
Following the general method as outlined in Intermediate 5, starting from 5-(6-fluoro-1 - (phenylsulfonyl)-l - -indol-3-yl)-1 H-indazole (Intermediate 12; 1 .50 g; 3.83 mmol) and te/t-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 C32H33FN4O4S+H+ [M+H]+: calcd. 589.2; found: 588.8.
Intermediate 15: terf-butyl 4-((5-(6-fluoro-1 H-indol-3-yl)-1 H-indazol-1 - yl)methyl)piperidine-1 -carboxylate
Figure imgf000096_0001
To a solution of terf-butyl 4-((5-(6-fluoro-1 -(phenylsulfonyl)-1 -/-indol-3-yl)-1 -/-indazol-1 - yl)methyl)piperidine-1 -carboxylate and te/t-butyl 4-((5-(6-fluoro-1 -(phenylsulfonyl)-1 -/- indol-3-yl)-2 -/-indazol-2-yl)methyl)piperidine-1 -carboxylate (Intermediate 14; 2.00 g; 3.40 mmol) in MeOH (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/EtOAc = 3/1 ) to afford 1 .18 g (77%) of the title compound as a yellow solid. LC-MS for C26H29FN4O2+H+ [M+H]+: calcd. 449.2; found: 448.9
Intermediate 16: 3-(5-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-1 H-indazol-1 - yl)propanamide and 3-(5-(6-fluoro-1 -(phenylsulfonyl)-l -/-indol-3-yl)-2 -/-indazol-2- yl)propanamide
Figure imgf000096_0002
Following the general method as outlined in Intermediate 8, starting from 5-(6-fluoro-1 - (phenylsulfonyl)-l H-indol-3-yl)-1 H-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 C24HigFN4O3S+H+ [M+H]+: calcd. 463.2; found: 462.8.
Intermediate 17: te/t-butyl 4-(5-(6-fluoro-1 -(phenylsulfonyl)-1 - -indol-3-yl)-1 - -indazol-1 - yl)piperidine-1 -carboxylate
Figure imgf000097_0001
To a mixture of 5-(6-fluoro-1 -(phenylsulfonyl)-1 - -indol-3-yl)-1 H-indazole (Intermediate 12; 1 .80 g; 4.60 mmol) and Cs2CO3 (3.75 g; 1 1 .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 EtOAc (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/EtOAc = 5/1 - 2/1 ) to afford 1 .75 g (66%) of the title compound as a yellow solid. LC-MS for
C3i H3i FN4O4S+H+ [M+H]+: calcd. 575.2; found: 574.9.
Intermediate 18: terf-butyl 4-(5-(6-fluoro-1 --indol-3-yl)-1 H-indazol-1 -yl)piperidine-1 - carboxylate
Figure imgf000097_0002
To a solution of te/t-butyl 4-(5-(6-fluoro-1 -(phenylsulfonyl)-1 - -indol-3-yl)-1 - -indazol-1 - yl)piperidine-1 -carboxylate (Intermediate 17; 1 .75 g; 3.05 mmol) in MeOH (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 EtOAc (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/EtOAc = 5/1 - 2/1 ) to afford 600 mg (45%) of the title compound as a yellow oil. LC-MS for C25H27FN4O2+H+-(CH3)2C=CH2 [M+H-(CH3)2C=CH2]+: calcd. 379.2; found: 378.9.
Intermediate 19: 1 -(4-((6-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-2H-indazol-2- yl)methyl)piperidin-1 -yl)ethanone
Figure imgf000098_0001
358 mg (54%) of the title compound was obtained as a yellow solid after purification by preparative TLC (EtOAc) as a regio-isomer with intermediate 7. LC-MS for C29H27FN4O3S+H+ [M+H]+: calcd. 531 .2; found: 530.9.
Intermediate 20: 3-(6-(6-fluoro-1 -(phenylsulfonyl)-1 H-indol-3-yl)-2H-indazol-2- yl)propanamide
Figure imgf000098_0002
The title compound (70 mg, 29%) was obtained as a yellow solid after purification by silica gel chromatography (petroleum ether/EtOAc = 2/1 - 0/1 ) during the preparation of Intermediate 8. Intermediate 21 : fert-butyl 4-((5-(6-fluoro-1 H-indol-3-yl)-2H-indazol-2- yl)methyl)piperidine-1 -carboxylate
Figure imgf000099_0001
The title compound (377 mg, 25%) was obtained as a yellow solid after purification by silica gel chromatography (petroleum ether/EtOAc = 3/1 ) during the preparation of Intermediate 15. LC-MS for C26H29FN4O2+H+ [M+H]+: calcd. 449.2; found: 448.9 Intermediate 22: 5-(6-fluoro-1 H-indol-3-yl)-2-(piperidin-4-ylmethyl)-2H-indazole
Figure imgf000099_0002
A solution of terf-butyl 4-((5-(6-fluoro-1 H-indol-3-yl)-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 EtOAc (50 mLx3). The aqueous layer was basified with aqueous NaOH to pH = 13 and extracted with EtOAc (80 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by preparative TLC (DCM/MeOH = 10/1 ) to afford 136 mg (93%) of the title compound as a yellow solid. LC-MS for C2iH2iFN4+H+ [M+H]+: calcd. 349.2; found: 348.9.
Intermediate 23: terf-butyl 4-(5-(6-fluoro-1 -(phenylsulfonyl)-1 H-indol-3-yl)-2H-indazol-2- yl)piperidine-1 -carboxylate
Figure imgf000100_0001
The title compound (380 mg, 14%) was obtained as a yellow solid after purification by silica gel chromatography (petroleum ether/EtOAc = 5/1 - 2/1 ) during the preparation of Intermediate 17. LC-MS for C3iH3iFN4O4S+H+ [M+H]+: calcd. 575.2; found: 574.9. Intermediate 24: terf-butyl 4-(5-(6-fluoro-1 H-indol-3-yl)-2H-indazol-2-yl)piperidine-1 - carboxylate
Figure imgf000100_0002
Following the general method as outlined in Intermediate 15, starting from te/t-butyl 4- (5-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-2H-indazol-2-yl)piperidine-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/EtOAc = 5/1 - 2/1 ). LC-MS for C25H27FN4O2+H+ [M+H]+: calcd. 435.5; found: 434.9.
Intermediate 25: te/t-butyl 5-bromo-1 -/-benzo[ |imidazole-1 -carboxylate and terf-butyl 6- bromo-1 -/-benzo[ |imidazole-1 -carboxylate
Figure imgf000101_0001
To a mixture of 5-bromo-1 H-benzo[ |imidazole (1 .00 g; 5.08 mmol) in THF (50 mL) was added Boc2O (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 EtOAc (150 mL), washed with H2O (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
Figure imgf000101_0002
[M+H- (CH3)2C=CH2]+: calcd. 241 .0; found: 240.9. 1H NMR (300 MHz, CDCI3) δ [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, 1 H), 1 .71 (s, 9H) as a mixture of tautomers.
Intermediate 26: terf-butyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzo[c ]imidazole-1 -carboxylate and terf-butyl 6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-benzo[ |imidazole-1 -carboxylate
Figure imgf000101_0003
Following the general method as outlined in Intermediate 3, starting from terf-butyl 5- bromo-1 H-benzo[ |imidazole-1 -carboxylate and terf-butyl 6-bromo-1 H- benzo[c ]imidazole-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 Ci8H25BN2O4+H+ [M+H]+: calcd. 345.2; found: 345.0.
Intermediate 27: 5-(6-fluoro-1 -(phenylsulfonyl)-l - -indol-3-yl)-1 H-benzo[ |imidazole
Figure imgf000102_0001
Following the general method as outlined in Intermediate 4, starting from terf-butyl 5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzo[c ]imidazole-1 -carboxylate and te/t-butyl 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzo[ |imidazole-1 - carboxylate (Intermediate 26; 730 mg crude; 0.46 mmol) and 6-fluoro-3-iodo-1 -
(phenylsulfonyl)-l /-/-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 C2i H14FN3O2S+H+ [M+H]+: calcd. 392.1 ; found: 391 .9.
Intermediate 28: terf-butyl 5-bromo-2-methyl-1 /-/-benzo[ |imidazole-1 -carboxylate
Figure imgf000102_0002
Following the general method as outlined in Intermediate 25, starting from 5-bromo-2- methyl-1 /-/-benzo[ |imidazole (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/EtOAc = 8/1 - 5/1 ). LC-MS for
Figure imgf000102_0003
[M+H- (CH3)2C=CH2]+: calcd. 256.0; found: 256.8. 1H NMR (300 MHz, CDCI3) δ [ppm]: 7.79 (d, J = 8.7 Hz, 1 H), 7.79 (d, J= 2.0 Hz, 1 H), 7.76 (m, 2H), 7.41 (dd, J = 8.7, 2.0 Hz, 1 H), 2.82 (s, 3H), 1.72 (s, 9H).
Intermediate 29: terf-butyl 2-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzo[ |imidazole-1 -carboxylate
Figure imgf000102_0004
feoc Following the general method as outlined in Intermediate 3, starting from terf-butyl 5- bromo-2-methyl-1 -/-benzo[ /|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/EtOAc = 5/1 ). LC-MS for Ci9H27BN2O4+H+ [M+H]+: calcd. 359.2; found: 359.0. 1H NMR (400 MHz, DMSO-cfe) δ
[ppm]: 7.91 (d, J = 8.2 Hz, 1 H), 7.84 (s, 1 H), 7.64 (d, J = 8.2 Hz, 1 H), 2.72 (s, 3H), 1.66 (s, 9H), 1.32 (s, 12H).
5-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-2-methyl-1 H-
Figure imgf000103_0001
Following the general method as outlined in Intermediate 4, starting from terf-butyl 2- methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-benzo[aflimidazole-1 - carboxylate (Intermediate 29; 1 .08 g; 3.01 mmol) and 6-fluoro-3-iodo-1 -(phenylsulfonyl) 1 /-/-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/MeOH = 40/1 - 20/1 ). LC-MS for C22Hi6FN3O2S+H+ [M+H]+: calcd. 406.1 ; found 405.8.
Intermediate 31 : 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzene-1 ,2-diamine
Figure imgf000103_0002
To a mixture of 4-bromobenzene-1 ,2-diamine (10.8 g; 57.7 mmol), KOAc (17.0 g; 173 mmol) and 44,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (16.1 g; 63.4 mmol) in dioxane (200 ml_) was added Pd(dppf)CI2-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/EtOAc =5/1 - 2/1 ) to afford 1 1 .6 g (86%) of the title compound as a brown oil. LC- MS for Ci2H19BN2O2+H+ [M+H]+: calcd. 235.2; found: 235.0. 1H NMR (400 MHz, CDCI3) δ [ppm]: 7.22 (d, J = 7.7 Hz, 1 H), 7.16 (s, 1 H), d, J = 7.7 Hz, 1 H, 1 .32 (s, 12H).
Intermediate 32: 4-(6-fluoro-1 -(phenylsulfonyl)-l - -indol-3-yl)benzene-1 ,2-diamine
Figure imgf000104_0001
A mixture of 6-fluoro-3-iodo-1 -(phenylsulfonyl)-l /-/-indole (Intermediate 1 ; 19.9 g; 49.6 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzene-1 ,2-diamine
(Intermediate 31 ; 1 1 .6 g; 49.6 mmol), Pd(dppf)CI2-DCM (2.0 g; 2.45 mmol), K2CO3 (20.5 g; 148 mmol) in dioxane (300 imL) and water (60 imL) 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/MeOH = 200/1 - 20/1 ) to afford 7.0 g (37%) of the title compound as a brown oil. LC-MS for C2oHi6FN3O2S+H+ [M+H]+: calcd. 382.1 ; found: 381 .8. 1 H NMR (400 MHz, CDCI3) δ [ppm]: 7.90 (d, J = 7.6 Hz, 1 H), 7.77 (dd, J = 9.7, 2.0 Hz, 1 H), 7.68 (dd, J = 8.7, 5.3 Hz, 1 H), 7.58 - 7.53 (m, 2H), 7.49 - 7.43 (m, 2H), 7.01 (ddd, J = 9.3, 8.7, 2.3 Hz, 1 H), 6.94 - 6.89 (m, 2H), 6.78 (d, J = 7.6 Hz, 1 H). Intermediate 33: 5-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-2-(2-(methylthio)ethyl)-1 H- benzo[ |imidazole
Figure imgf000105_0001
To a mixture of 4-(6-fluoro-1 -(phenylsulfonyl)-l - -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 reflux for 16 hours. The reaction mixture was
concentrated in vacuo and purified by a silica gel chromatography (petroleum
ether/EtOAc = 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 C24H2oFN3O2S2+H+
[M+H]+: calcd. 466.1 ; found: 465.8.
Intermediate 34: 5-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-2-(2-(methylsulfonyl)ethyl)- 1 H-benzo[ |imidazole
Figure imgf000105_0002
To a solution of 5-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-2-(2-(methylthio)ethyl)-1 H- benzo[c/|imidazole (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 satured aqueous NaHSO3 (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 C24H2oFN3O4S2-H" [M-H]": calcd. 496.1 ; found: 495.9. 1 H NMR (300 MHz, CDCI3) δ [ppm]: 7.97 - 7.89 (m, 2H), 7.83 - 7.75 (m, 1 H), 7.75 - 7.66 (m, 3H), 7.65 - 7.52 (m, 2H), 7.51 - 7.41 (m, 3H), 7.09 - 6.98 (m, 1 H), 3.70 - 3.61 (m, 2H), 3.59 - 3.48 (m, 2H), 2.97 (s, 3H).
Intermediate 35:
te/t-butyl 2-(2-amino-5-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)phenylamino)-2- oxoethyl(methyl)carbamate and te/t-butyl 2-(2-amino-4-(6-fluoro-1 -(phenylsulfonyl)-1 H- indol-3-yl)phenylamino)-2-oxoethyl(methyl)carbamate
Figure imgf000106_0001
To a solution of 2-(te/t-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 -(phenylsulfonyl)-l H-indol-3-yl) 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 EtOAc (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 C22Hi7CIFN3O3S+H+-(CH3)2C=CH2 [M+H-(CH3)2C=CH2]+: calcd. 497.1 ; found: 496.8. Intermediate 36: terf-butyl (5-(6-fluoro-1 -(phenylsulfonyl)-1 H-indol-3-yl)-1 H- benzo[ |imidazol-2-yl)methyl(methyl)carbamate
Figure imgf000107_0001
A mixture of te/t-butyl 2-(2-amino-5-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3- yl)phenylamino)-2-oxoethyl(methyl)carbamate and terf-butyl 2-(2-amino-4-(6-fluoro-1 - (phenylsulfonyl)-l -/-indol-3-yl)phenylamino)-2-oxoethyl(methyl)carbamate (Intermediate 35, 670 mg crude, 0.87 mmol) in AcOH (10 imL) 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 EtOAc (50 ml_x3). 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 C28H27FN4O4S+H+ [M+H]+: calcd. 535.2; found: 534.8.
Intermediate 37: terf-butyl (5-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[c/|imidazol-2- yl)methyl(methyl)carbamate
Figure imgf000107_0002
Following the general method as outlined in Intermediate 15, starting from te/t-butyl (5- (6-fluoro-1 -(phenylsulfonyl)-l - -indol-3-yl)-1 H-benzo[ |imidazol-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 C22H23FN4O2+H+[M+H]+: calcd. 395.2; found: 394.9.
Intermediate 38: A/-(2-amino-5-(6-fluoro-1 -(phenylsulfonyl)-l - -indol-3-yl)phenyl)-2- chloroacetamide and A/-(2-amino-4-(6-fluoro-1 -(phenylsulfonyl)-1 H-indol-3-yl)phenyl) chloroacetamide
Figure imgf000108_0001
To a stirred solution of 4-(6-fluoro-1 -(phenylsulfonyl)-l - -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 EtOAc (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 C22H17CIFN3O3S+H+ [M+H]+: calcd. 458.1 ; found: 457.7.
Intermediate 39: 2-(chloromethyl)-5-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-1 H- benzo[ |imidazole
Figure imgf000109_0001
A mixture of A/-(2-amino-5-(6-fluoro-1 -(phenylsulfonyl)-1 H-indol-3-yl)phenyl)-2- chloroacetamide and A/-(2-amino-4-(6-fluoro-1 -(phenylsulfonyl)-1 - -indol-3-yl)phenyl)-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 EtOAc (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/ MeOH = 200/1 - 50/1 ) to afford 3.20 g (84%) of the title compound as a brown solid. LC-MS for C22Hi5CIFN3O2S+H+ [M+H]+: calcd. 440.1 ; found: 439.8.
Intermediate 40: 3-(5-(6-fluoro-1 -(phenylsulfonyl)-1 - -indol-3-yl)-1 H-benzo[ |imidazol-2- yl)propanoic acid
Figure imgf000109_0002
A solution of 4-(6-fluoro-1 -(phenylsulfonyl)-l - -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/MeOH = 18/1 ) to afford 0.60 g (99%) of the title compound as a white solid. LC-MS for C24H18FN3O4S+H+ [M+H]+: calcd. 464.1 ; found: 464.0. 1H NMR (400 MHz, DMSO-cfe) δ [ppm]: 12.30 (s, 1 H), 8.15 (d, J = 7.7 Hz, 2H), 8.06 (s, 1 H), 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, 1 H), 7.44 (d, J= 8.3 Hz, 1 H), 7.24 (ddd, J= 9.3, 8.7, 2.2 Hz, 1 H), 3.57 (s, 1 H), 3.07 (t, J = 7.1 Hz, 2H), 2.82 (t, J = 7.1 Hz, 2H).
Intermediate 41 : 6-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-2,3-dihydro-1 H- benzo[ |pyrrolo[1 ,2-a]imidazol-1 -one
Figure imgf000110_0001
To a solution of 3-(5-(6-fluoro-1 -(phenylsulfonyl)-l - -indol-3-yl)-1 H-benzo[ |imidazol-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 NH4CI (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 EtOAc (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 C24H16FN3O3S+H+ [M+H]+: calcd. 446.1 ; found: 446.0.
Intermediate 42: 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzo[ |oxazole
Figure imgf000110_0002
Following the general method as outlined in Intermediate 3, starting from 5- bromobenzo[ |oxazole (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 /EtOAc = 100/1 - 30/1 ). LC-MS for Ci3H16BNO3+H+ [M+H]+: calcd. 246.1 ; found: 246.0. 1H NMR (400 MHz, CDCI3) δ [ppm]: 8.26 (s, 1 H), 8.10 (s, 1 H), 7.86 (d, J = 8.0 Hz, 1 H), 7.58 (d, J = 8.0 Hz, 1 H), 1 .37 (s, 12H).
Intermediate 43: 5-(6-fluoro-1 -(phenylsulfonyl)-l /-/-indol-3-yl)benzo[c/]oxazole
Figure imgf000111_0001
Following the general method as outlined in Intermediate 4, starting from 5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzo[ |oxazole (Intermediate 42, 330 mg, 1 .35 mmol) and 6-fluoro-3-iodo-1 -(phenylsulfonyl)-l /-/-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 MeOH. LC-MS for C2i H13FN2O3S+H+[M+H]+: calcd 393.1 ; found: 392.8. 1H NMR (400 MHz, CDCI3) δ [ppm]: 8.16 (s, 1 H), 7.99 - 7.93 (m, 3H), 7.81 (dd, J = 9.5, 2.1 Hz, 1 H), 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, 1 H).
Intermediate 44: 2-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzo[ |oxazole
Figure imgf000111_0002
Following the general method as outlined in Intermediate 3, starting from 5-bromo-2- methylbenzo[ |oxazole (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.
MS for Ci4H18BNO3+H+ [M+H]+: calcd. 260.1 ; found: 260.0.
Intermediate 45: 5-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-2-methylbenzo[c ]oxazole
Figure imgf000112_0001
Following the general method as outlined in Intermediate 4, starting from 2-methyl-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzo[ |oxazole (Intermediate 44, 688 mg, 2.66 mmol) and 6-fluoro-3-iodo-1 -(phenylsulfonyl)-1 /-/-indole (Intermediate 1 , 71 1 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/EtOAc = 5/1 - 2/1 ). LC-MS for C22Hi5FN2O3S+H+ [M+H]+: calcd. 407.1 ; found: 406.8. 1 H NMR (400 MHz, DMSO-afe) δ [ppm]: 8.20 - 8.14 (m, 3H), 7.97 (d, J = 0.8 Hz, 1 H), 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, 1 H), 2.65 (s, 3H) .
Intermediate 46: terf-butyl (2-((2-amino-5-(6-fluoro-1 -(phenylsulfonyl)
yl)phenyl)amino)-2-oxoethyl)carbamate
Figure imgf000112_0002
To a stirred solution of te/t-butoxycarbonylamino-acetic acid (153 mg, 0.87 mmol) and DIEA (188.14 mg, 1 .46 mmol) in anhydrous THF /DMF (10 mL l\ mL) was added HATU (363.66 mg, 0.96 mmol) at 0 °C. The mixture was stirred for 10 mins and 4-(1 - Benzenesulfonyl-6-fluoro-1 /-/-indol-3-yl)-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 imL) and extracted with EtOAc (30 ml_x3) . The combined organic layer was washed with brine (20 ml_x3) , dried over anhydrous Na2SO4 and 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 C27H27FN4O5S+H+: [M+H]+: calcd. 539.2 ; found: 538.8
Intermediate 47: terf-butyl ((6-(6-fluoro- 1 -(phenylsulfonyl)- 1 H-indol-3-yl)- 1 H- benzo[d]imidazol-2-yl)methyl)carbamate
Figure imgf000113_0001
A mixture of te/t-butyl (2-((2-amino-5-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3- yl)phenyl)amino)-2-oxoethyl)carbamate (Intermediate 46, 678 mg, 1 .31 mmol) in AcOH (10 imL) was stirred at 51 °C for 6 hours under nitrogen. The mixture was neutralized with aqueous of Na2CO3 to pH= 8 and extracted with EtOAc (50 ml_x3) . The combined organic layer was washed with brine (100 imL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford 637 mg (93 %) of the title compound as a black semi-solid, which was used directly without further purification. LC-MS for C27H25FN4O4S+H+ [M+H]+: calcd. 521 .2; found: 520.8. 1 H NMR (400 MHz, DMSO-afe) δ [ppm]:12.29 (d, J = 20.0 Hz, 1 H), 8.16 (d, J = 7.8 Hz, 2H), 8.08 (d, J = 11 .5 Hz, 1 H), 7.87 - 7.80 (m, 2H), 7.74 (ddd, J = 11 .4, 3.6, 1 .2 Hz, 1 H), 7.69 - 7.60 (m, 2H), 7.57 - 7.44 (m, 3H), 7.29 - 7.21 (m, 1 H), 4.38 (d, J = 5.7 Hz, 2H), 2.70 (d, J = 8.2 Hz, 1 H), 1 .42 (s, 9H).
Intermediate 48: terf-butyl ((6-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2- yl)methyl)carbamate
Figure imgf000114_0001
To a solution of ((6-(6-fluoro-1 -(phenylsulfonyl)-1 - -indol-3-yl)-1 H-benzo[d]imidazol-2- yl)methyl)carbamate (Intermediate 47, 587 mg, 1 .13 mmol) in MeOH (30 imL) 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 C2i H2i FN4O2+H+ [M+H]+: calcd. 381 .2; found: 380.9.
Intermediate 49: A/-(2-amino-5-(6-fluoro-1 -(phenylsulfonyl)-l - -indol-3-yl)phenyl)-2- (dimethylamino)acetamide
Figure imgf000114_0002
To a stirred solution of dimethylamino-acetic acid (110 mg, 0.79 mmol) and DIEA (201 mg, 1 .56 mmol) in anhydrous THF (10 imL) was added HATU (385 mg, 1 .01 mmol) at 0 °C. The mixture was stirred for 10 mins and 4-(1 -benzenesulfonyl-6-fluoro-1 H-indol-3- yl)-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 imL) and extracted with EtOAc (30 ml_x3). The combined organic layer was washed with brine (20 ml_x3), 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 C24H23FN4O3S+H+ [M+H]+: calcd. 467.2 found: 466.8.
Intermediate 50: 1 -(6-(6-fluoro-1 -(phenylsulfonyl)-l - -indol-3-yl)-1 - -benzo[d]imidazol-2- yl)-N,A/-dimethylmethanamine
Figure imgf000115_0001
A mixture of A/-[2-amino-5-(1 -benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-phenyl]-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 EtOAc (50 ml_x3). 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 C24H2iFN4O2S+H+ [M+H]+: calcd. 449.1 ; found: 449.0.
Intermediate 51 : tert-butyl (2-(((6-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2- yl)methyl)amino)-2-oxoethyl)carbamate
Figure imgf000115_0002
To a stirred solution of te/t-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-1 H-indol-3- yl)-1 H-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 EtOAc (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 C23H24FN5O3+H+ [M+H]+: calcd. 438.2; found: 437.9
Intermediate 52: 2-acetamido-A/-(2-amino-5-(6-fluoro-1 -(phenylsulfonyl)-1 H-indol-3- yl)phenyl)acetamide
Figure imgf000116_0001
To a solution of A/-acetylglycine (102 mg, 0.87 mmol) and DIPEA (226 mg, 1 .75 mmol) in THF (10 mL) and DMF (1 ml_) was added HATU (365 mg, 0.96 mmol). The reaction mixture was stirred at 0 °C for 20 minutes before 4-(6-fluoro-1 -(phenylsulfonyl)-1 H-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 EtOAc (50ml_) and water (40ml_). The organic layer was dried over anhydrous Na2SO4, 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
C24H2i FN4O4S+H+ [M+H]+: calcd. 481 .1 ; found: 480.8.
Intermediate 53: A/-((6-(6-fluoro-1 -(phenylsulfonyl)-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2- yl)methyl)acetamide
Figure imgf000116_0002
A mixture of 2-acetamido-A/-(2-amino-5-(6-fluoro-1 -(phenylsulfonyl)-1 H-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 EtOAc (20 imL). 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 C24H-i9FN4O3S+l- [M+H]+: calcd. 463.1 ; found: 462.8.
Intermediate 54: terf-butyl 4-((2-amino-5-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3- yl)phenyl)carbamoyl)piperidine-1 -carboxylate
Figure imgf000117_0001
A mixture of 1 -(te/t-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 imL) was stirred at room temperature for 15 minutes before 4-(6-fluoro-1 - (phenylsulfonyl)-l - -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 EtOAc. 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 C3i H33FN4O5S+H+ [M+H]+: calcd. 593.2; found: 592.9.
Intermediate 55: terf-butyl 4-(6-(6-fluoro-1 -(phenylsulfonyl)-1 H-indol-3-yl)-1 H- benzo[d]imidazol-2-yl)piperidine-1 -carboxylate
Figure imgf000118_0001
A mixture of te/t-butyl 4-((2-amino-5-(6-fluoro-1 -(phenylsulfonyl)-1 H-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 = 1 1 with aqueous
K2CO3 and extracted with EtOAc. 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
C3i H3i FN4O4S+H+ [M+H]+: calcd. 575.2; found: 574.9.
Intermediate 56: terf-butyl 4-(6-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2- yl)piperidine-1 -carboxylate
Figure imgf000118_0002
Following the general method as outlined in Compound 1 , starting from terf-butyl 4-(6- (6-fluoro-1 -(phenylsulfonyl)-l - -indol-3-yl)-1 H-benzo[ |imidazol-2-yl)piperidine-1 - carboxylate (Intermediate 55, 660 mg, 1 .1 5 mmol), 600 mg (>1 00%) of the crude title compound was obtained as a black oil, which was used directly without further
purification. LC-MS for C25H27FN4O2+H+ [M+H]+: calcd. 435.2; found: 434.9.
Intermediate 57: 2-amino-5-(6-fluoro-1 - -indol-3-yl)phenol
Figure imgf000119_0001
To a solution of 6-(1 -benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-benzooxazole (702 mg, 1 .81 mmol) in MeOH (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 C14HnFN2O+H+ [M+H]+: calcd. 243.1 ; found: 243.2.
Intermediate 58: A/-[2-amino-5-(1 -benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-phenyl]-2- chloro-acetamide & A/-[2-amino-4-(1 -benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-phenyl]-2- chloro-acetamide
Figure imgf000119_0002
To a stirred solution of 4-(1 -benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-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 EtOAc (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 C22Hi7CIFN3O3S+H+ [M+H]+: calcd. 458.1 ; found: 457.7.
Intermediate 59: 6-(1 -benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-2-chloromethyl-1 H- benzoimidazole
Figure imgf000120_0001
A mixture of A/-[2-amino-5-(1 -benzenesulfonyl-6-fluoro-1 H-indol-3-yl)-phenyl]-2-chloro- acetamide & A/-[2-amino-4-(1 -benzenesulfonyl-6-fluoro-1 H-indol-3-yl)-phenyl]-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 EtOAc (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/ MeOH =200/1 - 50/1 ) to afford 3.20 g (84%) of the title compound as a brown solid. LC-MS for C22Hi5CIFN3O2S+H+ [M+H]+: calcd. 440.1 ;
found: 439.8.
Intermediate 60: 6-(6-fluoro-1 -(phenylsulfonyl)-l - -indol-3-yl)-2-((4-methylpiperazin-1 - yl)methyl)-1 - -benzo[d]imidazole
Figure imgf000120_0002
A mixture of 6-(1 -benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-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 C27H26FN5O2S+H+ [M+H]+: calcd. 504.2; found: 503.8. Intermediate 61 : 2-(((6-(6-fluoro-1 -(phenylsulfonyl)-l - -indol-3-yl)-1 - -benzo[d]imidazol- 2-yl)methyl)amino)ethanol
Figure imgf000121_0001
A mixture of 6-(1 -benzenesulfonyl-6-fluoro-1 H-indol-3-yl)-2-chloromethyl-1 H- benzoimidazole (Intermediate 59, 200 mg, 0.456 mmol), 2-amino-ethanol (55 mg, 0.91 1 mmol) and TEA (92 mg, 0.91 1 mmol) in DMF (3 mL) was stirred at 50 °C for 2 hours. Then it was diluted with EtOAc (50 mL), washed with brine (30 mLx2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to dryness to afford 1 1 6 mg (55%) of the crude title compound as a brown solid. LC-MS for C24H2i FN4O3S+H+ [M+H]+: calcd. 465.1 ; found: 464.9.
Intermediate 62: 6-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-2-(piperazin-1 -ylmethyl)- 1 - -benzo[d]imidazole
Figure imgf000121_0002
A mixture of 6-(1 -benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-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 EtOAc (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/MeOH = 20/1 to 5/1 ) to afford 176 mg (36%) of the title compound as a yellow solid.
LC-MS for C26H24FN5O2S+H+ [M+H]+: calcd. 490.2; found: 490.5. Intermediate 63: terf-butyl (2-(6-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-1 H- benzo[d]imidazol-2-yl)ethyl)carbamate
NHBoc
Figure imgf000122_0001
The solution of 3-ieri-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 -(phenylsulfonyl)-1 - -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 EtOAc (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 EtOAc (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 -(phenylsulfonyl)-1 - -indol-3-yl)-1 - -benzo[d]imidazol-2- yl)ethanamine
Figure imgf000122_0002
{2-[6-(1 -Benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-1 H-benzoimidazol-2-yl]-ethyl}-carbamic acid te/t-butyl ester (Intermediate 63, 4.17 g, 7.80 mmol) was dissolved in HCI /CH3OH (40 mL) and stirred at r. t for 1 h. The mixture was diluted with EtOAc (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. 1 H NMR (400 MHz, CDCI3) δ [ppm]: 7.93 (d, J = 8.8 Hz, 2H), 7.80 (dd, J = 9.6, 2.0 Hz, 1 H), 7.74 - 7.67 (m, 1 H), 7.65 (s, 1 H), 7.59 - 7.55 (m, 2H), 7.49 - 7.39 (m, 4H), 7.04 (td, J = 8.8, 1 .6 Hz, 1 H), 3.24 (t, J = 5.6 Hz, 2H), 3.06 (t, J = 5.2 Hz, 2H).
