WO2006104406A1 - Tricyclic 1,2,4-triazine oxides and compositions therefrom for therapeutic use in cancer treatments - Google Patents

Tricyclic 1,2,4-triazine oxides and compositions therefrom for therapeutic use in cancer treatments Download PDF

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Publication number
WO2006104406A1
WO2006104406A1 PCT/NZ2006/000064 NZ2006000064W WO2006104406A1 WO 2006104406 A1 WO2006104406 A1 WO 2006104406A1 NZ 2006000064 W NZ2006000064 W NZ 2006000064W WO 2006104406 A1 WO2006104406 A1 WO 2006104406A1
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dihydro
indeno
triazin
nhr
nhc
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PCT/NZ2006/000064
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French (fr)
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Michael Patrick Hay
Adrian Blaser
William Alexander Denny
Kevin Owen Hicks
Ho Huat Lee
Karin Pchalek
Frederik Bastiaan Pruijn
Bronwyn Gae Siim
William Robert Wilson
Shangjin Yang
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Auckland Uniservices Limited
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Priority to CA2603088A priority Critical patent/CA2603088C/en
Priority to US11/887,368 priority patent/US7989451B2/en
Priority to DK06733153.8T priority patent/DK1866292T3/en
Priority to DE602006018883T priority patent/DE602006018883D1/en
Priority to AT06733153T priority patent/ATE491695T1/en
Priority to AU2006229566A priority patent/AU2006229566B2/en
Priority to EP06733153A priority patent/EP1866292B1/en
Publication of WO2006104406A1 publication Critical patent/WO2006104406A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/08—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 condensed with carbocyclic rings or ring systems
    • C07D253/10—Condensed 1,2,4-triazines; Hydrogenated condensed 1,2,4-triazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • the present invention relates to novel tricyclic 1 , 2, 4-triazine-1 -oxides and novel tricyclic 1,2,4-triazine-1,4-dioxides and related analogues, to their preparation, and to their use as hypoxia-selective drugs and radiosensitizers for cancer therapy, both alone or in combination with radiation and/or other anticancer drugs.
  • hypoxic cells in tumours are resistant to ionising radiation, and are a major cause of treatment failure in radiation therapy (Movsas et al., Cancer 2000, 89, 2018; Rudat et al., Radiother. Oncol. 2000, 57, 31). Hypoxic cells are also considered to compromise response of solid tumours to cytotoxic chemotherapy (Brown and Giaccia, Cancer Res. 1998, 58, 1408).
  • the 1 ,2,4-benzotriazine di-N-oxide tirapazamine (TPZ) is selectively toxic to hypoxic cells because of its metabolic activation to a cytotoxic species by one- electron reduction (Baker et al., Cancer Res.
  • the initial one-electron reduction product TPZ * is reoxidised to the starting compound by dioxygen, thereby preventing cytotoxicity in oxic cells.
  • TPZ is therefore of interest for killing hypoxic cells in tumours, thereby improving overall response during radiation therapy.
  • TPZ also has potential for combination with standard cytotoxic chemotherapy (Dorie and Brown, Cancer Res. 1993, 53, 4633; Langmuir et al., Cancer Res. 1994, 54, 2845; Dorie and Brown, Cancer Chemother. Pharmacol. 1997, 39, 361), with (at least) two mechanisms of therapeutic synergy.
  • the first mechanism is the killing of resistant hypoxic cells (analogous to the mechanism of interaction with radiotherapy), and the second is the interference with repair of chemotherapy-induced DNA damage in hypoxic cells as has been demonstrated for cisplatin (Kovacs et al., Br. J. Ca ⁇ cer 1999, 80, 1245; Peters et al., Cancer Res. 2001, 61, 5425).
  • TPZ has already demonstrated significant antitumour activity in early phase human clinical trials in combination with ionising radiation and/or cisplatin chemotherapy (for a review, see Denny and Wilson, Exp. Opin. Invest. Drugs 2000, 9, 2889), and a multicentre phase III trial of TPZ in combination with cisplatin and radiation for treatment of head and neck tumours is in progress (Rischin et al., J. Clin. Oncol. 2005, 23, 79-87). While TPZ shows promising indications of clinical activity, it also displays considerable toxicity, such as neutropenia, thrombocytopenia, nausea, vomiting, diarrhoea and muscle cramping.
  • the present invention provides a compound of Formula I or a pharmacologically acceptable salt thereof,
  • each X at one or more of the available carbons 5-8 on the benzo ring is independently selected from the following groups, H, halo, R, OH, OR, OC(O)H, OC(O)R, OC(O)NH 2 , OC(O)NHR, OC(O)NRR, OP(O)(OH) 2 , OP(O)(OR) 2 , NO 2 , NH 2 , NHR, NRR, NHC(O)H, NHC(O)R, NRC(O)R, NHC(O)NH 2 , NHC(O)NRR, NRC(O)NHR, SH, SR, S(O)H, S(O)R, SO 2 R, SO 2 NH 2 , SO 2 NHR, SO 2 NRR, CF 3 , CN, CO 2 H, CO 2 R, CHO, C(O)R, C(O)NH 2 , C(O)NHR, C(O)
  • each R is independently selected from an optionally substituted C 1-6 alkyl, an optionally substituted C 2-4 alkenyl group or an optionally substituted C 3 . 7 cyclic alkyl group, and wherein the one or more optional substituents are each independently selected from; halo, OH, OR 1 , OC(O)R 1 , OC(O)NH 21 OC(O)NHR 1 , OC(O)NR 1 R 1 , OP(O)(OH) 2 , OP(O)(OR 1 ) 2 , NO 21 NH 2 , NHR 1 , NR 1 R 1 , N + C-O)R 1 R 1 , NHC(O)H, NHC(O)R 1 , NR 1 C(O)R 1 , NHC(O)NH 2 , NHC(O)NR 1 R 1 , NR 1 C(O)NHR 1 , SH, SR 1 , S(O)H, S(O)R 1 , SO 2 R
  • each R 2 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, OH 1 OMe, NO 2, NH 2 , CF 3 , CN, CO 2 H or SH; and
  • W represents NH, NMe, CH 2 , SO, SO 2 , or O;
  • A represents H or an optionally substituted C 1 ⁇ alkyl group or an optionally substituted C 2-6 alkenyl group or an optionally substituted C 3-7 cyclic alkyl group wherein the one or more optional substituents are each independently selected from halo, OH, OR 3 , OC(O)R 3 , OC(O)NH 2 , OC(O)NHR 3 , OC(O)NR 3 R 3 , OP(O)(OH) 2 , OP(O)(OR 3 ) 2 , NO 2, NH 2 , NHR 3 , NR 3 R 3 , N + KOR 3 R 3 , NHC(O)H, NHC(O)R 3 , NR 2 C(O)R 3 , NHC(O)NH 2 , NHC(O)NR 3 R 3 , NR 2 C(O)NHR 3 , SH, SR 3 , S(O)H, S(O)R 3 , SO 2 R 3 , SO 2 NH
  • A represents an optionally substituted C 4 -C 8 aryl or an optionally substituted heteroaryl group having up to 12 carbon atoms, and wherein the one or more optional substituents are each independently selected from; halo, OH, OR 3 , OC(O)R 3 , OC(O)NH 2 , OC(O)NHR 3 , OC(O)NR 3 R 3 , OP(O)(OH) 2 , OP(O)(OR 3 ) 2 , NO 2, NH 2 , NHR 3 , NR 3 R 3 , N + (-O " )R 3 R 3 , NHC(O)H, NHC(O)R 3 , NR 2 C(O)R 3 , NHC(O)NH 2 , NHC(O)NR 3 R 3 , NR 2 C(O)NHR 3 , SH, SR 3 , S(O)H, S(O)R 3 , SO 2 R 3 , SO 2 NH 2 , SO 2
  • Z represents an optionally substituted 4-8 membered saturated ring system fused to the benzo ring in the 6,7-positions or the 7,8-positions;
  • the one or more optional substituents of the ring system are each independently selected from halo, R 5 , OH, OR 5 , OC(O)R 5 , OC(O)NH 2 OC(O)NHR 5 , OC(O)NR 5 R 5 , OP(O)(OH) 2 , OP(O)(OR 5 ) 2 , NO 2, NH 2 , NHR 5 , NR 5 R 5 , N + (-O-)R 5 R 5 , NHC(O)H, NHC(O)R 5 , NR 5 C(O)R 5 , NHC(O)NH 2 , NHC(O)NR 5 R 5 , NR 5 C(O)NHR 5 , SH, SR 5 , S(O)H 1 S(O)R 5 , SO 2 R 5 , SO 2 NH 2 , SO 2 NHR 5 , SO 2 NR 5 R 5 , CF 3 , CN, CO 2 H, CO 2 R, CHO
  • the optionally substituted 4-8 membered ring system includes one or more carbon atoms and/or one or more ring system moieties selected from O, NH, NR 7 , CONH, CONR 7 , NHCO, NR 7 CO, wherein each R 7 is independently selected from an optionally substituted C 1 ⁇ alkyl, an optionally substituted C 2 .
  • each X on the benzo ring is H.
  • Z represents an optionally substituted 5-7 membered saturated ring system fused to the benzo ring in the 6,7-positions or the 7,8-positions; wherein the one or more optional substituents of the ring system are each independently selected from halo, C 1 -C 6 alkyl, OH, OC r C 6 alkyl, OC(O)C r C ⁇ alkyl, OC(O)NH 2 , OC(O)NHC r C 6 alkyl, OC(O)N(C 1 - C 6 alkyl) 2 , OP(O)(OH) 2 , OP(O)(O C r C 6 alkyl) 2 , NO 2 , NH 2 , NHC r C 6 alkyl, N(C r C 6 alkyl) 2> N + (- O )(C 1 -C 6 alkyl) 2 , NHC(O)H, NHC(O)C r C 6 alkyl, N(C )
  • Z represents a 5, 6 or 7 membered ring, optionally substituted with one or more substituents selected from C 1-6 alkyl wherein the alkyl is optionally substituted with one or more OH; NH and N(C 1 -C 6 alkyl) 2 , and wherein the ring optionally includes one or more O, NH or N(C 1 -C 6 alkyl) moieties.
  • Z represents a 5, 6 or 7 membered ring, optionally substituted with CH 3 , CH 2 OH, N(CH 3 ) 2 , CH 2 CH 3 , (CH 2 ) 2 OH, and wherein the ring optionally includes one or more O, NH or N(C 1 -C 6 alkyl) moieties.
  • Z represents a 5 or 6 membered ring optionally substituted with CH 3 , CH 2 OH, N(CH 3 ) 2 , CH 2 CH 3 , (CH 2 ) 2 OH, and wherein the 5 or 6 membered ring is selected from the following:
  • Z represents an unsubstituted 5 membered carbon ring.
  • W represents -NH, or -CH 2 .
  • A represents H or an optionally substituted Ci -6 alkyl group or an optionally substituted C 2 . 6 alkenyl group wherein the one or more optional substituents are each independently selected from halo, OH, OCL 6 alkyl, OC(O) C 1-6 alkyl, OC(O)NH 2 , OC(O)NH C 1-6 alkyl, OC(O)N(C 1 ⁇ alkyl) 2l OP(O)(OH) 2 , OP(O)(O C 1-6 alkyl) 2 , NO 2 , NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , , NHC(O)H, NHC(O)C L6 alkyl, NR 2 C(O)C 1-6 alkyl, NHC(O)NH 2 , NHC(O)N(C 1- ⁇ alkyl) 2 , N(C 1-6 alkyl)C(O)NHC 1-6 alkyl,
  • A represents an optionally substituted -C r C 6 alkyl, C r C 6 alkyl OH, -N(C 1 - C 6 alkyl) 2 , -N( d-CsalkyOOCrCsalkyl, -C r C 6 alkylN(CrC 6 alkyl) 2l -C 1 -C 6 alky)N(C 1 -C 6 alkyl) C r C 6 alkylOC r C 6 alkyl, -CrCsalkylOCrCealkyl, -d-CealkylNazetidine, -CrC 6 alkyl OP(O)(OH) 2 , -d-CealkylNpyrrolidine, -d-CealkylNpiperidine, -C r C 6 alkyl N(2,6-(di C r C 6 alkyl) piperidine), -d-CealkylNmorpholine
  • W and A together represent H, halo, NH 2 , NHCH 2 CH 3 , -CH 2 CH 2 CH 2 NMe 2 , -CH 2 CH 2 CH 2 OH, -NH(CH 2 ) 2 N(Me) 2 , -NHCH 2 CH 2 OH 1 -NHCH 2 CH 2 NEt 2 , -NHCH 2 CH 2 NPr 2 , -CHCH 2 CH 2 N(Me)CH 2 CH 2 OMe, -N(CH 2 CH 2 OMe) 2 , -NHCH 2 CH 2 N(Me)CH 2 CH 2 CH 2 OMe, -NHCHaCHzNazetidine-S-OMe, -CH 2 CH 2 CH 2 OP(O)(OH) 2 ,
  • W and A together represent halo, - NHCH 2 CH 2 CH 2 Nmorpholine, NHCH 2 CH 2 N(Me) 2 or -CH 2 CH 2 CH 2 NMe 2 .
  • the compound is selected from one or more of the following:
  • the compound of Formula I is 3-[3-(4-Morpholinyl)propyl]-7,8-dihydro-6H- indeno[5,6-e][1,2,4]triazine 1 ,4-Dioxide or ⁇ /-[3-(4-Morpholinyl)propyl]-7,8-dihydro-6H- indeno[5,6-e][1 ,2,4]triazin-3-amine 1 ,4-dioxide.
  • the invention provides a method of therapy for treating cancers including the step of administering a compound of Formula I as defined above in a therapeutically effective amount to tumour cells in a subject.
  • tumour cells are in a hypoxic environment.
  • the method of therapy further includes the step of administering radiotherapy to the tumor cells before, during or after the administration of the compound of Formula I as defined above to the tumour cells.
  • the method of therapy further includes the step of administering one or more chemotherapeutic agents to the tumor cells before, during or after the administration of the compound of Formula I as defined above to the tumour cells.
  • While these compounds will typically be used in cancer therapy of human subjects, they can be used to target tumor cells in other warm blooded animal subjects such as other primates, farm animals such as cattle, and sports animals and pets such as horses, dogs, and cats.
  • a “therapeutically effective amount” is to be understood as an amount of a compound of Formula I as defined above that is sufficient to show benefit to a patient.
  • the actual amount, rate and time-course of administration, will depend on the nature and severity of the disease being treated. Prescription of treatment is within the responsibility of general practitioners and other medical doctors.
  • a hypoxic environment is to be understood as either an in vitro environment with an oxygen concentration less than 10 ⁇ M, or an in vivo environment having a lower oxygen tension than normal tissues. It is to be understood that the compound of Formula I can be administered alone or in combination with other chemotherapeutic agents or treatments, especially radiotherapy, either simultaneously or sequentially dependent upon the condition to be treated.
  • Preferred chemotherapeutic agents can be selected from: Cisplatin or other platinum-based derivatives, Temozolomide or other DNA methylating agents, Cyclophosphamide or other DNA alkylating agents, Doxorubicin, mitoxantrone, camptothecin or other topoisomerase inhibitors, Methotrexate, gemcitabine or other antimetabolites and Docetaxel or other taxanes.
  • a pharmaceutical composition including a therapeutically effective amount of a compound of formula I, a pharmaceutically acceptable excipient, adjuvant, carrier, buffer or stabiliser.
  • the pharmaceutically acceptable excipient, adjuvant, carrier, buffer or stabiliser should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • the precise nature of the carrier or other material will depend on the route of administration, which can be oral, or by injection, such as cutaneous, subcutaneous, or intravenous injection.
  • compositions for oral administration can be in tablet, capsule, powder or liquid form.
  • a tablet can comprise a solid carrier or an adjuvent.
  • Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol can be included.
  • a capsule can comprise a solid carrier such as gelatin.
  • the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has a suitable pH, isotonicity and stability.
  • a parenterally acceptable aqueous solution which is pyrogen-free and has a suitable pH, isotonicity and stability.
  • Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride injection, Ringer's injection, Lactated Ringer's injection.
  • Preservatives, stabilisers, buffers antioxidants and/or other additives can be included as required.
  • a fourth aspect of the present invention there is provided a method of making a compound of Formula I or a pharmacologically acceptable salt thereof,
  • n, X, Z, W and A are as defined above;
  • the method may include the steps of converting a monoxide of Formula III
  • halo of formula III represents chloro, bromo or iodo.
  • composition comprising a compound of
  • the tumour cells are in a hypoxic environment.
  • halo or halogen group used throughout the specification is to be taken as meaning a fluoro, chloro, bromo or iodo group.
  • variables of the Formula I to V as defined above are optionally substituted by one or more imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl groups that the linkage to the relevant variable may be through either one of the available nitrogen or carbon ring atoms of these groups.
  • pharmacologically acceptable salt used throughout the specification is to be taken as meaning any acid or base derived salt formed from hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic, isoethonic acids and the like and potassium carbonate sodium or potassium hydroxide ammonia, triethylamine, triethanolamine and the like.
  • Figure 1 illustrates the activity of compound 77 against hypoxic cells in HT29 tumours
  • Figure 2 illustrates by way of a plot the activity of a single dose (0.75 x MTD) TPZ and compounds 61 and 77 against hypoxic cells in three human tumour xenograft models: HT29, human colon carcinoma; SiHa, human cervical carcinoma; H460, non-small cell lung carcinoma.