Intermediate 65: A/-{2-[6-(1 -Benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-1 H-benzoimidazol- 2-yl]-ethyl}-methanesulfonamide
Figure imgf000123_0001
To a solution of 2-[6-(1 -Benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-1 - -benzoimidazol-2-yl]- 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: A/-(2-(6-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-1 H- benzo[d]imidazol-2-yl)ethyl)acetamide
Figure imgf000124_0001
To a solution of 2-[6-(1 -Benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-1 - -benzoimidazol-2-yl]- 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 -(phenylsulfonyl)-l H-indol-3-yl)-2-((4- (methylsulfonyl)piperazin-l -yl)methyl)-1 - -benzo[d]imidazole
Figure imgf000124_0002
To a stirred solution of 6-(1 -benzenesulfonyl-6-fluoro-1 H-indol-3-yl)-2-piperazin-1 - ylmethyl-1 H-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 EtOAc (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/MeOH = 100/1 to 20/1 ) to afford 80 mg (72%) of the title compound as a brown solid. Intermediate 68: 2-(5-(6-fluoro-1 -/-indol-3-yl)-1 -/-benzo[d]imidazol-2-yl)acetonitrile
Figure imgf000125_0001
To a stirred solution of 4-(6-fluoro-1 - -indol-3-yl)-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 EtOAc (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, 1 M) and extracted with EtOAc (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/MeOH = 100/1 to 20/1 ) to afford 186 mg (52%) of the title compound as a brown solid. LC-MS for Ci7H-nFN4+H+ [M+H]+: calcd. 291 .1 ; found: 291 .3.
Intermediate 69: 2-amino-5-(6-fluoro-1 -(phenylsulfonyl)-l - -indol-3-yl)phenol
Figure imgf000125_0002
Following the general method as outlined in Intermediate 32, starting from 6-fluoro-3- iodo-1 -(phenylsulfonyl)-1 /-/-indole (Intermediate 1 , 6.0 g, 25.53 mmol) and 2-amino-5- (4,4,5,5-tetramethyl-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 C2oH-i5FN2O3S-H- [M-H]": calcd. 381 .1 ; found: 381 .3. 1 H NMR (300 MHz, DMSO-tf6) δ [ppm]: 9.20 (s, 1 H), 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, 1 H), 6.95 (s, 1 H), 6.89 (d, J= 7.9 Hz, 1 H), 6.67 (d, J = 8.1 Hz, 1 H), 4.77(s, 2H).
Intermediate 70: 2-amino-4-(6-fluoro-1 -(phenylsulfonyl)-l - -indol-3-yl)phenol
Figure imgf000126_0001
Following the general method as outlined in Intermediate 32, starting from 2-amino-4- (4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenol (1 1 .0 g, 46.7 mmol) and 6-fluoro-3- iodo-1 -(phenylsulfonyl)-l H-indole (Intermediate 1 , 1 2.5 g, 31 .2 mmol), 7.2 g (60%) of the title compound was obtained as a brown solid. 1 H NMR (400 MHz, CDCI3) δ [ppm]: 7.91 (s, 1 H), 7.89 (s, 1 H), 7.77 (dd, J = 1 0.0, 2.0 Hz, 1 H), 7.66 (dd, J = 8.8, 4.8 Hz, 1 H), 7.59 - 7.53 (m, 2H), 7.51 - 7.44 (m, 2H), 7.02 (td, J = 8.8, 2.0 Hz, 1 H), 6.94 (s, 1 H), 6.89 - 6.85 (m, 1 H), 6.83 - 6.79 (m, 1 H), 4.99 (brs, 1 H), 3.80 - 3.69 (m, 2H).
Intermediate 71 : 2-(chloromethyl)-5-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3- yl)benzo[d]oxazole
Figure imgf000126_0002
To a stirred mixture of 2-amino-4-(1 -benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-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 1 6 hours. Then it was cooled to room temperature and concentrated. The residue was suspended with sat.NaHCO3 (50 mL) and extracted with EtOAc (50 mLx2). The combined organic layer was washed with brine (30 ml_x2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by a silica gel column chromatography (petroleum ether/EtOAc = 10/1 - 5/1 ) to afford 1 .1 g (38%) of the title compound as a brown solid. LC-MS for C22Hi4CIFN2O3S+l- [M+H]+: calcd. 441 .0; found: 441 .4.
Intermediate 72: 5-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-2-(piperazin-1 - ylmethyl)benzo[d]oxazole
Figure imgf000127_0001
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 -(phenylsulfonyl)-1 H-indol-3- yl)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 EtOAc (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 C26H23FN4O3S+H+ [M+H]+: calcd. 491 .2; found: 491 .6.
Intermediate 73: 5-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-2-((4-methylpiperazin-1 - yl)methyl)benzo[d]oxazole
Figure imgf000127_0002
2-(chloromethyl)-5-(6-fluoro-1 -(phenylsulfonyl)-1 - -indol-3-yl)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 EtOAc (50 imL). The organic layer was washed with brine (30 ml_x3), dried over anhydrous Na2SO4 and filtered. The filtrate was
concentrated to dryness to afford 1 60 mg (70%) of the title compound as a brown solid. LC-MS for C27H22FN4O3S+H+ [M+H]+: calcd. 505.2 ; found: 505.5.
Intermediate 74: 5-(6-fluoro- 1 -(phenylsulfonyl)-l - -indol-3-yl)-2- (morpholinomethyl)benzo[d]oxazole
Figure imgf000128_0001
To a stirred solution of morpholine (391 mg, 4.5 mmol) in DMF (5 imL) was added 2- (chloromethyl)-5-(6-fluoro- 1 -(phenylsulfonyl)-l - -indol-3-yl)benzo[d]oxazole
(Intermediate 71 , 200 mg, 0.45 mmol) at 60 °C. The mixture was stirred for 30 minutes, cooled and diluted with EtOAc (50 imL). The organic layer was washed with brine (30 ml_x3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to dryness to afford 1 00 mg (45%) of the title compound as a brown solid. LC-MS for C26H22FN3O4S+H+ [M+H]+: calcd. 492.1 ; found: 492.5.
Intermediate 75: 6-(6-fluoro-1 -(phenylsulfonyl)-l -/-indol-3-yl)benzo[d]oxazol-2(3 -/)-one
Figure imgf000128_0002
To a stirred solution of 2-amino-5-(6-fluoro- 1 -(phenylsulfonyl)- 1 - -indol-3-yl)phenol (Intermediate 69, 500 mg, 1 .3 mmol) and CDI (233 mg, 1 .43 mmol) in anhydrous THF (20 imL) was added TEA ( 1 .08 imL) 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 EtOAc (60 mLx3). The combined organic layer was washed with water (60 mLx3), dried over anhydrous Na2SO4 and filtered. The filtrate was
concentrated to afford 531 mg (100%) of the title compound as a red solid. LC-MS for C2i H13FN2O4S-H" [M-H]" : calcd. 407.1 ; found: 406.8. 1 H NMR (400 MHz, DMSO-afe) δ [ppm]:11 .94 (s, 1 H), 8.14 (d, J = 8.5 Hz, 1 H), 7.87 - 7.78 (m, 1 H), 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, 1 H), 7.02 (s, 2H).
Intermediate 76: 2-(6-(6-fluoro-1 -(phenylsulfonyl)-1 - -indol-3-yl)-2-oxobenzo[d]oxazol- 3(2H)-yl)acetamide
Figure imgf000129_0001
To a stirred solution of 6-(6-fluoro-1 -(phenylsulfonyl)-1 -/-indol-3-yl)benzo[d]oxazol- 2(3H)-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 EtOAc (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 C23Hi6FN3O5S+H+ [M+H]+ : calcd. 466.1 ; found: 465.8.
Intermediate 77: 5-(1 -Benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-1 ,3-dihydro- benzoimidazol-2-one
Figure imgf000130_0001
To a solution of 4-(1 -Benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-benzene-1 ,2-diamine (Intermediate 32, 200 mg, 0.50 mmol) in THF was added CDI (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 C2i Hi4FN3O3S+H+ [M+H]+: calcd. 408.1 ; found: 408.4.
Intermediate 78: 2-chloro-A/-(4-(6-fluoro-1 -(phenylsulfonyl)-1 H-indol-3-yl)-2- hydroxyphenyl)acetamide
Figure imgf000130_0002
To a stirred solution of 2-amino-5-(6-fluoro-1 -(phenylsulfonyl)-1 - -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 EtOAc, 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 -(phenylsulfonyl)
yl)benzo[d]oxazole
Figure imgf000131_0001
To a stirred solution of 2-chloro-A/-(4-(6-fluoro-1 -(phenylsulfonyl)-1 - -indol-3-yl)-2- hydroxyphenyl)acetamide (Intermediate 78, 1 .22 g, 2.7 mmol) in xylem (5 imL) 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 imL) and extracted with EtOAc (50 ml_x3) . 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 C22Hi4CIFN2O3S+l-r [M+H]+: calcd. 441 .0; found: 441 .0.
Intermediate 80: 6-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-2- (morpholinomethyl)benzo[d]oxazole
Figure imgf000131_0002
To a stirred solution of 2-(chloromethyl)-6-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3- yl)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 EtOAc (50 imL) and washed with water (40 ml_x4) . 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 C26H22FN3O4S+H+ [M+H]+: calcd. 492.1 ; found: 492.1 . Intermediate 81 : 3-(6-(6-fluoro-1 -(phenylsulfonyl)-1 H-indol-3-yl)-2-oxobenzo[d]oxazol- 3(2 -/)-yl)propanamide
Figure imgf000132_0001
To a stirred solution of 6-(6-fluoro-1 -(phenylsulfonyl)-1 -/-indol-3-yl)benzo[d]oxazol- 2(3H)-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 EtOAc (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 C24H18FN3O5S-H" [M-H]": calcd. 478.1 ; found: 477.7.
Intermediate 82: 6-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-2-((4-methylpiperazin-1 - yl)methyl)benzo[d]oxazole
Figure imgf000132_0002
To a stirred solution of 2-(chloromethyl)-6-(6-fluoro-1 -(phenylsulfonyl)-1 H-indol-3- yl)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 1 hours, cooled to room temperature and concentrated. The residue was diluted with EtOAc (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 C27H25FN4O3S+H+ [M+H]+: calcd. 505.2; found: 504.9.
Intermediate 83: 5-(6-fluoro-1 -(phenylsulfonyl)-1 -/-indol-3-yl)benzo[d]oxazol-2(3 -/)-one
Figure imgf000133_0001
A solution of 2-amino-4-(6-fluoro-1 -(phenylsulfonyl)-1 - -indol-3-yl) phenol (Intermediate 70, 1 .00 g, 2.61 mmol) and CDI (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 C2iH13FN2O4S+H+ [M+H]+: calcd. 409.1 ; found: 408.8.
Intermediate 84: 2-(5-(6-fluoro-1 -(phenylsulfonyl)-1 - -indol-3-yl)-2-oxobenzo[d]oxazol- 3(2H)-yl)acetamide
Figure imgf000133_0002
A mixture of 5-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl) benzo[ |oxazol-2(3 -/)-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 EtOAc. 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 C23Hi6FN3O5S+H+ [M+H]+: calcd. 466.1 ; found: 465.8.
Intermediate 85: 6-(6-fluoro-1 -(phenylsulfonyl)-l - -indol-3-yl)-1 /- -benzo[d]imidazol-2- amine
Figure imgf000134_0001
Following the general method as outlined in Intermediate 32, starting from 6-fluoro-3- iodo-1 -(phenylsulfonyl)-1 /-/-indole (Intermediate 1 , 1 .55 g, 3.86 mmol) and 6-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-benzo[ |imidazol-2-amine (1 .30 g, 5.02 mmol; prepared as described in US200701 17818), 260 mg (17%) of the title compound was obtained as a brown solid. LC-MS for C2i H15FN4O2S+H+ [M+H]+: calcd. 407.1 ; found: 407.4.
Intermediate 86: terf-butyl ((5-(6-fluoro-1 -(phenylsulfonyl)-1 /-/-indol-3-yl)benzo[d]oxazol- 2-yl)methyl)(methylsulfonyl)carbamate
Figure imgf000134_0002
A mixture of (terf-butoxy)-/V-(methylsulfonyl) carboxamide (53 mg, 0.273 mmol), 2- (chloromethyl)-5-(6-fluoro-1 -(phenylsulfonyl)-1 /- -indol-3-yl)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 EtOAc (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/EtOAc = 4/1 ) to afford 50 mg (37%) of the title compound as a yellow solid. LC-MS for C28H26FN3O7S2+H' [M+H]+: calcd. 600.1 ; found: 600.5.
Intermediate 87: A/-((5-(6-fluoro-1 -(phenylsulfonyl)-l - -indol-3-yl)benzo[d]oxazol-2- yl)methyl)methanesulfonamide
Figure imgf000135_0001
To a solution of A/-[5-(1 -benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-benzooxazol-2- ylmethyl]-methanesulfonamide (Intermediate 86, 100 mg, 0.17 mmol) in EtOAc (2 mL) was added HCI/EtOAc (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 C23Hi8FN3O5S2+H+ [M+H]+: calcd. 500.1 ; found 499.9.
Intermediate 88: 3-(5-(6-fluoro-1 -(phenylsulfonyl)-1 -/-indol-3-yl)-2-oxobenzo[d]oxazol- 3(2 -/)-yl)propanamide
Figure imgf000135_0002
The mixture of 5-(1 -benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-3 - -benzooxazol-2- one(lntermediate 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
C24H18FN3O5S-H" [M-H]": calcd. 408.1 ; found: 477.8. Intermediate 89: 2-Benzo[b]thiophen-5-yl-4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolane
Figure imgf000136_0001
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) δ 8.31 (s, 1 H), 7.89 (d, J= 8.0 Hz, 1 H), 7.75 (d, J = 8.0 Hz, 1 H), 7.41 (d, J = 5.4 Hz, 1 H), 7.35 (d, J = 5.2 Hz, 1 H), 1 .37 (s, 12H).
Intermediate 90: 3-(benzo[b]thiophen-5-yl)-6-fluoro-1 -(phenylsulfonyl)-l /-/-indole
Figure imgf000136_0002
&02Ph
The mixture of 6-fluoro-3-iodo-1 -(phenylsulfonyl)-1 /-/-indole (Intermediate 1 , 401 mg, 1 .0 mmol) , 2-benzo[b]thiophen-5-yl-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)CI2 (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 : te/t-butyl ((6-(6-fluoro-1 -(phenylsulfonyl)-1 /-/-indol-3-yl)benzo[d]oxazol- 2-yl)methyl)(methylsulfonyl)carbamate
Figure imgf000137_0001
To a stirred solution of te/t-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 - (phenylsulfonyl)-l -/-indol-3-yl)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 EtOAc (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 C28H26FN3O7S2+H+ [M+H]+ : calcd. 600.1 ; found: 599.8.
Intermediate 92: terf-butyl ((6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2- yl)methyl)(methylsulfonyl)carbamate
Figure imgf000137_0002
To a stirred solution of te/t-butyl ((6-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3- yl)benzo[d]oxazol-2-yl)methyl)(methylsulfonyl)carbamate (Intermediate 91 , 148 mg, 0.25 mmol) in MeOH (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 EtOAc (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 C22H22FN3O5S+H+ [M- Boc+H]+: calcd. 360.1 ; found: 360.0.
Intermediate 93: terf-butyl A/-({6-[1 -(benzenesulfonyl)-6-fluoro-1 H-indol-3-yl]-1 ,3- benzoxazol-2-yl}methyl)-A/-[(ieri-butoxy)carbonyl]carbamate
c
Figure imgf000138_0001
To a stirred solution of di-terf-butyl iminodicarboxylate (640 mg, 2.95 mmol), K2CO3 (900 mg, 6.5 mmol) and Kl(34 mg, 0.2 mmol ) in DMF (30 mL) was added 2-(chloromethyl)-6- (6-fluoro-1 -(phenylsulfonyl)-1 -/-indol-3-yl)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 EtOAc (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 C32H32FN3O7S2+H+ [M-Boc+H]+ : calcd. 522.2 ; found: 522.9.
Intermediate 94: terf-butyl A/-[(ieri-butoxy)carbonyl]-A/-{[6-(6-fluoro-1 H-indol-3-yl)-1 ,3- benzoxazol-2-yl]methyl}carbamate
c
Figure imgf000138_0002
To a stirred solution of terf-butyl A/-({6-[1 -(benzenesulfonyl)-6-fluoro-1 -/-indol-3-yl]-1 ,3- benzoxazol-2-yl}methyl)-A/-[(ieri-butoxy)carbonyl]carbamate (Intermediate 93; 1 .36 g, 2.20 mmol) in MeOH (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 EtOAc (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/ EtOAc =6/1 - 2/1 ) to afford 406 mg (39%) of the title compound as a yellow solid. LC-MS for C26H28FN3O5+H+ [M- Boc+H]+ : calcd. 382.2; found: 381 .9.
Intermediate 95: 6-(6-fluoro-1 -(phenylsulfonyl)-l -/-indol-3-yl)-2-(piperazin-1 - ylmethyl)benzo[d]oxazole
Figure imgf000139_0001
To a stirred solution of 2-(chloromethyl)-6-(6-fluoro-1 -(phenylsulfonyl)-1 H-indol-3- yl)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 1 hour before it was cooled to room temperature and concentrated. The residue was diluted with water (20 mL) and extracted with EtOAc (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 C26H23FN4O3S+H+ [M+H]+: calcd. 491 .2; found: 490.8.
Intermediate 96: 2-(benzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane
Figure imgf000139_0002
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'-octamethyl-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-yl)-6-fluoro-1 -(phenylsulfonyl)-l /-/-indole
Figure imgf000140_0001
Following the general method as outlined in Intermediate 90, starting from 6-fluoro-3- iodo-1 -(phenylsulfonyl)-1 /-/-indole (Intermediate 1 , 500 mg, 1 .2 mmol) and 2- (benzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-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 -(phenylsulfonyl)-l H-indol-3-yl)-2-(2- (methylthio)ethyl)benzo[d]oxazole
Figure imgf000140_0002
To a stirred solution of 3-methylsulfanyl-propionic acid (198 mg, 1 .65 mmol) in DCM (1 5 imL) at -1 0 °C was added TEA (31 7 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 -benzenesulfonyl-6-fluoro-1 /-/-indol-3-yl)-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 (1 0 mL), refluxed for 1 6 hours, cooled to room temperature and concentrated. The residue was suspended with aqueous NaHCO3 (30 mL), extracted with EtOAc (40 ml_x2). The combined organic layer was washed with brine (30 ml_x2), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated and purified by silica gel column chromatography (petroleum ether/EtOAc = 20/1 to 5/1 ) to afford 320 mg (44%) of the title compound as a brown solid. LC-MS for C24Hi9FN2O3S2+H+ [M+H]+: calcd. 467.1 ; found: 467.5. 1H NMR (400 MHz, CDCI3) δ [ppm]: 7.97 - 7.92 (m, 2H), 8.85 (d, J = 1 .6 Hz, 1 H), 7.80 (dd, J = 9.6, 2.4 Hz, 1 H), 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, 1 H), 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-1 H-indol-3-yl)-2-(2-(methylthio)ethyl)benzo[d]oxazole
Figure imgf000141_0001
A mixture of 5-(1 -benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-2-(2-methylsulfanyl-ethyl)- benzooxazole (320 mg, 0.687 mmol) and NaOH (137 mg, 3.43 mmol) in MeOH (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 EtOAc (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/EtOAc = 20/1 to 5/1 ) to afford 70 mg (31 %) of the title compound as a yellow solid. LC-MS for C18H15FN2OS+H+ [M+H]+: calcd. 327.1 ; found: 327.4. 1H NMR (400 MHz, DMSO-afe) δ [ppm]: 8.28 (brs, 1 H), 7.91 (s, 1 H), 7.82 (dd, J = 8.8, 5.2 Hz, 1 H), 7.59 - 7.53 (m, 2H), 7.34 (d, J = 2.4 Hz, 1 H), 7.13 (dd, J = 9.6, 2.4 Hz, 1 H), 6.96 (td, J = 9.2, 2.0 Hz, 1 H), 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-yl)-1 H- indole-1 -carboxylate
Figure imgf000141_0002
To a solution of 5-(6-fluoro-1 - -indol-3-yl)-2-(2-methylsulfanyl-ethyl)-benzooxazole (70 mg, 0.215 mmol) in DCM (10 mL) was added Boc2O (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 C23H23FN2O3S+H+ [M+H]+: calcd. 427.1 ; found: 427.6.
Intermediate 101 : tert-butyl 6-fluoro-3-(2-(2-(methylsulfonyl)ethyl)benzo[d]oxazol-5-yl)- 1 /-/-indole-1 -carboxylate
Figure imgf000142_0001
To a stirred solution of 6-fluoro-3-[2-(2-methylsulfanyl-ethyl)-benzooxazol-5-yl]-indole-1 - carboxylic acid te/t-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 EtOAc (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/EtOAc = 3/1 ) to afford 45 mg (75%) of the title compound as a white solid. LC-MS for C23H23FN2O5S+H+ [M+H]+: calcd. 459.1 ; found: 459.6. 1H NMR (400 MHz, CDCI3) δ [ppm]: 8.18-8.00 (m, 1 H), 7.99 - 7.90 (m, 1 H), 7.88 (s, 1 H), 7.72 - 7.66 (m, 1 H), 7.58 - 7.50 (m, 1 H), 7.40 - 7.30 (m, 1 H), 7.04 (td, J = 8.8, 2.0 Hz, 1 H), 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: terf-butyl A/-({5-[1 -(benzenesulfonyl)-6-fluoro-1 H-indol-3-yl]-1 ,3- benzoxazol-2-yl}methyl)-A/-[(ieri-butoxy)carbonyl]carbamate
Figure imgf000143_0001
A mixture of 5-( 1 -benzenesulfonyl-6-fluoro- 1 - -indol-3-yl)-2-chloromethyl-benzooxazole (Intermediate 71 , 1 00 mg, 0.227 mmol), terf-butyl [(ieri-butoxy)carbonylamino]formate (1 48 mg, 0.682 mmol), Kl (38 mg, 0.227 mmol) and K2CO3 (94 mg, 0.682 mmol) in DMF (5 imL) was stirred at 60 °C for 5 hours. Then it was cooled to room temperature, diluted with EtOAc (30 imL), washed with brine (20 ml_x2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by a silica gel column
chromatography (petroleum ether/EtOAc = 50/1 to 1 5/1 ) to afford 1 1 4 mg (81 %) of the title compound as a yellow solid. LC-MS for C32H32FN3O7S+H+ [M+H]+: calcd. 622.2 ; found: 622.7.
Intermediate 1 03: tert-butyl ((5-(6-fluoro- 1 H-indol-3-yl)benzo[d]oxazol-2- yl)methyl)carbamate
Figure imgf000143_0002
To a solution of te/t-butyl A/-({5-[1 -(benzenesulfonyl)-6-fluoro-1 -/-indol-3-yl]-1 ,3- benzoxazol-2-yl}methyl)-A/-[(ieri-butoxy)carbonyl]carbamate (Intermediate 102, 1 14 mg, 0.183 mmol) in MeOH (8 imL) was added NaOH (73 mg, 1 .83 mmol). The mixture was refluxed for 4 hours before it was cooled to room temperature. The solvent was removed. The residue was diluted with water (20 imL) and extracted with EtOAc (20 ml_x2) . The combined organic layer was washed with brine (20 ml_x2), dried over anhydrous
Na2SO4 and filtered. The filtrate was concentrated and purified by a silica gel column chromatography (petroleum ether/EtOAc = 10/1 to 3/1 ) to afford 63 mg (90%) of the title compound as a brown oil. 1H NMR (300 MHz, CDCI3) δ [ppm]: 8.31 (brs, 1 H), 7.92 (s, 1 H), 7.82 (dd, J = 9.3, 5.4 Hz, 1 H), 7.63 - 7.54 (m, 2H), 7.35 (d, J = 2.4 Hz, 1 H), 7.13 (dd, J = 9.3, 2.4 Hz, 1 H), 6.97 (td, J = 9.3, 2.4 Hz, 1 H), 4.66 (d, J = 5.7 Hz, 2H), 1 .49 (s, 9H).
Intermediate 104: 3-(benzofuran-5-yl)-6-fluoro-1 -(phenylsulfonyl)-l /-/-indole
Figure imgf000144_0001
Following the general method as outlined in Intermediate 90, starting from 6-fluoro-3- iodo-1 -(phenylsulfonyl)-1 /-/-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 C22Hi4FNO3S+H+ [M+H]+: calcd. 392.1 ; found: 391 .8. 1 H NMR (400 MHz, DMSO-afe) δ [ppm]: 8.17 - 8.13 (m, 2H), 8.12 (s, 1 H), 8.06 (d, J = 2.2 Hz, 1 H), 7.99 (d, J = 1 .8 Hz, 1 H), 7.87 (dd, J = 8.8, 5.3 Hz, 1 H), 7.82 (dd, J = 9.9, 2.4 Hz, 1 H), 7.76 - 7.69 (m, 2H), 7.67 - 7.60 (m, 3H), 7.24 (ddd, J = 9.5, 8.8, 2.4 Hz, 1 H), 7.02 (d, J = 2.0 Hz, 1 H).
Intermediate 105: te/t-butyl 4-(6-(6-fluoro-1 -(phenylsulfonyl)-'
yl)benzo[d]oxazol-2-yl)piperidine-1 -carboxylate
Figure imgf000144_0002
To a solution of 4-carbamoyl-piperidine-1 -carboxylic acid te/t-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 -benzenesulfonyl-6-fluoro-1 /-/-indol-3-yl)- 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 ml_x3). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was
concentrated and purified by silica gel chromatography (PE/EtOAc = 2/1 ) to afford 540 mg (54%) of the title compound as a brown solid. LC-MS for CaiHaoFNaOsS+hT [M+H]+: calcd. 576.2; found: 576.7. 1 H NMR (400 MHz, DMSO-cfe) δ [ppm]: 8.21 (s, 1 H), 8.15 (d, J = 7.6 Hz, 2H), 8.04 (s, 1 H), 7.89 (dd, J= 4.8, 8.8 Hz, 1 H), 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, 1 H), 3.97 (d, J = 12.8 Hz, 2H), 3.32 - 3.25 (m, 1 H), 3.01 (brs, 2H), 2.1 1 (d, J = 10.8 Hz, 2H), 1 .75 - 1 .65 (m, 2H), 1 .42 (s, 9H).
Intermediate 106: te/t-butyl 4-(6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)piperidine-1 carboxylate
Figure imgf000145_0001
To a solution of te/t-butyl 4-(6-(6-fluoro-1 -(phenylsulfonyl)-l -/-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 EtOAc (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 C25H26FN3O3+H+ [M+H]+: calcd. 436.2; found: 436.6.
Intermediate 107: methyl 3-(6-(6-fluoro-1 -(phenylsulfonyl)-1 - -indol-3-yl)benzo[d]oxazol- 2-yl)propanoate
Figure imgf000146_0001
To a stirred solution of succinamic acid methyl ester (500 mg, 3.82 mmol) in 1 , 2- dichloro-ethane (10 imL) 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 -benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-phenol (Intermediate 69, 1 .46 g, 3.82 mmol) in anhydrous MeOH (15 imL) was added. The mixture was stirred for a further 3 hours before it was quenched with aqueous NaHCO3 (50 imL) and extracted with EtOAc (30 ml_x3). The combined organic layer was washed with brine (20 ml_x2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by a silica gel column chromatography (petroleum ether/EtOAc = 10/1 to 5/1 ) to afford 1 10 mg (6%) of the title compound as a brown solid. LC-MS for C25Hi9FN2O5S+H+ [M+H]+: calcd. 479.1 ; found: 479.6. 1H NMR (400 MHz, DMSO- /6) δ [ppm]: 8.21 (s, 1 H), 8.16 (d, J= 8.1 Hz, 2H), 8.04 (s, 1 H), 7.93-7.59 (m, 7H), 7.23 (td, J = 9.0, 1 .8 Hz, 1 H), 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-1 -/-indol-3-yl)benzo[d]oxazol-2-yl)propanoic acid
Figure imgf000146_0002
A mixture of 3-[6-(1 -benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-benzooxazol-2-yl]-propionic acid methyl ester (Intermediate 107, 60 mg, 0.126 mmol) and NaOH (50 mg, 1 .26 mmol) in EtOH (8 imL) was stirred at 76 °C for 1 hour. Then it was cooled to room temperature and concentrated. The mixture was diluted with water (10 imL) and suspended with petroleum ether/EtOAc = 1 /1 (10 imL, v/v). The aqueous layer was acified with 1 M HCI to pH = 4 and extracted with EtOAc (20 ml_x3). The combined organic layer was washed with brine (20 ml_x2), 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 C18H13FN2O3+H+ [M+H]+: calcd. 325.1 ; found: 325.3.
Intermediate 109: 2-(6-(6-fluoro-1 -(phenylsulfonyl)-l - -indol-3-yl)-1 - -benzo[d]imidazol- 1 -yl)acetamide & 2-(5-(6-fluoro-1 -(phenylsulfonyl)-l -/-indol-3-yl)-1 -/-benzo[d]imidazol-1 - yl)acetamide
Figure imgf000147_0001
A mixture of 5-(6-fluoro-1 -(phenylsulfonyl)-l - -indol-3-yl)-1 H-benzo[ |imidazole
(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 imL) was stirred at room temperature for 48 hours. The mixture was added into water dropwise. The yellow precipitate was collected by vacuum filtration. The solid was dissolved in EtOAc, washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel chromatography (DCM - DCM/MeOH = 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 -(phenylsulfonyl)-1 H-indol-3- yl)-1 H-benzo[ |imidazol-1 -yl)acetamide as a white solid. LC-MS for C23Hi7FN4O3S+H+ [M+H]+: calcd. 449.1 ; found: 448.8.
Intermediate 1 10: ethyl 3-(5-(6-fluoro-1 -(phenylsulfonyl)-1 H-indol-3-yl)-1 H-indazol-1 - yl)propanoate
Figure imgf000148_0001
A mixture of 5-(1 -benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-1 - -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 imL) was stirred at room temperature for 3 hrs. Then the reaction mixture was poured into water and extracted with EtOAc (50 ml_x3). 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/EtOAc = 5/1 - 1 /1 ) to afford 3.5 g (43%) of the title compound as a white solid. LC- MS for C26H22FN3O4S+H+ [M+H]+: calcd. 492.1 ; found: 491 .8. 1H NMR (400 MHz, DMSO-cfe) δ [ppm]: 8.16-8.13 (m, 4H), 8.08 (s, 1 H), 7.91 - 7.87 (m, 1 H), 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, 1 H), 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 1 1 1 : 3-(5-(6-fluoro-1 -/-indol-3-yl)-1 /-/-indazol-1 -yl)propanoic acid
Figure imgf000148_0002
A mixture of NaOH (855 mg, 21 .4 mmol) and 3-[5-(1 -Benzenesulfonyl-6-fluoro-1 H-indol- 3-yl)-indazol-1 -yl]-propionic acid ethyl ester (Intermediate 1 10, 3.5 g, 7.13 mmol) in 50 imL 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 Ci8H14FN3O2+H+ [M+H]+: calcd. 324.1 ; found: 323.9. Intermediate 1 12: tert-butyl 4-(3-(5-(6-fluoro-1 H-indol-3-yl)-1 H-indazol-1 - yl)propanoyl)piperazine-1 -carboxylate
Figure imgf000149_0001
A mixture of 3-[5-(6-fluoro-1 -/-indol-3-yl)-indazol-1 -yl]-propionic acid (Intermediate 1 1 1 , 300 mg, crude, 0.93 mmol), Piperazine-1 -carboxylic acid terf-butyl ester (173 mg, 0.93 mmol), HATU (530 mg, 1 .4 mmol) and DIEA (360 mg, 2.8 mmol) in DMF (5 imL) was stirred at room temperature for 2 hrs. Then the mixture was poured into water, extracted with EtOAc (50 ml_x3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (CH3CN/H2O = 30% - 75%, NH4HCO3) to afford 98 mg (21 %) of the title compound as a yellow solid. LC-MS for C27H3oFN5O3+H+ [M+H]+: calcd. 492.2; found: 491 .9.