  • Figure 3 illustrates by way of a plot the activity of fractionated dose TPZ and compound 77 against hypoxic cells in three human tumour xenograft models: H460, non-small cell lung carcinoma; HT29, human colon carcinoma; SiHa, human cervical carcinoma. Drugs (1.0 x fractionated MTD) were administered 30 min before each of 8 x 2.5 Gy doses of radiation.
  • Reagents a) Ac 2 O, dioxane; b) KNO 3 , CH 2 SO 4 ; c) 5 M HCI; d) NH 2 CN, HCI; then NaOH; e) NaNO 21 TFA; f) POCI 3 , DMF; g) NH 2 CH 2 CH 2 NMe 21 DME; h) CF 3 CO 3 H, CF 3 CO 2 H, DCM.
  • reaction of 5 with a variety of amines gave 1 -oxides 8, 10, 12, and 14 that were oxidised to the corresponding 1 ,4-dioxides 9, 11, 13, and 15 (Scheme 2).
  • Reagents a) amine, DME; b) CF 3 CO 3 H, CF 3 CO 2 H, DCM.
  • Reagents a) Ac 2 O, dioxane; b) CHNO 3 , HOAc; c) CHCI 1 EtOH; d) NH 2 CN, HCI; then NaOH; e) CF 3 CO 3 H, CF 3 CO 2 H, DCM; f) NaNO 21 TFA; g) POCI 31 DMF; h) NH 2 CH 2 CH 2 NMe 2 , DME.
  • reaction of 21 with a variety of amines gave 1 -oxides 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, and 62 which were oxidised to the corresponding 1 ,4-dioxides 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, and 63 (Scheme 4).
  • Reagents a) te/f-Butyl nitrite, DMF; b) CF 3 CO 3 H 1 DCM.
  • iodide 66 Diazotisation of amine 19 in the presence of iodine and copper iodide gave iodide 66 (Scheme 6). Negishi reaction of iodide 66 with ethyl magnesium bromide gave 3-ethyl-1- oxide 67 that was oxidised to 1,4-dioxide 68. Alternatively, Stille coupling of chloride 21 with tetraethyltin gave 67. Scheme 6
  • Reagents a) terf-BuNOz, CH 2 I 2 , CuI, THF; b) EtMgBr, ZnCI 2 Et 2 O, Pd(PPh 3 ) 4 , THF; c) CF 3 CO 3 H 1 DCM d) Et 4 Sn, Pd(dppf)CI 2 , THF.
  • Reagents a) AIIyISnBu 3 , Pd(PPh 3 ) 4 , THF; b) 9-BBN, THF; NaOH, H 2 O 2 ; c) Allyl alcohol, Pd(OAc) 2 , nBu 4 NCI, NaHCO 3 , MeCN ; d) NaBH 4 , MeOH, -40 0 C e) CF 3 CO 3 H, DCM.
  • Reaction of the alcohol 70 with di-terf-butyldiethylphosphoramidite in the presence of tetrazole with subsequent oxidation of the intermediate phosphite gave phosphate ester 72 (Scheme 8). Oxidation of ester 72 gave 1 ,4-dioxide 73, which was deprotected to give phosphate 74.
  • Reagents a) Di-tert-butyldiethylphosphoramidite, tetrazole, THF, then MCPBA; b) MCPBA, NaHCO 3 , DCM; c) CF 3 CO 2 H, DCM.
  • Reagents a) Allyl alcohol, Pd(OAc) 2 , nBu 4 NBr, NaHCO 3 , DMF; b) Morpholine, NaBH 3 CN, EtOH; then HOAc; c) CF 3 CO 3 H, CF 3 CO 2 H, DCM.
  • a similar sequence of reactions converted 66 to 1 -oxides 78, 82, 82, 84, and 86, which were oxidised to the corresponding 1 ,4-dioxides 79, 81, 83, 85, and 87 (Scheme 10).
  • Reagents a) AIIyI alcohol, Pd(OAc) 2 , nBu 4 NBr, NaHCO 3 , DMF; b) Amine, NaBH 3 CN, EtOH; then HOAc; c) CF 3 CO 3 H, CF 3 CO 2 H, DCM.
  • Nitration of 2-methyl-1-indanone (88) gave a mixture of nitroindanones 89 and 90 (Scheme 11). Reduction of nitroindanone 90 and acetylation gave acetamide 91 that was nitrated to give nitroacetamide 92. Hydrolysis of 92 gave the nitroaniline 93. Treatment of nitroaniline 93 with cyanamide under acidic conditions followed by cyclisation under basic conditions gave 1 -oxide 94. Diazotisation and chlorination of 1 -oxide 94 gave chloride 95. Reaction of chloride 95 with ⁇ /,/V-dimethylethylenediamine gave 1 -oxide 96 which was oxidised to 1 ,4-dioxide 97.
  • Reagents a) fHNO 3 ; b) H 2 , Pd/C, EtOH, aq HCI; c) Ac 2 O, dioxane; d) HNO 3 , CF 3 CO 2 H; e) cHCI, EtOH; f) NH 2 CN, HCI; then NaOH; g) NaNO 21 TFA; h) POCI 3 , DMF; i) NH 2 CH 2 CH 2 NMe 2 , DME; j) CF 3 CO 3 H, CF 3 CO 2 H, DCM.
  • Reagents a) NH 2 CH 2 CH 2 CH 2 Nmorpholine, Et 3 N, DME; b) CF 3 CO 3 H, CF 3 CO 2 H, DCM.
  • Diazotisation of amine 94 in the presence of diiodomethane gave iodide 100 (Scheme 13).
  • Heck coupling of iodide 100 with allyl alcohol gave the unstable aldehyde 101 which underwent reductive amination with morpholine to give 1 -oxide 102.
  • Alcohol 103 was also isolated from the reaction mixture. Oxidation of 1 -oxides 102 and 103 gave 1 ,4-dioxides 104 and 105, respectively.
  • Reagents a) JBuNO 2 , CH 2 I 2 , CuI, THF; b) Allyl alcohol, Pd(OAc) 2 , nBu 4 NBr, NaHCO 3 , DMF; c) Morpholine, NaBH 3 CN, EtOH; then HOAc; d) CF 3 CO 3 H, CF 3 CO 2 H, DCM.
  • Reagents a) MsCI 1 JPr 2 NEt 1 DCM; b) aq. HNMe 2 , DMF; c) CHNO 3 , CF 3 CO 2 H; d) H 2 , Pd/C, EtOH; e) Ac 2 O, dioxane; f) CHNO 31 CF 3 CO 2 H; g) CHCI 1 EtOH; h) NH 2 CN, HCI; then NaOH; i) NaNO 2 , TFA; j) POCI 3 , DMF; k) aq. EtNH 2 , DME;
  • Reagents a) Et 4 Sn, Pd(PPh 3 ) 4 , DME; b) CF 3 CO 3 H, CF 3 CO 2 H, DCM.
  • Reagents a) KNO 3 , CH 2 SO 4 ; b) NaH, CH 2 (CO 2 Et) 2 , Et 2 O; c) 2 M NaOH, EtOH; then 1 M HCI; d) Reflux, xylene; e) BH 3 DMS 1 THF; f) H 2 , Pd/C, MeOH; g) Ac 2 O 1 Et 3 N 1 DCM; h) CHNO 31 CF 3 CO 2 H; i) 5 M HCI, MeOH; j) NH 2 CN, HCI; then NaOH; k) NaNO 21 HBr 1 DMF; I) aq. EtNH 2 , DME; m) H 2 O 2 , CH 3 CO 2 H.
  • Reagents a) cHCI, dioxane; b) CHNO 31 CF 3 CO 2 H; c) BH 3 DMS 1 THF; d) H 2 , Pd/C, MeOH; e) Ac 2 O, Et 3 N, DCM; f) CHNO 31 CF 3 CO 2 H; g) 5 M HCI, MeOH; h) NH 2 CN, HCI; then NaOH; i) TBDMSCI, JPr 2 NEt, DMF; j) ferf-BuNO 2) CH 2 I 2 , CuI 1 THF; k) Et 4 Sn, Pd(PPh 3 ).), DME;
  • Reagents a) AIIyIBu 3 Sn, Pd(PPh 3 ) 4 , DME; b) 9-BBN, THF, 3M NaOAc, 70% H 2 O 2 ; c) MsCI, JPr 2 NEt, DCM; d) Morpholine; e) 1 M HCI, MeOH; f) CF 3 CO 3 H, CF 3 CO 2 H, DCM.
  • Reagents a) 1 M HCI, MeOH; b) MsCI, JPr 2 NEt, DCM; c) Morpholine; d) CH 3 CO 3 H, CH 3 CO 2 H, DCM.
  • nitroacetanilide 155 was isolated by crystallisation. Hydrolysis of nitroacetanilide 155 gave nitroaniline 156. Treatment of nitroaniline 156 with cyanamide under acidic conditions followed by cyclisation under basic conditions gave amine 157. Diazotisation of amine 157 in the presence of iodine and CuI gave iodide 158 that was protected as the tetrahydropyranyl ether 159. Stille coupling of iodide 159 with tetraethyltin gave 1 -oxide 160, which was deprotected to give alcohol 161 and then oxidised to give 1 ,4-dioxide 162.
  • Reagents a) aq. glyoxylic acid, CH 2 SO 4 ; b) H 2 , Pd/C, MeOH, dioxane; c) CH 2 SO 41 EtOH; d) LiAIH 41 THF; e) Ac 2 O, pyridine, DMAP, DCM; f) Ac 2 O, Cu(NO 3 ) 2 -3H 2 O, DCM; g) H 2 , Pd/C, MeOH; h) Ac 2 O, dioxane; i) CHNO 3 , CF 3 CO 2 H; j) 5 M HCI, MeOH; k) NH 2 CN, HCI; then NaOH;
  • Reagents a) MsCI, NEt 3 , DCM; b) morpholine; c) CF 3 CO 3 H, CF 3 CO 2 H, DCM.
  • Reagents a) KNO 3 , CH 2 SO 4 ; b) H 2 , Pd/C, EtOH, EtOAc, HCI; c) Ac 2 O, dioxane; d) KNO 3 , CH 2 SO 4 ; e) 6 M HCI; f) NH 2 CN, HCI; g) NaOH; h) NaNO 2 , TFA; i) POCI 3 , DMF; j) NH 2 CH 2 CH 2 NMe 2 , DME; k) CF 3 CO 3 H, CF 3 CO 2 H, DCM.
  • Reagents a) HCI; b) NH 2 CN, HCI; then NaOH; c) NaNO 21 TFA; d) POCI 3 , DMF; e) NH 2 CH 2 CH 2 NMe 21 DME; f) CF 3 CO 3 H, CF 3 CO 2 H, DCM.
  • Reagents a) NH 2 CH 2 CH 2 CH 2 Nmorpholine, Et 3 N, DME; b) CF 3 CO 3 H, CF 3 CO 2 H, DCM.
  • Reagents a) fHNO 3 , CH 2 SO 4 ; b) H 2 , Pd/C, EtOH/EtOAc; c) Ac 2 O, dioxane; d) KNO 31 CH 2 SO 4 ; e) 5 M HCI; f) NH 2 CN, HCI; then NaOH; g) NaNO 21 TFA; h) POCI 3 , DMF; i) NH 2 CH 2 CH 2 NMe 2 , DME; j) CF 3 CO 3 H, CF 3 CO 2 H, DCM.
  • Reagents a) AICI 31 ACCI 1 DCM; b) NH 2 OH HCI, pyridine, MeOH; then Ac 2 O, HOAc, HCI; c) KNO 31 CH 2 SO 4 ; d) 5 M HCI; e) NH 2 CN, HCI; f) NaOH; g) NaNO 21 TFA; h) POCI 3 , DMF; i) NH 2 CH 2 CH 2 NMe 2 , DME; j) CF 3 CO 3 H, CF 3 CO 2 H, DCM.
  • Reagents a) NaNO 2 , CH 2 SO 4 ; b) 50% aq. H 3 PO 2 ; c) H 2 , PtO 2 , EtOH; d) Ac 2 O, dioxane; e) 70% HNO 3 , HOAc; f) cHCI, EtOH; g) NH 2 CN, HCI; then NaOH; h) CF 3 CO 3 H, CF 3 CO 2 H, DCM.
  • Reagents a) NaNO 21 TFA; b) POCI 3 , DMF; c) Amine, DME; d) CF 3 CO 3 H 1 CF 3 CO 2 H 1 DCM.
  • iodide 213 Diazotisation of amine 204 in the presence of diiodomethane and CuI gave iodide 213 (Scheme 30). Heck coupling of iodide 213 with allyl alcohol gave the unstable aldehyde 214 which underwent reductive amination with morpholine to give 1 -oxide 215. Oxidation of 1 -oxide 215 gave 1 ,4-dioxide 216.
  • Reagents a) tert-BuNO 2 , CH 2 I 2 , CuI, THF; b) allyl alcohol, Pd(OAc) 2 , nBu 4 NBr, NaHCO 3 , DMF; c) morpholine, NaBH 3 CN, EtOH; then HOAc; d) CF 3 CO 3 H, CF 3 CO 2 H, DCM.
  • Nitroaniline 220 was prepared from 3,4-methylendioxyaniline (217) according to the method of Krasso (Krasso, A. & Ramuz, H., US Patent 4599347, 1986). Thus, acetylation of 3,4-methylenedioxyaniline (217) gave acetamide 218 (Scheme 31). Nitration of acetamide 218 gave nitroacetamide 219, which was hydrolysed to give nitroaniline 220. Treatment of nitroaniline 220 with cyanamide under acidic conditions followed by cyclisation under basic conditions gave amine 221. Diazotisation and chlorination of 221 gave chloride 222. Reaction of the chloride 222 with ⁇ /, ⁇ /-dimethylethylendiamine gave 1- oxide 223, which was oxidised to 1 ,4-dioxide 224.
  • Reagents a) Ac 2 O, dioxane; b) CHNO 3 , HOAc; c) NaOMe, MeOH; d) NH 2 CN, HCI; then NaOH; e) NaNO 21 TFA; f) POCI 3 , DMF; g) NH 2 CH 2 CH 2 NMe 21 DME; h) CF 3 CO 3 H, CF 3 CO 2 H, DCM.
  • Nitration of 4-chromanone (225) gave nitrochromanone isomers 226 and 227 (Scheme 32). Reduction of nitrochromanone 227 and acetylation gave acetamide 228. Alternatively, reduction of chromanone 225 gave chroman 229 which underwent Friedel-Crafts acylation to give ketone 230. Reaction of ketone 230 with hydroxylamine gave the oxime which underwent Beckmann rearrangement to give acetamide 228. Further nitration of 228 gave nitroacetamides 231 and 232. Hydrolysis of acetamide 231 gave nitroaniline 233.
  • Reagents a) KNO 3 , CH 2 SO 4 ; b) H 2 , Pd/C, EtOH/EtOAc, HCI; c) Ac 2 O, dioxane; d) Zn, HOAc; e) AICI 3 , AcCI, DCM; f) NH 2 OH HCI, pyridine, MeOH; g) Ac 2 O, HOAc, HCI; h) KNO 31 CH 2 SO 4 ; i) NaOH, aq EtOH; j) NH 2 CN, HCI; k) NaOH;
  • Reagents a) HCI, aq EtOH; b) NH 2 CN 1 HCI; c) NaOH; d) NaNO 21 TFA; e) POCI 31 DMF; f) NH 2 CH 2 CH 2 NMe 2 , DME; g) CF 3 CO 3 H, CF 3 CO 2 H, DCM; h) NH 2 CH 2 CH 2 CH 2 Nmorpholine, DME.
  • Reagents a) EtNH 2 , Et 3 N, DMF; b) H 2 , Pd/C, MeOH; c) Ac 2 O, dioxane; d) KNO 3 , CH 2 SO 4 ; e) 5 M HCI; f) NH 2 CN, HCI; then NaOH; g) H 2 O 2 , CF 3 CO 2 H, DCM.
  • Reagents a) Ac 2 O, HCO 2 H, THF; b) BH 3 DMS 1 THF; c) H 2 , Pd/C, EtOH; d) Ac 2 O, dioxane; e) KNO 31 CH 2 SO 4 ; f) 5 M HCI; g) NH 2 CN, HCI; then NaOH; h) NaNO 21 TFA; i) POCI 3 , DMF; j) EtNH 2 , DME; k) CF 3 CO 3 H, CF 3 CO 2 H, DCM.
  • Reagents a) NH 2 CN, HCI; then NaOH; b) NaNO 2 , TFA; c) POCI 3 , DMF; d) Et 4 Sn, Pd(PPh 3 ) 4 , DME; e) CF 3 CO 3 H, CF 3 CO 2 H, DCM.
  • Reagents a) aq. Glycolonitrile; b) H 2 , Raney Nickel, cNH 3 , EtOH. Protection of amine 269 as the carbamate 270, followed by O-alkylation to give ether 271 and deprotection gave amine 272. Reaction of amine 272 with glycolonitrile gave nitrile 273 which was reduced to diamine 274 (Scheme 39).
  • Reagents a) Di-ferf-butyl dicarbonate , CHCI 3 ) b) KOH, MeI; c) HCI, dioxane; d) aq. Glycolonitrile, Et 3 N; e) H 2 , Raney Nickel, CNH 3 , EtOH.
  • Reagents a) aq. Glycolonitrile; b) H 2 , Raney Nickel, cNH 3 , EtOH.