Intermediate 1 13: 6-(6-fluoro-1 -(phenylsulfonyl)-l - -indol-3-yl)indolin-2-one
Figure imgf000149_0002
To a mixture of 6-fluoro-3-iodo-1 -(phenylsulfonyl)-1 /-/-indole (Intermediate 1 , 600 mg, 1 .50 mmol), 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)indolin-2-one (259 mg, 1 .00 mmol, prepared as described in WO2014140075) and K2CO3 (276 mg, 2.00 mmol) in dioxane (10 imL) and water (1 imL) was added Pd(PPh3)4 (1 16 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/EtOAc = 5/1 , v/v) to afford 400 mg (98%) of the title compound as a yellow solid. 1 H NMR (300 MHz, CDCI3) δ [ppm]: 7.96 - 7.90 (m, 2H), 7.81 (dd, J = 9.6, 2.4 Hz, 1 H), 7.70 - 7.63 (m, 3H), 7.61 - 7.56 (m, 1 H), 7.54 - 7.45 (m, 2H), 7.31 (d, J = 7.7 Hz, 1 H), 7.22 (dd, J = 7.7, 1 .5 Hz, 1 H), 7.10 - 7.01 (m, 2H), 3.59 (s, 2H).
Intermediate 1 14: 3-(6-(6-fluoro-1 -(phenylsulfonyl)-l - -indol-3-yl)-1 - -benzo[d]imidazol- 1 -yl)propanamide & 3-(5-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-1 H- benzo[d]imidazol-1 -yl)propanamide
Figure imgf000150_0001
A mixture of 5-(6-fluoro-1 -(phenylsulfonyl)-l - -indol-3-yl)-1 H-benzo[ |imidazole
(Intermediate 27, 1 .66 g, 4.24 mmol), 3-bromopropionamide (970 mg, 6.38 mmol), Kl (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 EtOAc (50 mLx3). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered,
concentrated, and purified by silica gel chromatography (DCM - DCM/MeOH = 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 -(phenylsulfonyl)-l -/-indol-3-yl)-1 H-benzo[ |imidazol-1 -yl)propanamide as a white solid. LC-MS for C24H19FN4O3S+H+ [M+H]+: calcd. 463.1 ; found: 462.8.
Intermediate 1 15: 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)indolin-2-one
Figure imgf000150_0002
Following the general method as outlined in Intermediate 3, starting from 5-Bromo-1 ,3- dihydro-indol-2-one(1 .00 g, 4.72 mmol) and 4,4,5,5,4',4',5',5'-Octamethyl- [2,2']bi[[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 C H18BNO3+H+ [M+H]+: calcd. 2620.1 ; found: 260.4.
Intermediate 1 16: 1 -Benzenesulfonyl-6-fluoro-1 ',3'-dihydro-1 - -[3,5']biindolyl-2'-one
Figure imgf000151_0001
Following the general method as outlined in Intermediate 32, starting from 6-fluoro-3- iodo-1 -(phenylsulfonyl)-l /-/-indole (Intermediate 1 , 0.96 g, 2.4 mmol) and 5-(4,4,5,5- Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-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
C22Hi5FN2O3S-H- [M-H]": calcd. 405.1 ; found: 405.4. 1 H NMR (400 MHz, DMSO) δ 10.49 (s, 1 H), 8.12 (d, J = 7.6 Hz, 2H), 8.01 (s, 1 H), 7.86 - 7.76 (m, 2H), 7.72 (t, J = 7.5 Hz, 1 H), 7.62 (t, J = 7.7 Hz, 2H), 7.55 (s, 1 H), 7.51 (d, J = 7.9 Hz, 1 H), 7.22 (td, J = 9.1 , 2.3 Hz, 1 H), 6.91 (d, J = 8.0 Hz, 1 H), 3.54 (s, 2H).
Intermediate 1 17: 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2- amine
Figure imgf000151_0002
Following the general method as outlined in Intermediate 3, starting from 6-Bromo- benzooxazol-2-ylamine (2.40 g, 1 1 .3 mmol) and 4,4,5,5,4',4',5',5'-Octamethyl- [2,2']bi[[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 Ci3H17BN2O3+H+ [M+H]+: calcd. 261 .1 ; found: 261 .4. 1 H NMR (300 MHz, DMSO-dg) δ [ppm]: 7.58 (s, 2H), 7.48 (s, 1 H), 7.46 - 7.43 1 H), 7.18 (d, J = 7.8 Hz, 1 H), 1 .29 (s, 12H).
Intermediate 1 18: 6-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)benzo[d]oxazol-2-amine
Figure imgf000152_0001
Following the general method as outlined in Intermediate 90, starting from 6-fluoro-3- iodo-1 -(phenylsulfonyl)-1 /-/-indole (Intermediate 1 , 2.77 g, 6.90 mmol) and 6-(4,4,5,5- Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-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
C2i H14FN3O3S+H+ [M+H]+: calcd. 408.1 ; found: 408.5.
Intermediate 1 19: A/-((6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2- yl)methyl)ethenesulfonamide
Figure imgf000152_0002
To a stirred solution of (6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)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 EtOAc (60 mL) and filtered. The filtrate was
concentrated and purified by silica gel column (petroleum ether/ EtOAc = 2/1 ) to afford 147 mg (32%) of the title compound as yellow oil. LC-MS for Ci8H14FN3O3S+H+ [M+H]+ : calcd. 372.1 ; found: 372.5. Intermediate 120: 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2-vinylbenzo[d]oxazole
Figure imgf000153_0001
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) δ [ppm]: 7.95 (s, 1 H), 7.78 (d, J = 8.0 Hz, 1 H), 7.69 (d, J = 8.0 Hz, 1 H), 6.76 (dd, J = 17.6, 1 1 .2 Hz, 1 H), 6.50 (dd, J = 17.6, 0.8 Hz, 1 H), 5.88 (dd, J = 1 1 .6, 0.8 Hz, 1 H), 1 .37 (s, 12 H).
Intermediate 121 : te/t-butyl 6-fluoro-3-(2-vinylbenzo[d]oxazol-6-yl)-1 /-/-indole-1 carboxylate
Figure imgf000153_0002
Following the general method as outlined in Intermediate 32, starting from 6-(4, 4, 5, 5- tetramethyl-[1 , 3, 2]dioxaborolan-2-yl)-2-vinyl-benzooxazole (700 mg, 2.58 mmol) and 3- bromo-6-fluoro-indole-1 -carboxylic acid terf-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) δ [ppm]: 7.96 (d, J = 8.8 Hz, 1 H), 7.78 (dd, J = 8.4, 0.4 Hz, 1 H), 7.76 - 7.70 (m, 3H), 7.59 (dd, J = 8.0, 1 .6 Hz, 1 H), 7.07 (td, J = 8.8, 2.4 Hz, 1 H), 6.79 (dd, J = 17.6, 1 1 .2 Hz, 1 H), 6.50 (dd, J = 17.6, 0.8 Hz, 1 H), 5.89 (dd, J = 1 1 .2, 0.8 Hz, 1 H), 1 .70 (s, 9H).
Intermediate 122: tert-butyl 6-fluoro-3-(2-(2-(methylthio)ethyl)benzo[d]oxazol-6-yl)-1 H- indole-1 -carboxylate
Figure imgf000154_0001
To a solution of 6-fluoro-3-(2-vinyl-benzooxazol-6-yl)-indole-1 -carboxylic acid terf-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 EtOAc (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/EtOAc = 20/1 to 10/1 ) to afford 480 mg (82%) of the title compound as a white solid. 1H NMR (400 MHz, CDCI3) δ [ppm]: 7.96 (d, J = 9.2 Hz, 1 H), 7.78 - 7.69 (m, 4H), 7.57 (dd, J = 8.0, 1 .2 Hz, 1 H), 7.06 (td, J = 8.8, 2.4 Hz, 1 H), 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-(methylsulfonyl)ethyl)benzo[d]oxazol-6-yl)- 1 /-/-indole-1 -carboxylate
Figure imgf000154_0002
To a solution of 6-fluoro-3-[2-(2-methylsulfanyl-ethyl)-benzooxazol-6-yl]-indole-1 - carboxylic acid te/t-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 EtOAc (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/EtOAc = 10/1 to 3/1 ) to afford 390 mg (75%) of the title compound as a yellow solid. LC-MS for C23H23FN2O5S+H+ [M+H]+: calcd. 459.1 ; found: 459.6. 1H NMR (300 MHz, CDCI3) δ [ppm]: 7.96 (d, J = 8.7 Hz, 1 H), 7.78-7.68 (m, 4H), 7.59 (dd, J = 8.4, 1 .5 Hz, 1 H), 7.07 (td, J = 9.0, 2.4 Hz, 1 H), 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: A/-(6-(6-fluoro-1 -(phenylsulfonyl)-1 H-indol-3-yl)benzo[d]oxazol-2- yl)methanesulfonamide
Figure imgf000155_0001
To a solution of 6-(1 -benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-benzooxazol-2-ylamine (Intermediate 1 1 8, 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 ml_x2) 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 C22H16FN3O5S2-H" [M-H]": calcd. 484.1 ; found: 484.4.
Intermediate 1 25: 2-(2-chloroethyl)-6-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3- yl)benzo[d]oxazole
I
Figure imgf000155_0002
A solution of 2-amino-5-(6-fluoro-1 -(phenylsulfonyl)-1 - -indol-3-yl) 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 EtOAc (100 mLx3) and the organic layer was concentrated and purified by flash chromatography on silica gel (Petroleum Ether/EtOAc=5/1 ) to afford 280 mg (15%) of the title compound as a yellow solid. LC-MS for C23H16CIFN2O3S+H+ [M +H]+: calcd. 454.1 ; found: 455.5. 1 H NMR (400 MHz, CDCI3) δ [ppm]: 7.95 (d, J = 7.9 Hz, 2H), 7.81 (dd, J = 9.2, 1 .6 Hz, 1 H), 7.77 (d, J = 8.0 Hz, 1 H), 7.73 -7.66 (m, 3H), 7.59 (t, J = 7.3 Hz, 1 H), 7.54-7.48 (m, 3H), 7.07 (td, J= 9.2, 2.4 Hz, 1 H), 4.04 (t, J = 6.8Hz, 2H), 3.45 (t, J= 6.8 Hz, 2H).
Intermediate 126: 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzo[d]oxazole
Figure imgf000156_0001
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 Ci3Hi6BNO3+H+ [M+H]+: calcd. 246.1 ; found: 246.4. 1 H NMR (300 MHz, CDCI3) δ 8.15 (s, 1 H), 8.05 (s, 1 H), 7.84 (dd, J = 8.0, 0.8 Hz, 1 H), 7.80 (dd, J = 8.0, 0.5 Hz, 1 H), 1 .39 (s, 12H).
Intermediate 127: 6-(1 -(phenylsulfonyl)-l - -indol-3-yl)benzo[d]oxazole
Figure imgf000156_0002
Following the general method as outlined in Intermediate 90, starting from 1 - Benzenesulfonyl-3-iodo-1 /-/-indole (500 mg, 1 .30 mmol) and 6-(4,4,5,5- Tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-benzooxazole (442 mg, 1 .43 mmol), the title compound (340 mg, 70%) was obtained as a black solid. LC-MS for C2iH14N2O3S+H+ [M+H]+: calcd. 375.1; found: 375.5.
Intermediate 128: 6-(6-fluoro-1 -(phenylsulfonyl)-l --indol-3-yl)-2-vinylbenzo[d]oxazole
Figure imgf000157_0001
Following the general method as outlined in Intermediate 32, starting from 6-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2-vinylbenzo[d]oxazole (3.0 g, 11.07 mmol) and 6- fluoro-3-iodo-1-(phenylsulfonyl)-1 /-/-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 C23H 5FN2O3S+H+ [M+H]+: calcd.419.1; found: 419.6. 1H NMR (400 MHz, CDCI3) δ [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, 1 H), 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 -(phenylsulfonyl)-l /-/-indol-3-yl)benzo[d]oxazole
Figure imgf000157_0002
Following the general method as outlined in Intermediate 32, starting from 1- benzenesulfonyl-6-chloro-3-iodo-1 /-/-indole (568 mg, 1.36 mmol) and 5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)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 C2iH13CIN2O3S+H+ [M+H]+: calcd.409.0; found: 409.5. 1H NMR (300 MHz, DMSO-de) δ [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, 1 H), 7.88 (m, 2H), 7.85 (dd, J= 8.4, 1.7 Hz, 1 H), 7.73 (d, J= 7.5 Hz, 1 H), 7.64 (t, J= 7.6 Hz, 2H), 7.41 (dd, J= 8.6, 1.9 Hz, 1 H). Intermediate 130: 6-(6-fluoro-1 -(phenylsulfonyl)-l - -indol-3-yl)benzo[d]oxazole-2-thiol
Figure imgf000158_0001
The mixture of 2-amino-5-(1 -benzenesulfonyl-6-fluoro-1 H-indol-3-yl)- phenol(lntermediate 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 yellow solid. LC-MS for C2i H13FN2O3S2-H" [M-H]": calcd. 423.1 ; found: 423.3.
Intermediate 131 : te/t-butyl 4-((6-(6-fluoro-1 -(phenylsulfonyl)
yl)benzo[d]oxazol-2-yl)methyl)piperidine-1 -carboxylate
Figure imgf000158_0002
To a solution of te/t-butyl 4-(2-amino-2-oxoethyl)piperidine-1 -carboxylate (500 mg, 2.07 mmol) in DCM (25 imL) 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 -
(phenylsulfonyl)-l -/-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 C32H32FN3O5S+H+ [M+H]+: calcd. 590.2; found: 590.2.
Figure imgf000159_0001
To a solution of te/t-butyl 4-((6-(6-fluoro-1 -(phenylsulfonyl)-l -/-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 1 hr. The mixture was concentrated to afford the title product (249 mg, 100%) as a yellow solid. LC-MS for C27H24FN3O3S+H+ [M+H]+: calcd. 490.2; found: 490.2.
Intermediate 133: te/t-butyl methylsulfonyl((6-(1 -(phenylsulfonyl)
yl)benzo[d]oxazol-2-yl)methyl)carbamate
Figure imgf000159_0002
To a solution of terf-butyl methylsulfonylcarbamate (900 mg, 4.62 mmol), K2CO3 (1 .3 g, 9.63 mmol) in DMF (60 mL) was added 2-(chloromethyl)-6-(1 -(phenylsulfonyl)-l H-indol- 3-yl)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 EtOAc (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/ EtOAc =6/1 - 3/1 ) to afford 1 .25 g (61 %) of the title compound as a yellow solid. LC-MS for
C28H27N3O7S2+H+ [M+H]+ : calcd. 582.1 ; found: 582.7. 1H NMR (400 MHz, DMSO-afe) δ [ppm]:8.22 (s, 1 H), 8.13 (d, J = 1 .1 Hz, 1 H), 8.11 (s, 1 H), 8.09 (d, J = 1 .3 Hz, 1 H), 8.05 (d, J = 8.3 Hz, 1 H), 7.89 (d, J = 7.9 Hz, 1 H), 7.85 (d, J = 8.3 Hz, 1 H), 7.76 (dd, J = 8.3, 1 .5 Hz, 1 H), 7.73 - 7.68 (m, 1 H), 7.61 (t, J = 7.7 Hz, 2H), 7.47 - 7.42 (m, 1 H), 7.39 - 7.34 (m, 1 H), 5.17 (s, 2H), 3.57 (s, 3H), 1 .43 (s, 9H).
Intermediate 134: 6-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-2- methoxybenzo[d]oxazole
Figure imgf000160_0001
A mixture of 2-amino-5-(1 -benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-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/EtOAc = 20/1 to 5/1 ) to afford 120 mg (54%) of the title compound as a white solid. LC-MS for C22Hi5FN2O4S+H+ [M+H]+: calcd. 423.1 ; found: 423.6. 1H NMR (400 MHz, CDCI3) δ [ppm]: 7.95 (s, 1 H), 7.92 (d, J = 1 .6 Hz, 1 H), 7.80 (dd, J = 9.6, 2.4 Hz, 1 H), 7.72 - 7.67 (m, 1 H), 7.66 (s, 1 H), 7.60 - 7.54 (m, 3H), 7.52 - 7.48 (m,2H), 7.45 (dd, J = 8.0, 1 .6 Hz, 1 H), 7.06(td, J = 9.2, 2.4 Hz, 1 H), 4.26 (s, 3H).
Intermediate 135: ieri-Butoxycarbonylamino{[6-(6-fluoroindol-3-yl)benzoxazol-2- yl]methyl} Sulfonamide
Figure imgf000161_0001
The solution of chloride sulfonyl isocyanate (0.95 mL, 1 .1 mmol) in dichloromethane (0.87 mL) was cooled in ice bath. 7e/t-butanol(0.1 1 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- indol-3-yl) -benzooxazol-2-yl]-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 terfbuyl[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/Methanol=40/1 -20/1 ) to afford 240 mg (52%) as a yellow solid. LC-MS for C2iH2i FN4O5S+H+ [M+H]+: calcd. 461 .1 ; found: 461 .6. 1H NMR (400 MHz, DMSO) δ 1 1.48 (s, 1 H), 1 1.02 (s, 1 H), 8.55 (t, J= 6.0 Hz, 1 H), 7.92 (d, J = 1.0 Hz, 1 H), 7.87 (dd, J = 8.8, 5.4 Hz, 1 H), 7.80 - 7.70 (m, 2H), 7.69 (dd, J = 8.3, 1.5 Hz, 1 H), 7.24 (dd, J = 9.9, 2.4 Hz, 1 H), 6.97 (td, J = 9.6, 2.4 Hz, 1 H), 4.49 (d, J = 6.0 Hz, 2H), 1.34 (s, 9H).
Intermediate 136: 5-(1 -(phenylsulfonyl)-l -/-indol-3-yl)benzo[d]oxazole
Figure imgf000161_0002
Following the general method as outlined in Intermediate 32, starting from 3-iodo-1 - (phenylsulfonyl)-l /-/-indole (625 mg, 1 .63 mmol) and 5-(4,4,5,5-Tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-benzooxazole (400 mg, 1 .63 mmol), 525 mg (86%) of the title compound was obtained as a yellow solid.
LC-MS for C2i H14N2O3S+H+ [M+H]+: calcd. 375.1 ; found: 375.4
1H NMR (300 MHz, DMSO-cfe) δ [ppm]: 8.81 (s, 1 H), 8.17 (s, 1 H), 8.15 - 8.07 (m, 3H), 8.04 (d, J = 8.2 Hz, 1 H), 7.90 - 7.81 (m, 2H), 7.79 (dd, J = 8.4, 1 .8 Hz, 1 H), 7.70 - 7.58 (m, 3H), 7.43 - 7.38 (m, 1 H), 7.37-7.35 (m, 1 H).
Intermediate 137: 6-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-2-((1 - (methylsulfonyl)piperidin-4-yl)methyl)benzo[d]oxazole
Figure imgf000162_0001
To a solution of 6-(6-fluoro-1 -(phenylsulfonyl)-1 H-indol-3-yl)-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. H2O (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 C28H26FN3O5S2+H+ [M+H]+: calcd. 568.1 ; found: 568.1 .
Intermediate 138: 6-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-2-((1 -methylpiperidin-4- yl)methyl)benzo[d]oxazole
Figure imgf000163_0001
To a solution of 6-(6-fluoro-1 -(phenylsulfonyl)-1 H-indol-3-yl)-2-(piperidin-4- ylmethyl)benzo[d]oxazole (Intermediate 132, 330 mg, 0.67 mmol) in DCM/MeOH
(6/3ml_) was added AcOH (122 mg, 2.02 mmol), CH2O/H2O (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 H2O (10 imL). The mixture was extracted with DCM (15ml_x3). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column with DCM-MeOH (100/2) to afford 250 mg (74%) of the title compound as a yellow solid. LC-MS for C28H26FN3O3S+H+ [M+H]+: calcd.504.2; found: 504.2.
Intermediate 139: A/-(2,4-dibromophenyl)-2-(2,5-dioxoimidazolidin-4-yl)acetamide
Figure imgf000163_0002
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, 1 1 .7 mmol) in DMF (50 imL) 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 EtOAc. 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
Figure imgf000163_0003
[M+H]+: calcd. 389.9; found: 389.6. 1 H NMR (300 MHz, DMSO-afe) δ [ppm]: 10.62 (br s, 1 H), 9.64 (br s, 1 H), 7.90 ( s, 2H), 7.64 - 7.56 (m, 2 H), 4.31 (td, J - 6.6, 4.2 Hz, 1 H), 2.89 - 2.83 (m, 1 H), 2.75 -2.50 (m, 1 H).
Intermediate 140: 5-((6-bromobenzo[d]oxazol-2-yl)methyl)imidazolidine-2,4-dione
Figure imgf000164_0001
A mixture of A/-(2,4-dibromophenyl)-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 EtOAc and saturated aqueous NaHCO3. The organic layer was dried over anhydrous Na2SO4, filtered, concentrated and purified by silica gel chromatography (petroleum ether/EtOAc = 1 /1 - EtOAc) to afford 75 mg (47%) of the title compound as a yellow semisolid. LC-MS for
Cn HgBrNgOg-H" [M-H]": calcd. 308.0; found: 307.8.
Intermediate 141 : te/t-butyl 3-(2-((2,5-dioxoimidazolidin-4-yl)methyl)benzo[d]oxazol-6- yl)-6-fluoro-1 /-/-indole-1 -carboxylate
Figure imgf000164_0002
Following the general method as outlined in Intermediate 32, starting from 5-((6- bromobenzo[ |oxazol-2-yl)methyl)imidazolidine-2,4-dione (Intermediate 142, 310 mg, 1 .00 mmol) and terf-butyl 6-fluoro-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- indole-1 -carboxylate (Intermediate 2, 543 mg, 1 .50 mmol), 50 mg (1 1 %) of the title compound was obtained as a yellow solid. LC-MS for C24H2iFN4O5+H+ [M+H]+: calcd.465.2; found: 464.8. 1H NMR (400 MHz, MeOH-tf4) δ [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, 1 H), 7.76 (d, J= 8.4 Hz, 1 H), 7.66 (dd, J= 8.4, 1.6 Hz, 1 H), 7.11 (ddd, J= 9.6, 8.7, 2.3 Hz, 1 H), 4.70 (dd, J= 7.2, 4.6 Hz, 1 H), 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 -(phenylsulfonyl)-l --indol-3-yl)benzo[d]oxazol-2(3-/)-one
Figure imgf000165_0001
To a stirred solution of 2-amino-5-(1-benzenesulfonyl-5-fluoro-1 --indol-3-yl)-phenol (770 mg, 2.01 mmol) and CDI (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 EtOAc (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 C2iH 3FN2O4S-H" [M-H]" : calcd.
407.1; found: 407.5. 1H NMR (400 MHz, DMSO-afe) δ [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, 1 H), 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 -(phenylsulfonyl)-l --indol-3-yl)-2-oxobenzo[d]oxazol- 3(2H)-yl)acetamide
Figure imgf000166_0001
To a solution of 6-(5-fluoro-1 -(phenylsulfonyl)-1 -/-indol-3-yl)benzo[d]oxazol-2(3 -/)-one (400 mg, 0.98 mmol) and K2CO3 (542 mg, 3.92 mmol) in NMP (20 imL) 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 imL) and extracted with EtOAc (60 ml_x3). The combined organic layer was washed with water (60 ml_x3) , 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 C23H16FN3O5S-H" [M-H]" : calcd. 464.1 ; found:464.4. 1 H NMR (400 MHz, DMSO-de) δ [ppm]: 8.22 (s, 1 H), 8.13 - 8.07 (m, 2H), 8.04 (dd, J = 9.2, 4.4 Hz, 1 H), 7.82 - 7.75 (m, 2H), 7.72 (t, J = 7.2 Hz, 1 H), 7.66 - 7.55 (m, 4H), 7.40 (s, 1 H), 7.33 - 7.26 (m, 2H), 4.50 (s, 2H).
Intermediate 144: dimethyl 4-(1 -(ferf-butoxycarbonyl)-6-fluoro-1 /- -indol-3-yl)phthalate
Figure imgf000166_0002
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-yl)-indole-1 -carboxylic acid te/t-butyl ester (Intermediate 2, 400 mg, 1 .10 mmol), the title compound (400 mg, 72%) was obtained as a red solid. LC-MS for C23H22FNO6+H+ [M+H]+: calcd. 428.1 ; found: 428.6. 1H NMR (400 MHz, CDCI3) δ [ppm] : 7.97 (d, J= 10.0 Hz, 1 H), 7.91 (d, J= 2.0 Hz, 1 H), 7.88 (d, J = 8.4 Hz, 1 H), 7.78 (dd, J= 8.0, 2.0 Hz, 1 H),7.77(s, 1 H), 7.70 (dd, J = 8.8, 5.2 Hz, 1 H), 7.07 (td, J
3H), 3.94 (s, 3H), 1 .70 (s, 9H).
Intermediate 145: 4-(6-fluoro-1 -/-indol-3-yl)phthalic acid
Figure imgf000167_0001
To the solution of 6-fluoro-3-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl) -indole-1 - carboxylic acid te/t-butyl ester (Intermediate 146, 360 mg, 0.84 mmol) in methanol (10 imL) was added NaOH (1 35 mg, 3.37 mmol) and the mixture was stirred at room temperature. After 2 hrs NaOH (1 35 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 (1 0 imL) and the pH was adjusted to 1 ~2. The mixture was extracted with EA (20 ml_x3).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 Ci6Hi0FNO4-H" [M-H]": calcd. 298.1 ; found: 298.4. 1 H NMR (400 MHz, DMSO-cfe) δ [ppm]: 12.99 (brs, 2H), 1 1 .64 (s, 1 H), 7.92 (d, J = 2.4 Hz, 1 H), 7.88 (dt, J = 6.6, 3.0 Hz, 3H), 7.79 (d, J= 8.0 Hz, 1 H), 7.25 (dd, J= 10.0, 2.4 Hz, 1 H), 7.01 (td, J = 9.4, 2.4 Hz, 1 H).
Intermediate 146: te/t-butyl 3-(2-(ie/ -butoxycarbonyl)isoindolin-5-yl)-6-fluoro-1 H-indole- 1 -carboxylate
Figure imgf000167_0002
Following the general method as outlined in Intermediate 32, starting from te/t-butyl 6- fluoro-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-indole-1 -carboxylate (Intermediate 2, 260 mg, 0.72 mmol) and 5-bromo-1 ,3-dihydro-isoindole-2-carboxylic acid te/t-butyl ester (278 mg, 0.93 mmol), 178 mg (55%) of the title compound was obtained as a white solid. LC-MS for C26H29FN2O4+H+-56 [M+H-56]+: calcd. 397.2; found: 397.6. 1H NMR (400 MHz, CDCI3) δ [ppm]: 7.97 - 7.93 (m, 1 H), 7.74 - 7.59 (m, 2H), 7.53-7.45(m, 2H), 7.37-7.28 (m, 1 H), 7.07 - 7.02 (m, 1 H), 4.76 - 4.71 (m, 4H), 1 .69 (s, 9H), 1 .54 (s, 9H).
Intermediate 147: te/t-butyl 3-(1 ,1 -dioxido-2,3-dihydrobenzo[d]isothiazol-6-yl)-6-fluoro- 1 /-/-indole-1 -carboxylate
Figure imgf000168_0001
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- tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-indole-1 -carboxylic acid terf-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-afe) δ [ppm]: 8.13 (d, J = 8.7 Hz, 2H), 8.03 (dd, J = 8.4, 1 .2 Hz, 1 H), 7.92 - 7.83 (m, 3H), 7.67 (d, J = 8.1 Hz, 1 H), 7.24 (td, J = 9.0, 1 .5 Hz, 1 H), 4.46 (s, 2H), 1 .66 (s, 9H).
Intermediate 148: 4-(1 -(te/t-butoxycarbonyl)-6-fluoro-1 H-indol-3-yl)-2-(A - methylsulfamoyl)benzoic acid
Figure imgf000168_0002
hoc
Following the general method as outlined in Intermediate 32, starting from 6-bromo-2- methylbenzo[d]isothiazol-3(2 -/)-one1 ,1 -dioxide (400 mg, 1 .4 mmol) and 6-fluoro-3- (4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-indole-1 -carboxylic acid terf-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-afe) δ [ppm]: 9.65 (s, 1 H), 7.98 - 7.75 (m, 6H), 7.27 (td, J = 9.2, 2.8 Hz, 1 H), 2.39 (s, 3H), 1 .66 (s, 9H).
Intermediate 149: terf-butyl 6-fluoro-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-1 H-indole- 1 -carboxylate
Figure imgf000169_0001
Following the general method as outlined in Intermediate 32, starting from 6-bromo-3 - - benzooxazol-2-one (600 mg, 2.80 mmol) and 6-fluoro-3-(4,4,5,5-tetramethyl-
[1 ,3,2]dioxaborolan-2-yl)-indole-1 -carboxylic acid te/t-butyl ester (Intermediate 2, 1 .21 g, 3.36 mmol), 450 mg (45%) of the title compound was obtained as a white solid. 1 H NMR (400 MHz, CDCI3) δ [ppm]: 8.56 (s, 1 H), 7.95 (d, J = 9.6 Hz, 1 H), 7.69-7.64 (m, 1 H), 7.46 (s, 1 H), 7.42 (dd, J = 8.0, 1 .6 Hz, 1 H), 7.16 (d, J = 8.0 Hz, 1 H), 7.06 (td, J = 8.8, 2.4 Hz, 1 H), 3.71 (s, 1 H), 1 .70 (s, 9H).
Intermediate 150: te/t-butyl 3-(3-(1 -(te/t-butoxycarbonyl)piperidin-4-yl)-2-oxo-2,3- dihydrobenzo[d]oxazol-6-yl)-6-fluoro-1 /-/-indole-1 -carboxylate
Figure imgf000169_0002
To a stirred solution of 6-fluoro-3-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-indole-1 - carboxylic acid te/t-butyl ester (Intermediate 151 , 450 mg, 1 .22 mmol), 4-hydroxy- piperidine-1 -carboxylic acid terf-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 EtOAc (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/EtOAc = 30/1 to 10/1 ) and preparative TLC (petroleum ether/EtOAc = 10/1 ) to afford 125 mg (17%) of the title compound as a white solid. LC-MS for C3oH34FN3O6+H+ [M+H]+: calcd. 552.2; found: 552.8. 1 H NMR (400 MHz, CDCI3) δ [ppm]: 7.94 (d, J = 10.0 Hz, 1 H), 7.69 - 7.61 (m, 2H), 7.46 (s, 1 H), 7.40 (dd, J = 8.0, 2.0 Hz, 1 H), 7.18 (d, J = 8.0 Hz, 1 H), 7.06 (td, J = 8.8, 2.4 Hz, 1 H), 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 : te/t-butyl 6-fluoro-3-(2-methyl-1 ,1 -dioxido-3-oxo-2,3- dihydrobenzo[ |isothiazol-5-yl)-1 /-/-indole-1 -carboxylate
Figure imgf000170_0001
To a solution of te/t-butyl 3-(1 ,1 -dioxido-3-oxo-2,3-dihydrobenzo[ /|isothiazol-5-yl)-6- fluoro-1 -/-indole-1 -carboxylate (Compound 130 Step 1 , 246 mg, 0.59 mmol) and K2CO3 (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 MeOH to afford 60 mg (24%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-cfe) δ [ppm]: 8.43 - 8.38 (m, 2H), 8.35 (s, 1 H), 8.33 (s, 1 H), 7.97 - 7.91 (m, 2H), 7.28 (td, J = 9.2, 2.4 Hz, 1 H), 3.21 (s, 3H), 1.67 (s, 9H).
Intermediate 152: terf-butyl 6-(2-(6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)ethyl)- 2,6-diazaspiro[3.3]heptane-2-carboxylate
Figure imgf000171_0001
To a stirred solution of 6-(6-fluoro-1 -(phenylsulfonyl)-1 - -indol-3-yl)-2- vinylbenzo[d]oxazole (Intermediate 128, 100 mg, 0.24 mmol) in dry MeOH (10 mL) at 50 °C was added 2,6-diaza-spiro[3.3]heptane-2-carboxylic acid terf-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 Na2SO4 and concentrated to afford 200 mg of the title compound as a white solid, which was used for next step without further purification.
Intermediate 153: terf-butyl 3-(benzofuran-6-yl)-6-fluoro-1 -/-indole-1 -carboxylate
Figure imgf000171_0002
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-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indole-1 - carboxylate (Intermediate 2, 180 mg, 0. 507 mmol), K2CO3 (210 mg, 1 .52 mmol) and Pd(dppf)CI2 (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
(EtOAc/Petroleum Ether=1 /10) to afford 1 12.8 mg (63%) of the title compound. LC-MS for C2iH18FNO3+H+ [M+H]+ : calcd: 351 .1 ; found: 351 .8. 1 H NMR (400 MHz, CDCI3) δ [ppm]: 7.96 (d, J = 4.8 Hz, 1 H), 7.79-7.76 (m, 2H),7.71 -7.67 (m, 3H),7.50 (dd, J = 8.0 Hz,1 .6Hz, 1 H),7.06 (dd, J = 8.8, 2.4 Hz, 1 H), 6.82 (d, J = 1 .0 Hz, 1 H), 1 .70 (s, 9H). 1.2. SYNTHESIS OF FINAL COMPOUNDS Compound 1 : 6-(6-fluoro-1 - -indol-3-yl)-1 H-indazole
To a solution of 6-(6-fluoro-1 -(phenylsulfonyl)-1 - -indol-3-yl)-1 H-indazole (Intermediate 4; 390 mg; 1 .00 mmol) in MeOH (15 ml_) was added a solution of NaOH (200 mg; 5.00 mmol) in water (2 imL). The reaction mixture was stirred at 80°C for 2 hours,
concentrated, and purified by a silica gel chromatography (petroleum ether/EtOAc = 5/1 - 2/1 ) to afford 50 mg (20%) of the title compound as a white solid. LC-MS for
Ci5H10FN3+H+ [M+H]+: calcd. 252.1 ; found: 252.1 . 1 H NMR (300 MHz, DMSO-afe) δ
[ppm]: 12.94 (s, 1 H), 1 1 .45 (s, 1 H), 8.05 (s, 1 H), 7.88 (dd, J = 8.8, 5.4 Hz, 1 H), 7.79 (d, J = 8.4 Hz, 1 H), 7.77 - 7.73 (m, 2H), 7.44 (d, J = 8.4 Hz, 1 H), 7.24 (dd, J = 10.0, 2.2 Hz, 1 H), 6.99 (ddd, J = 9.3, 8.8, 2.2 Hz, 1 H).
Compound 2: 2-(6-(6-fluoro-1 H-indol-3-yl)-1 H-indazol-1 -yl)acetamide
A mixture of 6-(6-fluoro-1 -(phenylsulfonyl)-1 H-indol-3-yl)-1 H-indazole (Intermediate 4; 300 mg; 0.77 mmol), 2-bromoacetamide (1 .05 g; 7.61 mmol), Kl (290 mg; 1 .75 mmol), K2CO3 (986 mg; 7.13 mmol) in DMF (16.5 imL) was stirred at 60°C for 48 hours under nitrogen. The mixture was cooled to room temperature, diluted with EtOAc (100 imL), filtered, concentrated, and purified by preparative HPLC to afford 25mg (1 1 %) of the title compound as a yellow solid. LC-MS for Ci7Hi3FN4O+H+ [M+H]+: calcd. 309.1 ; found: 308.9. 1H NMR (400 MHz, DMSO-cfe) δ [ppm]: 11 .46 (s, 1 H), 8.03 (s, 1 H), 7.96 (dd, J= 8.7, 5.4 Hz, 1 H), 7.80 - 7.77 (m, 2H), 7.76 - 7.73 (m, 2H), 7.55 (br s, 1 H), 7.46 (dd, J= 8.3, 1.3 Hz, 1 H), 7.26 (br s, 1 H), 7.22 (dd, J = 9.9, 2.4 Hz, 1 H), 6.96 (ddd, J= 9.6, 8.8, 2.4, 1 H), 5.11 (s, 2H).
Compound 3: 6-(6-fluoro-1 H-indol-3-yl)-1 -(piperidin-4-ylmethyl)-1 H-indazole
hydrochloride
Following the general method as outlined in Compound 1 , starting from 6-(6-fluoro-1 - (phenylsulfonyl)-l H-indol-3-yl)-1 -(piperidin-4-ylmethyl)-1 H-indazole hydrochloride and 6- (6-fluoro-1 -(phenylsulfonyl)-1 H-indol-3-yl)-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 C2iH2iFN4+H+ [M+H]+: calcd.349.2; found: 349.0. 1H NMR (300 MHz, DMSO-cfe) δ [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, 1 H), 6.97 (ddd, J= 9.4, 8.8, 2.3 Hz, 1 H), 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, 1 H), 1.73 - 1.59 (m, 2H), 1.58 - 1.40 (m, 2H).
Compound 4: 1 -(4-((6-(6-fluoro-1 --indol-3-yl)-1 /-/-indazol-1 -yl)methyl)piperidin-1 - yl)ethanone Following the general method as outlined in Compound 1 , starting from 1 -(4-((6-(6- fluoro-1 -(phenylsulfonyl)-l --indol-3-yl)-1 /-/-indazol-1 -yl)methyl)piperidin-1 -yl)ethanone (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 C23H23FN4O-H" [M-H]": calcd.389.2; found: 389.0. 1H NMR (400 MHz, DMSO-cfe) δ [ppm]: 11.51 (s, 1 H), 8.05 (s, 1H),7.95(dd, J=8.8, 5.4 Hz, 1H), 7.87 (s, 1 H), 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, 1 H), 2.50 - 2.40 (m, 1 H), 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-1 /-/-indol-3-yl)-1 /-/-indazol-1 -yl)propanamide
Following the general method as outlined in Compound 1, starting from 3-(6-(6-fluoro-1- (phenylsulfonyl)-l /-/-indol-3-yl)-1 /-/-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 (EtOAc). LC-MS for C18H15FN4O+H+ [M+H]+: calcd. 323.1; found: 323.1. 1H NMR (300 MHz, DMSO-de) δ [ppm]: 11.48 (s, 1H), 8.05 (dd, J= 8.8, 5.6 Hz, 1H), 8.03 (s, 1H), 7.89 (s, 1 H), 7.79 - 7.73 (m, 2H), 7.45 (d, J = 8.4 Hz, 1 H), 7.40 (br s, 1 H), 7.24 (dd, J = 9.9, 2.2 Hz, 1 H), 6.99 (ddd, J = 9.4, 8.8, 2.2 Hz, 1 H), 6.87 (br s, 1 H), 4.64 (t, J = 6.6 Hz, 2H), 2.70 (t, J =6.6 Hz, 2H). Compound 6: 6-(6-fluoro-1 - -indol-3-yl)-1 -(piperidin-4-yl)-1 H-indazole
Following the general method as outlined in Compound 1 , starting from 6-(6-fluoro-1 - (phenylsulfonyl)-l H-indol-3-yl)-1 -(piperidin-4-yl)-1 H-indazole hydrochloride and 6-(6- fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-2-(piperidin-4-yl)-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 C2oHi9FN4+H+ [M+H]+: calcd. 335.2; found: 334.9. 1H NMR (300 MHz, DMSO-cfe) δ [ppm]: 1 1 .49 (s, 1 H), 8.04 (s, 1 H), 7.94 (dd, J = 9.0, 5.4 Hz, 1 H), 7.88 (s, 1 H), 7.80 - 7.75 (m, 2H), 7.46 (dd, J = 8.4, 1.3 Hz, 1 H), 7.25 (dd, J= 9.8, 2.4 Hz, 1 H), 6.99 (ddd, J = 9.7, 8.9, 2.4 Hz, 1 H), 4.87 - 4.75 (m, 1 H), 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-1 - -indol-3-yl)-1 /-/-indazol-1 -yl)piperidin-1 -yl)ethanone
To a solution of 6-(6-fluoro-1 -/-indol-3-yl)-1 -(piperidin-4-yl)-1 H-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 ml_x2). 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 C22H2iFN4O+H+ [M+H]+: calcd. 377.2; found: 376.9. 1H NMR (400 MHz, DMSO-cfe) δ [ppm]: 1 1.49 (s, 1 H), 8.05 (s, 1 H), 7.96 (dd, J = 8.8, 5.4 Hz, 1 H), 7.91 (s, 1 H), 7.81 - 7.76 (m, 2H), 7.47 (dd, J = 8.4, 1 .2 Hz, 1 H), 7.25 (dd, J = 9.9, 2.4 Hz, 1 H), 6.99 (ddd, J = 9.6, 8.8, 2.4 Hz, 1 H), 5.08 - 4.95 (m, 1 H), 4.58 - 4.48 (m, 1 H), 4.03 - 3.93 (m, 1 H), 3.33 - 3.27 (m, 1 H), 2.90 - 2.78 (m, 1 H), 2.07 (s, 3H), 2.10 - 1 .88 (m, 4H).
Compound 8: 5-(6-fluoro-1 - -indol-3-yl)-1 H-indazole
Following the general method as outlined in Compound 1 , starting from 5-(6-fluoro-1 - (phenylsulfonyl)-l - -indol-3-yl)-1 H-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 Ci5H10FN3+H+ [M+H]+: calcd. 252.1 ; found: 252.1 . 1H NMR (300 MHz, DMSO-cfe) δ [ppm]: 13.02 (s, 1 H), 1 1.34 (s, 1 H), 8.08 (s, 1 H), 7.99 (s, 1 H), 7.86 (dd, J= 8.8, 5.4 Hz, 1 H), 7.66 (dd, J = 9.0, 1.5 Hz, 1 H), 7.64 (d, J = 1 .5 Hz, 1 H), 7.59 (d, J= 9.0 Hz, 1 H), 7.22 (dd, J= 10.0, 2.4 Hz, 1 H), 6.95 (ddd, J = 9.7, 8.8, 2.4 Hz, 1 H).
Compound 9: 2-(5-(6-fluoro-1 -/-indol-3-yl)-1 -/-indazol-1 -yl)acetamide
Following the general method as outlined in Compound 1 , starting from 2-(5-(6-fluoro-1 - (phenylsulfonyl)-l -/-indol-3-yl)-1 -/-indazol-1 -yl)acetamide and 2-(5-(6-fluoro-1 - (phenylsulfonyl)-l H-indol-3-yl)-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
Ci7H13FN4O+H+ [M+H]+: calcd. 309.1 ; found: 308.9. 1H NMR (300 MHz, DMSO-ci6) δ
[ppm]: 1 1.39 (s, 1 H), 8.08 (s, 1 H), 7.99 (s, 1 H), 7.87 (dd, J= 8.8, 5.3 Hz, 1 H), 7.72 - 7.61 (m, 3H), 7.58 (br s, 1 H), 7.30 (br s, 1 H), 7.23 (dd, J= 10.0, 2.3 Hz, 2H), 6.99 (dd, J = 9.5, 8.8, 2.3 Hz, 1 H), 5.08 (s, 2H).
Compound 10: 5-(6-fluoro-1 /- -indol-3-yl)-1 -(piperidin-4-ylmethyl)-1 /-/-indazole
A solution of terf-butyl 4-((5-(6-fluoro-1 /- -indol-3-yl)-1 /- -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 EtOAc (50 mLx3). The aqueous layer was basified with aqueous NaOH to pH = 13 and extracted with EtOAc (100 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by preparative TLC (DCM/MeOH = 8/1 ) to afford 31 mg (33%) of the title compound as a yellow solid. LC-MS for C2iH2iFN4+H+ [M+H]+: calcd. 349.2; found: 349.0. 1H NMR (300 MHz, DMSO-cfe) δ [ppm]: 11.42 (s, 1 H), 8.60 (br s, 1 H), 8.09 (s, 1 H), 8.00 (s, 1 H), 7.86 (dd, J = 8.8, 5.3 Hz, 1 H), 7.79 - 7.65 (m, 3H), 7.30 (dd, J= 10.0, 2.4 Hz, 1 H), 6.96 (ddd, J = 9.6, 8.8, 2.4 Hz, 1 H), 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, 1 H), 1.72 - 1 .60 (m, 2H), 1.55 - 1.36 (m, 2H). Compound 1 1 : 1 -(4-((5-(6-fluoro-1 - -indol-3-yl)-1 - -indazol-1 -yl)methyl)piperidin-1 - yl)ethanone
Following the general method as outlined in Compound 7, starting from 5-(6-fluoro-1 H- indol-3-yl)-1 -(piperidin-4-ylmethyl)-1 H-indazole (Compound 1 0; 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. 1 H NMR (300 MHz, DMSO-cfe) δ [ppm]: 11.38 (s, 1 H), 8.08 (s, 1 H), 7.99 (s, 1 H), 7.87 (dd, J = 8.9,
5.5 Hz, 1 H), 7.76 (d, J = 8.8 Hz, 1 H), 7.71 - 7.66 (m, 2H), 7.22 (dd, J = 10.0, 2.4 Hz, 1 H), 6.96 (ddd, J = 9.6, 8.9, 2.3 Hz, 1 H), 4.39 - 4.30 (m, 3H), 3.83 - 3.73 (m, 1 H), 3.00 - 2.87 (m, 1 H), 2.50 - 2.40 (m, 1 H), 2.26 - 2.10 (m, 1 H), 1 .96 (s, 3H), 1 .54 - 1 .43 (m, 2H), 1 .30 - 1 .00 (m, 2H).
Compound 12: 3-(5-(6-fluoro-1 -/-indol-3-yl)-1 /-/-indazol-1 -yl)propanamide
Following the general method as outlined in Compound 1 , starting from 3-(5-(6-fluoro-1 - (phenylsulfonyl)-l /-/-indol-3-yl)-1 /-/-indazol-1 -yl)propanamide and 3-(5-(6-fluoro-1 - (phenylsulfonyl)-l H-indol-3-yl)-2/-/-indazol-2-yl)propanamide (Intermediate 1 6; 492 mg;
1 .06 mmol), 33.9 mg (1 0%) of the title compound was obtained as a white solid after purification by preparative HPLC and chiral preparative HPLC. LC-MS for
Ci8Hi5FN4O+H+ [M+H]+: calcd. 323.1 ; found: 322.9. 1 H NMR (300 MHz, DMSO-cfe) δ
[ppm]: 1 1 .34 (s, 1 H), 8.27 (d, J = 0.8 Hz, 1 H), 7.93 - 7.91 (m, 1 H), 7.88 (dd, J = 8.8, 5.4 Hz, 1 H), 7.67 - 7.61 (m, 2H), 7.56 (dd, J = 9.0, 1 .6 Hz, 1 H), 7.43 (br s, 1 H), 7.21 (dd, J = 10.0, 2.3 Hz, 1 H), 6.95 (ddd, J = 9.6, 8.8, 2.3 Hz, 1 H), 6.92 (br s, 1 H), 4.62 (t, J = 6.8 Hz, 2H), 2.79 (t, J = 6.9 Hz, 2H).
Compound 13: 5-(6-fluoro-1 /- -indol-3-yl)-1 -(piperidin-4-yl)-1 H-indazole To a solution of te/t-butyl 4-(5-(6-fluoro-1 /-/-indol-3-yl)-1 /-/-indazol-1 -yl)piperidine-1 - carboxylate (Intermediate 18; 1 80 mg; 0.41 mmol) in 1 ,4-dioxane (20 imL) was added saturated HCI in 1 ,4-dioxane (1 0 imL). 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 C20Hi9FN4+H+ [M+H]+: calcd. 335.2; found: 334.9. 1 H NMR (300 MHz, DMSO-cfe) δ [ppm]: 1 1 .36 (s, 1 H), 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, 1 H), 4.73 - 4.60 (m, 1 H), 3.14 - 3.04 (m, 2H), 2.76 - 2.64 (m, 2H), 2.20 (br s, 1 H), 2.05 - 1.93 (m, 2H), 1.91 - 1.82 (m, 2H).
Compound 14: 1 -(4-(5-(6-fluoro-1 --indol-3-yl)-1 --indazol-1 -yl)piperidin-1 -yl)ethanone
Following the general method as outlined in Compound 7, starting from 5-(6-fluoro-1 H- indol-3-yl)-1 -(piperidin-4-yl)-1 H-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 C22H2iFN4O+H+ [M+H]+: calcd.377.2; found: 376.9. 1H NMR (300 MHz, MeOH-d*) δ [ppm]: 8.25 (s, 1 H), 7.92 - 7.89 (m, 1 H), 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, 1 H), 4.86 - 4.66 (m, 2H), 4.16 - 4.06 (m, 1 H), 3.42 - 3.32 (m, 1 H), 2.93 - 2.81 (m, 1 H), 2.32-2.00 (m,4H), 2.18 (s, 3H).
Compound 15: 2-(6-(6-fluoro-1 H-indol-3-yl)-2H-indazol-2-yl)acetamide
A mixture of 6-(6-fluoro-1-(phenylsulfonyl)-1 --indol-3-yl)-1 H-indazole (Intermediate 4; 300 mg; 0.77 mmol), 2-bromoacetamide (1.05 g; 7.61 mmol), Kl (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 EtOAc (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 Ci7H13FN4O+H+ [M+H]+: calcd.309.1 ; found: 308.9. 1H NMR (400 MHz, DMSO-cfe) δ [ppm]: 11.42(s, 1H), 8.32 (s, 1 H), 7.90 (dd, J = 8.8, 5.4 Hz, 1 H), 7.80 (s, 1 H), 7.81 - 7.72 (m, 2H), 7.66 (br s, 1 H), 7.39 (dd, J= 8.7, 1.4 Hz, 1 H), 7.35 (br s, 1 H), 7.24 (dd, J = 10.0, 2.4 Hz, 1 H), 6.97 (ddd, J = 9.6, 8.8, 2.4 Hz, 1 H), 5.09 (s, 2H).
Compound 16: 1 -(4-((6-(6-fluoro-1 H-indol-3-yl)-2H-indazol-2-yl)methyl)piperidin-1 - yl)ethanone Following the general method as outlined in Compound 1 , starting from 1 -(4-((6-(6- fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-2H-indazol-2-yl)methyl)piperidin-1 -yl)ethanone (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-cfe) δ [ppm]: 1 1.43 (s, 1 H), 8.32 (s, 1 H), 7.90 (dd, J= 8.8, 5.4 Hz, 1 H), 7.80 (s, 1 H), 7.77 - 7.71 (m, 2H), 7.39 (d, J= 8.6 Hz, 1 H), 7.23 (dd, J = 10.0, 2.3 Hz, 1 H), 6.97 (dd, J =9.6, 8.8,
2.3 Hz, 1 H), 4.40 - 4.30 (m, 3H), 3.85 - 3.75 (m, 1 H), 3.05 - 2.90 (m, 1 H), 2.50 - 2.42 (m, 1 H), 2.31 - 2.22 (m, 1 H), 1.97 (s, 3H), 1 .60 - 1.40 (m, 2H), 1.30 - 1.00 (m, 2H).
Compound 17: 3-(6-(6-fluoro-1 H-indol-3-yl)-2H-indazol-2-yl)propanamide
Following the general method as outlined in Compound 1 , starting from 3-(6-(6-fluoro-1 - (phenylsulfonyl)-l H-indol-3-yl)-2H-indazol-2-yl)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 (EtOAc). LC-MS for Ci8H15FN4O+H+ [M+H]+: calcd. 323.1 ; found: 323.1 . 1H NMR (300 MHz, MeOH-tf4) δ [ppm]: 8.16 (s, 1 H), 7.87 (dd, J = 8.8, 5.3 Hz, 1 H), 7.81 (s, 1 H), 7.70 (d, J = 8.7 Hz, 1 H), 7.52 (s, 1 H), 7.41 (d, J = 8.7 Hz, 1 H), 7.13 (dd, J = 9.8, 2.3 Hz, 1 H), 6.90 (ddd, J = 9.6, 8.8, 2.3 Hz, 1 H), 4.73 (t, J = 6.7 Hz, 2H), 2.94 (t, J = 6.7 Hz, 2H).
Compound 18: 6-(6-fluoro-1 H-indol-3-yl)-2-(piperidin-4-yl)-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 C2oHigFN4+H+ [M+H]+: calcd. 335.2; found: 334.9. 1H NMR (400 MHz, DMSO-cfe) δ [ppm]: 1 1.41 (s, 1 H), 8.36 (s, 1 H), 7.91 (dd, J= 8.6, 5.4 Hz, 1 H), 7.83 (s, 1 H), 7.75 - 7.70 (m, 2H), 7.39 (d, J= 8.6,
1.4 Hz, 1 H), 7.24 (dd, J = 10.0, 2.4 Hz, 1 H), 6.97 (ddd, J= 9.6, 8.8, 2.4 Hz, 1 H), 4.62 - 4.50 (m, 1 H), 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-1 H-indol-3-yl)-2H-indazol-2-yl)piperidin-1 -yl)ethanone Following the general method as outlined in Compound 7, starting from 6-(6-fluoro-1 H- indol-3-yl)-2-(piperidin-4-yl)-2H-indazole (Compound 1 8; 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 C22H2i FN4O+H+ [M+H]+: calcd. 377.2; found: 376.9. 1 H NMR (400 MHz, DMSO-cfe) δ [ppm]: 1 1 .42 (s, 1 H), 8.40 (s, 1 H), 7.89 (dd, J = 8.7, 5.4 Hz, 1 H), 7.80 (s, 1 H), 7.75 - 7.71 (m, 2H), 7.39 (d, J = 8.5 Hz, 1 H), 7.23 (dd, J = 10.0, 2.3 Hz, 1 H), 6.96 (dd, J = 9.4, 8.7, 2.3 Hz, 1 H), 4.81 - 4.71 (m, 1 H), 4.56 - 4.43 (m, 1 H), 4.02 - 3.94 (m, 1 H), 3.32 - 3.22 (m, 1 H), 2.82 - 2.73 (m, 1 H), 2.21 - 1 .86 (m, 4H), 2.07 (s, 3H).
Compound 20: 2-(5-(6-fluoro-1 H-indol-3-yl)-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 Ci7H13FN4O+H+ [M+H]+: calcd. 309.1 ; found: 308.9. 1 H NMR (300 MHz, DMSO-d6) δ [ppm]: 11.38 (s, 1 H), 8.31 (s, 1 H), 7.97 (s, 1 H), 7.90 (dd, J = 8.7, 5.5 Hz, 1 H), 7.70 - 7.55 (m, 4H), 7.37 (s, 1 H), 7.22 (dd, J = 9.9, 2.3 Hz, 1 H), 6.96 (ddd, J = 9.6, 8.7 2.3 Hz, 1 H), 5.08 (s, 2H).
Compound 21 : 1 -(4-((5-(6-fluoro-1 H-indol-3-yl)-2H-indazol-2-yl)methyl)piperidin-1 - yl)ethanone
Following the general method as outlined in Compound 7, starting from 5-(6-fluoro-1 H- indol-3-yl)-2-(piperidin-4-ylmethyl)-2H-indazole (Intermediate 22; 1 00 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 C23H23FN4O+H+ [M+H]+: calcd. 391 .2; found: 390.9. 1 H NMR (400 MHz, MeOH-tf4) δ [ppm]: 8.14 (s, 1 H), 7.90 (s, 1 H), 7.84 (dd, J = 8.8, 5.4 Hz, 1 H), 7.68 - 7.61 (m, 2H), 7.46 (s, 1 H), 7.12 (dd, J = 9.8, 2.3 Hz, 1 H), 6.89 (dd, J = 9.7, 8.8, 2.3 Hz, 1 H), 4.54 - 4.47 (m, 1 H), 4.1 1 (d, J = 7.0 Hz, 2H), 3.92 - 3.85 (m, 1 H), 3.09 - 3.00 (m, 1 H), 2.62 - 2.53 (m, 1 H), 2.37 - 2.24 (m, 1 H), 2.06 (s, 3H), 1 .63 - 1 .54 (m, 2H), 1 .34 - 1 .13 (m, 2H).
Compound 22: 3-(5-(6-fluoro-1 H-indol-3-yl)-2/-/-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 Ci8H15FN4O+H+ [M+H]+: calcd.323.1 ; found: 322.9. 1H NMR (300 MHz, DMSO-cfe) δ [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, 8.72.0 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-1 H-indol-3-yl)-2-(piperidin-4-yl)-2H-indazole
To the solution of terf-butyl 4-(5-(6-fluoro-1 H-indol-3-yl)-2H-indazol-2-yl)piperidine-1 - carboxylate (Intermediate 24; 180 mg; 0.41 mmol) in 1 ,4-dioxane (20 imL) was added saturated HCI in 1 ,4-dioxane (10 imL). 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 C2oHi9FN4+H+ [M+H]+: calcd.335.4; found: 334.9. 1H NMR (300 MHz, DMSO-cfe) δ [ppm]: 11.37 (s, 1 H), 8.36 (s, 1 H), 7.92 (s, 1 H), 7.87 (dd, J= 8.8, 5.4 Hz, 1 H), 7.68 - 7.63 (m, 2H), 7.55 (dd, J= 9.0, 1.6 Hz, 1 H), 7.22 (dd, J =
10.0, 2.4 Hz, 1H), 6.96 (ddd, J= 9.7, 8.8, 2.4 Hz, 1 H), 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-1 H-indol-3-yl)-2H-indazol-2-yl)piperidin-1 -yl)ethanone Following the general method as outlined in Compound 7, starting from 5-(6-fluoro-1 H- indol-3-yl)-2-(piperidin-4-yl)-2 -/-indazole (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 C22H2iFN4O+H+ [M+H]+: calcd.377.4; found: 376.9. 1H NMR (300 MHz, DMSO-cfe) δ [ppm]: 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, 1 H), 7.11 (dd, J= 9.8, 2.4 Hz, 1 H), 6.88 (ddd, J= 9.6, 8.8, 2.4 Hz, 1 H), 4.78 - 4.67 (m, 2H), 4.15 - 4.06 (m, 1 H), 3.40 - 3.34 (m, 1 H), 2.91 - 2.80 (m, 1 H), 2.30 - 2.00 (m,4H),2.17(s, 3H).
Compound 25: 5-(6-fluoro-1 --indol-3-yl)-1 H-benzo[ |imidazole Following the general method as outlined in Compound 1 , starting from 5-(6-fluoro-1- (phenylsulfonyl)-l -/-indol-3-yl)-1 -/-benzo[ |imidazole (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: 252.0. 1H NMR (300 MHz, DMSO-cfe) δ [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-1 --indol-3-yl)-2-methyl-1 H-benzo[ |imidazole Following the general method as outlined in Compound 1, starting from 5-(6-fluoro-1- (phenylsulfonyl)-l --indol-3-yl)-2-methyl-1 H-benzo[ |imidazole (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 Ci6Hi2FN3+H+ [M+H]+: calcd. 266.1; found: 265.9. 1H NMR (400 MHz, DMSO-d6) δ [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-1 --indol-3-yl)-1 H-benzo[d]imidazol-2-yl)methanamine
Figure imgf000181_0001
To a solution of terf-butyl ((6-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2- yl)methyl)carbamate (Intermediate 48, 429 mg, 1.13 mmol) in THF (30 imL) was added HCI (12 M, 3 imL). 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 imL) and extracted with EtOAc (30 mLx2). The aqueous phase was basified with NH4OH to pH=13 and extracted with EtOAc (80 mLx3). The combined organic layer was washed with brine (30 imL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by preparative HPLC to afford 70 mg (22 %) of the title compound as a white solid. LC-MS for Ci6Hi3FN4+H+ [M+H]+ :calcd. 281 .1 ; found: 280.9. 1 H NMR (400 MHz, DMSO-afe) δ [ppm]:11 .34 (s, 1 H), 7.82 (dd, J = 8.8, 5.5 Hz, 1 H), 7.70 (s, 1 H), 7.61 (s, 1 H), 7.54 (d, J = 8.2 Hz, 1 H), 7.42 (d, J = 8.3 Hz, 1 H), 7.22 (dd, J = 9.9, 2.3 Hz, 1 H), 6.95 (td, J = 9.4, 2.1 Hz, 1 H), 3.94 (s, 2H).
Compound 28: 1 -(6-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2-yl)-A/,A/- dimethylmethanamine
Figure imgf000182_0001
Following the general method as outlined in Compound 1 , starting from 1 -(6-(6-fluoro-1 - (phenylsulfonyl)-l - -indol-3-yl)-1 - -benzo[d]imidazol-2-yl)-A/,A/-dimethylmethanamine (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 . 1 H NMR (400 MHz, CDCI3) δ [ppm]: 10.06- 9.46 (m, 1 H), 8.31 (s, 1 H), 7.86 (dd, J = 8.6, 5.3 Hz, 1 H), 7.80 - 7.62 (m, 1 H), 7.52 (d, J = 6.8 Hz, 1 H), 7.35 (d, J = 2.3 Hz, 1 H), 7.12 (dd, J = 9.5, 2.2 Hz, 1 H), 6.96 (td, J = 9.3, 2.3 Hz, 1 H), 3.80 (s, 2H), 2.38 (s, 6H).
Compound 30: A/-((6-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2- yl)methyl)acetamide
Figure imgf000182_0002
Following the general method as outlined in Compound 1 , starting from A/-((6-(6-fluoro- 1 -(phenylsulfonyl)-l - -indol-3-yl)-1 H-benzo[ |imidazol-2-yl)methyl)acetamide
(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 Ci8H15FN4O+H+ [M+H]+: calcd. 323.1 ; found: 322.1 . 1 H NMR (400 MHz, MeOH-tf4) δ [ppm]: 7.76 (dd, J = 8.8, 5.2 Hz, 1 H), 7.71 (s, 1 H), 7.53 (d, J = 8.4 Hz, 1 H), 7.48 (d, J = 8.4 Hz, 1 H), 7.38 (s, 1 H), 7.07 (d, J = 9.6 Hz, 1 H), 6.83 (td, J = 9.2, 2.4 Hz, 1 H), 4.59 (s, 2H), 2.03 (s, 3H).
Compound 31 : 2-amino-A/-((6-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2- yl)methyl)acetamide
Figure imgf000183_0001
To a stirred solution of tert-butyl (2-(((6-(6-fluoro-1 H-indol-3-yl)-1 H-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 EtOAc (30 mLx2). The aqueous phase was basified with NH4OH till pH=13 and extracted with EtOAc (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 Ci8H16FN5O+H+ [M+H]+ : calcd. 338.1 ; found: 337.9. 1 H NMR (400 MHz, DMSO-afe) δ [ppm]: 11 .36 (s, 1 H), 8.55 (s, 1 H), 7.83 (dd, J = 8.7, 5.4 Hz, 1 H), 7.73 (s, 1 H), 7.63 (d, J = 1 .7 Hz, 1 H), 7.56 (d, J = 8.3 Hz, 1 H), 7.45 (d, J = 8.3 Hz, 1 H), 7.22 (dd, J = 10.0, 2.2 Hz, 1 H), 6.95 (td, J = 9.5, 2.2 Hz, 1 H), 4.55 (s, 2H), 3.22 (s, 2H).
Compound 32: A/-((6-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2- yl)methyl)methanesulfonamide
Figure imgf000184_0001
To a stirred solution of c-[6-(6-fluoro-1 - -indol-3-yl)-1 H-benzoimidazol-2-yl]-methylamine (Compound 27, 300 mg, 1 .07 mmol) and Et3N (270 mg, 2.68 mmol) in anhydrous DCM (24 imL) was added MsCI (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 EtOAc (80 imL) 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 Ci7H15FN4O2S-H" [M-H]": calcd. 357.1 ; found: 356.9. 1H NMR (400 MHz, MeOD) δ [ppm]:7.74 (dd, J = 8.8, 5.3 Hz, 1 H), 7.70 (s, 1 H), 7.52 (d, J = 8.4 Hz, 1 H), 7.46 (dd, J = 8.4, 1 .2 Hz, 1 H), 7.35 (s, 1 H), 7.04 (dd, J = 9.8, 2.3 Hz, 1 H), 6.80 (td, J = 9.3, 2.3 Hz, 1 H), 4.46 (s, 2H), 2.92 (s, 3H).