  • Reagents a) aq. Glycolonitrile; b) H 2 , Raney Nickel, cNH 3 , EtOH.
  • Reagents a) aq. Glycolonitrile, Et 3 N; b) H 2 , Raney Nickel, cNH 3 , EtOH.
  • Reagents a) aq. Glycolonitrile; b) H 2 , Raney Nickel, cNH 3 , EtOH.
  • Reagents a) aq. Glycolonitrile; b) H 2 , Raney Nickel, cNH 3 , EtOH.
  • Reagents a) ⁇ /-(2-Bromoethyl)phthalimide, K 2 CO 3 , DMF; b) N 2 H 4 H 2 O 1 EtOH.
  • Reagents a) ⁇ /-(2-Bromopropyl)phthalimide, K 2 CO 3 , DMF; b) N 2 H 4 H 2 O 1 EtOH.
  • Reagents a) ⁇ /-(2-Bromopropyl)phthaIimide, K 2 CO 3 , DMF; b) N 2 H 4 H 2 O, EtOH.
  • Reagents a) ⁇ /-(2-Bromopropyl)phthalimide, K 2 CO 3 , DMF; b) N 2 H 4 H 2 O 1 EtOH.
  • Reagents c) ⁇ /-(2-Bromopropyl)phthalimide, K 2 CO 3 , DMF; d) N 2 H 4 H 2 O, EtOH.
  • Reagents e) ⁇ /-(2-Bromob ⁇ tyl)phthalimide, K 2 CO 3 , DMF; f) N 2 H 4 H 2 O, EtOH.
  • Reagents a) Me 2 NCH 2 CH 2 CH 2 CO 2 H, DCC, DCM; b) ⁇ /BOC-L-valine, DCC 1 DCM; It is to be appreciated that many variations and modifications of the reagents and starting materials in the schemes above could be readily brought about by a skilled artisan to make further compounds of Formula I without departing from the scope of the invention as defined.
  • the benzo ring of the compounds of Formula I could be substituted with X groups, where X is other than H, by making or obtaining an appropriately substituted nitroaniline compound and where necessary protecting that substituent with appropriate protecting groups throughout the rest of the synthesis to ensure that the desired substitutent is carried through to the compound of Formula I.
  • Low resolution mass spectra were gathered by direct injection of methanolic solutions into a Surveyor MSQ mass spectrometer using an atmospheric pressure chemical ionization (APCI) mode with a corona voltage of 50 V and a source temperature of 400 0 C. Low resolution mass spectra were also determined on a VG-70SE mass spectrometer using an ionizing potential of 70 eV at a nominal resolution of 1000. High-resolution spectra were obtained at nominal resolutions of 3000, 5000, or 10000 as appropriate. All spectra were obtained as electron impact (El) spectra using PFK as the reference unless otherwise stated. Solutions in organic solvents were dried with anhydrous Na 2 SO 4 .
  • Solvents were evaporated under reduced pressure on a rotary evaporator. Thin-layer chromatography was carried out on aluminum-backed silica gel plates (Merck 60 F 254 ) with visualization of components by UV light (254 nm) or exposure to I 2 . Column chromatography was carried out on silica gel (Merck 230-400 mesh).
  • Ac 2 O refers to acetic anhydride
  • DCM dichloromethane
  • DME dimethoxyethane
  • DMF dry /V, ⁇ /-dimethylformamide
  • ether refers to diethyl ether
  • EtOAc refers to ethyl acetate
  • EtOH refers to ethanol
  • HOAc refers to acetic acid
  • MeOH refers to methanol
  • ether refers to petroleum ether, boiling range 40-60 0 C
  • TFA refers to trifluoroacetic acid
  • TFAA trifluoroacetic anhydride
  • THF tetrahydrofuran dried over sodium benzophenone ketyl.
  • Example 2 3-Chloro-8,9-dihydro-7H-indeno[5,4-e][1 ,2,4]triazine 1 -Oxide (5).
  • NaNO 2 167 mg, 2.4 mmol
  • TFA 10 ml_
  • the solution was poured into ice/water, stirred for 30 minutes, filtered, washed with water (3 x 30 mL) and dried.
  • the solid was suspended in POCI 3 (20 mL) and DMF (0.3 mL) and stirred at 100 0 C for 1 h.
  • Example 3 ethanediamine (6). ⁇ /, ⁇ /-Dimethyl-1 ,2-ethanediamine (0.28 mL, 2.5 mmol) was added to a stirred solution of chloride 5 (187 mg, 0.8 mmol) in DME (30 mL), and the solution stirred at reflux temperature for 2 h. The solvent was evaporated and the residue was partitioned between DCM (100 ml_) and dilute aqueous NH 3 solution (50 mL). The organic fraction was dried and the solvent evaporated.
  • Example 4 ethanediamine (7).
  • H 2 O 2 (70%, 0.33 mL, ca. 6.7 mmol) was added dropwise to a stirred solution of TFAA (0.94 mL, 6.7 mmol) in DCM (10 mL) at 0 0 C.
  • the solution was stirred at 0 0 C for 5 min, warmed to 20 0 C for 10 min, then cooled to 0 0 C and added to a stirred solution of 1-oxide 6 (182 mg, 0.7 mmol) and TFA (0.10 mL, 1.3 mmol) in CHCI 3 (15 mL) at 0 0 C.
  • Example 6 2- ethanediamine (9). H 2 O 2 (70%, 0.37 mL, ca. 7.3 mmol) was added dropwise to a stirred solution of TFAA (1.0 mL, 7.3 mmol) in DCM (10 mL) at 0 0 C. The solution was stirred at 0 °C for 5 min, warmed to 20 °C for 10 min, then cooled to 0 0 C and added to a stirred solution of 1-oxide 8 (219 mg, 0.7 mmol) and TFA (280 ⁇ l_, 3.6 mmol) in DCM (15 mL) at 0 0 C.
  • Example 9 /V-[2-(1-Piper ⁇ dinyl)ethyl]-8,9-dihydro-7H-indeno[5,4-e][1,2,4]triazin-3-amine 1 -Oxide (12).
  • 2-(1-Piperidinyl)ethylamine (0.32 mL, 2.2 mmol) was added to a stirred solution of chloride 5 (165 mg, 0.7 mmol) in DME (30 mL) and the solution stirred at reflux temperature for 5 h. The solvent was evaporated and the residue was partitioned between DCM (100 mL) and dilute aqueous NH 3 solution (50 mL). The organic fraction was dried and the solvent evaporated.
  • Example 13 7,8-Dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-amine 1 -Oxide (19).
  • Ac 2 O (44.6 mL, 473 mmol) was added dropwise to a stirred solution of 5-indanamine (1) (30 g, 225 mmol) in dioxane (120 mL) at 0 0 C and the solution stirred at 20 0 C for 48 h.
  • the solution was diluted with water (500 mL), stirred 20 min and the precipitate filtered.
  • 6-Nitro-5-indanamine (2) A suspension of the mixture of acetamides 17 and 18 in EtOH (400 mL) and cHCI (180 mL) was stirred at 80 °C for 6 h. The resulting solution was cooled and diluted with water (400 mL) and allowed to stand for 16 h. The precipitate was filtered, washed with water, and air-dried to give amine 2 (27.52 g, 73%, from 16) as an orange powder: mp 129-131 0 C [lit. (Schroeder, E.; et al., European J. Med. Chem.
  • Example 16 W 1 , ⁇ / 1 -Dimethyl- ⁇ / 2 -(1-oxido-7,8-dihydro-6W-indeno[5,6-e][1,2,4]trlazin-3-yl)-1,2- ethanediamine (22).
  • ⁇ /,/V-Dimethyl-1 ,2-ethanediamine (0.45 mL, 4.1 mmol) was added to a stirred solution of chloride 21 (305 mg, 1.4 mmol) in DME (30 ml_) and the solution stirred at reflux temperature for 2 h. The solvent was evaporated and the residue was partitioned between DCM (100 mL) and dilute aqueous NH 3 solution (50 mL).
  • Example 17 yV 1 -(1,4-Dioxido-7,8-dihydro-6//-indeno[5,6-e][1 ) 2,4]triazin-3-yl)-/V 2 , ⁇ / 2 -dimethyl-1 ) 2- ethanediamine (23).
  • H 2 O 2 (70%, 0.54 mL, ca. 10.8 mmol) was added dropwise to a stirred solution of TFAA (1.5 mL, 10.8 mmol) in DCM (10 mL) at 0 0 C. The solution was stirred at
  • the hydrochloride salt was crystallised from MeOH/EtOAc. Anal, calcd for C 14 H 20 CIN 5 O 2 - 1 Z 4 CH 3 OH: C 1 49.7; H 1 6.8; N, 19.3. Found: C, 49.4; H, 7.0; N, 19.8%.
  • H 2 O 2 (70%, 0.5 mL, ca. 10 mmol) was added dropwise to a stirred solution of TFAA (1.4 mL, 10 mmol) in DCM (20 mL) at 0 0 C.
  • the solution was stirred at 0 0 C for 5 min, warmed to 20 0 C for 10 min, then cooled to 0 0 C and added to a stirred solution of 1 -oxide 24 (246 mg, 1.0 mmol) and TFA (0.28 mL, 2.0 mmol) in DCM (20 mL) at 0 0 C.
  • the solution was stirred at 0 0 C for 1 h and then at 20 0 C for 30 h, diluted with dilute aqueous NH 3 solution (10 mL) and extracted with DCM (5 x 50 mL). The combined organic fraction was dried and the solvent evaporated.
  • Example 21 ⁇ / 1 -(1,4-Dioxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-yl)- ⁇ / 2 ,/V 2 -diethyl-1,2- ethanediamine (27).
  • H 2 O 2 (70%, 0.52 mL, ca. 10.4 mmol) was added dropwise to a stirred solution of TFAA (1.5 mL, 10.4 mmol) in DCM (15 mL) at 0 0 C.
  • Example 24 N 1 -(1-Oxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-yl)-W 2 -(2-methoxyethyl)- ⁇ / 2 - methy!-1,2-ethanediamine (30).
  • the solution was stirred at 20 °C for 10 min, then cooled to 0 0 C, added to a solution of 1 -oxide 32 (1.7 g, 5.0 mmol) and TFA (1.9 mL, 25 mmol) in DCM (50 mL) at 0 0 C.
  • the solution was stirred at 20 0 C for 6 h, diluted with dilute aqueous NH 3 solution (80 mL) and extracted with DCM (4 x 125 ml_). The combined organic fraction was dried and the solvent evaporated.
  • H 2 O 2 (70%, 1.4 mL, ca. 28 mmol) was added dropwise to a stirred solution of TFAA (4.0 mL, 28 mmol) in DCM (30 mL) at 0 0 C.
  • Example 32 yV-[2-(2,6-Dimethyl-1-piperidinyl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3- amine 1 -Oxide (38).
  • 2-(2,6-Dimethyl-1-piperidinyl)ethylamine (280) (0.66 g, 4.3 mmol) was added to a stirred solution of chloride 21 (314 mg, 1.4 mmol) in DME (50 ml_) and the solution stirred at reflux temperature for 3 h. The solvent was evaporated and the residue partitioned between DCM (100 ml_) and dilute aqueous NH 3 solution (50 ml_).
  • Example 33 yV-[2-(2,6-Dimethyl-1-piperidinyl)ethyl]-7,8-dihydro-6W-indeno[5,6-e][1,2,4]triazin-3- amine 1,4-Dioxide (39).
  • H 2 O 2 (70%, 0.46 mL, ca. 9.2 mmol) was added dropwise to a stirred solution of TFAA (1.3 mL, 9.2 mmol) in DCM (20 mL) at 0 0 C.
  • Example 36 Example 36 /V-[2-(4-Methoxy-1 -piperidinyl)ethyl]-7,8-dihydro-6H-indenol5,6-e][1 ,2,4]triazin-3- amine 1-Oxide (42).
  • Crude 2-(4-methoxy-1 ⁇ piperidinyl)ethylamine (288) (3.8 g, 23.9 mmol) was added to a stirred solution of chloride 21 (1.77 g, 8.0 mmol) and Et 3 N (2.2 mL, 16.0 mmol) in DME (80 mL) and the solution stirred at reflux temperature for 6 h.
  • Example 38 ⁇ /-[2-(4-Morpholinyl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-amine 1- Oxide (44).
  • 2-(4-Morpholinyl)ethylamine (3.93 ml_, 30.0 mmol) was added to a stirred solution of chloride 21 (2.21 g, 10.0 mmol) in DME (50 ml.) and the solution stirred at reflux temperature for 3 h. The solvent was evaporated and the residue stirred with water (150 ml.) at room temperature for 30 min.
  • Example 39 A/-[2-(4-Morpholinyl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-amine 1,4- Dioxide (45).
  • H 2 O 2 (70%, 0.50 ml_, ca. 10.0 mmol) was added to a stirred solution of 1- oxide 44 (3.00 g, 9.52 mmol) in a mixture of TFA (30 mL) and water (2 mL) at 20 0 C.
  • Ten more aliquots of 70% H 2 O 2 (0.5 mL) were added in 30 min intervals and the reaction mixture was stirred at 20 °C for 26 h.
  • the hydrochloride salt was crystallised as a red solid: mp (MeOH/DCM) 184-185 0 C.
  • Example 41 yV-[2-(1-Azepanyl)ethyl]-7,8-dihydro-6 «-indeno[5,6-e][1,2,4]triazin-3-amine 1,4- Dioxide (47).
  • H 2 O 2 (70%, 0.37 mL, ca. 7.3 mmol) was added dropwise to a stirred solution of TFAA (1.0 mL, 7.3 mmol) in DCM (20 mL) at 0 0 C.
  • Example 43 yV-p-li ⁇ -Oxazepan ⁇ -yOethylJ-T.S-dihydro-e/y-indenotS. ⁇ -eJti ⁇ ltriazin-S-amine 1,4-Dioxide (49).
  • H 2 O 2 (70%, 1.25 ml_, ca. 25.8 mmol) was added dropwise to a stirred solution of TFAA (3.6 mL, 25.8 mmol) in DCM (35 ml_) at 0 0 C.
  • Example 44 3-[(1-Oxido-7,8-dihydro-6W-indeno[5,6-e]
  • 3- Aminopropanol (0.99 mL, 12.9 mmol) was added to a stirred solution of chloride 21 (956 mg, 4.3 mmol) in DME (80 mL) and the solution stirred at reflux temperature for 6 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH 3 solution (50 mL). The organic fraction was dried and the solvent evaporated.
  • the solution was stirred at 20 0 C for 10 min, then cooled to 0 0 C, and added to a solution of 1- oxide 52 (2.0 g, 6.04 mmol) and TFA (1.0 mL, 13.0 mmol) in CHCI 3 (80 mL) at 0 0 C and the solution stirred at 20 0 C for 18 h.
  • the solution was made basic with dilute aqueous NH 3 solution and extracted with CHCI 3 (3 x 100 mL). The combined organic fraction was dried and the solvent evaporated.
  • Example 48 yV-[3-(3-Methoxy-1-azetidinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3- amine 1-Oxide (54).
  • the solution was stirred at 20 0 C for 10 min, then cooled to 0 0 C, added to a solution of 1 -oxide 54 (1.3 g, 4.0 mmol) and TFA (1.5 mL, 20 mmol) in DCM (50 mL) at 0 0 C.
  • the solution was stirred at 20 0 C for 26 h, diluted with dilute aqueous NH 3 solution (80 mL) and extracted with DCM (4 x 125 mL). The combined organic fraction was dried and the solvent evaporated.
  • Example 51 1 - ⁇ 3-[(1 ,4-Dioxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)amino]propyl ⁇ -3- pyrrolidinecarbonitrile (57).
  • H 2 O 2 (70%, 0.67 mL, ca. 13.3 mmol) was added dropwise to a stirred solution of TFAA (1.9 mL, 13.3 mmol) in DCM (20 mL) at 0 0 C.
  • Example 52 yV- ⁇ S-t ⁇ Methoxy-i-piperidinylJpropyq-Tj ⁇ -dihydro- ⁇ H-indenoI ⁇ .e-elli ⁇ . ⁇ triazin-S- amine 1 -Oxide (58). 3-(4-Methoxy-1-piperidinyl)propylamine (304) (0.59 g, 3.4 mmol) was added to a stirred solution of chloride 21 (505 mg, 2.3 mmol) and Et 3 N (0.64 mL, 2.6 mmol) in DME (50 mL) and the solution stirred at reflux temperature for 16 h.
  • Example 53 ⁇ /-[3-(4-Methoxy-1 -piperidinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3- amine 1,4-Dioxide (59).
  • H 2 O 2 (70%, 0.92 mL, ca. 18.3 mmol) was added dropwise to a stirred solution of TFAA (2.6 ml_, 18.3 mmol) in DCM (20 ml_) at 0 0 C.
  • Example 65 3-(1 -Oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)-1 -propanol (70).
  • a solution of 9-BBN in THF (31.1 mL, 15.6 mmol) was added dropwise to a stirred solution of alkene (2.95 g, 13.0 mmol) in THF (150 mL) and the solution stirred at 20 0 C for 3 h.
  • Example 66 3-(1-Oxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-yl)-1-propanol (70).