Compound 33: 6-(6-fluoro-1 H-indol-3-yl)-2-((4-methylpiperazin-1 -yl)methyl)-1 H- benzo[d]imidazole
Figure imgf000184_0002
Following the general method as outlined in Compound 1 , starting from 6-(1 - benzenesulfonyl-6-fluoro-1 H-indol-3-yl)-2-(4-methyl-piperazin-1 -ylmethyl)-1 H- benzoimidazole (Intermediate 60, 290 mg, 0.45 mmol, crude), 18 mg (1 1 %) of the title compound was obtained as a brown solid. LC-MS for C2i H22FN5+H+ [M+H]+: calcd. 364.2; found: 364.2. 1H NMR (400 MHz, DMSO-afe) δ [ppm]: 1 1 .69 (br s, 1 H), 1 1 .10 (br s, 1 H), 7.99 (s, 1 H), 7.86 - 7.84 (m, 4H), 7.28 (dd, J = 9.8, 2.0 Hz, 1 H), 7.02 (td, J = 9.6, 2.0 Hz, 1 H), 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-1 - -indol-3-yl)-2-((4-(methylsulfonyl)piperazin-1 -yl)methyl)- 1 - -benzo[d]imidazole
Figure imgf000185_0001
Following the general method as outlined in Compound 1 , starting from 6-(1 - benzenesulfonyl-6-fluoro-1 H-indol-3-yl)-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 C2iH22FN5O2S+H+ [M+H]+: calcd. 428.2; found: 428.2. 1H NMR (400 MHz, CD3OD) δ [ppm]: 7.72 (dd, J = 8.8, 5.2 Hz, 1 H), 7.67 (s, 1 H), 7.49 (d, J = 8.8 Hz, 1 H), 7.43 (dd, J = 8.4, 0.9 Hz, 1 H), 7.33 (s, 1 H), 7.02 (dd, J = 9.6, 2.0 Hz, 1 H), 7.78 (d, J = 8.8, 2.0 Hz, 1 H), 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-1 - -indol-3-yl)-1 H-benzo[d]imidazol-2-yl)ethanamine
Figure imgf000185_0002
Following the general method as outlined in Compound 1 , starting from 2-[6-(1 - Benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-1 H-benzoimidazol-2-yl]-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 . 1 H NMR (400 MHz, CD4O-tf4) δ [ppm]: 7.86 - 7.82 (m, 2H), 7.61 - 7.53 (m, 2H), 7.46 (s, 1 H), 7.14 (dd, J = 10.0, 2.4 Hz, 1 H), 6.91 (td, J = 9.2, 2.4 Hz, 1 H), 3.28 - 3.22 (m, 2H), 3.16 - 3.08 (m, 2H). Compound 36: A/-(2-(6-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2- yl)ethyl)acetamide
Figure imgf000186_0001
Following the general method as outlined in Compound 1 , starting from A/-{2-[6-(1 - Benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-1 H-benzoimid-azol-2-yl]-ethyl}-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 . 1H NMR (400 MHz, CD4O-tf4) δ [ppm]: 7.70 (dd, J = 8.8, 5.6 Hz, 2H), 7.64 (s, 1 H), 7.47 - 7.40 (m, 2H), 7.32 (s, 1 H), 7.02 (dd, J = 9.6, 2.2 Hz, 1 H), 6.77 (td, J = 9.2, 2.4Hz, 1 H), 3.54 (t, J = 6.8 Hz, 2H), 2.99 (t, J= 6.8 Hz, 2H).
Compound 37: A/-(2-(6-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2- yl)ethyl)methanesulfonamide
Figure imgf000186_0002
Following the general method as outlined in Compound 1 , starting from A/-{2-[6-(1 - Benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-1 - -benzoimida-zol-2-yl]-ethyl}- methanesulfonamide (Intermediate 65, 430 mg, 0.840 mmol), the title compound (36 mg, 11 %) was botained as a white solid. LC-MS for Ci8H17FN4O2S+H+ [M+H]+: calcd. 373.1 ; found: 373.1 . 1H NMR (400 MHz, CD4O-tf4) δ [ppm]: 7.73 - 7.66 (m, 2H), 7.51 - 7.44 (m, 2H), 7.34 (s, 1 H), 7.02 (dd, J = 10.0, 2.0 Hz, 1 H), 6.78 (td, J
3.48 (t, J = 7.0 Hz, 2H), 3.1 1 (m, J = 7.0 Hz, 2H), 2.81 (s, 3H).
Compound 38: 5-(6-fluoro-1 H-indol-3-yl)-2-(2-(methylsulfonyl)ethyl)-1 H- benzo[d]imidazole
Following the general method as outlined in Compound 1 , starting from 5-(6-fluoro-1 - (phenylsulfonyl)-l H-indol-3-yl)-2-(2-(methylsulfonyl)ethyl)-1 H-benzo[ |imidazole
(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/MeOH = 10/1 ) and preparative HPLC. LC-MS for Ci8H16FN3O2S+H+ [M+H]+: calcd. 358.1 ; found: 358.1 . 1 H NMR (400 MHz, DMSO-afe) δ [ppm]: 12.35 (s, 0.45H), 12.35 (s, 0.55H), 1 1 .37 (s, 0.55H), 1 1 .33 (s, 0.45H), 7.85 - 7.79 (m, 1 H), 7.77 (s, 0.45H), 7.66 - 7.63 (m, 1 H), 7.62 - 7.57 (m, 1 H), 7.52 - 7.41 (m, 1 .55H), 7.24 - 7.19 (m, 1 H), 6.99 - 6.91 (m, 1 H), 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-1 -/-indol-3-yl)-2-(piperidin-4-yl)-1 -/-benzo[d]imidazole
Figure imgf000187_0001
To a solution of te/t-butyl 4-(6-(6-fluoro-1 -/-indol-3-yl)-1 H-benzo[ |imidazol-2- yl)piperidine-1 -carboxylate (Intermediate 56, 550 mg crude, 1 .05 mmol) in THF (5ml_) was added concentrated aqueous HCI (1 imL). The reaction mixture was stirred at 50 °C for 3 hours before it was concentrated. The mixture was poured into brine and extracted with EtOAc. 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 C20Hi9FN4+H+ [M+H]+: calcd. 335.2; found: 335.1 . 1 H NMR (400 MHz, MeOH-tf4) δ
[ppm]: 7.84 (dd, J = 8.8, 5.2 Hz, 1 H), 7.79 (s, 1 H), 7.62 (d, J = 8.4 Hz, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 7.46 (s, 1 H), 7.15 (dd, J = 9.8, 2.2 Hz, 1 H), 6.91 (td, J = 9.2, 2.0 Hz, 1 H), 3.54 - 3.51 (m, 2H), 3.31 -3.28 (m, 1 H), 3.21 - 3.15 (m, 2H), 2.38 - 2.35 (m, 2H), 2.20 - 2.13 (m, 2H).
Compound 40: 6-(6-fluoro-1 - -indol-3-yl)-2-(1 -(methylsulfonyl)piperidin
benzo[d]imidazole
Figure imgf000188_0001
To a solution of 6-(6-fluoro-1 - -indol-3-yl)-2-(piperidin-4-yl)-1 H-benzo[ |imidazole (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
C2i H2i FN4O2S+H+ [M+H]+: calcd. 413.1 ; found: 413.1 . 1 H NMR (400 MHz, MeOH-tf4) δ [ppm]: 7.72 (dd, J = 8.4, 5.2 Hz, 1 H), 7.65 (s, 1 H), 7.47 (d, J = 8.4 Hz, 1 H), 7.41 (d, J = 8.4, 1 H), 7.33 (s, 1 H), 7.02 (dd, J= 9.8, 2.4 Hz, 1 H), 6.78 (td, J = 9.2, 2.0 Hz, 1 H), 3.75 (d, J = 12.0 Hz, 2H), 3.02 (tt, J = 1 1 .7, 3.6 Hz, 1 H), 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-1 - -indol-3-yl)-1 H-benzo[d]imidazol-2-amine
NH2
HN^N Following the general method as outlined in Compound 1 , starting from 6-(6-fluoro-1 - (phenylsulfonyl)-l - -indol-3-yl)-1 H-benzo[ |imidazol-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 C15H11FN4+H+ [M+H]+: calcd. 267.1 ; found: 267.1 . 1 H NMR (400 MHz, DMSO-afe) δ [ppm]: 1 1 .21 (br s, 1 H), 10.61 (br s, 1 H), 7.78 (dd, J = 8.8, 5.5 Hz, 1 H), 7.49 (d, J = 2.0 Hz, 1 H), 7.34 (s, 1 H), 7.18 (dd, J = 10.1 , 2.2 Hz, 1 H), 7.16 - 7.1 1 (m, 2H), 6.92 (ddd, J = 9.6, 8.6, 2.2 Hz, 1 H), 6.1 1 (br s, 2H).
Compound 44: 1 -(5-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[ |imidazol-2-yl)-A/- methylmethanamine
To a solution of te/t-butyl (5-(6-fluoro-1 -/-indol-3-yl)-1 H-benzo[ |imidazol-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 EtOAc (50 mLx3). The aqueous layer was basified with aqueous NaOH to pH = 13 and extracted with EtOAc (80 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by preparative TLC (DCM/MeOH = 10/1 ) and preparative HPLC to afford 40 mg (16%) of the title compound as a white solid. LC-MS for Ci7H15FN4+H+ [M+H]+: calcd. 295.1 ; found: 294.9. 1 H NMR (400 MHz, DMSO-afe) δ [ppm]: 11 .34 (s, 1 H), 7.82 (dd, J = 8.7, 5.4 Hz, 1 H), 7.70 (s, 1 H), 7.61 (s, 1 H), 7.53 (d, J = 8.7 Hz, 1 H), 7.42 (d, J = 8.7 Hz, 1 H), 7.22 (dd, J = 10.0, 2.3 Hz, 1 H), 6.95 (ddd, J =9.4, 8.7, 2.3 Hz, 1 H), 3.87 (s, 2H), 2.34 (s, 3H).
Compound 45: 4-((5-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[ |imidazol-2- yl)methyl)morpholine
Step 1 : 4-((5-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-1 H-benzo[c/|imidazol-2- yl)methyl)morpholine
A solution of 2-(chloromethyl)-5-(6-fluoro-1 -(phenylsulfonyl)-l - -indol-3-yl)-1 H- benzo[ |imidazole (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 EtOAc (50 ml_), washed with H2O (20 ml_), brine (30 mLx2), dried over anhydrous Na2SO4, filtered, concentrated, and purified by preparative TLC (DCM/ MeOH =20/1 ) to afford 56 mg (50%) of the title compound as a brown solid. LC-MS for
C26H23FN4O3S+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 - (phenylsulfonyl)-l - -indol-3-yl)-1 H-benzo[ |imidazol-2-yl)methyl)morpholine (Step 1 ; 56 mg; 0.1 1 mmol), 13 mg (32%) of the title compound was obtained as a white solid after purification by preparative TLC (DCM/MeOH = 20/1 ). LC-MS for C2oHi9FN4O+H+ [M+H]+: calcd. 351 .2; found: 351 .2. 1 H NMR (400 MHz, MeOH- /4) δ [ppm]: 7.71 (dd, J = 8.4, 5.2 Hz, 1 H), 7.67 (s, 1 H), 7.49 (d, J = 8.4 Hz, 1 H), 7.41 (d, J = 8.4 Hz, 1 H), 7.33 (s, 1 H), 7.01 (dd, J = 10.0, 2.4 Hz, 1 H), 6.78 (ddd, J = 9.2, 8.4, 2.4 Hz, 1 H), 3.72 (s, 1 H), 3.66 - 3.61 (m, 4H), 2.50 - 2.44 (m, 4H).
Compound 46: 3-(5-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2-yl)propanamide
Step 1 : 3-(5-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-1 H-benzo[c/|imidazol-2- yl)propanamide
A solution of 6-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)-2,3-dihydro-1 H- benzo[ |pyrrolo[1 ,2-a]imidazol-1 -one (Intermediate 41 ; 456 mg crude; 0.92 mmol) in saturated NH3 in THF (100 imL) 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 C24H19FN4O3S+H+ [M+H]+: calcd. 463.1 ; found: 462.8.
Step 2: To a solution of 3-(5-(6-fluoro-1 -(phenylsulfonyl)-l - -indol-3-yl)-1 H-benzo[ |imidazol-2- yl)propanamide (Step 1 ; 480 mg crude; 0.92 mmol) in EtOH (10 imL) was added KOH (1 16 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 Ci8Hi5FN4O+H+ [M+H]+: calcd.323.1 ; found: 322.9. 1H NMR (400 MHz, DMSO-cfe) δ
[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, 1 H), 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-1 H-indol-3-yl)benzo[c]oxazole
Following the general method as outlined in Compound 1 , starting from 5-(6-fluoro-1- (phenylsulfonyl)-l -/-indol-3-yl)benzo[ |oxazole (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/EtOAc = 100/1 - 6/1 ). LC-MS for
C15H9FN2O+H+ [M+H]+: calcd.253.1 ; found: 253.0. 1H NMR (400 MHz, CDCI3) δ [ppm]: 8.30 (br s, 1 H), 8.14 (s, 1 H), 8.03 (s, 1 H), 7.84 (dd, J= 8.8, 5.2 Hz, 1 H), 7.69 - 7.63 (m, 2H), 7.37 (d, J= 2.4 Hz, 1 H), 7.14 (dd, J= 9.4, 2.2 Hz, 1 H), 6.98 (ddd, J= 9.4, 8.8, 2.2 Hz, 1H).
Compound 48: 5-(6-fluoro-1 H-indol-3-yl)-2-methylbenzo[c]oxazole
Following the general method as outlined in Compound 1 , starting from 5-(6-fluoro-1- (phenylsulfonyl)-l H-indol-3-yl)-2-methylbenzo[c]oxazole (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/EtOAc = 4/1. LC-MS for
Ci6HnFN2O+H+ [M+H]+: calcd.267.1 ; found: 267.0. 1H NMR (400 MHz, DMSO-afe) δ [ppm]: 11.45 (s, 1 H), 7.87 (s, 1 H), 7.83 (dd, J= 8.8, 5.2 Hz, 1 H), 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-1 -/-indol-3-yl)benzo[d]oxazole
Figure imgf000192_0001
A mixture of 2-amino-5-(6-fluoro-1 - -indol-3-yl)-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 EtOAc (5 mL) and petroleum ether (20 mL) to afford 160 mg (35%) of the title compound as a white solid. LC-MS for Ci5H9FN2O+H+ [M+H]+: calcd. 253.1 ; found: 253.0. 1H NMR (400 MHz, DMSO-afe) δ [ppm]: 8.43 (s, 1 H), 7.89 (s, 1 H), 7.84 - 7.82 (m, 1 H), 7.75 (d, J = 8.0Hz, 1 H), 7.70 (dd, J = 8.4, 1 .6 Hz, 1 H), 7.52 (s, 1 H), 7.12 (dd, J = 10, 2.4 Hz, 1 H), 6.90 (m, 1 H).
Compound 54: 6-(6-fluoro-1 - -indol-3-yl)-2-methylbenzo[d]oxazole
Figure imgf000192_0002
A mixture of 2-amino-5-(6-fluoro-1 - -indol-3-yl)-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 EtOAc (5 mL) and petroleum ether (20 mL) to afford 140 mg (30%) of the title compound as a white solid. LC-MS for Ci6HnFN2O+H+ [M+H]+: calcd. 267.1 ; found: 267.1 . 1 H NMR (400 MHz, DMSO-afe) δ [ppm]: 7.85 (dd, J = 8.8, 5.6 Hz, 1 H), 7.82 (s, 1 H), 7.66 (s, 2H), 7.53 (s, 1 H), 7.16 (dd, J = 9.6, 2.4 Hz, 1 H), 6.93 (td, J = 9.2, 2.0 Hz, 1 H), 2.67 (s, 3H).
Compound 55: 6-(6-fluoro-1 -/-indol-3-yl)-2-(piperidin-4-yl)benzo[d]oxazole
Figure imgf000193_0001
A mixture of te/t-butyl 4-(6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)piperidine-1 - carboxylate (Intermediate 106, 1 .23 g, 2.82 mmol) in HCI/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 EtOAc (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 C2oHi8FN3O+H+ [M+H]+: calcd. 335.1 ; found: 336.1 . 1H NMR (400 MHz, DMSO-cfe) δ [ppm]: 1 1.49 (br s, 1 H), 7.91 (s, 1 H), 7.89 (dd, J= 8.8, 3.2 Hz, 1 H), 7.75 (d, J= 1 .6 Hz, 1 H), 7.73 (d, J= 8.4 Hz, 1 H), 7.66 (dd, J= 8.6, 1.4 Hz, 1 H), 7.25 (dd, J= 9.8, 2.6 Hz, 1 H), 6.97 (td, J = 10.6, 2.5 Hz, 1 H), 3.13 - 3.02 (m, 3H), 2.64 (t, J = 1 1 .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-1 -/-indol-3-yl)benzo[d]oxazol-2-yl)piperidin-1 - yl)ethanone
Figure imgf000193_0002
To a stirred solution of 6-(6-fluoro-1 -/-indol-3-yl)-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 Na2SO4 and 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 C22H2oFN3O2+H+: [M+H]+: calcd. 378.2;found: 378.1 . 1H NMR (400 MHz, DMSO-dfe) δ [ppm]: 1 1.48 (s, 1 H), 7.92 (s, 1 H), 7.89 (dd, J = 5.6, 8.8 Hz, 1 H), 7.75 (d, J = 2.8 Hz, 1 H), 7.73 (d, J = 7.2 Hz, 1 H), 7.66 (dd, J = 1 .6, 8.0 Hz, 1 H), 7.23 (dd, J= 2.4, 10.0 Hz, 1 H), 6.97 (td, J= 2.4, 9.6 Hz, 1 H), 4.32 (d, J = 13.6 Hz, 1 H), 3.87 (d, J = 13.6 Hz, 1 H), 3.35 - 3.27 (m, 2H), 2.88 (t, J = 1 1.2 Hz, 1 H), 2.13 (t, J= 14.0 Hz, 2H), 2.04 (s, 3H), 1.88-1.77 (m, 1 H), 1.72 - 1.62 (m, 1 H).
Compound 58: A/-(6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methanesulfonamide
Figure imgf000194_0001
To the mixture of A/-[6-(1 -Benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-benzooxazol-2-yl] - methanesulfonamide (Intermediate 124, 350 mg 0.72 mmol) in ethanol (20 imL) 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/methanol=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
Ci6Hi2FN3O3S+H+ [M+H]+: calcd. 346.1 ; found: 346.0. 1H NMR (400 MHz, DMSO-cfe) δ [ppm]: 12.51 (s, 1 H), 1 1.44 (s, 1 H), 7.86 (dd, J= 9.2, 5.6 Hz, 1 H), 7.76 (s, 1 H), 7.72 (d, J = 2.0 Hz, 1 H), 7.59 (d, J = 8.0 Hz, 1 H), 7.36 (d, J = 8.4 Hz, 1 H), 7.22 (dd, J = 10.0, 2.4 Hz, 1 H), 6.98 - 6.94 (m, 1 H), 3.08 (s, 3H).
Compound 59: 6-(6-fluoro-1 -/-indol-3-yl)-2-(piperazin-1 -ylmethyl)-1 -/-benzo[d]imidazole
Figure imgf000195_0001
Following the general method as outlined in Compound 1 , starting from 6-(1 - benzenesulfonyl-6-fluoro-1 H-indol-3-yl)-2-piperazin-1 -ylmethyl-1 H-benzoimidazole (Intermediate 62, 80 mg, 0.16 mmol) , 35 mg (62%) of the title compound was obtained as a white solid. LC-MS for C20H2oFN5+H+ [M+H]+: calcd. 350.2; found: 350.1 . 1 H NMR (400 MHz, CD3OD) δ [ppm]: 7.73 (dd, J = 8.8, 5.2 Hz, 1 H), 7.70 (s, 1 H), 7.50 (d, J = 8.8 Hz, 1 H), 7.44 (d, J = 8.4 Hz, 1 H), 7.34 (s, 1 H), 7.03 (dd, J = 9.6, 2.0 Hz, 1 H), 7.79 (d, J = 8.8, 2.0 Hz, 1 H), 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-1 -/-indol-3-yl)-1 H-benzo[d]imidazol-2-yl)acetamide
Figure imgf000195_0002
To a stirred solution of [5-(6-fluoro-1 - -indol-3-yl)-1 H-benzoimidazol-2-yl]-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 H2O2 (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 EtOAc (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/MeOH = 20/1 to 5/1 ) to give the solid. The solid was suspended with DCM/MeOH = 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 Ci7Hn FN4O+H+ [M+H]+: calcd. 309.1 ; found: 309.3. 1 H NMR (400 MHz, DMSO-afe) δ [ppm]: 12.19 (d, J = 24.0 Hz, 1 H), 1 1 .33 (d, J = 12.8 Hz, 1 H), 7.82 (dd, J = 8.4, 5.2 Hz, 1 H), 7.76 - 7.66 (m, 2H), 7.61 (dd, J = 9.6, 2.4 Hz, 1 H), 7.59 - 7.47 (m, 1 H), 7.43 (td, J = 9.6, 2.4 Hz, 1 H), 7.25 - 7.16 (m, 2H), 6.99 - 6.91 (m, 1 H), 3.73 (s, 2H). Compound 61 : 5-(6-fluoro-1 -/-indol-3-yl)-2-(piperazin-1 -ylmethyl)benzo[d]oxazole
Figure imgf000196_0001
Following the general method as outlined in Compound 1, starting from 5-(1- benzenesulfonyl-6-fluoro-1 H-indol-3-yl)-2-piperazin-1 -ylmethyl-benzooxazole
(Intermediate 72, 80 mg, 0.16 mmol) in MeOH (10 mL), 30 mg (52%) of the title compound was obtained as a white solid. LC-MS for C2oHi9FN4O+H+ [M+H]+: calcd. 351.2; found: 351.1. 1H NMR (400 MHz, CD3OD) δ [ppm]: 7.77 (s, 1 H), 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, 1 H), 6.78 (td, J= 9.6, 2.0 Hz, 1 H), 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-1 H-indol-3-yl)-2-((4-methylpiperazin-1 - yl)methyl)benzo[d]oxazole
Figure imgf000196_0002
Following the general method as outlined in Compound 1, starting from 5-(1- benzenesulfonyl-6-fluoro-1 --indol-3-yl)-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 C2iH2iFN4O+H+ [M+H]+: calcd.365.2; found: 365.1. 1H NMR (400 MHz, CD3OD) δ [ppm]: 7.89 (d, J= 0.8 Hz, 1 H), 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, 1 H), 6.89 (td, J= 9.6, 2.0 Hz, 1 H), 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-1 - -indol-3-yl)-2-(morpholinomethyl)benzo[d]oxazole
Figure imgf000197_0001
Following the general method as outlined in Compound 1 , starting from 5-(1 - benzenesulfonyl-6-fluoro-1 H-indol-3-yl)-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 C2oHi8FN3O2+H+ [M+H]+: calcd. 352.1 ; found:
352.1 . 1 H NMR (400 MHz, CD3OD) δ [ppm]: 7.86 (s, 1 H), 7.75 (dd, J = 8.8, 5.6 Hz, 1 H), 7.62 (d, J = 8.4 Hz, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 7.44 (s, 1 H), 7.12 (dd, J = 9.6, 1 .6 Hz, 1 H), 6.87 (td, J = 9.6, 2.0 Hz, 1 H), 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-1 H-indol-3-yl)-2-oxobenzo[d]oxazol-3(2H)-yl)acetamide
Figure imgf000197_0002
Following the general method as outlined in Compound 1 , starting from 2-(6-(6-fluoro-1 - (phenylsulfonyl)-l -/-indol-3-yl)-2-oxobenzo[d]oxazol-3(2 -/)-yl)acetamide (Intermediate 76, 183 mg, 0.4 mmol), 50 mg (38 %) of the title compound was obtained as a white solid. LC-MS for Ci7H12FN3O3+H]+ [M+H]+ : calcd. 326.1 ; found: 325.8. 1H NMR (400 MHz, DMSO-de) δ [ppm]: 11 .43 (br s, 1 H), 10.97 (br s, 1 H), 9.81 (br s, 1 H), 7.81 (dd, J = 8.4, 5.2 Hz, 1 H), 7.65 (d, J = 2.4 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 1 H), 7.24 - 7.21 (m, 2H), 7.12 (dd, J= 8.0, 1 .2 Hz, 1 H), 6.97 (td, J = 9.2, 2.0 Hz, 1 H), 4.28 (s, 2H).
Compound 65: 5-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2(3H)-one
Figure imgf000198_0001
Following the general method as outlined in Compound 1 , starting from 5-(1 - Benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-, 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 C15H10FN3O-H" [M-H]: calcd. 266.1 ; found: 265.9. 1H NMR (400 MHz, MeOD-tf4) δ [ppm]: 1 1 .30 (s, 1 H), 10.59 (s, 2H), 7.76 (dd, J1 = 8.4 Hz, J2 = 5.6 Hz, 1 H), 7.56 (d, J= 2.0 Hz, 1 H), 7.23 - 7.19 (m, 2H), 7.15 (s, 1 H), 6.98 (d, J= 7.6 Hz, 1 H), 6.94 (td, Jy = 9.2 Hz, J2 = 2.0 Hz, 1 H).
Compound 66: 6-(6-fluoro-1 H-indol-3-yl)-2-(morpholinomethyl)benzo[d]oxazole
Figure imgf000198_0002
Following the general method as outlined in Compound 1 , starting from 6-(6-fluoro-1 - (phenylsulfonyl)-l H-indol-3-yl)-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 C2oHi8FN3O2+H+ [M+H]+: calce. 352.1 ; found: 352.1 . 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 11 .51 (s, 1 H), 7.96 (s, 1 H), 7.91 - 7.88 (m, 1 H), 7.77 - 7.74 (m, 2H),7.69 - 7.67 (m, 1 H), 7.24 (dd, J = 2.0, 9.6 Hz, 1 H), 6.97 (td, J = 2.4, 9.6 Hz, 1 H), 3.87 (s, 2H), 3.61 - 3.59 (m, 4H), 2.56 - 2.54 (m, 4H).
Compound 67: 3-(6-(6-fluoro-1 H-indol-3-yl)-2-oxobenzo[d]oxazol-3(2/-/)-yl)propanamide
Figure imgf000199_0001
Following the general method as outlined in Compound 1 , starting from 3-(6-(6-fluoro-1 - (phenylsulfonyl)-l -/-indol-3-yl)-2-oxobenzo[d]oxazol-3(2 -/)-yl)propanamide
(Intermediate 81 , 280 mg, 0.58 mmol), 50 mg (25%) of the title compound was obtained as a white solid. LC-MS for Ci8H14FN3O3-H" [M-H]" : calcd. 338.1 ; found: 337.9. 1 H NMR (400 MHz, DMSO-afe) δ [ppm]: 11 .40 (br s, 1 H), 10.27 (br s, 1 H), 9.60 (br s, 1 H), 7.81 (dd, J = 8.8, 5.4 Hz, 1 H), 7.63 (d, J = 2.8 Hz, 1 H), 7.24-7.19 (m, 3H), 7.11 (dd, J = 8.0, 1 .6 Hz, 1 H), 6.97 (td, J = 9.6, 2.0 Hz, 1 H), 3.63 (t, J = 6.6 Hz, 2H), 2.70 (t, J = 6.8 Hz, 2H).
Compound 68: 6-(6-fluoro-1 H-indol-3-yl)-2-((4-methylpiperazin-1 - yl)methyl)benzo[d]oxazole
Figure imgf000199_0002
Following the general method as outlined in Compound 1 , starting from 6-(6-fluoro-1 - (phenylsulfonyl)-l H-indol-3-yl)-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 C2iH2i FN4O+H+ [M+H]+: calcd.365.2 ; found: 364.9. 1H NMR (400 MHz, DMSO-cfe) δ [ppm]: 11 .54 (s, 1 H), 7.95 - 7.88 (m, 2H), 7.76 - 7.67 (m, 3H), 7.24 (dd, J = 9.6, 1 .6 Hz, 1 H), 6.99 - 6.95 (m, 1 H), 3.84 (s, 2H), 2.55 (s, 4H), 2.34 (s, 4H), 2.15 (S,3H)
Compound 69: 2-(5-(6-fluoro-1 H-indol-3-yl)-2-oxobenzo[d]oxazol-3(2/-/)-yl)acetamide
Figure imgf000200_0001
Following the general method as outlined in Compound 1 , starting from 2-(5-(6-fluoro-1 - (phenylsulfonyl)-l -/-indol-3-yl)-2-oxobenzo[ /|oxazol-3(2 -/)-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 C17H12FN3O3-H" [M-H]": calcd. 324.1 ; found: 323.9. 1 H NMR (400 MHz, DMSO-afe) δ [ppm]: 1 1 .31 (br s, 1 H), 10.95 (br s, 1 H), 9.74 (br s, 1 H), 7.80 (dd, J = 8.7, 5.4 Hz, 1 H), 7.59 (d, J = 2.0 Hz, 1 H), 7.54 (d, J = 2.0 Hz, 1 H), 7.46 -7.43 (m, 1 H), 7.19 (dd, J = 10.0, 2.0 Hz, 1 H), 6.99 - 6.90 (m, 2H), 4.32 (s, 2H).
Compound 70: A/-((5-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2- yl)methyl)methanesulfonamide
Figure imgf000200_0002
Following the general method as outlined in Compound 1 , starting from A/-[5-(1 - benzenesulfonyl-6-fluoro-1 - -indol-3-yl)-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 C17H14FN3O3S+H+ [M+H]+: calcd. 360.1 ; found: 360.0. 1H NMR (400 MHz, DMSO-afe) δ [ppm]: 1 1 .45 (br s, 1 H), 8.01 (br s, 1 H), 7.95 (s, 1 H), 7.89- 7.81 (m, 1 H), 7.78 (d, J = 8.0 Hz, 1 H), 7.73 (d, J = 2.8 Hz, 1 H), 7.70 (d, J = 8.8 Hz, 1 H), 7.23 (dd, J = 10.0, 2.0 Hz, 1 H), 6.96 (td, J = 8.8, 2.0 Hz, 1 H), 4.54 (s, 2H), 3.04 (s, 3H). Compound 71 : 3-(5-(6-fluoro-1 -/-indol-3-yl)-2-oxobenzo[d]oxazol-3(2-/)-yl)propanamide)
Figure imgf000201_0001
Following the general method as outlined in Compound 1, starting from 3-[5-(1- Benzenesulfonyl-6-fluoro-1 --indol-3-yl)-2-oxo-benzooxazol -3-yl]-propionamide
(Intermediate 88, 270 mg, 0.56 mmol), the title compound (48 mg, 25%) was obtained as a white solid. LC-MS for Ci8H14FN3O3-H" [M-H]": calcd.338.1 ; found: 338.0. 1H NMR (400 MHz, DMSO) 511.30 (s, 1H), 10.31 (s, 1H),9.56 (s, 1H),7.78 (dd, J= 8.8, 5.6 Hz, 1 H), 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, 1 H), 6.98 (d, J= 8.4 Hz, 1 H), 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-yl)-6-fluoro-1 /-/-indole
Figure imgf000201_0002
Following the general method as outlined in Compound 1 , starting from 3- (benzo[b]thiophen-5-yl)-6-fluoro-1 -(phenylsulfonyl)-l /-/-indole (Intermediate 90, 300 mg, 0.74 mmol) , 3-Benzo[b]thiophen-5-yl-6-fluoro-1 /-/-indole(70 mg, 36%) was obtained as a white solid. LC-MS for Ci6H10FNS-H" [M-H]": calcd.266.1 ; found: 265.9. 1H NMR (400 MHz, DMSO) δ 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, 1 H), 6.97 (td, J= 9.2, 2.4 Hz, 1H).
Compound 73: A/-((5-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)acetamide
Figure imgf000202_0001
To a stirred mixture of C-[5-(6-fluoro-1 - -indol-3-yl)-benzooxazol-2-yl]-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 EtOAc (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/MeOH = 20/1 ) to afford 13 mg (32%) of the title compound as a yellow solid. LC-MS for Ci8Hi4FN3O2+H+ [M+H]+: calcd. 324.1 ; found: 324.1 . 1 H NMR (400 MHz, CD3OD) δ [ppm]: 7.90 (s, 1 H), 7.82 (dd, J = 8.8, 1 .6 Hz, 1 H), 7.70 (dd, J = 8.4, 1 .6 Hz, 1 H), 7.66 (d, J = 8.4 Hz, 1 H), 7.50 (s, 1 H), 7.16 (dd, J = 9.6, 2.0 Hz, 1 H), 6.92 (td, J = 9.6, 2.4 Hz, 1 H), 4.70 (s, 2H), 2.10 (s, 3H).
Compound 74: A/-((6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2- yl)methyl)methanesulfonamide
Figure imgf000202_0002
A mixture of te/t-butyl te/t-butyl ((6-(6-fluoro-1 -/-indol-3-yl)benzo[d]oxazol-2- yl)methyl)(methylsulfonyl)carbamate (Intermediate 92, 114 mg, 0.25 mmol) in HCI/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 Ci7H14FN3O3S+H+ [M + H]+ : calcd. 360.1 ;
found: 360.1 . 1H NMR (400 MHz, DMSO-afe) δ [ppm]: 11 .51 (s, 1 H), 8.03 - 7.99 (m, 1 H), 7.97 (s, 1 H), 7.90 (dd, J = 8.8, 5.4 Hz, 1 H), 7.80 - 7.75 (m, 2H), 7.70 (dd, J = 8.3, 1 .3 Hz, 1 H), 7.24 (dd, J = 10.2, 2.2 Hz, 1 H), 6.97 (td, J = 9.2, 2.1 Hz, 1 H), 4.54 (d, J = 4.4 Hz, 2H), 3.04 (s, 3H).
Compound 75: A/-((6-(6-fluoro-1 -/-indol-3-yl)benzo[d]oxazol-2-yl)methyl)acetamide
Figure imgf000203_0001
To a solution of (6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)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 Ci8H14FN3O2+H+ [M+H]+ : calcd. 324.1 ; found: 324.5. 1 H NMR (400 MHz, DMSO-de) δ [ppm]: 11 .50 (s, 1 H), 8.69 (t, J = 5.6 Hz, 1 H), 7.94 (s, 1 H), 7.89 (dd, J = 9.0, 5.4 Hz, 1 H), 7.77 (d, J = 2.5 Hz, 1 H), 7.74 (d, J = 8.2 Hz, 1 H), 7.69 - 7.67 (m, 1 H), 7.24 (dd, J= 9.9, 2.3 Hz, 1 H), 6.97 (td, J = 9.2, 2.0 Hz, 1 H), 4.57 (d, J = 5.6 Hz, 2H), 1 .93 (s, 3H).
Compound 76: (6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methanamine
Figure imgf000203_0002
A mixture of tert-butyl A/-[(iert-butoxy)carbonyl]-A/-{[6-(6-fluoro-1 H-indol-3-yl)-1 ,3- benzoxazol-2-yl]mef/7y/}carbamate (Intermediate 94; 376 mg, 0.78 mmol) in HCI/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 Ci6H13CIFN3O+H+ [M+H]+ :calcd. 282.1 ; found: 281 .9. 1 H NMR (400 MHz, DMSO- ck) δ [ppm]: 11 .51 (br s, 1 H), 7.92 (s, 1 H), 7.90 - 7.87 (m, 1 H), 7.77 (s, 1 H), 7.74 (d, J = 8.0 Hz, 1 H), 7.67 (d, J = 8.2 Hz, 1 H), 7.25 (d, J = 9.6 Hz, 1 H), 6.98 (t, J = 9.0 Hz, 1 H), 3.99 (s, 2H).
Compound 77: 5-(6-fluoro-1 H-indol-3-yl)-2-(piperidin-4-ylmethyl)-2H-indazole
Figure imgf000204_0001
A mixture of 4-[5-(6-Fluoro-1 - -indol-3-yl)-indazol-2-ylmethyl]-piperidine-1 -carboxylic acid te/t-butyl ester (Intermediate 5-2, 189 mg, 0.42 mmol) in HCI/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/MeOH = 10/1 ) to afford 136 mg (93%) of the title compound as a yellow solid. LC-MS for C2i H2i FN4+H+ [M+H]+: calcd. 349.2; found: 348.9
1H NMR (400 MHz, MeOD-tf4) δ [ppm]: 1 1 .35 (s, 1 H), 8.31 (s, 1 H), 7.92-7.86 (m, 2H), 7.66-7.63 (m, 2H), 7.55 (dd, J = 9.2, 1 .6 Hz, 1 H), 7.21 (dd, J = 9.6, 2.4 Hz, 1 H), 6.95 (td, J = 9.6, 2.4 Hz, 1 H), 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-1 -/-indol-3-yl)-2-(piperazin-1 -ylmethyl)benzo[d]oxazole
Figure imgf000205_0001
Following the general method as outlined in Compound 1 , starting from 6-(6-fluoro-1 - (phenylsulfonyl)-l -/-indol-3-yl)-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 C20Hi9FN4O+H+ [M+H]+: calcd. 351 .2; found: 351 .1 . 1H NMR (400 MHz, MeOD) δ [ppm]: 7.89 - 7.84 (m, 2H), 7.74 - 7.73 (m, 2H), 7.56 (s, 1 H), 7.16 (dd, J = 10, 2.4 Hz, 1 H), 6.94 (td, J = 9.2, 2.4 Hz, 1 H), 3.96 - 3.95 (m, 2H), 2.97 (br s, 4H), 2.71 (br s, 4H)
Compound 79: 3-(benzo[b]thiophen-6-yl)-6-fluoro-1 /-/-indole
Figure imgf000205_0002
Following the general method as outlined in Compound 1 , starting from 3- (benzo[b]thiophen-6-yl)-6-fluoro-1 -(phenylsulfonyl)-1 /-/-indole (Intermediate 97, 338 mg, 0.83 mmol) in MeOH (20 imL), 89 mg (40%) of the title compound was obtained as a yellow solid. LC-MS for Ci6H10FNS- H+ [M - H]+ : calcd.266.1 ; found: 266.0. 1H NMR (400 MHz, DMSO-cy δ [ppm]: 11.47 (s, 1 H), 8.29 (s, 1 H), 7.97 - 7.91 (m, 2H), 7.78 (d, J= 2.4 Hz, 1 H), 7.73 - 7.68 (m, 2H), 7.45 (d, J= 5.2 Hz, 1 H), 7.24 (dd, J = 10.0, 2.0 Hz, 1 H), 6.98 (td, J = 9.2, 2.4 Hz, 1 H).
Compound 80: 5-(6-fluoro-1 H-indol-3-yl)-2-(2-(methylsulfonyl)ethyl)benzo[d]oxazole
Figure imgf000206_0001
To a solution of 6-fluoro-3-[2-(2-methanesulfonyl-ethyl)-benzooxazol-5-yl]-indole-1 - carboxylic acid te/t-butyl ester (Intermediate 101 , 45 mg, 0.098 mmol) in MeOH (1 mL) was added HCI/Et2O (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 MeOH (5 mL) and basified with NH3/THF to pH = 8. The micture was concentrated and purified by a preparative TLC (DCM/MeOH = 20/1 ) to afford 6 mg (17%) of the title compound as an off-white solid. LC-MS for Ci8H15FN2O3S+H+ [M+H]+: calcd. 359.1 ; found: 359.0. 1H NMR (400 MHz, CDCI3) δ [ppm]: 8.26 (brs, 1 H), 7.91 (s, 1 H), 7.82 (dd, J = 8.8, 5.2 Hz, 1 H), 7.61 (d, J = 8.0 Hz, 1 H), 7.57 (d, J = 8.0 Hz, 1 H), 7.35 (d, J = 2.0 Hz, 1 H), 7.14 (d, J = 9.6, 2.0 Hz, 1 H), 6.97 (td, J = 8.8, 2.0 Hz, 1 H), 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-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methanamine
Figure imgf000206_0002
To a solution of [5-(6-fluoro-1 H-indol-3-yl)-benzooxazol-2-ylmethyl]-carbamic acid tert- butyl ester (Intermediate 103, 63 mg, 0.165 mmol) in MeOH (3 mL) was added HCI/Et2O (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 . 1 H NMR (400 MHz, DMSO-afe) δ [ppm]: 1 1 .53 (br s, 1 H), 8.83 (br s, 3H), 8.00 (s, 1 H), 7.86 - 7.82 (m, 2H), 7.77 - 7.75 (m, 2H), 7.25 (dd, J = 10.0, 2.4 Hz, 1 H), 6.98 (td, J = 8.8, 2.0 Hz, 1 H), 4.54 - 4.52 (m, 2H). Compound 82: 3-(benzofuran-5-yl)-6-fluoro-1 /-/-indole
Figure imgf000207_0001
Following the general method as outlined in Compound 1 , starting from 3-(benzofuran- 5-yl)-6-fluoro-1 -(phenylsulfonyl)-l H-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/EtOAc = 5/1 , v/v). LC-MS for Ci6H 0FNO-H" [M- H]": calcd. 250.1 ; found: 250.1 . 1H NMR (400 MHz, DMSO-afe) δ [ppm]: 1 1 .39 (br s, 1 H), 8.00 (d, J = 2.0 Hz, 1 H), 7.91 (d, J = 1 .8 Hz, 1 H), 7.85 (dd, J = 8.8, 5.5 Hz, 1 H), 7.66 (s, 1 H), 7.60 (dd, J = 8.4, 2.0 Hz, 2H), 7.23 (dd, J = 9.6, 2.4 Hz, 1 H), 6.70 - 6.93 (m, 2H).
Compound 83: 3-(6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)propanamide
Figure imgf000207_0002
To a mixture of 3-[6-(6-fluoro-1 /-/-indol-3-yl)-benzooxazol-2-yl]-propionic acid
(Intermediate 1 08, 52 mg, 0.1 7 mmol) and NH4CI (27 mg, 0.50 mmol) in anhydrous THF was added HATU (1 27 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 imL) and extracted with EtOAc (30 ml_x2). The combined organic layer was washed with 1 M NaOH ( 1 0 ml_x2) and brine (20 ml_x2) , dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated and purified by a
preparative TLC (DCM) and a preparative HPLC (NH3/H2O as additive) to afford 1 0 mg (20%) of the title compound as a white solid. LC-MS for C18H14FN3O2+H+ [M+H]+: calcd. 324.1 ; found: 324.1 . 1H NMR (400 MHz, DMSO-afe) δ [ppm]: 1 1 .48 (brs, 1 H), 7.92-7.86 (m, 2H), 7.75(d, J = 2.4 Hz, 1 H), 7.69 (d, J = 8.0 Hz, 1 H), 7.64 (dd, J = 8.0, 1 .6 Hz, 1 H), 7.47 (brs, 1 H), 7.24 (dd, J = 9.6, 2.0 Hz, 1 H), 6.96 (td, J = 8.4, 2.0 Hz, 1 H), 6.91 (brs, 1 H), 3.14 (t J = 7.2 Hz, 2H), 2.68 (t J = 7.2 Hz, 2H).
Compound 84: 2-(6-(6-fluoro-1 -/-indol-3-yl)-1 -/-benzo[d]imidazol-1 -yljacetamide
Figure imgf000208_0001
Following the general method as outlined in Compound 1 , starting from 2-(6-(6-fluoro-1 - (phenylsulfonyl)-l -/-indol-3-yl)-1 H-benzo[ |imidazol-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/MeOH = 10/1 , v/v). LC-MS for
C17H13FN4O+H+ [M+H]+: calcd. 309.1 ; found: 309.1 . 1 H NMR (400 MHz, DMSO-afe) δ [ppm]: 1 1 .48 (br s, 1 H), 8.14 (s, 1 H), 7.88 (dd, J = 8.8, 5.5 Hz, 1 H), 7.87 (br s, 1 H), 7.70 (d, J = 1 .6 Hz, 1 H), 7.68 (d, J = 8.4 Hz, 1 H), 7.65 (d, J = 2.4 Hz, 1 H), 7.50 (dd, J = 8.4, 1 .6 Hz, 1 H), 7.37 (br s, 1 H), 7.23 (dd, J = 9.9, 2.4 Hz, 1 H), 6.95 (m, 1 H), 4.98 (s, 2H).
Compound 85: 2-(5-(6-fluoro-1 -/-indol-3-yl)-1 -/-benzo[d]imidazol-1 -yl)acetamide
Figure imgf000208_0002
Following the general method as outlined in Compound 1 , starting from 2-(5-(6-fluoro-1 - (phenylsulfonyl)-l -/-indol-3-yl)-1 H-benzo[ |imidazol-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-afe) δ [ppm]: 1 1 .35 (br s, 1 H), 8.16 (s, 1 H), 7.87 (d, J = 1 .6 Hz, 1 H), 7.84 (dd, J = 8.8, 5.5 Hz, 1 H), 7.76 (br s, 1 H), 7.64 (d, J = 2.2 Hz, 1 H), 7.56 (dd, J = 8.4, 1 .6 Hz, 1 H), 7.50 (d, J = 8.4 Hz, 1 H), 7.37 (br s, 1 H), 7.22 (dd, J = 10.0, 2.4 Hz, 1 H), 6.95 (m, 1 H), 4.93 (s, 2H).
Compound 86: 3-(5-(6-fluoro-1 - -indol-3-yl)-1 /-/-indazol-1 -yl)-1 -morpholinopropan-1 -one
Figure imgf000209_0001
A mixture of 3-[5-(6-Fluoro-1 -/-indol-3-yl)-indazol-1 -yl]-propionic acid (Intermediate 1 1 1 , 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 EtOAc (50 ml_x3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (CH3CN/H2O = 30% - 75%, NH4HCO3) to afford 10 mg (5%) of the title compound as a white solid. LC-MS for C22H2i FN4O2+H+ [M+H]+: calcd. 393.1 ; found: 393.1 . 1H NMR (400 MHz, DMSO-afe) δ [ppm]: 1 1 .37 (br s, 1 H), 8.08 (br s, 1 H), 7.98 (br s, 1 H), 7.86 (dd, J = 8.8, 5.6 Hz, 1 H), 7.74 - 7.67 (m, 3H), 7.22 (dd, J = 9.6, 2.4 Hz, 1 H), 6.96 (td, J = 9.4, 2.4 Hz, 1 H), 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-1 - -indol-3-yl)-1 /-/-indazol-1 -yl)-1 -(4-methylpiperazin-1 yl)propan-1 -one
Figure imgf000209_0002
A mixture of 3-[5-(6-Fluoro-1 H-indol-3-yl)-indazol-1 -yl]-propionic acid (Intermediate 1 1 1 , 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 imL of DMF was stirred at room
temperature for 2 hr. Then the mixture was poured into water and extracted with EtOAc (50 ml_x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (CH3CN/H2O = 30% - 75%, NH4HCO3) to afford 76 mg (20%) of the title compound as a white solid. LC-MS for C23H24FN5O+H+ [M+H]+: calcd. 406.2; found: 406.2. 1H NMR (400 MHz, DMSO-afe) δ [ppm]: 11 .36 (s, 1 H), 8.08 (s, 1 H), 7.98 (s, 1 H), 7.88 - 7.84 (m, 1 H), 7.73 - 7.66 (m, 3H), 7.22 (dd, J = 10.0, 2.4 Hz, 1 H), 6.96 (td, J = 8.8, 2.4 Hz, 1 H), 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: A/-(2-(dimethylamino)ethyl)-3-(5-(6-fluoro-1 H-indol-3-yl)-1 H-indazol-1 - yl)propanamide
Figure imgf000210_0001
A mixture of 3-[5-(6-Fluoro-1 -/-indol-3-yl)-indazol-1 -yl]-propionic acid (Intermediate 1 1 1 , 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 imL of DMF was stirred at room temperature for 2 hr. Then the mixture was poured into water and extracted with EtOAc (50 ml_x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (CH3CN/H2O = 30% - 75%, NH4HCO3) to afford 60 mg (16%) of the title compound as a white solid. LC-MS for C22H24FN5O+H+ [M+H]+: calcd. 394.2; found: 394.2. 1H NMR (400 MHz, DMSO-afe) δ [ppm]: 11 .37 (br s, 1 H), 8.07 (s, 1 H), 7.97 (s, 1 H), 7.88 - 7.84 (m, 2H), 7.72 - 7.66 (m, 3H), 7.22 (dd, J = 10.0, 1 .6 Hz, 1 H), 6.96 (t, J = 5.2 Hz, 1 H), 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).
Figure imgf000211_0001
A mixture of 3-[5-(6-Fluoro-1 H-indol-3-yl)-indazol-1 -yl]-propionic acid (Intermediate 1 1 1 , 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 imL of DMF was stirred at room temperature for 2 hr. Then the mixture was poured into water and extracted with EtOAc (50 ml_x3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (CH3CN/H2O = 30% - 75%, NH4HCO3) to afford 53 mg (1 6%) of the title compound as a white solid. LC-MS for C2oHi9FN4O2+H+ [M+H]+: calcd. 367.2; found: 367.1 . 1 H NMR (400 MHz, DMSO-afe) δ [ppm]: 11 .37 (br s, 1 H), 8.07 (br s, 1 H), 7.98 - 7.94 (m, 2H), 7.88 - 7.85 (m, 1 H), 7.70 - 7.67 (m, 3H), 7.22 (d, J = 1 0.0 Hz, 1 H), 6.96 (t, J = 9.2 Hz, 1 H), 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-1 H-indol-3-yl)-1 H-indazol-1 -yl)-A/-(2- (methylsulfonyl)ethyl)propanamide
Figure imgf000211_0002
A mixture of 3-[5-(6-Fluoro-1 -/-indol-3-yl)-indazol-1 -yl]-propionic acid (Intermediate 1 1 1 , 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 imL of DMF was stirred at room temperature for 2 hr. Then the mixture was poured into water and extracted with EtOAc (50 ml_x3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (CH3CN/H2O = 30% - 75%, NH4HCO3) to afford 64 mg (16%) of the title compound as a white solid. LC-MS for C2i H21 FN4O3S+H+ [M+H]+: calcd. 429.1 ; found: 429.1 . 1H NMR (400 MHz, DMSO-afe) δ [ppm]: 11 .37 (br s, 1 H), 8.25 (t, J = 5.6 Hz, 1 H), 8.07 (s, 1 H), 7.98 (s, 1 H), 7.89 - 7.85 (m, 1 H), 7.70 (s, 2H), 7.67 (s, 1 H), 7.22 (dd, J = 10.0, 2.0 Hz, 1 H), 6.96 (td, J = 9.2, 2.0 Hz, 1 H), 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-1 -/-indol-3-yl)-1 /-/-indazol-1 -yl)-1 -(piperazin-1 -yl)propan-1 - one
Figure imgf000212_0001
A solution of 4-{3-[5-(6-Fluoro-1 -/-indol-3-yl)-indazol-1 -yl]-propionyl}-piperazine-1 - carboxylic acid tert-butyl ester (Intermediate 1 12, 98 mg, 0.2 mmol) in HCI/EtOAc (25%, 10 imL) was stirred at room temperature for 2 hr. Then the mixture was concentrated. The residue was purified by preparative HPLC (CH3CN/H2O = 30% - 75%, NH4HCO3) to afford 34 mg (43%) of the title compound as a white solid. LC-MS for C22H22FN5O+H+ [M+H]+: calcd. 392.2; found: 392.1 . 1 H NMR (400 MHz, DMSO-afe) δ [ppm]: 11 .37 (br s, 1 H), 8.07 (s, 1 H), 7.97 (s, 1 H), 7.88 - 7.85 (m, 1 H), 7.74 - 7.66 (m, 3H), 7.22 (dd, J = 10.0, 2.4 Hz, 1 H), 6.96 (td, J = 9.2, 2.4 Hz, 1 H), 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-1 - -indol-3-yl)indolin-2-one
Figure imgf000213_0001
A mixture of 6-(6-fluoro-1 -(phenylsulfonyl)-l H-indol-3-yl)indolin-2-one (Intermediate 1 13, 400 mg, 0.98 mmol), Mg turnings (200 mg, 8.2 mmol ) and NH4CI (106 mg, 2.0 mmol) in THF (2 mL) and MeOH (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/EtOAc = 3/1 ) to afford 26 mg (10%) of the title compound as a yellow solid. LC-MS for
Figure imgf000213_0002
[M-H]": calcd. 265.1 ; found: 265.1 . 1H NMR (400 MHz, MeOH-tf4) δ [ppm]: 7.68 (dd, J = 8.8, 5.2 Hz, 1 H), 7.33 (s, 1 H), 7.18 (s, 1 H), 7.07 (s, 2H), 7.01 (dd, J = 9.8, 2.2 Hz, 1 H), 6.77 (td, J= 9.1 , 2.4 Hz, 1 H), 3.45 (s, 2H).
Compound 93: 3-(6-(6-fluoro-1 -/-indol-3-yl)-1 -/-benzo[d]imidazol-1 -yl)propanamide
Figure imgf000213_0003
Following the general method as outlined in Compound 1 , starting from 3-(6-(6-fluoro-1 - (phenylsulfonyl)-l -/-indol-3-yl)-1 H-benzo[ |imidazol-1 -yl)propanamide (Intermediate 1 14A, 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 Ci8H15FN4O+H+ [M+H]+: calcd. 323.1 ; found: 323.2. 1H NMR (400 MHz, DMSO-afe) δ [ppm]: 1 1 .51 (br s, 1 H), 8.13 (s, 1 H), 7.96 (dd, J = 8.8, 5.6 Hz, 1 H), 7.85 (s, 1 H), 7.69 -7.67(m, 2H). 7.51 (d, J = 8.0 Hz, 1 H), 7.47 (br s, 1 H), 7.24 (dd, J = 9.8, 2.2 Hz, 1 H), 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-1 -/-indol-3-yl)-1 -/-benzo[d]imidazol-1 -yl)propanamide
Figure imgf000214_0001
Following the general method as outlined in Compound 1 , starting from 3-(5-(6-fluoro-1 - (phenylsulfonyl)-l -/-indol-3-yl)-1 -/-benzo[ |imidazol-1 -yl)propanamide (Intermediate 1 14B,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 Ci8Hi5FN4O+H+ [M+H]+: calcd. 323.1 ; found: 323.2. 1H NMR (400 MHz, DMSO-afe) δ [ppm]: 1 1 .37 (br s, 1 H), 8.16 (s, 1 H), 7.87 (s, 1 H), 7.84 (dd, J = 8.4, 5.6 Hz, 1 H), 7.68 (d, J = 8.0 Hz, 1 H), 7.64 (d, J = 2.4 Hz, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 7.42 (s, 1 H), 7.22 (dd, J = 10.0, 2.4 Hz, 1 H), 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-1 -/-indol-3-yl)benzo[d]oxazol-2-yl)piperidin-1 - yl)ethanone
Figure imgf000214_0002
To a stirred solution of 6-(6-fluoro-1 -/-indol-3-yl)-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 Na2SO4 and 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 C22H2oFN3O2+H+: [M+H]+: calcd. 378.2;found: 378.1. 1H NMR (400 MHz, DMSO-cfe) δ [ppm]: 11.48(s, 1H), 7.92 (s, 1H), 7.89 (dd, J= 5.6, 8.8 Hz, 1 H), 7.75 (d, J = 2.8 Hz, 1 H), 7.73 (d, J = 7.2 Hz, 1 H), 7.66 (dd, J= 1.6, 8.0 Hz, 1 H), 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, 1 H), 1.72 - 1.62 (m, 1 H).
Compound 96: 6-(6-fluoro-1 --indol-3-yl)-2-(1 -(methylsulfonyl)piperidin-4- yl)benzo[d]oxazole
Figure imgf000215_0001
A solution of 6-(6-fluoro-1 -/-indol-3-yl)-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 1hour. 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 C2iH2oFN3O3S+H+
[M+H]+: calcd.414.12; found: 414.10. 1H NMR (400 MHz, DMSO-afe) δ [ppm]: 11.48 (s, 1H), 7.93 (s, 1H), 7.88 (dd, J=5.6, 8.8 Hz, 1H), 7.75 (s, 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, 1 H), 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-1 --indol-3-yl)indolin-2-one
Figure imgf000216_0001
The mixture of 1-benzenesulfonyl-6-fluoro-1',3'-dihydro-1 --[3,5']biindolyl-2'- one(lntermediate 116, 300 mg, 0.74 mmol), Mg(178 mg, 7.4 mmol) and NH4CI(12 mg, 0.22 mmol) in MeOH 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/methanol=20/1) to get the title compound (60 mg, 30%) as a yellow solid. LC-MS for Ci6HnFN20-H" [M-H]": calcd.265.1 ; found:
265.1. 1H NMR (400 MHz, DMSO-afe) δ [ppm]: 11.31 (s, 1H), 10.38 (s, 1H), 7.78 (dd, J = 8.8, 5.6 Hz, 1 H), 7.56 (d, J = 2.4 Hz, 1 H), 7.50 (s, 1 H), 7.46 (d, J = 8.0 Hz, 1 H), 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-1 --indol-3-yl)benzo[d]oxazol-2-amine
Figure imgf000216_0002
The mixture of 6-(1 -Benzenesulfonyl-6-fluoro-1 --indol-3-yl)-benzooxazol-2-ylamine
(Intermediate 118, 300 mg, 0.74 mmol), Mg (178 mg, 7.4 mmol) and NH4CI (12 mg, 0.22 mmol) in MeOH 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/methanol=20/1) to get the title compound (40mg, 25%) as a yellow solid. LC-MS for C15H10FN3O+H+ [M+H]+: calcd.268.1 ; found: 268.0. 1H NMR (400 MHz, DMSO) δ 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: A/-((6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)-2- methoxyethanesulfonamide
Figure imgf000217_0001
To a stirred solution of (6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)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 Ci9H 8FN3O4S+H+ [M+H]+ : Calcd. 404.1 ; found: 403.8. 1H NMR (400 MHz, MeOD ) δ [ppm]: 7.77 - 7.71 (m, 2H), 7.63 - 7.58 (m, 2H), 7.43 (s, 1 H), 7.04 (dd, J= 10.0, 2.4 Hz, 1 H), 6.82 (td, J = 9.2, 2.4 Hz, 1 H), 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)-A/-((6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2- yl)methyl)ethanesulfonamide
Figure imgf000217_0002
To a stirred solution of A/-((6-(6-fluoro-1 -/-indol-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 imL) and extracted with EtOAc (60 ml_x3). The combined organic layer was washed with water (60 ml_x3), 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 C2oH2i FN4O3S+H+ [M+H]+: calcd.417.1 ; found: 417.5. 1H NMR (400 MHz, CDCI3 ) δ [ppm]: 8.33 (s, 1 H), 7.82 (dd, J = 8.8, 5.2 Hz, 1 H), 7.76 (d, J = 0.9 Hz, 1 H), 7.74 (d, J = 8.3 Hz, 1 H), 7.62 (dd, J = 8.2, 1 .4 Hz, 1 H), 7.38 (d, J = 2.3 Hz, 1 H), 7.14 (dd, J = 9.4, 2.2 Hz, 1 H), 6.99 (td, J = 9.2, 2.3 Hz, 1 H), 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-1 - -indol-3-yl)-2-(2-(methylsulfonyl)ethyl)benzo[d]oxazole
Figure imgf000218_0001
A mixture of 6-fluoro-3-[2-(2-methanesulfonyl-ethyl)-benzooxazol-6-yl]-indole-1 - carboxylic acid tert-butyl ester (Intermediate 123, 390 mg, 0.852 mmol) in HCI/EtOAc (5 imL, 2M) was stirred at room temperature for 3 hours. The mixture was diluted with EtOAc (50 ml_), washed with aq.NaHCO3 (20 ml_) and brine (20 ml_x2), 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 Ci8H15FN2O3S+H+ [M+H]+: calcd. 359.1 ; found: 359.1 . 1 H NMR (400 MHz, DMSO-afe) δ [ppm]: 1 1 .49 (br s, 1 H), 7.93 (d, J = 1 .2 Hz, 1 H), 7.88 (dd, J = 8.8, 1 .6 Hz, 1 H), 7.76 (d, J = 2.4 Hz, 1 H), 7.73 (d, J = 8.0 Hz, 1 H), 7.68 (dd, J = 8.4, 1 .6 Hz, 1 H), 7.24 (dd, J = 9.6, 2.4 Hz, 1 H), 6.97 (td, J = 9.6, 2.4 Hz, 1 H), 3.73 (t, J = 7.6 Hz, 2H), 3.44 (t, J = 7.8 Hz, 2H), 3.1 1 (s, 3H).
Compound 102: 1 -((6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)urea
Figure imgf000219_0001
To a solution of (6-(6-fluoro-1 -/-indol-3-yl)benzo[ |oxazol-2-yl)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 Ci7H13FN4O2+H+ [M+H]+: calcd. 325.1 ; found: 325.1 . 1H NMR (400 MHz, DMSO-afe) δ [ppm]: 1 1 .48 (br s, 1 H), 7.92 (s, 1 H), 7.89 (dd, J = 8.8, 5.5 Hz, 1 H), 7.76 (d, J = 1 .8 Hz, 1 H), 7.72 (d, J = 8.4 Hz, 1 H), 7.67 (dd, J = 8.4, 1 .8 Hz, 1 H), 7.24 (dd, J = 9.9, 2.2 Hz, 1 H), 6.97 (t, J = 2.0 Hz, 1 H), 6.69 (t, J = 6.0 Hz, 1 H), 5.77 (br s, 2H), 4.50 (d, J = 6.0 Hz, 2H).
Compound 103: 1 -carbamoyl-1 -((6-(6-fluoro-1 -/-indol-3-yl)benzo[d]oxazol-2- yl)methyl)urea
Figure imgf000219_0002
The title compound (5 mg, 3%) was obtained as a by-product during the synthesis described for Compound 102. LC-MS for C18H14FN5O3+H+ [M+H]+: calcd. 368.1 ; found: 368.1 . 1 H NMR (400 MHz, DMSO-afe) δ [ppm]: 1 1 .49 (br s, 1 H), 8.92 (s, 1 H), 8.30 (br t, 1 H), 7.95 (s, 1 H), 7.90 (dd, J = 8.8, 5.5 Hz, 1 H), 7.76 (d, J = 2.2 Hz, 1 H), 7.74 (d, J = 8.4 Hz, 1 H), 7.68 (d, J = 8.4 Hz, 1 H), 7.24 (dd, J = 10.0, 2.2 Hz, 1 H), 6.96 (m, 1 H), 6.7d (br s, 2H), 4.66 (d, J = 5.7 Hz, 2H).
Compound 104: 5-(1 H-indol-3-yl)-1 H-indazole
Figure imgf000220_0001
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
C15H11 N3+H+ [M+H]+: calcd. 234.1 ; found: 234.1 . 1H NMR (400 MHz, DMSO-afe) δ
[ppm]: 13.01 (br s, 1 H), 1 1 .27 (br s, 1 H), 8.09 (s, 1 H), 8.01 (s, 1 H), 7.90 (d, J = 7.8 Hz, 1 H), 7.69 (d, J = 8.6 Hz, 1 H), 7.65 (d, J = 2.3 Hz, 1 H), 7.59 (d, J = 8.6 Hz, 1 H), 7.45 (d, J = 8.0 Hz, 1 H), 7.18-7.08 (m, 2H).
Compound 105: 6-(6-fluoro-1 H-indol-3-yl)-2-(2-(4-methylpiperazin-1 - yl)ethyl)benzo[d]oxazole
Figure imgf000220_0002
A solution of 2-(2-chloroethyl)-6-(6-fluoro-1 -(phenylsulfonyl)-1 H-indol-3- yl)benzo[d]oxazole (Intermediate 125, 100 mg, 0.22 mmol), sodium hydroxide (44 mg, 1 .10 mmol) and A/-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 EtOAc (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. 1 H NMR (400 MHz, CDCI3) δ [ppm]: 8.28 (s, 1 H), 7.86 - 7.82 (m 1 H), 7.76 - 7.67 (m, 2H), 7.58 (d, J= 8.1 Hz, 1 H), 7.37 (d, J = 1 .9 Hz, 1 H), 7.13 (dd, J = 9.5, 2.1 Hz, 1 H), 7.01 - 6.96 (m, 1 H), 3.19 - 3.15 (m, 2H), 3.01 - 2.97 (m, 2H), 2.66 - 2.47 (m, 8H), 2.32 (s, 3H).