  • Pd(OAc) 2 (18 mg, 0.08 mmol) was added to a degassed solution of iodide 66 (250 mg, 0.80 mmol), allyl alcohol (0.27 mL, 3.40 mmol), tetrabutylammonium chloride (182 mg, 0.80 mmol) and NaHCO 3 (147 mg, 1.76 mmol) in acetonitrile (12.5 mL) and the solution irradiated in a Milestone MicroSYNTH reactor for 15 min at 150 0 C (max.
  • Example 67 3-(1,4-Dioxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-yl)-1-propanol (71).
  • H 2 O 2 (70%, 1.6 mL, ca. 33 mmol) was added dropwise to a stirred solution of TFAA (4.6 mL, 33 mmol) in DCM (30 mL) at 0 0 C. The solution was stirred at 0 0 C for 5 min, warmed to 20 0 C for 10 min, then cooled to 0 0 C.
  • the solution was diluted with DCM (100 mL) and washed with diluted with dilute aqueous NH 3 solution (3 x 60 mL) and extracted with DCM (3 ⁇ 20 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 10% MeOH/EtOAc.
  • Example 74 ⁇ /-[3-(1,4-Dioxido-7,8-dihydro-6W-mdeno[5,6-e][1,2,4]triazin-3-yl)propyl]- ⁇ /,yV- dimethylamine (79).
  • H 2 O 2 (70%, 0.65 mL, 13 mmol) was added dropwise to a stirred solution of TFAA (1.8 mL, 13 mmol) in DCM (20 mL) at 0 0 C.
  • Example 75 ⁇ /,/V-Bis(2-methoxyethyl)-3-(1-oxido-7,8-dihydro-6W-indeno[5,6-e][1,2,4]triazin-3-yl)- 1-propanamine (80).
  • Bis-(2-methoxyethyl)amine (3. 0 g, 22.5 mmol) was added to a stirred solution of propanal 75 (1.2 g, 4.9 mmol) in MeOH (100 ml) at 0 °C and the solution stirred for 30 min.
  • Example 76 W-[3-(1,4-Dioxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-yl)propyl]-W,W-bis(2- methoxyethyl)amine (81). H 2 O 2 (70%, 2.0 mL, 39 mmol) was added dropwise to a stirred solution of TFAA (5.4 mL, 39 mmol) in DCM (50 mL) at 0 0 C.
  • the solution was stirred at 0 0 C for 5 min, warmed to 20 0 C for 10 min, then cooled to 0 0 C and added to a stirred solution of 1-oxide 80 (1.50 g, 4.2 mmol) and TFA (1.5 mL, 1.95 mmol) in DCM (50 mL) at 0 0 C.
  • the solution was stirred at 20 0 C for 6 h, diluted with dilute aqueous NH 3 solution (36 mL) and extracted with DCM (3 x 150 mL). The combined organic fraction was dried and the solvent evaporated.
  • the solution was stirred at 0 0 C for 5 min, warmed to 20 0 C for 10 min, then cooled to 0 0 C and added to a stirred solution of 1- oxide 82 (0.93 g, 3.0 mmol) and TFA (1.5 mL, 19.5 mmol) in DCM (50 mL) at 0 0 C.
  • the solution was stirred at 20 0 C for 8 h, diluted with dilute aqueous NH 3 solution (30 mL) and extracted with DCM (3 x 150 mL). The combined organic fraction was dried and the solvent evaporated.
  • the solution was stirred at 0 0 C for 5 min, warmed to 20 0 C for 10 min, then cooled to 0 0 C and added to a stirred solution of 1 -oxide 84 (1.50 g, 4.6 mmol) and TFA (1.5 mL, 19.5 mmol) in DCM (50 mL) at 0 0 C.
  • the solution was stirred at 20 0 C for 6 h, diluted with dilute aqueous NH 3 solution (30 mL) and extracted with DCM (3 x 150 mL). The combined organic fraction was dried and the solvent evaporated.
  • Example 83 7-Methyl-7,8-dihydro-6W-indeno[5,6-e][1,2,4]triazin-3-amine 1 -Oxide (94).
  • 2-Methyl-6-nitro-1-indanone 89.
  • 2-Methyl-1-indanone (88) (18.74 g, 128 mmol) was added dropwise to stirred fuming HNO 3 (100 mL) at -10 0 C over 1 h. The mixture was stirred at -10 0 C for 10 min then poured into ice/water (1 L) and the mixture stirred for 1 h. The precipitate was filtered and the filtrate extracted with DCM (4 x 80 mL). The combined organic fraction was dried and the solvent evaporated.
  • N-(2-WIethyl-6-nitro-2,3-dihydro-1H-inden-5-yl)acetamide (92).
  • a solution of nitric acid (70%, 3.2 mL, 50.3 mmol) in TFA (5 mL) was added dropwise to a stirred solution of acetamide 91 (3.93 g, 16.8 mmol) in TFA (40 mL) and the solution stirred at 20 0 C for 2 h.
  • the solution was poured into ice/water (400 mL) and stirred for 30 min.
  • the precipitate was filtered, washed with water (3 x 30 mL), and dried.
  • the solid was purified by chromatography, eluting with 10% EtOAc/pet.
  • the mixture was cooled to 50 0 C, 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100 0 C for 3 h.
  • the mixture was cooled, diluted with water (100 mL), filtered, washed with water (2 x 30 mL), and dried.
  • 1,2-ethanediamine (96).
  • a solution of chloride 95 (240 mg, 0.9 mmol), ⁇ / 1 , ⁇ / 1 -dimethyl- 1 ,2-ethanediamine (0.26 mL, 2.4 mmol) and Et 3 N (0.33 mL, 2.4 mmol) in DME (50 mL) was stirred at reflux temperature for 4 h.
  • the solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH 3 solution (50 mL). The organic fraction was dried and the solvent evaporated.
  • Example 86 ⁇ . ⁇ -Dimethyl- ⁇ T-methyl-i ⁇ -dioxido-T.S-dihydro- ⁇ H-indenoIS. ⁇ -elfi ⁇ ltriazin-S- yl)-1,2-ethanediamine (97).
  • H 2 O 2 (70%, 0.65 ml_, ca. 12.9 mmol) was added dropwise to a stirred solution of TFAA (1.8 mL, 12.9 mmol) in DCM (20 mL) at 0 °C.
  • Iodide 100 (1.53 g, 4.7 mmol) was added to a degassed solution of allyl alcohol (0.89 mL, 13.1 mmol), Pd(OAc) 2 (52 mg, 0.23 mmol), nBu 4 NBr (1.35 g, 4.2 mmol) and NaHCO 3 (0.86 g, 10.3 mmol) in DMF (40 mL) and the solution was stirred at 50 0 C for 24 h under N 2 . The mixture was quenched with saturated aqueous NH 4 CI solution (50 mL) and filtered. The filtrate was extracted with EtOAc (5 x 50 mL), dried and the solvent evaporated.
  • Example 92 7-Methyl-3-[3-(4-morpholinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 ,4- Dioxide (104).
  • H 2 O 2 (70%, 0.49 mL, ca. 9.7 mmol) was added dropwise to a stirred solution of TFAA (1.4 mL, 9.7 mmol) in DCM (10 mL) at 0 0 C.
  • Methanesulfonyl chloride (11.5 mL, 149 mmol) was added dropwise to a stirred solution of 2-indanol (106) (20 g, 149 mmol) and JPr 2 NEt (28.6 mL, 164 mmol) in DCM (300 mL) at 0 0 C, and the solution stirred at 20 0 C for 16 h.
  • the solution was washed with 1 M HCI (80 mL), aqueous saturated NaHCO 3 solution (80 mL) and brine (100 mL), dried and the solvent evaporated.
  • the mixture was cooled to 50 0 C, 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100 0 C for 3 h.
  • the mixture was cooled, diluted with water (30 mL), filtered, washed with water (2 x 10 mL), and dried.
  • Example 95 3-Chloro-W,W-dimethyl-7,8-dihydro-6W-indeno[5,6-e][1,2,4]triazin-7-amine 1 -Oxide (112).
  • NaNO 2 100 mg, 1.4 mmol
  • TFA 10 mL
  • the solution was poured into ice/water (50 mL) and stirred for 30 minutes.
  • the solvent was evaporated and the residue dried.
  • the solid was suspended in POCI 3 (5 mL) and DMF (3 drops) and stirred at 80 °C for 1 h.
  • Example 98 7-(Dimethylamino)-3-ethyl-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1 -Oxide (115).
  • Pd(PPh 3 ) 4 (240 mg, 0.21 mmol) was added to a N 2 -purged, stirred solution of chloride 112 (550 mg, 1.9 mmol) and SnEt 4 (800 mg, 3.4 mmol) in DME (55 mL), and the mixture stirred at 85 0 C under N 2 for 16 h.
  • Example 100 (3-Amino-1-oxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]tria2in-7-yl)methanol (124). 1,2-Bis(brornornethyl)-4-nitrobenzene (118). KNO 3 (33.0 g, 330 mmol) was added in small portions, over 1 h, to a stirred solution of 1 ,2-bis(bromomethyl)benzene (117) (72.2 g, 300 mmol) in CH 2 SO 4 (600 ml_) at 0 0 C. After the addition was completed, the mixture was stirred at 0 0 C for 3 h.
  • Example 103 [3-(Ethylamino)-1,4-dioxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-7-yl]methanol (127).
  • H 2 O 2 (70%, 1.0 mL, ca. 20.0 mmol) was added dropwise to a stirred solution of 1- oxide 126 (71 mg, 0.27 mmol) in HOAc (3 mL) at 50 0 C and the reaction was stirred at 50 0 C for 20 h.
  • the mixture was diluted with aqueous NaHCO 3 solution and extracted with DCM (5 x 50 mL). The combined organic fraction was dried and the solvent evaporated.
  • 2-lndanecarboxylic Acid (129).
  • Example 106 7-( ⁇ [fe/t-Butyl(dimethyl)silyl]oxy ⁇ methyl)-3-iodo-7,8-dihydro-6H-indeno[5,6- e][1,2,4]triazine 1 -Oxide (133) and 7-( ⁇ [ferf-Butyl(dimethyl)silyl]oxy ⁇ methyl)-7,8- dihydro-6H-indeno[5,6-e][1,2,4]triazine 1 -Oxide (134).
  • Example 109 3-Allyl-7-( ⁇ [te/t-butyl(dimethyl)silyl]oxy ⁇ methyl)-7,8-dihydro-6W-indeno[5,6- e][1,2,4]triazine 1-0xide (137). Allyltributyltin (4.35 m!_, 14.1 mmol) and Pd(PPh 3 ) 4 (0.72 g, 0.64 mmol) were added to a N 2 -purged, stirred solution of iodide 133 (5.88 g, 12.9 mmol) in DME (80 ml.) at 20 0 C and the reaction mixture was stirred at reflux temperature under N 2 for 8 h.
  • Example 111 7-( ⁇ [fert-Butyl(dimethyl)silyl]oxy ⁇ methyl)-3-[3-(4-morphormyl)propyl]-7,8-dihydro-6H- indeno[5,6-e][1,2,4]triazine 1 -Oxide (139).
  • Methanesulfonyl chloride 54 ⁇ l_, 1.32 mmol was added dropwise to a stirred solution of alcohol 138 (467 mg, 1.20 mmol), and JPr 2 NEt (0.42 mL, 2.40 mmol) in DCM (15 mL) at 0 0 C, and the solution was stirred at 0 0 C for 20 min.
  • reaction mixture was poured into ice-water/cNH 3 (2.5:1 , 3.5 L) and the layers separated.
  • the aqueous layer was extracted with EtOAc (2 x 500 mL), the combined organic layer dried, the solvent evaporated and the residue was purified by chromatography, eluting with 20% EtOAc/pet.
  • HNO 3 (70%, 13.6 ml_, 214 mmol) was added dropwise to a solution of the acetates (153 and 154) (27 g, 103 mmol) in TFA (120 ml_) at 0 0 C and the solution allowed to warm to 20 0 C over 1.5 h.
  • the mixture was poured into ice/water (500 mL) and made basic with cNH 3 (ca. 150 ml_).
  • the mixture was extracted with DCM (3 x 250 mL), the combined organic layer dried and the solvent evaporated.
  • the residue was filtered through a plug of silica, eluting with 50% EtOAc/pet. ether, the solvent evaporated and the residue recrystallised from EtOAc/pet.
  • Example 126 3-Chloro-7,8,9,10-tetrahydronaphtho[2,1-e][1,2,4]triazine 1 -Oxide (171).
  • NaNO 2 73 mg, 1.0 mmol
  • TFA 5 ml_
  • the solution was poured into ice/water, stirred 30 minutes, filtered, washed with water (3 x 30 mL) and dried.
  • the solid was suspended in POCI 3 (10 mL) and DMF (0.2 mL) and stirred at 100 °C for 1 h.
  • Example 127 W 1 , ⁇ / 1 -Dimethyl-W 2 -(1-oxido-7,8,9,10-tetrahydronaphtho[2,1-e][1,2,4]triazin-3-yl)-1,2- ethanediamine (172).
  • ⁇ /, ⁇ /-Dimethyl-1,2-ethanediamine (0.12 mL, 1.0 mmol) was added to a stirred solution of chloride 171 (83 mg, 0.4 mmol) in DME (20 mL) and the solution stirred at reflux temperature for 3 h. The solvent was evaporated and the residue partitioned between DCM (50 mL) and dilute aqueous NH 3 solution (50 mL).
  • Example 134 yV-[3-(4-Morpholinyl)propyl]-6,7,8,9-tetrahydronaphtho[2,3-e][1,2,4]triazin-3-amine 1,4-Dioxide (180).
  • H 2 O 2 (70%, 0.36 mL, ca. 6.0 mmol) was added dropwise to a stirred solution of TFAA (0.96 mL, 6.0 mmol) in DCM (5 mL) at 0 0 C.
  • Example 135 T ⁇ IO-Tetrahydro- ⁇ W-cycloheptatgHi ⁇ benzotriazin-S-amine 1-0xide (186). 3-Nitro-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-2-amine (185). A solution of fHNO 3 (7.5 mL) in CH 2 SO 4 (50 ml.) was added dropwise to a stirred suspension of 1- benzosuberone (181) (20 g, 124.8 mmol) in CH 2 SO 4 (400 mL) at 0 0 C. The mixture was stirred a further 30 min and poured into ice/water.
  • NaNO 2 (151 mg, 2.2 mmol) was added in small portions to a stirred solution of amine 186 (252 mg, 1.1 mmol) in TFA (10 mL) at 0 0 C and the solution stirred at 20 0 C for 2 h.
  • the solution was poured into ice/water, stirred for 30 min, filtered, washed with water (3 x 10 mL) and dried.
  • the solid was suspended in POCI 3 (10 mL) and DMF (0.1 mL) and stirred at 100 0 C for 1 h.
  • the solution was cooled, poured into ice/water, stirred for 30 minutes, filtered, washed with water (3 x 5 mL) and dried.
  • Example 137 3-yl)-1,2-ethanediamine (188). ⁇ /,/V-Dimethyl-1 ,2-ethanediamine (0.23 mL, 2.1 mmol) was added to a stirred solution of chloride 187 (178 mg, 0.7 mmol) in DME (30 mL) and the solution stirred at reflux temperature for 2 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH 3 solution (50 mL). The organic fraction was dried and the solvent evaporated.

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Abstract

The invention relates to novel tricyclic 1,2,4-triazine-1-oxides and novel tricyclic 1,2,4-triazine-1,4-dioxides of formula: (I); and to related analogues, to their preparation, and to their use as hypoxia-selective drugs and radiosensitizers for cancer therapy, both alone or in combination with radiation and/or other anticancer drugs.

Description

TRICYCLIC 1,2,4-TRIAZINE OXIDES AND COMPOSITIONS THEREFROM FOR THERAPEUTIC USE IN CANCER TREATMENTS
REFERENCE TO GOVERNMENT CONTRACT A portion of this invention described herein was supported under grant or contract from the United States Department of Health and Human Services. The United States of America Government may have certain rights to this invention.
TECHNICAL FIELD The present invention relates to novel tricyclic 1 , 2, 4-triazine-1 -oxides and novel tricyclic 1,2,4-triazine-1,4-dioxides and related analogues, to their preparation, and to their use as hypoxia-selective drugs and radiosensitizers for cancer therapy, both alone or in combination with radiation and/or other anticancer drugs.
BACKGROUND TO THE INVENTION
Hypoxic cells in tumours are resistant to ionising radiation, and are a major cause of treatment failure in radiation therapy (Movsas et al., Cancer 2000, 89, 2018; Rudat et al., Radiother. Oncol. 2000, 57, 31). Hypoxic cells are also considered to compromise response of solid tumours to cytotoxic chemotherapy (Brown and Giaccia, Cancer Res. 1998, 58, 1408). The 1 ,2,4-benzotriazine di-N-oxide tirapazamine (TPZ) is selectively toxic to hypoxic cells because of its metabolic activation to a cytotoxic species by one- electron reduction (Baker et al., Cancer Res. 1988, 48, 5947; Laderoute et al., Biochem. Pharmacol. 1988, 37, 1487; Brown, Br. J. Cancer 1993, 67, 1163). As shown below, the initial one-electron reduction product TPZ* is reoxidised to the starting compound by dioxygen, thereby preventing cytotoxicity in oxic cells.
Figure imgf000002_0001
TPZ is therefore of interest for killing hypoxic cells in tumours, thereby improving overall response during radiation therapy. TPZ also has potential for combination with standard cytotoxic chemotherapy (Dorie and Brown, Cancer Res. 1993, 53, 4633; Langmuir et al., Cancer Res. 1994, 54, 2845; Dorie and Brown, Cancer Chemother. Pharmacol. 1997, 39, 361), with (at least) two mechanisms of therapeutic synergy. The first mechanism is the killing of resistant hypoxic cells (analogous to the mechanism of interaction with radiotherapy), and the second is the interference with repair of chemotherapy-induced DNA damage in hypoxic cells as has been demonstrated for cisplatin (Kovacs et al., Br. J. Caπcer 1999, 80, 1245; Peters et al., Cancer Res. 2001, 61, 5425).
TPZ has already demonstrated significant antitumour activity in early phase human clinical trials in combination with ionising radiation and/or cisplatin chemotherapy (for a review, see Denny and Wilson, Exp. Opin. Invest. Drugs 2000, 9, 2889), and a multicentre phase III trial of TPZ in combination with cisplatin and radiation for treatment of head and neck tumours is in progress (Rischin et al., J. Clin. Oncol. 2005, 23, 79-87). While TPZ shows promising indications of clinical activity, it also displays considerable toxicity, such as neutropenia, thrombocytopenia, nausea, vomiting, diarrhoea and muscle cramping. These toxicity limitations preclude administration of doses that are either high enough or sufficient enough to exploit hypoxia fully during cancer treatment. Although the mechanisms of TPZ toxicity towards normal tissues are not fully understood, it is considered that the toxicity arises at least in part because of redox cycling (Elwell et al., Biochem. Pharmacol. 1997, 54, 249; Wouters et al., Cancer Res. 2001, 61 , 145), and is therefore considered to be distinct from the mechanism of hypoxic cell killing.
There have been only limited structure-activity studies on analogues of TPZ. Kelson et al (Anti-Cancer Drug Design 1998, 13, 575-592) disclosed compounds of type A, where X was H or an electron-withdrawing group, n was 2 or 3, and R was Me or Et. The main conclusion from this paper was that compounds with dialkylaminoalkyl side chains showed decreased hypoxic selectivity in vitro and comparable but not superior activity to TPZ in vivo. There was no clear relationship between the electron-withdrawing capability of the 7-substituent on the benzo ring and biological activity. Hay and Denny (Tet. Lett. 2002, 43, 9569-9571) and Kelson et al (Anti-Cancer Drug Design 1998, 13, 575-592) described compounds of type B, where X is H or hydroxyalkyl, n is 2 or 3, and R is OH or OMe, but did not describe any biological activity. Finally, Hay et al. (J. Med. Chem. 2003, 46, 169-182) showed, for compounds of type C, where X is NEt2, NMe2, OMe, Me, Cl, F, CF3, MeSO2, nBuSO2, and NO2, that oxic cytotoxicity in SCCVII cells in vitro correlated with one-electron reduction potential [E(I)], but there was not a clear relationship between in vitro hypoxic cytotoxicity and E(1). Further, there was no clear relationship between hypoxia-selectivity and E(1) and none of the compounds displayed improved in vitro activity compared to TPZ.
Figure imgf000004_0001
To a large extent the above efforts to identify analogues of TPZ with improved therapeutic activity have focused on compounds with higher reduction potentials, with the expectation that such compounds will be metabolically activated more rapidly than TPZ under hypoxic conditions and will therefore have improved activity against hypoxic cells in tumours.
In the present invention the inventors have unexpectedly found that certain tricyclic triazine compounds of the invention have activity against hypoxic tumor cells in vivo despite having lower reduction potentials than the corresponding compounds in the literature (Kelson et al, Anti-Cancer Drug Design 1998, 13, 575-592).
It is an object of the present invention to provide a range of novel tricyclic 1 ,2,4-triazine-1- oxides and novel tricyclic 1 ,2,4-triazine-1 ,4-dioxides and their related analogues, and to provide for their use as potentiators of the cytotoxicity of anticancer drugs and as radiosensitizers and as hypoxia-selective cytotoxins for cancer therapy in combination with radiation and/or with other anticancer agents, or to at least provide the public with a useful choice.
DISCLOSURE OF THE INVENTION
In a first aspect, the present invention provides a compound of Formula I or a pharmacologically acceptable salt thereof,
Figure imgf000004_0002
Formula
wherein
n = 0 or 1 ; and each X at one or more of the available carbons 5-8 on the benzo ring is independently selected from the following groups, H, halo, R, OH, OR, OC(O)H, OC(O)R, OC(O)NH2, OC(O)NHR, OC(O)NRR, OP(O)(OH)2, OP(O)(OR)2, NO2, NH2, NHR, NRR, NHC(O)H, NHC(O)R, NRC(O)R, NHC(O)NH2, NHC(O)NRR, NRC(O)NHR, SH, SR, S(O)H, S(O)R, SO2R, SO2NH2, SO2NHR, SO2NRR, CF3, CN, CO2H, CO2R, CHO, C(O)R, C(O)NH2, C(O)NHR, C(O)NRR, CONHSO2H, CONHSO2R, CONRSO2R, cyclic C3-C7 alkylamino, imidazolyl, CrC6 -alkylpiperazinyl and morpholinyl;
wherein each R is independently selected from an optionally substituted C1-6 alkyl, an optionally substituted C2-4 alkenyl group or an optionally substituted C3.7 cyclic alkyl group, and wherein the one or more optional substituents are each independently selected from; halo, OH, OR1, OC(O)R1, OC(O)NH21 OC(O)NHR1, OC(O)NR1R1, OP(O)(OH)2, OP(O)(OR1)2, NO21 NH2, NHR1, NR1R1, N+C-O)R1R1, NHC(O)H, NHC(O)R1, NR1C(O)R1, NHC(O)NH2, NHC(O)NR1R1, NR1C(O)NHR1, SH, SR1, S(O)H, S(O)R1, SO2R1, SO2NH2, SO2NHR1, SO2NR1R1, CF3, CN, CO2H, CO2R1, CHO, C(O)R1, C(O)NH2,
C(O)NHR1, C(O)NR1R1, C(O)NHSO2R1, C(O)NR1SO2R1, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more R1 groups, halo, OH, OR1, OC(O)R1, OC(O)NH2, OC(O)NHR1, OC(O)NR1R1, OP(O)(OH)2, OP(O)(OR1)2, NO2, NH2, NHR1, NR1R1, N+(-0"
)R1R\ NHC(O)H, NHC(O)R1, NR1C(O)R1, NHC(O)NH2, NHC(O)NR1R1, NR1C(O)NHR1, SH, SR1, S(O)H, S(O)R1, SO2R1, SO2NH2, SO2NHR1, SO2NR1R1, CF3, CN, CO2H, CO2R1, CHO, C(O)R1, C(O)NH2, C(O)NHR1, C(O)NR1R1, CONHSO2H, C(O)NHSO2R1 and C(O)NR1SO2R1; R can also represent an optionally substituted C4.8 aryl or an optionally substituted heteroaryl group having up to 12 carbon atoms, and wherein the one or more optional substituents are each independently selected from; halo, OH, OR1, OC(O)R1, OC(O)NH2, OC(O)NHR1, OC(O)NR1R1, OP(O)(OH)2, OP(O)(OR1)2, NO2, NH2, NHR1, NR1R1, N+(-O" )R1R\ NHC(O)H, NHC(O)R1, NR1C(O)R1, NHC(O)NH2, NHC(O)NR1R1, NR1C(O)NHR1, SH, SR1, S(O)H, S(O)R1, SO2R1, SO2NH2, SO2NHR1, SO2NR1R1, CF3, CN, CO2H, CO2R1, CHO, C(O)R1, C(O)NH2, C(O)NHR1, C(O)NR1R1, C(O)NHSO2R1, C(O)NR1SO2R1, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more R1 groups, halo, OH, OR1, OC(O)R1, OC(O)NH2, OC(O)NHR1, OC(O)NR1R1, OP(O)(OH)2,
OP(O)(OR1)2, NO21 NH2, NHR1, NR1R1, N+(-O )R1R1, NHC(O)H, NHC(O)R1, NR1C(O)R1, NHC(O)NH2, NHC(O)NR1R1, NR1C(O)NHR1, SH, SR1, S(O)H1 S(O)R1, SO2R1, SO2NH2, SO2NHR1, SO2NR1R1, CF3, CN, CO2H, CO2R1, CHO, C(O)R1, C(O)NH2, C(O)NHR1, C(O)NR1R1, CONHSO2H, C(O)NHSO2R1 and C(O)NR1SO2R1; and wherein each heteroaryl group contains one or more heteroatoms in its ring system which are each independently selected from O, N or S; wherein each R1 is independently selected from an optionally substituted C1-6 alkyl or an optionally substituted C2-6 alkenyl group and wherein the one or more optional substituents are each independently selected from; halo, OH, OR2, OC(O)R2, OC(O)NH2, OC(O)NHR2, OC(O)NR2R2, OP(O)(OH)2, OP(O)(OR2J2, NO2, NH2, NHR2, NR2R2, N+(-0" )R2R2, NHC(O)H, NHC(O)R2, NR2C(O)R2, NHC(O)NH2, NHC(O)NR2R2, NR2C(O)NHR2, SH, SR2, S(O)H, S(O)R2, SO2R2, SO2NH2, SO2NHR2, SO2NR2R2, CF3, CN, CO2H, CO2R2, CHO, C(O)R2, C(O)NH2, C(O)NHR2, C(O)NR2R2, C(O)NHSO2R2, C(O)NR2SO2R2, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more R2 groups, halo, OH, OR2, OC(O)R2, OC(O)NH2, OC(O)NHR2, OC(O)NR2R2, OP(O)(OH)2, OP(O)(OR2)2, NO2, NH2, NHR2, NR2R2, N+(O )R2R2, NHC(O)H, NHC(O)R2, NR2C(O)R2, NHC(O)NH2, NHC(O)NR2R2, NR2C(O)NHR2, SH, SR2, S(O)H1 S(O)R2, SO2R2, SO2NH2, SO2NHR2, SO2NR2R2, CF3, CN, CO2H, CO2R2, CHO, C(O)R2, C(O)NH2, C(O)NHR2, C(O)NR2R2, CONHSO2H, C(O)NHSO2R2 and C(O)NR2SO2R2;
wherein each R2 is independently selected from C1-6 alkyl, C2-6 alkenyl, OH1 OMe, NO2, NH2, CF3, CN, CO2H or SH; and
wherein W represents NH, NMe, CH2, SO, SO2, or O; and
A represents H or an optionally substituted C1^ alkyl group or an optionally substituted C2-6 alkenyl group or an optionally substituted C3-7 cyclic alkyl group wherein the one or more optional substituents are each independently selected from halo, OH, OR3, OC(O)R3, OC(O)NH2, OC(O)NHR3, OC(O)NR3R3, OP(O)(OH)2, OP(O)(OR3)2, NO2, NH2, NHR3, NR3R3, N+KOR3R3, NHC(O)H, NHC(O)R3, NR2C(O)R3, NHC(O)NH2, NHC(O)NR3R3, NR2C(O)NHR3, SH, SR3, S(O)H, S(O)R3, SO2R3, SO2NH2, SO2NHR3, SO2NR3R3, CF3, CN, CO2H1 CO2R, CHO, C(O)R3, C(O)NH2, C(O)NHR3, C(O)NR3R3, CONHSO2H, C(O)NHSO2R3, C(O)NR3SO2R3, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more R3 groups, halo, OH, OR3, OC(O)R3, OC(O)NH2, OC(O)NHR3, OC(O)NR3R3, OP(O)(OH)2, OP(O)(OR3)2, NO2, NH2, NHR3, NR3R3, N+(-O")R3R3, NHC(O)H, NHC(O)R3, NR3C(O)R3, NHC(O)NH2, NHC(O)NR3R3, NR3C(O)NHR3, SH, SR3, S(O)H, S(O)R3, SO2R3, SO2NH2, SO2NHR3, SO2NR3R3, CF3, CN, CO2H, CO2R3, CHO, C(O)R3, C(O)NH2, C(O)NHR3, C(O)NR3R3, CONHSO2H, C(O)NHSO2R3, and C(O)NR3SO2R3; or
A represents an optionally substituted C4-C8 aryl or an optionally substituted heteroaryl group having up to 12 carbon atoms, and wherein the one or more optional substituents are each independently selected from; halo, OH, OR3, OC(O)R3, OC(O)NH2, OC(O)NHR3, OC(O)NR3R3, OP(O)(OH)2, OP(O)(OR3)2, NO2, NH2, NHR3, NR3R3, N+(-O")R3R3, NHC(O)H, NHC(O)R3, NR2C(O)R3, NHC(O)NH2, NHC(O)NR3R3, NR2C(O)NHR3, SH, SR3, S(O)H, S(O)R3, SO2R3, SO2NH2, SO2NHR3, SO2NR3R3, CF3, CN, CO2H, CO2R, CHO, C(O)R3, C(O)NH2, C(O)NHR3, C(O)NR3R3, CONHSO2H, C(O)NHSO2R3, C(O)NR3SO2R3, cyclic C3- C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more R3 groups, halo, OH, OR3, OC(O)R3, OC(O)NH2, OC(O)NHR3, OC(O)NR3R3, OP(O)(OH)2, OP(O)(OR3)2, NO2, NH2, NHR3, NR3R3, N+(-O )R3R3, NHC(O)H, NHC(O)R3, NR3C(O)R3, NHC(O)NH2, NHC(O)NR3R3, NR3C(O)NHR3, SH, SR3, S(O)H, S(O)R3, SO2R3, SO2NH2, SO2NHR3, SO2NR3R3, CF3, CN, CO2H, CO2R3, CHO, C(O)R3, C(O)NH2, C(O)NHR3, C(O)NR3R3, CONHSO2H, C(O)NHSO2R3 and C(O)NR3SO2R3; and each heteroaryl group includes one or more heteroatoms in its ring system which are each independently selected from O, N or S; wherein each R3 is independently selected from an optionally substituted C1-6 alkyl or an optionally substituted C2.6 alkenyl group and wherein the one or more optional substituents are each independently selected from; halo, OH, OR4, OC(O)R4, 0C(0)NH2, OC(O)NHR4, OC(O)NR4R4, OP(O)(OH)2, OP(O)(OR4)2, NO2, NH2, NHR4, NR4R4, N+(-O")R4R4, NHC(O)H, NHC(O)R4, NR4C(O)R4, NHC(O)NH2, NHC(O)NR4R4, NR4C(O)NHR4, SH, SR4, S(O)H, S(O)R4, SO2R4, SO2NH2, SO2NHR4, SO2NR4R4, CF3, CN, CO2H, CO2R, CHO, C(O)R4, C(O)NH2, C(O)NHR4, C(O)NR4R4, CONHSO2H, C(O)NHSO2R4, C(O)NR4SO2R4, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more R4 groups, halo, OH, OR4, OC(O)R4, OC(O)NH2, OC(O)NHR4, OC(O)NR4R4, OP(O)(OH)2, OP(O)(OR4)2, NO2, NH2, NHR4, NR4R4, N+(-O" )R4R4, NHC(O)H, NHC(O)R4, NR4C(O)R4, NHC(O)NH21-NHC(O)NR4R4, NR4C(O)NHR4, SH, SR4, S(O)H, S(O)R4, SO2R4, SO2NH2, SO2NHR4, SO2NR4R4, CF3, CN, CO2H, CO2R, CHO, C(O)R4, C(O)NH2, C(O)NHR4, C(O)NR4R4, CONHSO2H, C(O)NHSO2R4 and C(O)NR4SO2R4; wherein each R4 is independently selected from Ci-4 alkyl, C2-4 alkenyl, halo, OH, OC1-C4, NO2, NH2, CF3, CN, CO2H, COCN or SH;