Compound 106: A/-((6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)-2- hydroxyethanesulfonamide
Figure imgf000221_0001
To a solution of A/-((6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)-2- 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 with EtOAc (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 Ci8H16FN3O4S+H+ [M+H]+ : calcd. 390.1 ; found: 390.5. 1 H NMR (400 MHz, CD3OH ) δ [ppm]: 7.77 (s, 1 H), 7.74 (dd, J = 8.8, 5.3 Hz, 1 H), 7.640 - 7.58 (m, 2H), 7.43 (s, 1 H), 7.04 (dd, J = 9.7, 2.3 Hz, 1 H), 6.81 (td, J= 9.2, 2.3 Hz, 1 H), 4.52 (s, 2H), 3.88 (t, J = 6.2 Hz, 2H), 3.29 (t, J = 6.2 Hz, 2H).
Compound 107: A/-((6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)-2- morpholinoethanesulfonamide
Figure imgf000222_0001
To a solution of A/-((6-(6-fluoro-1 -/-indol-3-yl)benzo[d]oxazol-2- yl)methyl)ethenesulfonamide (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 EtOAc (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 C22H23FN4O4S+H+ [M+H]+: calcd. 459.1 ; found: 458. 8. 1H NMR (400 MHz, CD3OH ) δ [ppm]: 7.90 (s, 1 H), 7.86 (dd, J = 8.7, 5.4 Hz, 1 H), 7.78 - 7.71 (m, 2H), 7.56 (s, 1 H), 7.17 (dd, J = 9.7, 2.3 Hz, 1 H), 6.94 (td, J = 9.1 , 2.2 Hz, 1 H), 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-(1 H-indol-3-yl)-1 H-indazole
Figure imgf000222_0002
To a solution of 6-(6-fluoro-1 -(phenylsulfonyl)-1 - -indol-3-yl)-1 H-indazole (Intermediate 4, 148 mg, 0.4 mmol) in MeOH (20 mL) was added a solution of NaOH(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/EtOAc = 1 /1 ) to afford 32 mg (36%) of the title compound as a yellow solid. LC-MS for Ci5HnN3+H+ [M + H]+ : calcd. 234.1 ; found: 234.0. 1H NMR (400 MHz, DMSO- cfe) δ [ppm]: 12.93 (s, 1 H), 11.40 (s, 1 H), 8.04 (s, 1 H), 7.91 (d, J = 7.6 Hz, 1 H), 7.80 - 7.76 (m, 3H), 7.47 (d, J= 8.4 Hz, 2H), 7.20 - 7.10 (m, 2H). Compound 109: 6-(1 -/-indol-3-yl)benzo[d]oxazole
Figure imgf000223_0001
Following the general method as outlined in Compound 1, starting from 6-(1- Benzenesulfonyl-1 --indol-3-yl)-benzooxazole (Intermediate 127, 330 mg, 0.88 mmol), 6-(1 -/-lndol-3-yl)-benzooxazole (100 mg, 49%) was obtained as a white solid. LC-MS for Ci5H10N2O+H+ [M+H]+: calcd.235.1 ; found: 235.5. 1H NMR (300 MHz, DMSO-d6) δ [ppm]: 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, 1 H), 7.79 (d, J= 2.6 Hz, 1 H), 7.75 (dd, J= 8.3, 1.5 Hz, 1 H), 7.48-7.45 (m, 1 H), 7.20 - 7.09 (m, 2H).
Compound 110: 6-(6-fluoro-1 -/-indol-3-yl)-2-(2-(piperazin-1 -yl)ethyl)benzo[d]oxazole
Figure imgf000223_0002
A solution of 6-(6-fluoro-1-(phenylsulfonyl)-1 --indol-3-yl)-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 EtOAc. 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 C2iH2iFN4O+H+ [M+H]+: calcd.365.1; found: 365.1. 1H NMR (400 MHz, DMSO-ak) δ [ppm]: 11.46 (br s, 1H), 7.90-7.86 (m, 2H), 7.74 (d, J= 2.4 Hz, 1 H), 7.70 (d, J= 8.2 Hz, 1 H), 7.64 (dd, J= 8.3, 1.5 Hz, 1 H), 7.23 (dd, J= 9.9, 2.4 Hz, 1 H), 6.96 (td, J= 9.5, 2.4 Hz, 1 H), 3.11 (t, J = 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-1 --indol-3-yl)benzo[d]oxazole
Figure imgf000224_0001
Following the general method as outlined in Compound 1, starting from 5-(6-chloro-1- (phenylsulfonyl)-l -/-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
C15H9CIN2O+H+ [M+H]+: calcd.269.0; found: 269.3. 1H NMR (400 MHz, DMSO-tf6) δ [ppm]: 11.52 (s, 1 H), 8.75 (s, 1 H), 8.02 (d, J= 1.3 Hz, 1 H), 7.88 (d, J= 8.6 Hz, 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 7.79 (d, J = 2.6 Hz, 1 H), 7.74 (dd, J = 8.6, 1.7 Hz, 1 H), 7.50 (d, J = 1.8 Hz, 1 H), 7.12 (dd, J = 8.6, 2.0 Hz, 1 H).
Compound 112: 6-(6-fluoro-1 --indol-3-yl)benzo[d]oxazole-2-thiol
Figure imgf000224_0002
Following the general method as outlined in Compound 1, starting from 6-(1- Benzenesulfonyl-6-fluoro-1 --indol-3-yl)-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 C15H9FN2OS-H" [M-H]": calcd.283.0; found: 283.0. 1H NMR (400 MHz, DMSO-d6) δ [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, 1 H), 6.97 (td, J= 9.6, 2.4 Hz, 1 H). Compound 1 13: 6-(6-fluoro-1 -/-indol-3-yl)-2-(piperidin-4-ylmethyl)benzo[d]oxazole
Figure imgf000225_0001
Following the general method as outlined in Compound 1 , starting from 6-(6-fluoro-1 - (phenylsulfonyl)-l - -indol-3-yl)-2-(piperidin-4-ylmethyl)benzo[d]oxazole (Intermediate 132, 290 mg, 0.59 mmol), the title compound (15 mg, 7%) was obtained as a white solid. LC-MS for C2iH2oFN3O+H+ [M+H]+: calcd. 350.2; found: 350.1 . 1 H NMR (400 MHz, MeOD) δ [ppm]: 7.73 -7.69 (m, 2H), 7.54 (d, J = 0.8 Hz, 2H), 7.40 (s, 1 H), 7.03 (dd, J = 10.0, 2.0 Hz, 1 H), 6.80 (td, J = 9.2, 2.0 Hz, 1 H), 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, 1 H), 1 .70 (d, J = 12.8 Hz, 2H), 1 .31 - 1 .20 (m,2H).
Compound 1 14: A/-((6-(1 - -indol-3-yl)benzo[d]oxazol-2-yl)methyl)methanesulfonamide
O
Figure imgf000225_0002
To a stirred solution of te/t-butyl methylsulfonyl((6-(1 -(phenylsulfonyl)-1 H-indol-3- yl)benzo[d]oxazol-2-yl)methyl)carbamate (Intermediate 133, 1 .25 g, 2.15 mmol) in
MeOH (30 mL) was added NaOH (420 mg, 10.75 mmol). The mixture was stirred at 85 °C for 2 hours. The reaction was neutralized with HCI (12 M). The mixture was diluted with water (60 mL) and extracted with EtOAc (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 Ci7H15N3O3S+H+ [M+H]+: deed. 342.1 ; found: 341 .9. 1 H NMR (400 MHz, DMSO-afe) δ [ppm]: 11 .44 (s, 1 H), 8.00 (s, 1 H), 7.98 (d, J = 0.9 Hz, 1 H), 7.92 (d, J = 7.8 Hz, 1 H), 7.78 (dd, J = 7.0, 5.5 Hz, 2H), 7.72 (dd, J = 8.3, 1 .5 Hz, 1 H), 7.47 (d, J = 8.0 Hz, 1 H), 7.20 - 7.15 (m, 1 H), 7.14 - 7.09 (m, 1 H), 4.54 (s, 2H), 3.04 (s, 3H).
Compound 1 15: (S)-A/-((6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)-1 - methylpyrrolidine-2-carboxamide
Figure imgf000226_0001
To a stirred solution of (2S)-1 -methylpyrrolidine-2-carboxylic acid (258 mg, 2.0 mmol) in THF/DMF(20 mL/2 imL) at room temperature was added HATU (760 mg, 2.0 mmol), DIPEA (387 mg, 3.0 mmol), and c-[5-(6-fluoro-1 H-indol-3-yl)-benzooxazol-2-yl]- methylamine hydrochloride (Compound 81 , 317 mg, 1 .0 mmol). The mixture was stirred at room temperature for 2 hours, concentrated ,deluted with EtOAC (100 imL) and washed with water (10ml_x4). 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 C22H2iFN4O2+H+ [M+H]+: calcd. 393.2; found: 393.1 . 1H NMR (400 MHz, DMSO-afe) δ [ppm]: 1 1 .48 (br s, 1 H), 8.49 (t, J= 5.6 Hz, 1 H), 7.91 - 7.87 (m, 2H), 7.76 (d, J = 2.8 Hz, 1 H), 7.72 (d, J = 8.4 Hz, 1 H)),7.66 (dd,J = 8.0, 1 .2 Hz, 1 H), 7.24 (dd, J = 10, 2.4 Hz, 1 H), 6.98 (m, 1 H), 4.62 - 4.57 (m, 2H), 3.08 - 3.07 (m, 1 H), 2.83 - 2.80 (m, 1 H), 2.36 (s, 3H), 2.30 - 2.28 (m, 1 H), 2.1 1 - 2.07 (m, 1 H), 1 .78 - 1 .74 (m, 3H).
Compound 1 16: 6-(6-fluoro-1 - -indol-3-yl)-2-methoxybenzo[d]oxazole
Figure imgf000226_0002
Following the general method as outlined in Compound 1, starting from 6-(1- benzenesulfonyl-6-fluoro-1 --indol-3-yl)-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 C16H11FN2O2+H+ [M+H]+: calcd.283.1 ; found: 283.0. 1H NMR (400 MHz, DMSO-afe) δ [ppm]: 11.43 (brs, 1 H), 7.86 (dd, J = 8.8, 5.6 Hz, 1 H), 7.79 (s, 1 H), 7.69 (s, 1 H), 7.59 (dd, J =8.0, 1.6 Hz, 1 H), 7.54 (d, J= 8.0 Hz, 1 H), 7.22 (dd, J= 9.6, 2.0 Hz, 1 H), 6.98 - 6.93 (m, 1 H), 4.19 (s, 3H).
Compound 117: Amino {[6-(6-fluoroindol-3-yl)benzoxazol-2-yl]methyl}sulfonamide
Figure imgf000227_0001
To the solution of terf-Butoxycarbonylamino {[6-(6-fluoroindol-3-yl) benzoxazol-2-yl] methyljsulfonamide (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/Methanol=10/1 ) to give the title compound (50 mg, 34%) as a white solid. LC-MS for Ci6H13FN4O3S+H+ [M+H]+: calcd.361.1 ; found: 361.0.1H NMR (400 MHz, DMSO) δ 11.49 (brs, 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=6.4Hz, 2H).
Compound 118: 5-(1 -/-indol-3-yl)benzo[d]oxazole
Figure imgf000227_0002
Following the general method as outlined in Compound 1 , starting from 5-(1 - (phenylsulfonyl)-l -/-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
C15H10N2O+H+ [M+H]+: calcd. 235.1 ; found: 235.1 . 1 H NMR (400 MHz, CDCI3) δ [ppm]: 8.30 (br s, 1 H), 8.13 (s, 1 H), 8.06 (d, J = 1 .1 Hz, 1 H), 7.95 (d, J = 7.9 Hz, 1 H), 7.71 (dd, J = 8.5, 1 .6 Hz, 1 H), 7.65 (dd, J = 8.5, 0.5 Hz, 1 H), 7.47 - 7.45 (m, 1 H), 7.41 (d, J = 2.8 Hz, 1 H), 7.30-7.20 (m, 2H).
Compound 1 19: 6-(6-fluoro-1 - -indol-3-yl)-2-((1 -(methylsulfonyl)piperidin-4- yl)methyl)benzo[d]oxazole
Figure imgf000228_0001
Following the general method as outlined in Compound 1 , starting from 6-(6-fluoro-1 - (phenylsulfonyl)-l - -indol-3-yl)-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 C22H22FN3O3S+H+ [M+H]+: calcd. 428.1 ; found: 428.1 . 1 H NMR (400 MHz, DMSO-cfe) δ [ppm]: 11 .47(s, 1 H), 7.90 - 7.86 (m, 2H),7.75 - 7.70 (m, 2H), 7.66 - 7.64 (m, 1 H), 7.23 (dd, J = 10, 2.4 Hz, 1 H), 6.96 (td, J = 9.6, 2.4 Hz, 1 H), 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, 1 H), 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-1 H-indol-3-yl)-2-(2-(4-(methylsulfonyl)piperazin-1 - yl)ethyl)benzo[d]oxazole
Figure imgf000229_0001
A solution of 2-(2-chloroethyl)-6-(6-fluoro-1 -(phenylsulfonyl)-1 H-indol-3- yl)benzo[d]oxazole (Intermediate 125, 1 10 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 EtOAc (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 C22H23 N4O3S+H+ [M+H]+: calcd. 443.2; found: 443.2. 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1 1 .47 (s, 1 H), 7.90-7.86 (m, 2H), 7.75 (d, J = 2.5 Hz, 1 H), 7.70 (d, J = 8.3 Hz, 1 H), 7.65 (dd, J = 8.2, 1 .5 Hz, 1 H), 7.23 (dd, J = 10.1 , 2.4 Hz, 1 H), 6.97 (td, J = 9.6, 2.6 Hz, 1 H), 3.15 (t, J = 7.2 Hz, 2H), 3.1 1 - 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-1 - -indol-3-yl)benzo[d]oxazole
Figure imgf000229_0002
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
C15H9CIN2O+H+ [M+H]+: calcd. 269.0; found: 268.9. 1 H NMR (400 MHz, DMSO-afe) δ [ppm]: 1 1 .60 (br s, 1 H), 8.76 (s, 1 H), 8.01 (d, J = 1 .8 Hz, 1 H), 7.85 - 7.81 (m, 3H), 7.73 (dd, J = 8.4, 1 .8 Hz, 1 H), 7.49 (d, J = 8.6 Hz, 1 H), 7.18 (dd, J = 8.6, 2.0 Hz, 1 H).
Figure imgf000230_0001
To a solution of A/-((6-(6-fluoro-1 -/-indol-3-yl)benzo[d]oxazol-2- yl)methyl)ethenesulfonamide (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 EtOAc (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 C23H26FN5O3S+H+ [M+H]+: calcd.472.2; found: 472.8. 1H NMR (400 MHz, DMSO-de) δ [ppm]: 11 .50 (s, 1 H), 8.02 (t, J = 6.0 Hz, 1 H), 7.96 (d, J = 1 .0 Hz, 1 H), 7.89 (dd, J = 8.8, 5.4 Hz, 1 H), 7.78 - 7.75 (m, 2H), 7.70 (dd, J = 8.3, 1 .5 Hz, 1 H), 7.24 (dd, J = 9.9, 2.3 Hz, 1 H), 6.97 (td, J = 9.6, 2.4 Hz, 1 H), 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: A/-((6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)-2-(piperazin- 1 -yl)ethanesulfonamide NH
Figure imgf000231_0001
To a solution of piperazine (752 mg, 8.73 mmol) in MeCN /THF(5 mL / 30mL) was added A/-((6-(6-fluoro-1 - -indol-3-yl)benzo[d]oxazol-2-yl)methyl)ethenesulfonamide
(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 C22H24FN5O3S+H+ [M+H]+ : calcd. 458.2; found: 457.8. 1 H NMR (400 MHz, DMSO- ofe) δ [ppm]: 11 .50 (s, 1 H), 7.96 (d, J = 1 .0 Hz, 1 H), 7.89 (dd, J = 8.8, 5.4 Hz, 1 H), 7.80 - 7.74 (m, 2H), 7.70 (dd, J = 8.3, 1 .5 Hz, 1 H), 7.24 (dd, J = 9.9, 2.3 Hz, 1 H), 6.97 (td, J = 9.5, 2.4 Hz, 1 H), 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: A/-((6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)-2-(pyrrolidin- 1 -yl)ethanesulfonamide
Figure imgf000231_0002
To a solution of pyrrolidine (752 mg, 8.73 mmol) in MeCN /THF(5 mL/30 mL) was added A/-((6-(6-fluoro-1 - -indol-3-yl)benzo[d]oxazol-2-yl)methyl)ethenesulfonamide
(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
C22H23FN4O3S+H+ [M+H]+: calcd. 443.2; found: 443.6. 1 H NMR (400 MHz, DMSO-afe) δ [ppm]: 11 .50 (s, 1 H), 8.03 (s, 1 H), 7.95 (d, J = 1 .0 Hz, 1 H), 7.89 (dd, J = 8.8, 5.4 Hz, 1 H), 7.79 - 7.74 (m, 2H), 7.70 (dd, J = 8.3, 1 .4 Hz, 1 H), 7.24 (dd, J = 9.9, 2.4 Hz, 1 H), 6.97 (td, J = 9.4, 2.4 Hz, 1 H), 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-1 H-indol-3-yl)-2-((1 -methylpiperidin-4- yl)methyl)benzo[d]oxazole
Figure imgf000232_0001
Following the general method as outlined in Compound 1 , starting from 6-(6-fluoro-1 - (phenylsulfonyl)-l - -indol-3-yl)-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 . 1 H NMR (400 MHz, DMSO-afe) δ [ppm]: 11 .47(s, 1 H), 7.89 - 7.86(m, 2H), 7.74(d,
J=2.4Hz,1 H), 7.70 (d, J=8.4Hz, 1 H), 7.64 (dd, J=1 .6Hz, J=8.8Hz, 1 H), 7.23(dd, J = 2.4Hz, J=9.6Hz, 1 H), 6.96 (td, J = 2.4Hz, J=9.6Hz, 1 H), 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: A/-((6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)-2-(4- (methylsulfonamido)piperidin-1 -yl)ethanesulfonamide
Figure imgf000233_0001
To a stirred solution of A/-(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-1 -/-indol-3-yl)benzo[d]oxazol-2-yl)methyl)ethenesulfonamide (Intermediate 119, 160 mg, 0.43 mmol). The mixture was stirred at room temperature for 3 hours before it was quenched with aqueous NH4CI (30 mL).The mixture was extracted with EA (60 imLx 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 C24H28FN5O5S2+H+ [M+H]+ : calcd. 550.2; found: 550.7. 1H NMR (400 MHz, DMSO-afe) δ [ppm]: 11 .51 (br s, 1 H), 8.06 - 8.01 (m, 1 H), 7.96 (d, J = 1 .0 Hz, 1 H), 7.89 (dd, J = 8.8, 5.4 Hz, 1 H), 7.80 - 7.75 (m, 2H), 7.70 (dd, J = 8.3, 1 .5 Hz, 1 H), 7.24 (dd, J = 9.9, 2.4 Hz, 1 H), 7.03 - 6.95 (m, 2H), 4.54 (d, J = 5.6 Hz, 2H), 3.30 (s, 2H), 3.08 (br s, 1 H), 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: A/-((6-(6-chloro-1 H-indol-3-yl)benzo[d]oxazol-2- yl)methyl)methanesulfonamide
Figure imgf000233_0002
Following the general method as outlined for Compound 74, the title compound was obtained as a yellow solid after purification by preparative TLC (DCM/MeOH = 10/1 , v/v). LC-MS for Ci7H14CIN3O3S+H+ [M+H]+: calcd. 376.0; found: 376.0. 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1 1 .58 (br s, 1 H), 7.98 - 7.95 (m, 2H), 7.92 (d, J= 8.6 Hz, 1 H), 7.83 (d, J = 2.5 Hz, 1 H), 7.77 (d, J = 8.4 Hz, 1 H), 7.70 (dd, J = 8.3, 1 .6 Hz, 1 H), 7.51 (d, J = 1 .9 Hz, 1 H), 7.12 (dd, J = 8.6, 2.0 Hz, 1 H), 4.54 (s, 2H), 3.03 (s, 3H).
Figure imgf000234_0001
Following the general method as outlined for Compound 74, the title compound was obtained as a yellow solid after purification by preparative TLC (DCM/MeOH = 10/1 , v/v). LC-MS for Ci7H14FN3O3S+H+ [M+H]+: calcd. 360.1 ; found: 360.1 . 1H NMR (400 MHz, DMSO-afe) δ [ppm]: 1 1 .59 (br s, 1 H), 8.02 (br t, J = 6.1 Hz, 1 H), 7.98 (d, J = 1 .6 Hz, 1 H), 7.87 (d, J = 2.2 Hz, 1 H), 7.76 (d, J = 8.4 Hz, 1 H), 7.70 (dd, J = 8.4, 1 .6 Hz, 1 H), 7.64 (dd, J = 10.6, 2.4 Hz, 1 H), 7.47 (dd, J = 8.8, 4.8 Hz, 1 H), 7.03 (ddd, J = 9.5, 8.8, 2.4 Hz, 1 H), 4.54 (d, J = 6.0 Hz, 2H), 3.04 (s, 3H).
Compound 129: 5-((6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)imidazolidine-
2,4-dione
Figure imgf000234_0002
To a solution of tert-butyl 3-(2-((2,5-dioxoimidazolidin-4-yl)methyl)benzo[ /|oxazol-6-yl)- 6-fluoro-1 - -indole-1 -carboxylate (Intermediate 141 , 50 mg, 0.1 1 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 EtOAc, washed with saturated aqueous NaHCO3, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by preparative TLC (DCM/MeOH = 5/1 , v/v) to afford 9 mg (23%) of the title compound as a yellow solid. LC-MS for Ci9Hi3FN4O3-H" [M-H]": calcd. 363.1 ; found: 363.1 . 1H NMR (400 MHz, MeOH-tf4) δ [ppm]: 7.74-7.71 (m, 2H), 7.60-
7.58 (m, 2H), 7.42 (s, 1 H), 7.09 (dd, J = 9.6, 2.0 Hz, 1 H), 6.81 (td, J = 8.8, 2.4 Hz, 1 H),
4.59 (dd, J = 7.2, 4.8 Hz, 1 H), 3.43 (dd, J = 16.4, 4.8 Hz, 1 H), 3.27-3.25 (m, 1 H).
Compound 130: 5-(6-fluoro-1 - -indol-3-yl)benzo[d]isothiazol-3(2 -/)-one 1 ,1 -dioxide
Figure imgf000235_0001
Step 1 : terf-butyl 3-(1 ,1 -dioxido-3-oxo-2,3-dihydrobenzo[ |isothiazol-5-yl)-6-fluoro-1 H- indole-1 -carboxylate
Figure imgf000235_0002
To a mixture of 5-bromobenzo[ /|isothiazol-3(2 -/)-one 1 ,1 -dioxide (310 mg, 1 .18 mmol, prepared as described in Tetrahedron 2006, 62, 7902.), terf-butyl 6-fluoro-3-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 -/-indole-1 -carboxylate (Intermediate 2, 514 mg, 1 .42 mmol) and K2CO3 (489 mg, 3.54 mmol) in dioxane (20 imL) and water (2 imL) was added Pd(PPh3)4 (69 mg, 0.06 mmol). The mixture was stirred at 1 10 °C for 2 hours before it was concentrated. The residue was diluted with EtOAc, washed with saturated aqueous NaHCO3, dried over anhydrous Na2SO4 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 terf-butyl 3-(1 ,1 -dioxido-3-oxo-2,3-dihydrobenzo[ |isothiazol-5-yl)-6-fluoro- 1 H-indole-1 -carboxylate (Step 1 , 300 mg, 0.72 mmol) in HCI/EtOAc (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 C15H9FN2O3S-H" [M-H]": calcd. 315.0; found: 315.0. 1H NMR (400 MHz, DMSO-cfe) δ [ppm]: 1 1.80 (br s, 1 H), 8.26 (dd, J = 8.4, 1.6 Hz, 1 H), 8.17 (d, J = 1 .6 Hz, 1 H), 8.12 (d, J = 8.4 Hz, 1 H), 8.10 (d, J= 2.4 Hz, 1 H), 7.93 (dd, J = 8.8, 5.3 Hz, 1 H), 7.28 (dd, J = 9.8, 2.4 Hz, 1 H), 7.05 (m, 1 H).
Compound 131 : 2-(6-(5-fluoro-1 H-indol-3-yl)-2-oxobenzo[d]oxazol-3(2/-/)-yl)acetamide
Figure imgf000236_0001
To a solution of 2-(6-(5-fluoro-1 -(phenylsulfonyl)-l -/-indol-3-yl)-2-oxobenzo[d]oxazol- 3(2H)-yl)acetamide (Intermediate 143, 281 mg, 0.6 mmol) in MeOH (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 EtOAc (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 100 mg (43%) of the title compound as a white solid. LC-MS for
Figure imgf000236_0002
[M-H]" : calcd. 324.1 ; found: 324.0. 1H NMR (400 MHz, DMSO-afe) δ [ppm]: 11 .48 (s, 1 H), 11 .00 (s, 1 H), 9.78 (s, 1 H), 7.74 (d, J = 2.6 Hz, 1 H), 7.54 (dd, J = 10.4, 2.4 Hz, 1 H), 7.45 (dd, J = 8.9, 4.7 Hz, 1 H), 7.30 (d, J = 8.1 Hz, 1 H), 7.24 (d, J = 1 .9 Hz, 1 H), 7.12 (dd, J = 8.1 , 1 .9 Hz, 1 H), 7.01 (td, J = 9.1 , 2.4 Hz, 1 H), 4.28 (s, 2H). Compound 132: 5-(6-fluoro-1 H-indol-3-yl)isoindoline-1 ,3-dione
Figure imgf000237_0001
A mixture of 4-(6-Fluoro-1 - -indol-3-yl)-phthalic acid (Intermediate 145, 1 36 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 1 50 °C in an oil bath for 3 hrs. The mixture was cooled down and poured into a 1 0% v/v aqueous HCI solution and stirred for 1 0 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 Ci6H9FN2O2-H" [M-H]": calcd. 279.1 ; found: 279.0. 1 H NMR (400 MHz, DMSO-afe) 6[ppm]: 1 1 .75 (br s, 1 H), 1 1 .25 (br s, 1 H), 8.14 (d, J = 8.0 Hz, 1 H), 8.06 (s, 1 H), 8.05 (s, 1 H),7.92 (dd, J = 8.8, 5.2 Hz, 1 H), 7.85 (d, J= 7.6 Hz, 1 H), 7.27 (dd, J= 9.8, 2.8 Hz, 1 H), 7.03 (td, J = 9.3, 2.4 Hz, 1 H).
Compound 133: 6-fluoro-3-(isoindolin-5-yl)-1 /-/-indole
Figure imgf000237_0002
A solution of terf-butyl 3-(2-(terf-butoxycarbonyl)isoindolin-5-yl)-6-fluoro-1 H-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 (1 00 mL) and extracted with EtOAc (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 (1 5%) of the title compound as a white solid. LC-MS for C16H13FN2+H]+ [M+H]+ : calcd. 253.1 ; found: 253.1 . 1 H NMR (400 MHz, MeOD) δ [ppm]: 7.81 - 7.78 (m, 1 H), 7.58 (s, 1 H), 7.54 (d, J = 7.6 Hz, 1 H), 7.45 (s, 1 H), 7.35 (d, J = 7.8 Hz, 1 H), 7.13 (dd, J = 9.9, 2.4 Hz, 1 H), 6.89 (td, J =9.6, 2.4 Hz, 1 H), 4.27 (d, J = 10.0 Hz, 4H).
Compound 134: 6-(6-fluoro-1 H-indol-3-yl)benzo[d]isothiazol-3(2/-/)-one 1 ,1 -dioxide
Figure imgf000238_0001
To a stirred mixture of 3-(1 ,1 -dioxo-2,3-dihydro-1 Η-λ l6-benzo[d]isothiazol-6-yl)-6-fluoro- indole-1 -carboxylic acid terf-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 dsHuFNsOsS-H" [M-H]": calcd. 301 .1 ; found: 301 .0. 1 H NMR (400 MHz, DMSO-de) δ [ppm]: 11 .60 (s, 1 H), 8.03-8.00 (m, 2H), 7.92 (d, J = 2.4 Hz, 1 H), 7.88 - 7.86 (m, 2H), 7.86 (s, 1 H), 7.62 (d, J = 8.0 Hz, 1 H), 7.26 (dd, J = 9.6, 2.0 Hz, 1 H), 7.03 - 6.99 (m, 1 H), 4.44 (s, 2H).
Compound 135: 5-(6-fluoro-1 H-indol-3-yl)-2,3-dihydrobenzo[d]isothiazole 1 ,1 -dioxide
Figure imgf000238_0002
Stepl : terf-butyl 3-(1 ,1 -dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)-6-fluoro-1 /-/-indole-1 - carboxylate
Figure imgf000239_0001
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-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indole- 1 - 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 (EtOAc/Petroleum Ether = 1 /3), 240 mg (74%) of the title compound as a white solid.
Step2: A solution of terf-butyl 3-(1 ,1 -dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)-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 (EtOAc/Petroleum Ether = 1/3), yielding 32 mg (17%) of the final product as a yellow solid. LC-MS for C15H11 FN2O2S-H" [M-H]": calcd. 301 .0; found: 301 .0. 1H NMR (400 MHz, DMSO-cfe) δ [ppm]: 1 1 .64 (br s, 1 H), 7.95 (dd, J = 8.4, 5.6 Hz, 1 H), 7.90 - 7.80 (m, 4H), 7.74 (s, 1 H), 7.27-7.25 (m, 1 H), 7.03 - 6.98 (m, 1 H), 4.45 (d, J = 4.3 Hz, 2H).
Compound 136: 6-(6-fluoro-1 H-indol-3-yl)-3-(piperidin-4-yl)benzo[d]oxazol-2(3H)-one
Figure imgf000239_0002
To a stirred solution of 3-[3-(1 -ie/ -butoxycarbonyl-piperidin-4-yl)-2-oxo-2,3-dihydro- benzooxazol-6-yl]-6-fluoro-indole-1 -carboxylic acid te/t-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 EtOAc (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 C2oHi8FN3O2+H+ [M+H]+: calcd. 352.1 ;
found: 352.1 . 1H NMR (400 MHz, DMSO-cfe) δ [ppm]: 1 1 .42 (br s, 1 H), 7.81 (dd, J = 8.8, 5.6 Hz, 1 H), 7.68 (d, J = 2.4 Hz, 1 H), 7.60 (s, 1 H), 7.53 - 7.45 (m, 2H), 7.22 (dd, J = 10.0, 2.4 Hz, 1 H), 6.95 (td, J = 9.2, 2.4 Hz, 1 H), 4.21 - 4.15 (m, 1 H), 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-1 H-indol-3-yl)-2-methylbenzo[d]oxazol-5-yl)methanol
Figure imgf000240_0001
To the solution of 6-(6-Fluoro-1 H-indol-3-yl)-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 1 M 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 NH4CI. The mixture was extracted with EtOAc (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/ methanol=20/1 ) and preparative HPLC to give to afford the title compound (23 mg, 1 1 %) as a white solid. LC-MS for
Ci7H13FN2O2+H+ [M+H]+: calcd. 297.1 ; found: 297.1 . 1H NMR (400 MHz, DMSO) δ 1 1 .40 (s, 1 H), 7.81 (s, 1 H), 7.59 (s, 1 H), 7.55 (d, J = 2.0 Hz, 1 H), 7.41 (dd, J = 8.4, 5.4 Hz, 1 H), 7.24 (dd, J = 10.0, 2.4 Hz, 1 H), 6.89 (td, J
Hz, 1 H), 4.50 (d, J = 5.6 Hz, 2H), 2.63 (s, 3H).