or wherein W and A together represent H or halo;
Z represents an optionally substituted 4-8 membered saturated ring system fused to the benzo ring in the 6,7-positions or the 7,8-positions;
wherein the one or more optional substituents of the ring system are each independently selected from halo, R5, OH, OR5, OC(O)R5, OC(O)NH2OC(O)NHR5, OC(O)NR5R5, OP(O)(OH)2, OP(O)(OR5)2, NO2, NH2, NHR5, NR5R5, N+(-O-)R5R5, NHC(O)H, NHC(O)R5, NR5C(O)R5, NHC(O)NH2, NHC(O)NR5R5, NR5C(O)NHR5, SH, SR5, S(O)H1 S(O)R5, SO2R5, SO2NH2, SO2NHR5, SO2NR5R5, CF3, CN, CO2H, CO2R, CHO, C(O)R5, C(O)NH2, C(O)NHR5, C(O)NR5R5, C(O)NHSO2H, C(O)NHSO2R5, C(O)NR5SO2R5, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more R5 groups halo, R5, OH, OR5, OC(O)R5, OC(O)NH2 OC(O)NHR5, OC(O)NR5R5, OP(O)(OH)2, OP(O)(OR5)2, NO2, NH2, NHR5, NR5R5, N+(-O")R5R5, NHC(O)H, NHC(O)R5, NR5C(O)R5, NHC(O)NH2, NHC(O)NR5R5, NR5C(O)NHR5, SH, SR5, S(O)H, S(O)R5, SO2R5, SO2NH2, SO2NHR5, SO2NR5R5, (R5)3SiO, CF3, CN, CO2H, CO2R, CHO, C(O)R5, C(O)NH2, C(O)NHR5, C(O)NR5R5, C(O)NHSO2H, C(O)NHSO2R5 and C(O)NR5SO2R5 wherein each R5 is independently selected from an optionally substituted C1-6 alkyl or an optionally substituted C2-6 alkenyl group or an optionally substituted C3.7 cyclic alkyl group and wherein the one or more optional substituents are each independently selected from; halo, R6, OH, OR6, OC(O)R6, OC(O)NHR6, OC(O)NR6R6, OP(O)(OH)2, OP(O)(OR6)2, NO2, NH2, NHR6, NR6R6, N+(-O")R6R6, NHC(O)R6, NR6C(O)R6, NHC(O)NR6R6, NR6C(O)NHR6, SH, SR6, S(O)R6, SO2R6, SO2NHR6, SO2NR6R6, CF3, CN, CO2H, CO2R, CHO, C(O)R6, C(O)NH2, C(O)NHR6, C(O)NR6R6, C(O)NHSO2R6, C(O)NR6SO2R6, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more R6 groups, halo, OH, OR6, OC(O)R6, OC(O)NH2 , OC(O)NHR6, OC(O)NR6R6, OP(O)(OH)2, OP(O)(OR6)2, NO2, NH2, NHR6, NR6R6, N+(-O-)R6R6, NHC(O)H, NHC(O)R6, NR6C(O)R6, NHC(O)NH2, NHC(O)NR6R6, NR6C(O)NHR6, SH, SR6, S(O)H, S(O)R6, SO2R6, SO2NH2, SO2NHR6, SO2NR6R6, CF3, CN, CO2H, CO2R6, CHO, C(O)R6, C(O)NH2, C(O)NHR6, C(O)NR6R6, C(O)NHSO2H, C(O)NHSO2R6 and C(O)NR6SO2R6 wherein each R6 is independently selected from Ci-6 alkyl, C2.6 alkenyl, halo, OH, OMe, NO2, NH2, CF3, CN, CO2H or SH; and
wherein the optionally substituted 4-8 membered ring system includes one or more carbon atoms and/or one or more ring system moieties selected from O, NH, NR7, CONH, CONR7, NHCO, NR7CO, wherein each R7 is independently selected from an optionally substituted C1^ alkyl, an optionally substituted C2.6 alkenyl group or an optionally substituted C3-7 cyclic alkyl group and wherein the one or more optional substituents are each independently selected from halo, R8, OH, OR8, OC(O)R8, OC(O)NH2, OC(O)NHR8, OC(O)NR8R8, OP(O)(OH)2, OP(O)(OR5)2, NO2, NH2, NHR8, NR8R8, N+(-O-)R8R8, NHC(O)H, NHC(O)R8, NR8C(O)R8, NHC(O)NH2, NHC(O)NR8R8, NR8C(O)NHR8, SH, SR8, S(O)H, S(O)R8, SO2R8, SO2NH2, SO2NHR8, SO2NR8R8, CF3, CN, CO2H, CO2R, CHO, C(O)R8, C(O)NH2, C(O)NHR8, C(O)NR8R8, C(O)NHSO2H, C(O)NHSO2R8,
C(O)NR8SO2R8, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more R8 groups, halo, R8, OH, OR8, OC(O)R8, OC(O)NH2, OC(O)NHR8, OC(O)NR8R8, OP(O)(OH)2, OP(O)(OR5)2, NO2, NH2, NHR8, NR8R8, N+(-O")R8R8,
NHC(O)H, NHC(O)R8, NR8C(O)R8, NHC(O)NH2, NHC(O)NR8R8, NR8C(O)NHR8, SH, SR8, S(O)H, S(O)R8, SO2R8, SO2NH2, SO2NHR8, SO2NR8R8, CF3, CN, CO2H, CO2R, CHO, C(O)R8, C(O)NH2, C(O)NHR8, C(O)NR8R8, C(O)NHSO2H, C(O)NHSO2R8 and C(O)NR8SO2R8; wherein each R8 is independently selected from an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl group or an optionally substituted C3-7 cyclic alkyl group and wherein the one or more optional substituents is each independently selected from; halo, OH, OR9, OC(O)R9, OC(O)NH2, OC(O)NHR9, OC(O)NR9R9, OP(O)(OH)2, OP(O)(OR9)2, NO2, NH2, NHR9, NR9R9, N+(-O")R9R9, NHC(O)H, NHC(O)R9, NR9C(O)R9, NHC(O)NH2, NHC(O)NR9R9, NR9C(O)NHR9, SH, SR9, S(O)H, S(O)R9, SO2R9, SO2NH2, SO2NHR9, SO2NR9R9, CF3, CN, CO2H, CO2R, CHO, C(O)R9, C(O)NH2, C(O)NHR9, C(O)NR9R9, C(O)NHSO2H, C(O)NHSO2R9, C(O)NR9SO2R9, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more R9 groups, halo, OH, OR9, OC(O)R9, OC(O)NH2, OC(O)NHR9, OC(O)NR9R9, OP(O)(OH)2, OP(O)(OR9)2, NO2, NH2, NHR9, NR9R9, N+(-O )R9R9, NHC(O)H, NHC(O)R9, NR9C(O)R9, NHC(O)NH2, NHC(O)NR9R9, NR9C(O)NHR9, SH, SR9, S(O)H, S(O)R9, SO2R9, SO2NH2, SO2NHR9, SO2NR9R9, CF3, CN, CO2H, CO2R, CHO, C(O)R9, C(O)NH2, C(O)NHR9, C(O)NR9R9, C(O)NHSO2H, C(O)NHSO2R9, and C(O)NR9SO2R9; wherein each R9 is independently selected from Ci-6 alkyl, C2.6 alkenyl, halo, OH, OMe, NO2, NH2, CF3, CN, CO2H or SH.
Preferably each X on the benzo ring is H.
Preferably Z represents an optionally substituted 5-7 membered saturated ring system fused to the benzo ring in the 6,7-positions or the 7,8-positions; wherein the one or more optional substituents of the ring system are each independently selected from halo, C1-C6 alkyl, OH, OCrC6alkyl, OC(O)CrCβalkyl, OC(O)NH2, OC(O)NHCrC6alkyl, OC(O)N(C1- C6alkyl)2, OP(O)(OH)2, OP(O)(O CrC6alkyl)2, NO2, NH2, NHCrC6alkyl, N(CrC6alkyl)2> N+(- O )(C1-C6 alkyl)2, NHC(O)H, NHC(O)CrC6alkyl, N(CrC6alkyl)C(O)CrC6 alkyl, NHC(O)NH2, NHC(O)N (CrC6alkyl)2, NC1-C6 alkylC(O)NHCrC6 alkyl, SH1 SC1-C6 alkyl, S(O)H, S(O)CrC6alkyl, SO2CrC6alkyl, SO2NH2, SO2NHC1-C6 alkyl, SO2N(C1-C6 alkyl)2, (C1-Ce)3SiO, CF3, CN, CO2H, CO2C1-C6 alkyl, CHO, C(O)C1-C6 alkyl, C(O)NH2, C^NHCrCealkyl, C(O)N(C1-C6 alkyl)2, C(O)NHSO2H, C(O)NHSO2C1-C6 alkyl, C(O)N(C1- C6 alkyl)SO2(CrC6 alkyl), cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the substituents are optionally substituted by one or more halo, C1-C6 alkyl, OH, O C1-C6 alkyl, and wherein the optionally substituted ring system includes one or more carbon atoms and/or one or more ring system moieties selected from O, NH, N(C1-C6 alkyl), CONH, CON(C1-C6 alkyl), NHCO, N(C1-C6 alkyl)CO, wherein each C1-C6 alkyl is optionally substitued with one or more halo, C1-C6 alkyl, OH, OC1-C6 alkyl, OP(O)(OH)2, OP(O)(O C1-C6 alkyl)2) NO2, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, SH, S(C1-C6 alkyl), S(O)H, S(O)C1-C6 alkyl, SO2 C1- C6 alkyl, SO2NH2, CF3, CN, CO2H, CO2R, CHO, C(O) C1-C6 alkyl, C(O)NH2, C(O)NH C1- C6 alkyl, C(O)N(C1-C6 alkyl)2, C(O)NHSO2H, C(O)NHSO2R8, C(O)NR8SO2R8, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl.
Preferably, Z represents a 5, 6 or 7 membered ring, optionally substituted with one or more substituents selected from C1-6 alkyl wherein the alkyl is optionally substituted with one or more OH; NH and N(C1-C6 alkyl)2, and wherein the ring optionally includes one or more O, NH or N(C1-C6 alkyl) moieties. More preferably, Z represents a 5, 6 or 7 membered ring, optionally substituted with CH3, CH2OH, N(CH3)2, CH2CH3, (CH2)2OH, and wherein the ring optionally includes one or more O, NH or N(C1-C6 alkyl) moieties.
Preferably, Z represents a 5 or 6 membered ring optionally substituted with CH3, CH2OH, N(CH3)2, CH2CH3, (CH2)2OH, and wherein the 5 or 6 membered ring is selected from the following:
Figure imgf000011_0001
Preferably, Z represents an unsubstituted 5 membered carbon ring.
Preferably W represents -NH, or -CH2.
Preferably A represents H or an optionally substituted Ci-6 alkyl group or an optionally substituted C2.6 alkenyl group wherein the one or more optional substituents are each independently selected from halo, OH, OCL6 alkyl, OC(O) C1-6 alkyl, OC(O)NH2, OC(O)NH C1-6 alkyl, OC(O)N(C1^ alkyl)2l OP(O)(OH)2, OP(O)(O C1-6 alkyl)2, NO2, NH2, NHC1-6 alkyl, N(C1-6 alkyl)2, , NHC(O)H, NHC(O)CL6 alkyl, NR2C(O)C1-6 alkyl, NHC(O)NH2, NHC(O)N(C1- β alkyl)2, N(C1-6 alkyl)C(O)NHC1-6 alkyl, CF3, CN, CO2H, CO2 C1-6 alkyl, CHO, C(O)C1-6 alkyl, C(O)NH2, C(O)NHC1-6 alkyl, C(O)N(C1-6 alkyl)2, CONHSO2H, C(O)NHSO2C1-6 alkyl, C(O)NC1-6 alkylSO2C1-6 alkyl, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more groups selected from halo, OH, OC1-6 alkyl, OC(O) C1-6 alkyl, OC(O)NH21 OC(O)NH C1-6 alkyl, OC(O)N(C1-6 alkyl)2, OP(O)(OH)2, OP(O)(OC1-6 alkyl)2, NO21 NH2, NHCv6 alkyl, N(C1-6 alkyl)2, NHC(O)H, NHC(O)C1-6 alkyl, NC1-6 alkylC(O)C1-6 alkyl, NHC(O)NH2, NHC(O)N(C1-6 alkyl)2, NC1-6 alkylC(O)NHC1-6 alkyl, CF3, CN, CO2H, CO2 C1-6 alkyl, CHO, C(O) C1-6a!kyl, C(O)NH2, C(O)NH Ch alky!, C(O)N(C1-6 alkyl), CONHSO2H, C(O)NHSO2(C1-6 alkyl), and C(O)NC1-6 alkylSO2C1-6 alkyl.
Preferably A represents an optionally substituted -CrC6alkyl, CrC6alkyl OH, -N(C1- C6alkyl)2, -N( d-CsalkyOOCrCsalkyl, -CrC6alkylN(CrC6alkyl)2l -C1-C6alky)N(C1-C6alkyl) CrC6alkylOCrC6alkyl, -CrCsalkylOCrCealkyl, -d-CealkylNazetidine, -CrC6alkyl OP(O)(OH)2, -d-CealkylNpyrrolidine, -d-CealkylNpiperidine, -CrC6alkyl N(2,6-(di CrC6alkyl) piperidine), -d-CealkylNmorpholine, -CrC6alkylazepane, -C1- C6alkylNoxazepine, CrC6alkylOC(O) CrC6alkylN(CrC6alkyl)2, C1-C6BIk^OC(O)C1- C6alkyl(NCO2CrC6alkyl) CrC6alkyl, wherein the one or more substituents are each independently selected from OH, CrC6alkyl, Od-C6alkyl or CN.
Preferably W and A together represent H, halo, NH2, NHCH2CH3, -CH2CH2CH2NMe2, -CH2CH2CH2OH, -NH(CH2)2N(Me)2, -NHCH2CH2OH1 -NHCH2CH2NEt2, -NHCH2CH2NPr2, -CHCH2CH2N(Me)CH2CH2OMe, -N(CH2CH2OMe)2, -NHCH2CH2N(Me)CH2CH2 CH2OMe, -NHCHaCHzNazetidine-S-OMe, -CH2CH2CH2OP(O)(OH)2,
-CHsCH≥CHzNpyrrolidine, -NHCHzCHaNpiperidine, -NHCH2CH2N-(2,6-diMepiperidine), -CHsCHaCHaNazetidine-S-OMe, -NHCHaCHsCHzNpiperidine-S-OMe, -NHCHaCHaNpiperidine-^OMe, -CH2CH2CH2Npiperidine, -NHCH2CH;>Nmorpholine, -NHCH2CH2Nazepane, -NHCH2CH2NoXaZePmO1-NHCH2CH2CH2OH, -NHCH2CH2CH2N(Me)CH2CH2OMe1 -NHCHzCHsCHsNazetidineOMe -NHCH2CH2CH2N(pyrrolidine-3-CN), -NHCH2CH2CH2Npiperidine-4-OMe, -NHCH2CH2CH2NmOrPhOUnB1 -NHCH2CH2CH2CH2NmOrPhOrInO, -CH2CH2CH2OC(O)CH2CH2CHN(Me)2, and -CH2CH2CH2OC(O)CH(NHCO2tBu)CH2Me2.
Preferably, W and A together represent halo, - NHCH2CH2CH2Nmorpholine, NHCH2CH2N(Me)2 or -CH2CH2CH2NMe2.
Preferably the compound is selected from one or more of the following:
8,9-Dihydro-7H-indeno[5,4-e][1 ,2,4]triazin-3-amine 1 -oxide;
S-Chloro-δ.θ-dihydro-yH-indenotS^-eiπ^^triazine 1 -oxide;
Λ/1,Λ/1-Dimethyl-Λ/2-(1-oxido-8,9-dihydro-7H-indeno[5l4-e][1,2)4]triazin-3-yl)-1l2- ethanediamine; Λ/\Λ/1-Dimethyl-Λ/2-(1 Λ-dioxido-S.Θ-dihydro-yH-indenotδ^-eKI ,2,4]triazin-3-yl)-1 ,2- ethanediamine; Λ/1 lΛ/1-Diethyl-Λ/2-(1-oxido-8,9-dihydro-7H-indeno[5,4-e][1,2,4]triazin-3-yl)-1 ,2- ethanediamine;
Λ/\Λ/1-Diethyl-Λ/2-(1 ,4-dioxido-8,9-dihydro-7W-indeno[5,4-e][1 ,2,4]triazin-3-yl)-1 ,2- ethanediamine; /V1-(1-Oxido-8,9-dihydro-7A7-indeno[5,4-e][1 ,2,4]tιϊazin-3-yl)-Λ/2,Λ/2-dipropyl-1 ,2- ethanediamine;
Λ/1-(1-Oxido-8,9-dihydro-7W-indeno[5,4-e][1,2,4]triazin-3-yl)-Λ/2,Λ/2-dipropyl-1 ,2- ethanediamine;
Λ/-[2-(1-Piperidinyl)ethyl]-8,9-dihydro-7/-/-indeπo[5,4-e][1 ,2,4]triazin-3-amine 1-oxide; Λ/-[2-(1-Piperidinyl)ethyl]-8,9-dihydro-7f/-indeno[5,4-e][1,2,4]triazin-3-amine 1 ,4-dioxide;
Λ/-[3-(1-Morpholinyl)propyl]-8,9-dihydro-7H-indeno[5,4-e][1,2,4]triazin-3-amine 1-oxide;
Λ/-[3-(1-Morpholinyl)propyl]-8,9-dihydro-7f/-indeno[5,4-e][1,2,4]triazin-3-amine 1,4-dioxide;
7,8-Dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1-oxide;
7,8-Dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 ,4-dioxide; 3-Chloro-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazine 1-oxide;
Λ/1,Λ/1-Dimethyl-Λ/2-(1-oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)-1 ,2- ethanediamine;
Λ/1-(1 ,4-Dioxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)-Λ/2,Λ/2-dimethyl-1 ,2- ethanediamine; 2-[(1 -Oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)amino]ethanol;
2-[(1 ,4-Dioxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)amino]ethanol;
Λ/1-(1-Oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)-Λ/2,Λ/2-diethyl-1 ,2- ethanediamine;
Λ/1-(1 ,4-Dioxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)-Λ/2,Λ/2-diethyl-1 ,2- ethanediamine;
Λ/1-(1-Oxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-yl)-Λ/2,W2-dipropyl-1 ,2- ethanediamine;
Λ/1-(1 ,4-Dioxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)-Λ/2,Λ/2-dipropyl-1 ,2- ethanediamine; Λ/1-(1 -Oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)-Λ/2-(2-methoxyethyl)-Λ/2- methyl-1 ,2-ethanediamine;
Λ/1-(1 ,4-dioxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)-Λ/2-(2-methoxyethyl)-Λ/2- methyl-1 ,2-ethanediamine;
Λ/1-(3-Methoxypropyl)-A/1-methyl-Λ/2-(1-oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3- yl)-1 ,2-ethanediamine; Λ/1-(1 ,4-Dioxido-7l8-dihydro-6/-/-indeno[5,6-e][1,2,4]triazin-3-yl)-N2-(3-methoxypropyl)-Λ/2- methyl-1 ,2-ethanediamine;
Λ/-[2-(3-Methoxy-1-azetidinyl)ethyl]-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazin-3-amine 1- oxide; /V-[2-(3-Methoxy-1-azetidinyl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 ,4- dioxide;
Λ/-[2-(1-Piperidinyl)ethyl]-7,8-dihydro-6f/-indeno[5,6-e][1,2,4]triazin-3-amine 1 -oxide;
/V-[2-(1 -Piperidinyl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 ,4-dioxide;
Λ/-[2-(2,6-Dimethyl-1-piperidinyl)ethyl]-7,8-dihydro-6/V-indeno[5,6-e][1,2,4]triazin-3-amine 1 -oxide;
/V-[2-(2,6-Dimethyl-1-piperidinyl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine
1 ,4-dioxide;
Λ/-[2-(3-Methoxy-1-piperidinyl)ethyl]-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazin-3-amine 1- oxide; Λ/-[2-(3-Methoxy-1-piperidinyl)ethyl]-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazin-3-amine
1 ,4-dioxide;
Λ/-[2-(4-Methoxy-1-piperidinyl)ethyl]-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazin-3-amine 1- oxide;
Λ/-[2-(4-Methoxy-1-piperidinyl)ethyl]-7,8-dihydro-6/-/-indeno[5,6-e][1,2,4]triazin-3-amine 1 ,4-dioxide;
Λ/-[2-(4-Morpholinyl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-amine 1 -oxide;
Λ/-[2-(4-Morpholinyl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 ,4-dioxide;
Λ/-[2-(1 -Azepanyl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 -oxide;
Λ/-[2-(1-Azepanyl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 ,4-dioxide; Λ/-[2-(1 ,4-Oxazepan-4-yl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1-oxide;
Λ/-[2-(1 ,4-Oxazepan-4-yl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 ,4- dioxide;
3-[(1 -Oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)amino]-1 -propanol;
3-[(1 ,4-Dioxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)amino]-1 -propanol; Λ/1-(1 -Oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)-Λ/3-(2-methoxyethyl)-Λ/3- methyl-1 ,3-propanediamine;
^-(i ^-Dioxido^.δ-dihydro-ΘH-indenofδ.β-elfi ^^ltriazin-S-yO-Λ^^-methoxyethyO-A/3- methyl-1 ,3-propanediamine;
Λ/-[3-(3-Methoxy-1 -azetidinyl)propyl]-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 - oxide; Λ/-[3-(3-Methoxy-1-azetidinyl)propyl]-7l8-dihydro-6/-/-indeno[5,6-e][1 )2,4]triazin-3-amine
1 ,4-dioxide;
I^S-^i-Oxido-y.δ-dihydro-ΘH-indenoCδ.δ-elti^^Jtriazin-S-yOaminolpropylJ-a- pyrrolidinecarbonitrile; 1-{3-[(1 ,4-Dioxido-7,8-dihydro-6f/-indeno[5,6-e][1 ,2,4]triazin-3-yl)amino]propy!}-3~ pyrrolidinecarbonitrile;
Λ/-[3-(4-Methoxy-1-piperidinyl)propyl]-7,8-dihydro-6f/-indeno[5,6-e][1 ,2,4]triazin-3-amine
1 -oxide;
Λ/-[3-(4-Methoxy-1-piperidinyl)propyl]-7,8-dihydro-6f/-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 ,4-dioxide;
Λ/-[3-(4-Morpholinyl)propyl]-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 -oxide;
Λ/-[3-(4-Morpholinyl)propyl]-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 ,4-dioxide;
Λ/-[4-(4-Morpholinyl)butyl]-7,8-dihydro-6/-/-indeno[5,6-e][1,2,4]triazin-3-amine 1 -oxide;
Λ/-[4-(4-Morpholinyl)butyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 ,4-dioxide; 7,8-Dihydro-6/-/-indeno[5,6-e][1,2,4]triazine 1 -oxide;
7,8-Dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazine 1 ,4-dioxide;
3-lodo-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1 -oxide;
Ethyl-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 -oxide;
3-Ethyl-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 ,4-dioxide; 3-Allyl-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazine 1 -oxide;
3-(1-Oxido-7,8-dihydro-6H-indeπo[5,6-e][1 ,2,4]triazin-3-yl)-1-propanol;
3-(1 ,4-Dioxido-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazin-3-yl)-1-propanol;
3-(3-(Di-terf-butoxyphosphoryloxy)propyl)-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 - oxide; 3-(3-(Di-tert-butoxyphosphoryloxy)propyl)-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 ,4- dioxide;
3-(1 ,4-Dioxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)propyl dihydrogen phosphate;
3-[3-(4-Morpholinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 -oxide; 3-[3-(4-Morpholinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 ,4-dioxide;
Λ/,Λ/-Dimethyl-3-(1-oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)-1-propanamine;
Λ/-[3-(1 ,4-Dioxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)propyl]-Λ/,Λ/- dimethylamine;
Λ/,Λ/-Bis(2-methoxyethyl)-3-(1-oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)-1- propanamine; Λ/-[3-(1 ,4-Dioxido-7)8-dihydro-6H-indeno[5,6-e][1 l2,4]tria2in-3-yl)propyl]-Λ/,Λ/-bis(2- methoxyethyl)amine;
3-[3-(3-Methoxy-1-azetidinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 -oxide;
3-[3-(3-Methoxy-1 -azetidinyl)propyl]-7,8-dihydro-6W-indeno[5,6-e][1 ,2,4]triazine 1 ,4- dioxide;
3-[3-(1-Pyrrolidinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1 -oxide;
3-[3-(1-Pyrrolidinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1 ,4-dioxide;
3-[3-(1-Piperidinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1 -oxide;
3-[3-(1-Piperidinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1 ,4-dioxide; 7-Methyl-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-amine 1 -oxide;
3-Chloro-7-methyl-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1 -oxide;
Λ/1,Λ/1-Dimethyl-Λ/2-(7-methyl-1-oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)-1 ,2- ethanediamine;
Λ/1,Λ/1-Dimethyl-Λ/2-(7-methyl-1 ,4-dioxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)- 1 ,2-ethanediamine;
7-Methyl-Λ/-[3-(4-morpholinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-amine 1- oxide;
7-Methyl-Λ/-[3-(4-morpholinyl)propyl]-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazin-3-amine
1 ,4-dioxide; 3-lodo-7-methyl-7,8-dihydro-6/-/-indeno[5,6-e][1,2,4]triazine 1 -oxide;
3-(7-Methyl-1-oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)propanal;
7-Methyl-3-[3-(4-morpholinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 -oxide;
7-Methyl-3-[3-(4-morpholinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 ,4- dioxide; 3-(7-Methyl-1 ,4-dioxido-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazin-3-yl)-1 -propanol;
Λ/7,Λ/7-Dimethyl-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine-3,7-diamine 1-oxide;
3-Chloro-Λ/,Λ/-dimethyl-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-7-amine 1-oxide;
Λ/3-Ethyl-Λ/7,Λ/7-dimethyl-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazine-3,7-diamine 1-oxide;
Λ/3-Ethyl-Λ/7,Λ/7-dimethyl-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine-3,7-diamine 1 ,4- dioxide;
7-(Dimethylamino)-3-ethyl-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 -oxide;
7-(Dimethylamino)-3-ethyl-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 ,4-dioxide;
(3-Amino-1-oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-7-yl)methanol;
(3-Bromo-1-oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-7-yl)methanol; [3-(Ethylamino)-1 -oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-7-yl]methanol;
[3-(Ethylamino)-1 ,4-dioxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-7-yl]methanol; 7-({[te/if-Butyl(dimethyl)siIyl]oxy}methyl)-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-amine
1 -oxide;
7-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-3-iodo-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine
1 -oxide; 7-({[te/τf-Butyl(dimethyl)silyl]oxy}methyl)-3-ethyl-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazine
1 -oxide;
(3-Ethyl-1 ,4-dioxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-7-yl)methanol;
3-Allyl-7-({[tenf-butyl(dimethyl)silyl]oxy}methyl)-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine
1 -oxide; 3-[7-({[ferf-Butyl(dimethyl)silyl]oxy}methyl)-1 -oxido-7,8-dihydro-6H-indeno[5,6- e][1 ,2,4]triazin-3-yl]-1 -propanol;
7-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-3-[3-(4-morpholinyl)propyl]-7,8-dihydro-6H- indeno[5,6-e][1 ,2,4]triazine 1 -oxide;
{3-[3-(4-Morpholinyl)propyl]-1-oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-7- yl}methanol;
{3-[3-(4-Morpholinyl)propyl]-1 ,4-dioxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-7- yljmethanol;
(3-EthyI-1-oxido-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazin-7-yl)methanol;
3-Ethyl-7-(4-morpholinylmethyl)-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 -oxide; 3-Ethyl-7-(4-morpholinylmethyl)-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 ,4-dioxide;
2-(3-Amino-1-oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-7-yl)ethanol;
2-(3-lodo-1-oxido-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazin-7-yl)ethanol;
3-lodo-7-(2-(tetrahydro-2/-/-pyran-2-yloxy)ethyl)-7,8-dihydro-6H-indeno[5,6- e][1,2,4]triazine 1 -oxide; 3-Ethyl-7-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-7,8-dihydro-6H-indeno[5,6- e][1,2,4]triazine 1 -oxide;
2-(3-Ethyl-1-oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-7-yl)ethanol;
2-(3-Ethyl-1 ,4-dioxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-7-yl)ethanol;
3-Ethyl-7-[2-(4-morpholinyl)ethyl]-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazine 1 -oxide; 3-Ethyl-7-[2-(4-morpholinyl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 ,4-dioxide;
7,8,9, 10-Tetrahydronaphtho[2, 1 -e][1 ,2,4]triazin-3-amine 1 -oxide;
3-Chloro-7,8,9,10-tetrahydronaphtho[2,1-e][1 ,2,4]triazine 1 -oxide;
Λ/1,Λ/1-Dimethyl-Λ/2-(1-oxido-7,8,9,10-tetrahydronaphtho[2,1-e][1 ,2,4]triazin-3-yl)-1 ,2- ethanediamine; Λ/1-(1 ,4-Dioxido-7,8,9,10-tetrahydronaphtho[2,1-e][1 ,2,4]triazin-3-yl)-Λ/2,Λ/2-dimethyl-1 ,2- ethanediamine; 6,7,8,9-Tetrahydronaphtho[2,3-e][1 ,2,4]triazin-3-amine 1 -oxide;
3-Chloro-6,7,8,9-tetrahydronaphtho[2,3-e][1 ,2,4]triazine 1 -oxide;
Λ/1-(1-Oxido-6,7,8,9-tetrahydronaphtho[2,3-e][1 ,2,4]triazin-3-yl)-Λ/2,Λ/2-dimethyl-1 ,2- ethaπediamine; A/1-(1 ,4-Dioxido-6,7,8,9-tetrahydronaphtho[2,3-e][1 ,2,4]triazin-3-yl)-Λ/2,Λ/2-dimethyl-1 ,2- ethanediamine;
Λ/-[3-(4-Morpholinyl)propyl]-6,7,8,9-tetrahydronaphtho[2,3-e][1 ,2,4]triazin-3-amine 1 -oxide;
Λ/-[3-(4-Morpholinyl)propyl]-6,7,8,9-tetrahydronaphtho[2,3-e][1 ,2,4]triazin-3-amine 1 ,4- dioxide; 7,8,9,10-Tetrahydro-6H-cyclohepta[g][1 , 2, 4]benzotriazin-3-amine 1 -oxide;
3-Chloro-7,8,9,10-tetrahydro-6/-/-cyclohepta[g][1 ,2,4]benzotriazine 1 -oxide;
Λ/1,Λ/1-Dimethyl-Λ/2-(1-oxido-7,8,9,10-tetrahydro-6H-cyclohepta[g][1 ,2,4]benzotriazin-3-yl)-
1 ,2-ethanediamine;
Λ/1-(1 ,4-Dioxido-7,8,9,10-tetrahydro-6H-cyclohepta[g][1 ,2,4]benzotriazin-3-yl)-Λ/2,Λ/2- dimethyl-1 ,2-ethanediamine;
6,7-Dihydrofuro[3,2-g][1 ,2,4]benzotriazin-3-amine 1 -oxide;
3-Chloro-6,7-dihydrofuro[3,2-g][1 ,2,4]benzotriazine 1 -oxide;
Λ/1,Λ/1-Dimethyl-Λ/2-(1-oxido-6,7-dihydrofuro[3,2-g][1 ,2,4]benzotriazin-3-yl)-1 ,2- ethanediamine; /V1-(1 ,4-Dioxido-6,7-dihydrofuro[3,2-g][1 ,2,4]benzotriazin-3-yl)-Λ/2,Λ/2-dimethyl-1 ,2- ethanediamine;
Λ/-[3-(4-Morpholinyl)propyl]-6,7-dihydrofuro[3,2-g][1 ,2,4]benzotriazin-3-amine 1 -oxide;
Λ/-[3-(4-Morpholinyl)propyl]-6,7-dihydrofuro[3,2-g][1 ,2,4]benzotriazin-3-amine 1 ,4-dioxide;
3-Amino-7,8-dihydrobenzofuro[6,5-e][1 ,2,4]triazine 1 -oxide; 1 ,4-Dioxido-7,8-dihydrofuro[2,3-g][1 ,2,4]benzotriazin-3-ylamine;
3-Chloro-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 -oxide;
Λ/1-(1-Oxido-7,8-dihydrofuro[2,3-g][1 ,2,4]benzotriazin-3-yl)-Λ/2,Λ/2-dimethyl-1 ,2- ethanediamine;
Λ/1-(1 ,4-Dioxido-7,8-dihydrofuro[2,3-g][1 ,2,4]benzotriazin-3-yl)-Λ/2,Λ/2-dimethyl-1 ,2- ethanediamine;
Λ/1-(1-Oxido-7,8-dihydrofuro[2,3-g][1 ,2,4]benzotriazin-3-yl)-Λ/2,Λ/2-diethyl-1 ,2- ethanediamine;
Λ/1-(1 ,4-Dioxido-7,8-dihydrofuro[2,3-g][1 ,2,4]benzotriazin-3-yl)-Λ/2,Λ/2-diethyl-1 ,2- ethanediamine; /V-[3-(4-Morpholinyl)propyl]-7,8-dihydrofuro[2,3-g][1 ,2,4]benzotriazin-3-amine 1 -oxide;
Λ/-[3-(4-Morpholinyl)propyl]-7,8-dihydrofuro[2,3-g][1 ,2,4]benzotriazin-3-amine 1 ,4-dioxide; 3-lodo-7,8-dihydrobenzofuro[6,5-e][1 ,2,4]triazine 1 -oxide;
3-(1-Oxido-7,8-dihydrofuro[2,3-g][1 ,2,4]benzotriazin-3-yl)propanal;
3-[3-(4-Morpholinyl)propyl]-7,8-dihydrofuro[2,3-g][1 ,2,4]benzotriazine 1-oxide;
3-[3-(4-Morpholinyl)propyl]-7,8-dihydrofuro[2,3-g][1 ,2,4]benzotriazine 1 ,4-dioxide; [1 ,3]Dioxolo[4,5-g][1 ,2,4]benzotriazin-3-amine 1-oxide;
3-Chloro[1 ,3]dioxolo[4,5-g][1 ,2,4]benzotriazine 1 -oxide;
Λ/1,Λ/1-DimethyI-Λ/2-(1-oxido[1 ,3]dioxolo[4,5-g][1 ,2,4]benzotriazin-3-yl)-1 ,2-ethanediamine;
Λ/1-(1 ,4-Dioxido[1 ,3]dioxolo[4,5-g][1 ,2,4]benzotriazin-3-yl)-Λ/2,Λ/2-dimethyl-1 ,2- ethanediamine; 9,10-Dihydro-8H-chromeno[6,5-e][1 ,2,4]triazin-3-amine 1-oxide;
3-Chloro-9, 10-dihydro-8H-chromeno[6,5-e][1 ,2,4]triazine 1 -oxide;
Λ/1 ,Λ/1-Dimethyl-Λ/2-(1 -oxido-9, 10-dihydro-8H-chromeno[6,5-e][1 ,2,4]triazin-3-yl)-1 ,2- ethanediamine;
Λ/1-(1 ,4-Dioxido-9, 10-dihydro-8H-chromeno[6,5-e][1 ,2,4]triazin-3-yl)-Λ/2,Λ/2-dimethyl-1 ,2- ethanediamine;
7,8-Dihydro-6H-chromeno[6,7-e][1 ,2,4]triazin-3-amine 1-oxide;
3-ChlorO-7,8-dihydro-6H-chromeno[6,7-e][1 ,2,4]triazine 1 -oxide;
Λ/1,Λ/1-Dimethyl-Λ/2-(1-oxido-7,8-dihydro-6H-chromeno[6,7-e][1 ,2,4]triazin-3-yl)-1 ,2- ethanediamine; Λ/1-(1 ,4-Dioxido-7,8-dihydro-6H-chromeno[6,7-e][1 ,2,4]triazin-3-yl)-Λ/2,Λ/2-dimethyl-1 ,2- ethanediamine;
/V-[3-(4-Morpholinyl)propyl]-7,8-dihydro-6H-chromeno[6,7-e][1 ,2,4]triazin-3-amine 1-oxide;
Λ/-[3-(4-Morpholinyl)propyl]-7,8-dihydro-6H-chromeno[6,7-e][1 ,2,4]triazin-3-amine 1 ,4- dioxide; 7-Ethyl-1 -oxido-7,8-dihydro-6H-[1 ,2,4]triazino[5,6-/]isoindol-3-ylamine;
7-Ethyl-1 ,4-dioxido-7,8-dihydro-6H-[1 ,2,4]triazino[5,6-/]isoindol-3-ylamine;
7-Methyl-6,7,8,9-tetrahydro[1 ,2,4]triazino[6,5-g]isoquinolin-3-amine 1-oxide;
3-Chloro-7-methyl-6,7,8,9-tetrahydro[1,2,4]triazino[6,5-g]isoquinoline 1-oxide;
Λ/-Ethyl-7-methyl-6,7,8,9-tetrahydro[1 ,2,4]triazino[6,5-g]isoquinolin-3-amine 1-oxide; Λ/-Ethyl-7-methyI-6,7,8,9-tetrahydro[1 ,2,4]triazino[6,5-g]isoquinolin-3-amine 1 ,4-dioxide;
3-Ethyl-7-methyl-6,7,8,9-tetrahydro[1 ,2,4]triazino[6,5-g]isoquinoline 1-oxide;
3-Ethyl-7-methyl-6,7,8,9-tetrahydro[1 ,2,4]triazino[6,5-g]isoquinoline 1 ,4-dioxide;
9-Methyl-7,8,9,10-tetrahydro[1 ,2,4]triazino[5,6-/7]isoquinolin-3-amine 1-oxide;
3-Chloro-9-methyl-7,8,9,10-tetrahydro[1,2,4]triazino[5,6-h]isoquinoline 1-oxide; 3-Ethyl-9-methyl-7,8,9,10-tetrahydro[1,2,4]triazino[5,6-/7]isoquinoline 1-oxide;
3-Ethyl-9-methyl-7,8,9, 10-tetrahydro[1 ,2,4]triazino[5,6-/?]isoquinoline 1 ,4-dioxide; 3-(3-(4-(Dimethylamino)butanoyloxy)propyl)-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]tria2ine 1- oxide; and
3-(3-(2-(tert-Butoxycarbonylamino)-3-methylbutanoyloxy)propyI)-7,8-dihydro-6H- indeno[5,6-e][1 ,2,4]triazine 1 -oxide.