Compound 138: 5-(6-fluoro-1 H-indol-3-yl)-2-methylbenzo[d]isothiazol-3(2H)-one 1 ,1 - dioxide
Figure imgf000241_0001
A solution of terf-butyl 6-fluoro-3-(2-methyl-1 ,1 -dioxido-3-oxo-2,3- dihydrobenzo[<^isothiazol-5-yl)-1 H-indole-1 -carboxylate (Intermediate 151 , 60 mg, 0.14 mmol) in HCI/EtOAc (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 C16HH FN2O3S-H" [M-H]": calcd. 329.0; found: 329.0.
1H NMR (400 MHz, DMSO-afe) δ [ppm]: 1 1 .86 (br s, 1 H), 8.35-8.29 (m, 3H), 8.16 (d, J = 2.4 Hz, 1 H), 7.95 (dd, J = 8.6, 5.0 Hz, 1 H), 7.29 (dd, J = 9.6, 2.0 Hz, 1 H), 7.06-7.05 (m, 1 H), 3.19 (s, 3H).
Compound 139: 2-(2-(c/'s-3,5-dimethylpiperazin-1 -yl)ethyl)-6-(6-fluoro-1 H-indol-3- yl)benzo[d]oxazole
Me
Figure imgf000241_0002
A solution of 6-(6-fluoro-1 -(phenylsulfonyl)-l - -indol-3-yl)-2-vinylbenzo[d]oxazole
(Intermediate 128, 100 mg, 0.24 mmol), sodium hydroxide (47.8 mg, 1 .19 mmol) and c/'s-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 EtOAc (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 C23H25FN4O+H+ [M+H]+: calcd.393.2; found: 393.2. 1 H NMR (400 MHz, DMSO-cfe) δ [ppm]: 1 1 .46 (br s, 1 H), 7.89 - 7.86 (m, 2H), 7.74 (s, 1 H), 7.70 (d, J = 8.3 Hz, 1 H), 7.64 (dd, J = 8.2, 1 .5 Hz, 1 H), 7.23 (dd, J = 9.9, 2.2 Hz, 1 H), 6.96 (td, J = 9.3, 2.4 Hz, 1 H), 3.1 1 (t, J = 7.3 Hz, 2H), 2.85 - 2.73 (m, 4H), 2.67 (s, 2H), 1 .82 (s, 1 H), 1 .54 (t, J = 10.3 Hz, 2H), 0.91 (d, J = 6.3 Hz, 6H).
Compound 140: 1 -(2-(6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)ethyl)piperidin-4-ol
Figure imgf000242_0001
A solution of 6-(6-fluoro-1 -(phenylsulfonyl)-1 - -indol-3-yl)-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 EtOAc (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 C22H22FN3O2+H]+ [M + H]+ : calcd. 380.2; found: 380.2. 1H NMR (400 MHz, DMSO-tf6) δ [ppm]: 1 1 .46 (br s 1 H), 7.90-7.86 (m, 2H), 7.74 (d, J = 2.5 Hz, 1 H), 7.70 (d, J = 8.4 Hz, 1 H), 7.64 (dd, J = 8.2, 1 .5 Hz, 1 H), 7.23 (dd, J = 10.0, 2.4 Hz, 1 H), 6.96-6.93 (m, 1 H), 4.51 (s,1 H), 3.34 - 3.29 (m, 1 H), 3.12 - 3.08 (m, 2H), 2.83 - 2.75 (m, 4H), 2.14 - 2.1 1 (m, 2H), 1 .71 - 1 .62 (m, 2H), 1 .39 - 1 .30 (m, 2H). Compound 141 : 2-(2-(frans-2,5-dimethylpiperazin-1 -yl)ethyl)-6-(6-f luoro-1 H-indol-3- yl)benzo[d]oxazole
Figure imgf000243_0001
A solution of 6-(6-fluoro-1 -(phenylsulfonyl)-1 - -indol-3-yl)-2-vinylbenzo[d]oxazole
(Intermediate 128, 1 10 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 EtOAc. 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. 1 H NMR (400 MHz, MeOD) δ [ppm]: 7.71 -7.68 (m, 2H), 7.52 (s, 2H), 7.38 (s, 1 H), 6.99 (dd, J = 10.0, 2.4 Hz, 1 H), 6.77 (td, J = 9.2, 2.4 Hz, 1 H), 3.25-3.19 (m, 1 H), 3.05-3.00 (m, 2H), 2.85-2.79 (m, 2H), 2.78-2.67 (m, 2H), 2.36-2.21 (m, 1 H), 2.20 (s, 1 H), 2.04 (t, J = 10.9 Hz, 1 H), 1 .10 (m, 6H).
Compound 142: (+)-2-(2-((3ft,5ft)-3,5-dimethylpiperazin-1 -yl)ethyl)-6-(6-fluoro-1 H-indol- 3-yl)benzo[d]oxazole
Figure imgf000243_0002
To a stirred solution of 6-(6-fluoro-1 -(phenylsulfonyl)-1 - -indol-3-yl)-2- vinylbenzo[d]oxazole (Intermediate 128, 100 mg, 0.24 mmol) in MeOH (10 mL) was added (2fl,6fl)-2,6-dimethylpiperazine (273 mg, 2.39 mmol; made according to the procedures reported by J. Org. C/7em.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 EtOAc (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 C23H25FN4O +H+ [M+H]+ : calcd: 393.2; found: 393.2
1H NMR (300 MHz, DMSO-afe) δ [ppm]: 1 1 .46 (br s, 1 H), 7.90-7.85 (m, 2H), 7.74 (d, J = 1 .8 Hz, 1 H), 7.69 (d, J = 8.1 Hz, 1 H), 7.64 (dd, J = 8.1 , 1 .8 Hz, 1 H), 7.23 (dd, J = 9.6, 2.4 Hz, 1 H), 6.96 (td, J = 9.6, 2.4 Hz, 1 H), 3.12-3.00 (m, 2H), 2.99-2.95 (m, 2H), 2.81 - 2.68 (m, 2H), 2.43-2.38 (m, 2H), 2.1 1 -2.08 (m, 2H), 1 .68 (brs, 1 H), 0.95 (d, J = 6.6 Hz, 6H).
[a]20D +10.9° (c=0.2,MeOH).
Compound 143: 2-(2-(2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-6-(6-fluoro-1 H-indol-3- yl)benzo[d]oxazole
Figure imgf000244_0001
To a solution of tert-butyl 6-(2-(6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)ethyl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (Intermediate 152, 170 mg, 0.35 mmol) in DCM (3 mL) was added TFA (1 mL). 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 C22H2i FN4O [M+ H]+: calcd. 376.2; found: 376.8. 1 H NMR (400 MHz, DMSO-afe) δ [ppm]: 1 1 .50 (br s, 1 H), 7.90-7.86 (m, 2H), 7.75 (s, 1 H), 7.71 -7.63 (m, 2H), 7.23 (dd, J = 10.0, 2.4 Hz, 1 H), 6.96 (td, J = 18.8, 2.0 Hz, 1 H), 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 -yl)ethyl)-6-(6-fluoro-1 H-indol- 3-yl)benzo[d]oxazole
Figure imgf000245_0001
To a stirred solution of 6-(6-fluoro-1 -(phenylsulfonyl)-l - -indol-3-yl)-2- vinylbenzo[d]oxazole (Intermediate 128, 100 mg, 0.24 mmol) in MeOH (10 mL) was added (2S,6S)-2,6-dimethylpiperazine (136 mg, 1 .19 mmol; made according to the procedures reported by J. Org. ChemA 995, 60, 4177) and NaOH (48 mg, 1 .20 mmol) at room temperature. The mixture was stirred at 50 °C under N2 for 16 hrs. MeOH 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 C23H25FN4O+H+ [M+H]+: calcd: 393.2; found: 393.2
1H NMR (400 MHz, DMSO-afe) δ [ppm]: 1 1 .48 (br s, 1 H), 7.89-7.86 (m, 2H), 7.75 (d, J = 2.4 Hz, 1 H), 7.67 (d, J = 13.6 Hz, 2H), 7.24 (dd, J = 10.0, 2.0 Hz, 1 H), 6.96 (td, J = 9.6, 2.4 Hz, 1 H), 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, 1 H), 0.97 (d, J = 6.4 Hz, 6H).
Compound 145: 4-(2-(6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)ethyl)piperazine-2- carboxylic acid
Figure imgf000245_0002
A solution of 6-(6-fluoro-1 -(phenylsulfonyl)-1 - -indol-3-yl)-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 EtOAc (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 C22H2iFN4O3+H+ [M + H]+: calcd: 409.2;
found: 408.8. 1H NMR (400 MHz, DMSO-cfe) δ [ppm]: 1 1 .51 (br s, 1 H), 7.90 - 7.87 (m, 2H), 7.75 (s, 1 H), 7.71 (d, J = 8.4 Hz, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.24 (d, J = 10.4 Hz, 1 H), 6.96 (t, J = 9.6 Hz, 1 H), 3.34-3.09 (m, 5H), 3.05 (d, J = 1 1 .6 Hz, 1 H), 2.92-2.87 (m, 3H), 2.78 (t, J = 1 1 .6 Hz, 1 H), 2.27 -2.18 (m, 2H).
Compound 146: 3-(benzofuran-6- -6-fluoro-1 /-/-indole
Figure imgf000246_0001
To a stirred solution of terf-butyl 3-(benzofuran-6-yl)-6-fluoro-1 /-/-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 (EtOAc/ Petroleum Ether=1 /5) and preparative HPLC to afford 16 mg of the title compound. LC- MS for Ci6H10FNO+H+ [M+H]+ : calcd: 252.1 ; found: 251 .9. 1 H NMR (400 MHz, DMSO- d6) δ [ppm]: 1 1 .47 (br s, 1 H), 7.98 (d, J = 1 .6 Hz, 1 H), 7.90 (dd, J =8.8, 5.2 Hz, 1 H), 7.84 (s, 1 H), 7.55 (d, J = 2.4 Hz, 1 H), 7.70 (d, J = 8.0 Hz, 1 H), 7.59 (d, J = 8.0 Hz, 1 H), 7.24 (dd, J = 9.8, 2.4 Hz, 1 H), 6.97 (td, J = 9.2, 2.4 Hz, 2H).
II. BIOLOGY EXAMPLES
11.1 . Assay for TDO2 enzymatic activity determination
The compounds of formula I inhibit the enzymatic activity of human TDO2.
To measure the TDO2 activity, the procedure described in Dolusic et al. J. Med. Chem.; 201 1 , 54, 5320-533was adapted: the reaction mixture contained (final concentrations) potassium phosphate buffer (50 imM, pH 7.5), ascorbic acid (0.25 M), methylene blue (0.125 μΜ), catalase (40 units/mL, from bovine liver, Sigma), and human recombinant TDO2 enzyme (prepared as described in Dolusic et al. J. Med. Chem.; 201 1 , 54, 5320- 5334; 0.9 pg) without or with the compounds of the present invention at the indicated concentrations (total volume 1 12.5 μΙ_). The reaction was initiated by the addition of 37.5 μΙ_ of L-Trp (final concentration 1 imM) at room temperature. The reaction was conducted at room temperature during one hour and stopped by the addition of 30 μΙ_ of 30% (w/v) trichloroacetic acid.
To convert A/-formylkynurenine into kynurenine, the reaction mixture was incubated at 65 °C for 30 min. Then 150 μΙ_ of the reaction mixture was mixed with 120 μΙ_ 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™ software (GraphPad Software, Inc.) using standard parameters.
The biological activity of representative Compounds is summarized in the following table:
Compound IC50 (nM)
1 586
2 946
3 2122
4 3179
5 1 166
6 7526
7 13770
8 609
9 645
10 427
1 1 680
12 709
13 407
14 2221
15 1 158
16 1990
17 935
18 948
19 2192
20 421
21 2667
22 539
23 322
24 924 Compound IC50 (nM)
Figure imgf000248_0001
In one embodiment, compounds having an IC50 < 2000 nm, preferably compound having an IC50< 1 000 nm are selected.
II.2. Cellular Assay for TDO2 Activity determination
II.2. a hTD02-overexpressing P815 cells The compounds of Formula I inhibit the activity of human TDO2 in cells.
The assay (adapted from Pilotte L et al., Proc Natl Acad Sci U S A, 2012, 1 09(7), 2497- 502) was performed in 96-well flat bottom plates seeded with murine mastocytoma P81 5 cells overexpressing hTDO2 (prepared as described in Pilotte et al., PNAS, 2012, 709(7 2497-2502), at a concentration of 5 χ 1 04 cells/well in a final volume of 200 μΙ_. 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- 64™ or commercially, e.g., from Sigma-Aldrich or Life Technologies.] The plates were then centrifuged 5 min at 1000 rpm, and 100 μΙ_ 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 μΙ_ of the supernatant were collected in a flat bottomed plate and 100 μΙ_ 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™ software (Graph Pad Software, Inc.) using standard parameters.
The biological activity of representative compounds is summarized in the following table
Compound IC50 (nM)
1 154
26 150
27 678
28 1447
30 896
31 2299
32 460
33 635
34 863
35 689
36 1 131
37 1534
38 505
39 2864
40 750
44 345
45 595
47 100
48 1 18
53 79
54 109
59 622
60 638
62 210
64 176
65 109
66 203
68 78
70 251
74 72 Compound IC50 (nM)
75 92
77 246
78 82
In one embodiment, compounds having an IC50 < 2000 nm are selected. In another embodiment, compounds having an IC50< 1000 nm are selected. ll.2.b A 172 cells
The compounds of formula I inhibit the activity of human TDO2 in cells that constitutively express TDO2, 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 (ATCC®) as CRL-1620™.
The assay (adapted from Pilotte L et 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 hTDO2 (prepared as described in Tilman et al., Mol Cancer, 2007, 17(6), 80), at a concentration of 1 .25 χ 104 cells/well in a final volume of 200 μΙ_. 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 μΙ_ 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 μΙ_ of the supernatant were collected in a flat bottomed plate and 100 μΙ_ 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™ software (Graph Pad Software, Inc.) using standard parameters.
The biological activity of representative compounds is summarized in the following table:
Compound IC50 (nM)
1 178
9 147
12 517 20 169
22 176
38 512
41 1092
47 479
55 171
56 31 1
58 3767
61 459
62 335
63 597
64 501
65 335
66 284
67 2520
68 218
69 3284
70 435
71 3532
72 442
73 363
74 152
75 143
76 440
77 265
78 149
79 802
80 842
81 1615
82 602
83 154
84 1020
85 1333
86 646
87 298
88 170
89 205
90 240
91 213
92 508
93 1 154
94 4643
95 31 1
96 589
97 284 98 293
99 351
100 345
101 153
102 261
103 427
104 464
105 223
106 326
107 677
108 599
109 446
110 239
111 18980
112 979
113 284
114 478
115 349
116 372
117 278
118 1529
119 1022
120 443
121 1772
122 344
123 498
124 334
125 148
126 826
127 3783
128 540
129 225
130 83
131 2385
132 197
133 292
134 771
135 74
136 320
137 30680
138 3681
139 383
140 447
141 340
142 480 143 610
144 460
145 26000
146 520
In one embodiment, compounds having an IC50 < 2000 nm are selected. In another embodiment, compounds having an ICso< 1000 nm are selected.
II.3. Pharmacodynamic assay for TDO2 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), Methocell™, Dow chemical) / 0.25% Tween® 20 (Signma Aldrich) at different doses (30, 60 and 10Omg/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 μιη, flow rate 0.8 imL/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 1 10 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,
Figure imgf000253_0001
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

1 . A compound of Formula I
Figure imgf000255_0001
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, SO2R4, SO2NR4R5, NR4SO2R5, SO2R4, 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;
oxo ;
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, arylalkyi, alkylaryl, heteroaryl, heteroarylalkyi, alkylheteroaryl, amino, CO-alkyl, or SO2R11 , wherein R11 represents a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyi, alkylaryl, heteroaryl, heteroarylalkyi, 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, arylalkyi, alkylaryl, heteroaryl, heteroarylalkyi, 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, arylalkyi, alkylaryl, heteroaryl, heteroarylalkyi, 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, arylalkyi, alkylaryl, heteroaryl, heteroarylalkyi, 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, arylalkyi, alkylaryl, heteroaryl, heteroarylalkyi, 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, arylalkyi, alkylaryl, heteroaryl, heteroarylalkyi, 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, arylalkyi, alkylaryl, heteroaryl, heteroarylalkyi, alkylheteroaryl, or amino; and wherein R11 represents a hydrogen atom or an optionally substituted group selected from aryl, arylalkyi, alkylaryl, heteroaryl, heteroarylalkyi, 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 I is not 3-(benzofuran-5-yl)-6-chloro-1 H-indole or 3- (benzo[d][1 ,3]dioxol-5-yl)-1 H-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 R8 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 ,
Figure imgf000258_0001
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.
1 1 . 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 1 1 , 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 1 1 , 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 -C2 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 1 1 , 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-1 H-indol-3-yl)-1 H-indazole;
- 2-(6-(6-fluoro-1 H-indol-3-yl)-1 H-indazol-1 -yl)acetamide;
- 6-(6-fluoro-1 H-indol-3-yl)-1 -(piperidin-4-ylmethyl)-1 H-indazole;
- 1 -(4-((6-(6-fluoro-1 H-indol-3-yl)-1 H-indazol-1 -yl)methyl)piperidin-1 - yl)ethanone;
- 3-(6-(6-fluoro-1 H-indol-3-yl)-1 H-indazol-1 -yl)propanamide; - 6-(6-fluoro-1 H-indol-3-yl)-1 -(piperidin-4-yl)-1 H-indazole;
- 1 -(4-(6-(6-fluoro-1 H-indol-3-yl)-1 H-indazol-1 -yl)piperidin-1 -yl)ethanone;
- 5-(6-fluoro-1 H-indol-3-yl)-1 H-indazole;
- 2-(5-(6-fluoro-1 H-indol-3-yl)-1 H-indazol-1 -yl)acetamide;
- 5-(6-fluoro-1 H-indol-3-yl)-1 -(piperidin-4-ylmethyl)-1 H-indazole;
- 1 -(4-((5-(6-fluoro-1 H-indol-3-yl)-1 H-indazol-1 -yl)methyl)piperidin-1 - yl)ethanone;
- 3-(5-(6-fluoro-1 H-indol-3-yl)-1 H-indazol-1 -yl)propanamide;
- 5-(6-fluoro-1 H-indol-3-yl)-1 -(piperidin-4-yl)-1 H-indazole;
- 1 -(4-(5-(6-fluoro-1 H-indol-3-yl)-1 H-indazol-1 -yl)piperidin-1 -yl)ethanone;
- 2-(6-(6-fluoro-1 H-indol-3-yl)-2H-indazol-2-yl)acetamide;
- 1 -(4-((6-(6-fluoro-1 H-indol-3-yl)-2H-indazol-2-yl)methyl)piperidin-1 - yl)ethanone;
- 3-(6-(6-fluoro-1 H-indol-3-yl)-2H-indazol-2-yl)propanamide;
- 6-(6-fluoro-1 H-indol-3-yl)-2-(piperidin-4-yl)-2H-indazole;
- 1 -(4-(6-(6-fluoro-1 H-indol-3-yl)-2H-indazol-2-yl)piperidin-1 -yl)ethanone;
- 2-(5-(6-fluoro-1 H-indol-3-yl)-2H-indazol-2-yl)acetamide;
- 1 -(4-((5-(6-fluoro-1 H-indol-3-yl)-2H-indazol-2-yl)methyl)piperidin-1 - yl)ethanone;
- 3-(5-(6-fluoro-1 H-indol-3-yl)-2H-indazol-2-yl)propanamide;
- 5-(6-fluoro-1 H-indol-3-yl)-2-(piperidin-4-yl)-2H-indazole;
- 1 -(4-(5-(6-fluoro-1 H-indol-3-yl)-2H-indazol-2-yl)piperidin-1 -yl)ethanone;
- 5-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazole;
- 5-(6-fluoro-1 H-indol-3-yl)-2-methyl-1 H-benzo[d]imidazole;
- (5-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2-yl)methanamine;
- 1 -(5-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2-yl)-N,N- dimethylmethanamine;
- 2-(((5-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2- yl)methyl)amino)ethanol;
- N-((5-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2-yl)methyl)acetamide;
- 2-amino-N-((5-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2- yl)methyl)acetamide;
- N-((5-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2- yl)methyl)methanesulfonamide; - 5-(6-fluoro-1 H-indol-3-yl)-2-((4-methylpiperazin-1 -yl)methyl)-1 H- benzo[d]imidazole;
- 5-(6-fluoro-1 H-indol-3-yl)-2-((4-(methylsulfonyl)piperazin-1 -yl)methyl)-1 H- benzo[d]imidazole;
- 2-(5-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2-yl)ethanamine;
- N-(2-(5-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2-yl)ethyl)acetamide;
- N-(2-(5-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2- yl)ethyl)methanesulfonamide;
- 5-(6-fluoro-1 H-indol-3-yl)-2-(2-(methylsulfonyl)ethyl)-1 H-benzo[d]imidazole;
- 5-(6-fluoro-1 H-indol-3-yl)-2-(piperidin-4-yl)-1 H-benzo[d]imidazole;
- 5-(6-fluoro-1 H-indol-3-yl)-2-(1 -(methylsulfonyl)piperidin-4-yl)-1 H- benzo[d]imidazole;
- 5-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2-amine;
- N-(5-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2-yl)acetamide;
- N-(5-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2-yl)methanesulfonamide;
- 1 -(5-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2-yl)-N- methylmethanamine;
- 4-((5-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2-yl)methyl)morpholine;
- 3-(5-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2-yl)propanamide;
- 5-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazole;
- 5-(6-fluoro-1 H-indol-3-yl)-2-methylbenzo[d]oxazole;
- 5-(6-fluoro-1 H-indol-3-yl)-2-(piperidin-4-yl)benzo[d]oxazole;
- 1 -(4-(5-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)piperidin-1 -yljethanone;
- N-(5-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)acetamide;
- N-(5-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methanesulfonamide;
- 6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazole;
- 6-(6-fluoro-1 H-indol-3-yl)-2-methylbenzo[d]oxazole;
- 6-(6-fluoro-1 H-indol-3-yl)-2-(piperidin-4-yl)benzo[d]oxazole;
- 1 -(4-(6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)piperidin-1 -yl)ethanone;
- N-(6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)acetamide;
- N-(6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methanesulfonamide;
- 6-(6-fluoro-1 H-indol-3-yl)-2-(piperazin-1 -ylmethyl)-1 H-benzo[d]imidazole;
- 2-(6-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2-yl)acetamide;
- 5-(6-fluoro-1 H-indol-3-yl)-2-(piperazin-1 -ylmethyl)benzo[d]oxazole; - 5-(6-fluoro-1 H-indol-3-yl)-2-((4-methylpiperazin-1 - yl)methyl)benzo[d]oxazole;
- 5-(6-fluoro-1 H-indol-3-yl)-2-(morpholinomethyl)benzo[d]oxazole;
- 2-(6-(6-fluoro-1 H-indol-3-yl)-2-oxobenzo[d]oxazol-3(2H)-yl)acetamide;
- 5-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-2(3H)-one;
- 6-(6-fluoro-1 H-indol-3-yl)-2-(morpholinomethyl)benzo[d]oxazole;
- 3-(6-(6-fluoro-1 H-indol-3-yl)-2-oxobenzo[d]oxazol-3(2H)-yl)propanamide;
- 6-(6-fluoro-1 H-indol-3-yl)-2-((4-methylpiperazin-1 - yl)methyl)benzo[d]oxazole;
- 2-(5-(6-fluoro-1 H-indol-3-yl)-2-oxobenzo[d]oxazol-3(2H)-yl)acetamide;
- N-((5-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2- yl)methyl)methanesulfonamide;
- 3-(5-(6-fluoro-1 H-indol-3-yl)-2-oxobenzo[d]oxazol-3(2H)-yl)propanamide;
- 3-(benzo[b]thiophen-5-yl)-6-fluoro-1 H-indole;
- N-((5-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)acetamide;
- N-((6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2- yl)methyl)methanesulfonamide;
- N-((6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)acetamide;
- (6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methanamine;
- 5-(6-fluoro-1 H-indol-3-yl)-2-(piperidin-4-ylmethyl)-2H-indazole;
- 6-(6-fluoro-1 H-indol-3-yl)-2-(piperazin-1 -ylmethyl)benzo[d]oxazole;
- 3-(benzo[b]thiophen-6-yl)-6-fluoro-1 H-indole;
- 5-(6-fluoro-1 H-indol-3-yl)-2-(2-(methylsulfonyl)ethyl)benzo[d]oxazole;
- (5-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methanamine;
- 3-(benzofuran-5-yl)-6-fluoro-1 H-indole;
- 3-(6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)propanamide;
- 2-(6-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-1 -yl)acetamide;
- 2-(5-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-1 -yl)acetamide;
- 3-(5-(6-fluoro-1 H-indol-3-yl)-1 H-indazol-1 -yl)-1 -morpholinopropan-1 -one;
- 3-(5-(6-fluoro-1 H-indol-3-yl)-1 H-indazol-1 -yl)-1 -(4-methylpiperazin-1 - yl)propan-1 -one;
- N-(2-(dimethylamino)ethyl)-3-(5-(6-fluoro-1 H-indol-3-yl)-1 H-indazol-1 - yl)propanamide; - 3-(5-(6-fluoro-1 H-indol-3-yl)-1 H-indazol-1 -yl)-N-(2- hydroxyethyl)propanamide;
- 3-(5-(6-fluoro-1 H-indol-3-yl)-1 H-indazol-1 -yl)-N-(2- (methylsulfonyl)ethyl)propanamide;
- 3-(5-(6-fluoro-1 H-indol-3-yl)-1 H-indazol-1 -yl)-1 -(piperazin-1 -yl)propan-1 -one;
- 6-(6-fluoro-1 H-indol-3-yl)indolin-2-one;
- 3-(6-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-1 -yl)propanamide;
- 3-(5-(6-fluoro-1 H-indol-3-yl)-1 H-benzo[d]imidazol-1 -yl)propanamide;
- 1 -(4-(6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)piperidin-1 -yl)ethanone;
- 6-(6-fluoro-1 H-indol-3-yl)-2-(1 -(methylsulfonyl)piperidin-4- yl)benzo[d]oxazole;
- 5-(6-fluoro-1 H-indol-3-yl)indolin-2-one;
- 6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-amine;
- N-((6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)-2- methoxyethanesulfonamide;
- 2-(dimethylamino)-N-((6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2- yl)methyl)ethanesulfonamide;
- 6-(6-fluoro-1 H-indol-3-yl)-2-(2-(methylsulfonyl)ethyl)benzo[d]oxazole;
- 1 -((6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)urea;
- 1 -carbamoyl-1 -((6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)urea;
- 5-(1 H-indol-3-yl)-1 H-indazole;
- 6-(6-fluoro-1 H-indol-3-yl)-2-(2-(4-methylpiperazin-1 - yl)ethyl)benzo[d]oxazole;
- N-((6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)-2- hydroxyethanesulfonamide;
- N-((6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)-2- morpholinoethanesulfonamide;
- 6-(1 H-indol-3-yl)-1 H-indazole;
- 6-(1 H-indol-3-yl)benzo[d]oxazole;
- 6-(6-fluoro-1 H-indol-3-yl)-2-(2-(piperazin-1 -yl)ethyl)benzo[d]oxazole;
- 5-(6-chloro-1 H-indol-3-yl)benzo[d]oxazole;
- 6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazole-2-thiol;
- 6-(6-fluoro-1 H-indol-3-yl)-2-(piperidin-4-ylmethyl)benzo[d]oxazole;
- N-((6-(1 H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)methanesulfonamide; - (S)-N-((6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)-1 - methylpyrrolidine-2-carboxamide;
- 6-(6-fluoro-1 H-indol-3-yl)-2-methoxybenzo[d]oxazole;
- Amino {[6-(6-fluoroindol-3-yl)benzoxazol-2-yl]methyl}sulfonamide;
- 5-(1 H-indol-3-yl)benzo[d]oxazole;
- 6-(6-fluoro-1 H-indol-3-yl)-2-((1 -(methylsulfonyl)piperidin-4- yl)methyl)benzo[d]oxazole;
- 6-(6-fluoro-1 H-indol-3-yl)-2-(2-(4-(methylsulfonyl)piperazin-1 - yl)ethyl)benzo[d]oxazole;
- 5-(5-chloro-1 H-indol-3-yl)benzo[d]oxazole;
- N-((6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)-2-(4- methylpiperazin-1 -yl)ethanesulfonamide;
- N-((6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)-2-(piperazin-1 - yl)ethanesulfonamide;
- N-((6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)-2-(pyrrolidin-1 - yl)ethanesulfonamide;
- 6-(6-fluoro-1 H-indol-3-yl)-2-((1 -methylpiperidin-4-yl)methyl)benzo[d]oxazole;
- N-((6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)-2-(4- (methylsulfonamido)piperidin-1 -yl)ethanesulfonamide;
- N-((6-(6-chloro-1 H-indol-3-yl)benzo[d]oxazol-2- yl)methyl)methanesulfonamide;
- N-((6-(5-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2- yl)methyl)methanesulfonamide
- 5-((6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)imidazolidine-2,4- dione;
- 5-(6-fluoro-1 H-indol-3-yl)benzo[d]isothiazol-3(2H)-one 1 ,1 -dioxide;
- 2-(6-(5-fluoro-1 H-indol-3-yl)-2-oxobenzo[d]oxazol-3(2H)-yl)acetamide;
- 5-(6-fluoro-1 H-indol-3-yl)isoindoline-1 ,3-dione;
- 6-fluoro-3-(isoindolin-5-yl)-1 H-indole;
- 6-(6-fluoro-1 H-indol-3-yl)benzo[d]isothiazol-3(2H)-one 1 ,1 -dioxide;
- 5-(6-fluoro-1 H-indol-3-yl)-2,3-dihydrobenzo[d]isothiazole 1 ,1 -dioxide;
- 6-(6-fluoro-1 H-indol-3-yl)-3-(piperidin-4-yl)benzo[d]oxazol-2(3H)-one;
- (6-(6-fluoro-1 H-indol-3-yl)-2-methylbenzo[d]oxazol-5-yl)methanol;
- 5-(6-fluoro-1 H-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-1 H-indol-3- yl)benzo[d]oxazole;
- 1 -(2-(6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)ethyl)piperidin-4-ol;
- 2-(2-(trans-2,5-dimethylpiperazin-1 -yl)ethyl)-6-(6-fluoro-1 H-indol-3- yl)benzo[d]oxazole;
- (+)-2-(2-((3R,5R)-3,5-dimethylpiperazin-1 -yl)ethyl)-6-(6-fluoro-1 H-indol-3- yl)benzo[d]oxazole;
- 2-(2-(2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-6-(6-fluoro-1 H-indol-3- yl)benzo[d]oxazole;
- (-)-2-(2-((3S,5S)-3,5-dimethylpiperazin-1 -yl)ethyl)-6-(6-fluoro-1 H-indol-3- yl)benzo[d]oxazole;
- 4-(2-(6-(6-fluoro-1 H-indol-3-yl)benzo[d]oxazol-2-yl)ethyl)piperazine-2- carboxylic acid; or
- 3-(benzofuran-6-yl)-6-fluoro-1 H-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 carcinoma, brain tumor, glioblastoma, 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, neuroblastoma, sarcoma, breast carcinoma, leukemia, renal cell carcinoma, colorectal carcinoma, head & neck carcinoma, lung carcinoma, brain tumor, glioblastoma, astrocytoma, myeloma and pancreatic carcinoma.
26. Process for manufacturing a compound of Formula I according to claims 1 to 18 or a pharmaceutically acceptable enantiomer, salt or solvate thereof, characterized in that it comprises:
(a1 ) reacting a compound of Formula (i)
Figure imgf000266_0001
0)
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)
Figure imgf000267_0001
(")
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),
Figure imgf000267_0002
(iii) wherein Z x X2, R1, R2, R3, A1 , A2, A3, Y1 , Y2 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 I.
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.
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