More preferably, the compound of Formula I is 3-[3-(4-Morpholinyl)propyl]-7,8-dihydro-6H- indeno[5,6-e][1,2,4]triazine 1 ,4-Dioxide or Λ/-[3-(4-Morpholinyl)propyl]-7,8-dihydro-6H- indeno[5,6-e][1 ,2,4]triazin-3-amine 1 ,4-dioxide.
In a second aspect the invention provides a method of therapy for treating cancers including the step of administering a compound of Formula I as defined above in a therapeutically effective amount to tumour cells in a subject.
Preferably the tumour cells are in a hypoxic environment.
It is preferred that the method of therapy further includes the step of administering radiotherapy to the tumor cells before, during or after the administration of the compound of Formula I as defined above to the tumour cells.
It is preferred that the method of therapy further includes the step of administering one or more chemotherapeutic agents to the tumor cells before, during or after the administration of the compound of Formula I as defined above to the tumour cells.
While these compounds will typically be used in cancer therapy of human subjects, they can be used to target tumor cells in other warm blooded animal subjects such as other primates, farm animals such as cattle, and sports animals and pets such as horses, dogs, and cats.
A "therapeutically effective amount", is to be understood as an amount of a compound of Formula I as defined above that is sufficient to show benefit to a patient. The actual amount, rate and time-course of administration, will depend on the nature and severity of the disease being treated. Prescription of treatment is within the responsibility of general practitioners and other medical doctors.
A hypoxic environment is to be understood as either an in vitro environment with an oxygen concentration less than 10 μM, or an in vivo environment having a lower oxygen tension than normal tissues. It is to be understood that the compound of Formula I can be administered alone or in combination with other chemotherapeutic agents or treatments, especially radiotherapy, either simultaneously or sequentially dependent upon the condition to be treated.
Preferred chemotherapeutic agents can be selected from: Cisplatin or other platinum-based derivatives, Temozolomide or other DNA methylating agents, Cyclophosphamide or other DNA alkylating agents, Doxorubicin, mitoxantrone, camptothecin or other topoisomerase inhibitors, Methotrexate, gemcitabine or other antimetabolites and Docetaxel or other taxanes.
In a third aspect of the present invention there is provided a pharmaceutical composition including a therapeutically effective amount of a compound of formula I, a pharmaceutically acceptable excipient, adjuvant, carrier, buffer or stabiliser.
The pharmaceutically acceptable excipient, adjuvant, carrier, buffer or stabiliser should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material will depend on the route of administration, which can be oral, or by injection, such as cutaneous, subcutaneous, or intravenous injection.
Pharmaceutical compositions for oral administration can be in tablet, capsule, powder or liquid form. A tablet can comprise a solid carrier or an adjuvent. Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol can be included. A capsule can comprise a solid carrier such as gelatin.
For intravenous, cutaneous or subcutaneous injection, the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has a suitable pH, isotonicity and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride injection, Ringer's injection, Lactated Ringer's injection. Preservatives, stabilisers, buffers antioxidants and/or other additives can be included as required. In a fourth aspect of the present invention there is provided a method of making a compound of Formula I or a pharmacologically acceptable salt thereof,
Figure imgf000022_0001
Formula I
wherein n, X, Z, W and A are as defined above;
the method including the steps of reacting a nitroaniline compound of Formula Il
Figure imgf000022_0002
Formula Il wherein X and Z are as defined above for a compound of Formula I, with cyanamide followed by a cyclisation step under basic conditions to give a mono-oxide compound of Formula I where n represents 0 and of optionally oxidising the mono-oxide compound of Formula I to form a dioxide compound of Formula I where n represents 1.
In a further embodiment, the method may include the steps of converting a monoxide of Formula III
Figure imgf000022_0003
Formula III wherein X and Z are as defined above for a compound of Formula I; to a mono-oxide compound of Formula IV
A
Figure imgf000022_0004
Formula IV wherein X and Z are as defined above for a compound of Formula III and W and A are as defined above for a compound of Formula I and together represent other than halo; and of optionally oxidising the resulting mono-oxide compound to form a dioxide compound of Formula I
Figure imgf000023_0001
Formula I where n represents 1 and X, Z, W and A are as defined above for a compound of Formula I.
In the method defined above the halo of formula III represents chloro, bromo or iodo.
In a further aspect there is provided a method of making a compound of Formula I as defined above including the step of reacting a nitroaniline compound of Formula Il
Figure imgf000023_0002
Formula Il Formula V wherein X and Z are as defined above for a compound of Formula I, with sodium hypochlorite in the presence of a base to form a furoxan of Formula V wherein X and Z are as defined above for a compound of Formula I, and reacting the compound of Formula V with a substituted cyanamide to give a dioxide compound of Formula I where n represents 1.
In a further aspect there is provided a compound of Formula I obtained by the methods defined above.
In another aspect there is provided a method of improving the response of tumours to radiotherapy, comprising the steps of:
(a) administering to the subject a pharmaceutical composition in an amount sufficient to kill or radiosensitise hypoxic cells in tumours, the composition comprising a compound of
Formula I as defined above and
(b) subjecting the tumour to radiation either before or after administration of the said pharmaceutical composition. In another aspect, there is provided the use in the manufacture of a medicament of a therapeutically effective amount of compound of Formula I as defined above for the treatment of tumour cells in a subject.
Preferably, the tumour cells are in a hypoxic environment.
It is to be recognised that certain compounds of the present invention may exist in one or more different enantiomeric or diastereomeric forms. It is to be understood that the enantiomeric or diasteriomeric forms are included in the above aspects of the invention.
The term halo or halogen group used throughout the specification is to be taken as meaning a fluoro, chloro, bromo or iodo group.
It is to be understood that where variables of the Formula I to V as defined above are optionally substituted by one or more imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl groups that the linkage to the relevant variable may be through either one of the available nitrogen or carbon ring atoms of these groups.
It is to be understood that where reference is made throught the specification to a CrC6 alkyl or C2-C6 alkenyl group, these groups may be unbranched or branched. For example it is intended that reference to a C1-C6 alkyl would include a tertbutyl (Me)3C- group.
The term pharmacologically acceptable salt used throughout the specification is to be taken as meaning any acid or base derived salt formed from hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic, isoethonic acids and the like and potassium carbonate sodium or potassium hydroxide ammonia, triethylamine, triethanolamine and the like.
Further aspects of the present invention will become apparent from the following description given by way of example only and with reference to the accompanying synthetic schemes and figures in which:
Figure 1 illustrates the activity of compound 77 against hypoxic cells in HT29 tumours, Figure 2 illustrates by way of a plot the activity of a single dose (0.75 x MTD) TPZ and compounds 61 and 77 against hypoxic cells in three human tumour xenograft models: HT29, human colon carcinoma; SiHa, human cervical carcinoma; H460, non-small cell lung carcinoma.
Figure 3 illustrates by way of a plot the activity of fractionated dose TPZ and compound 77 against hypoxic cells in three human tumour xenograft models: H460, non-small cell lung carcinoma; HT29, human colon carcinoma; SiHa, human cervical carcinoma. Drugs (1.0 x fractionated MTD) were administered 30 min before each of 8 x 2.5 Gy doses of radiation.
DETAILED DESCRIPTION OF THE INVENTION Methods for preparing compounds of Formula I of the invention. Acetylation of 5-aminoindan (1) followed by nitration, separation of the acetanilides and hydrolysis gave the nitroanilines 2 and 3 (Scheme 1). Treatment of nitroaniline 3 with cyanamide under acidic conditions followed by cyclisation under basic conditions gave amine 4. Diazotisation and chlorination of 4 gave chloride 5. Reaction of the chloride 5 with Λ/,Λ/-dimethylethylenediamine gave 1-oxide 6, which was selectively oxidised to 1 ,4- dioxide 7 using the trifluoroacetate salt of the aliphatic amine as a protecting group.
Scheme 1
Figure imgf000025_0001
Reagents: a) Ac2O, dioxane; b) KNO3, CH2SO4; c) 5 M HCI; d) NH2CN, HCI; then NaOH; e) NaNO21 TFA; f) POCI3, DMF; g) NH2CH2CH2NMe21 DME; h) CF3CO3H, CF3CO2H, DCM. Similarly, reaction of 5 with a variety of amines gave 1 -oxides 8, 10, 12, and 14 that were oxidised to the corresponding 1 ,4-dioxides 9, 11, 13, and 15 (Scheme 2).
Scheme 2
Figure imgf000026_0001
8, 10, 12, 14 9, 11, 13, 15
Reagents: a) amine, DME; b) CF3CO3H, CF3CO2H, DCM.
Figure imgf000026_0002
In an alternative preparation of nitroaniline 2, acetylation of 5-aminoindan (1) gave acetamide 16 (Scheme 3). Nitration of acetamide 16 with nitric acid in acetic acid gave predominantly 6-nitroacetanilide 17 with minor amounts of 4-nitroacetanilide 18. Hydrolysis of nitroacetanilide 17 with cHCI in EtOH gave nitroaniline 2. Treatment of nitroaniline 2 with cyanamide under acidic conditions followed by cyclisation under basic conditions gave 1 -oxide 19. Oxidation of 1 -oxide 19 gave 1 ,4-dioxide 20. Diazotisation and chlorination of 1-oxide 19 gave chloride 21. Reaction of the chloride 21 with N1N- dimethylethylenediamine gave 1-oxide 22 which was oxidised to 1 ,4-dioxide 23.
W
Scheme 3
Figure imgf000027_0001
Reagents: a) Ac2O, dioxane; b) CHNO3, HOAc; c) CHCI1 EtOH; d) NH2CN, HCI; then NaOH; e) CF3CO3H, CF3CO2H, DCM; f) NaNO21 TFA; g) POCI31 DMF; h) NH2CH2CH2NMe2, DME.
Similarly, reaction of 21 with a variety of amines gave 1 -oxides 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, and 62 which were oxidised to the corresponding 1 ,4-dioxides 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, and 63 (Scheme 4).
Scheme 4
33,
43,
53,
Figure imgf000027_0002
63 Reagents: a) amine, DME; or amine, Et3N, DME; b) CF3CO3H, CF3CO2H, DCM.
Figure imgf000028_0002
Reaction of amine 19 with tert-butyl nitrite in DMF gave the 1-oxide 64, which was oxidised to 1 ,4-dioxide 65 (Scheme 5).
Scheme 5
Figure imgf000028_0001
Reagents: a) te/f-Butyl nitrite, DMF; b) CF3CO3H1 DCM.
Diazotisation of amine 19 in the presence of iodine and copper iodide gave iodide 66 (Scheme 6). Negishi reaction of iodide 66 with ethyl magnesium bromide gave 3-ethyl-1- oxide 67 that was oxidised to 1,4-dioxide 68. Alternatively, Stille coupling of chloride 21 with tetraethyltin gave 67. Scheme 6
Figure imgf000029_0001
Reagents: a) terf-BuNOz, CH2I2, CuI, THF; b) EtMgBr, ZnCI2 Et2O, Pd(PPh3)4, THF; c) CF3CO3H1 DCM d) Et4Sn, Pd(dppf)CI2, THF.
Stille coupling of iodide 66 with allyltributyltin gave alkene 69 which underwent hydroboration to give alcohol 70 (Scheme 7). Alternatively, reaction of iodide 66 with allyl alcohol using Heck conditions followed by reduction of the intermediate aldehyde gave alcohol 70. Oxidation of alcohol 70 gave 1 ,4-dioxide 71.
Scheme 7
Figure imgf000029_0002
Reagents: a) AIIyISnBu3, Pd(PPh3)4, THF; b) 9-BBN, THF; NaOH, H2O2; c) Allyl alcohol, Pd(OAc)2, nBu4NCI, NaHCO3, MeCN ; d) NaBH4, MeOH, -40 0C e) CF3CO3H, DCM. Reaction of the alcohol 70 with di-terf-butyldiethylphosphoramidite in the presence of tetrazole with subsequent oxidation of the intermediate phosphite gave phosphate ester 72 (Scheme 8). Oxidation of ester 72 gave 1 ,4-dioxide 73, which was deprotected to give phosphate 74.
Scheme 8
Figure imgf000030_0001
Reagents: a) Di-tert-butyldiethylphosphoramidite, tetrazole, THF, then MCPBA; b) MCPBA, NaHCO3, DCM; c) CF3CO2H, DCM.
Heck reaction of iodide 66 with allyl alcohol gave the unstable aldehyde 75 that was converted to 1 -oxide 76 by reductive amination with morpholine and sodium cyanoborohydride (Scheme 9). Oxidation of 1 -oxide 76 with trifluoroperacetic acid gave 1 ,4-dioxide 77.
Scheme 9
Figure imgf000030_0002
Reagents: a) Allyl alcohol, Pd(OAc)2, nBu4NBr, NaHCO3, DMF; b) Morpholine, NaBH3CN, EtOH; then HOAc; c) CF3CO3H, CF3CO2H, DCM. A similar sequence of reactions converted 66 to 1 -oxides 78, 82, 82, 84, and 86, which were oxidised to the corresponding 1 ,4-dioxides 79, 81, 83, 85, and 87 (Scheme 10).
Scheme 10
Figure imgf000031_0001
Reagents: a) AIIyI alcohol, Pd(OAc)2, nBu4NBr, NaHCO3, DMF; b) Amine, NaBH3CN, EtOH; then HOAc; c) CF3CO3H, CF3CO2H, DCM.
Figure imgf000031_0002
Nitration of 2-methyl-1-indanone (88) gave a mixture of nitroindanones 89 and 90 (Scheme 11). Reduction of nitroindanone 90 and acetylation gave acetamide 91 that was nitrated to give nitroacetamide 92. Hydrolysis of 92 gave the nitroaniline 93. Treatment of nitroaniline 93 with cyanamide under acidic conditions followed by cyclisation under basic conditions gave 1 -oxide 94. Diazotisation and chlorination of 1 -oxide 94 gave chloride 95. Reaction of chloride 95 with Λ/,/V-dimethylethylenediamine gave 1 -oxide 96 which was oxidised to 1 ,4-dioxide 97.
Scheme 11
Figure imgf000032_0001
Reagents: a) fHNO3; b) H2, Pd/C, EtOH, aq HCI; c) Ac2O, dioxane; d) HNO3, CF3CO2H; e) cHCI, EtOH; f) NH2CN, HCI; then NaOH; g) NaNO21 TFA; h) POCI3, DMF; i) NH2CH2CH2NMe2, DME; j) CF3CO3H, CF3CO2H, DCM.
Similarly, reaction of chloride 95 with 3-(4-morpholinyl)propylamine gave 1 -oxide 98 which was oxidised to 1 ,4-dioxide 99 (Scheme 12).
Scheme 12
Figure imgf000032_0002
Reagents: a) NH2CH2CH2CH2Nmorpholine, Et3N, DME; b) CF3CO3H, CF3CO2H, DCM. Diazotisation of amine 94 in the presence of diiodomethane gave iodide 100 (Scheme 13). Heck coupling of iodide 100 with allyl alcohol gave the unstable aldehyde 101 which underwent reductive amination with morpholine to give 1 -oxide 102. Alcohol 103 was also isolated from the reaction mixture. Oxidation of 1 -oxides 102 and 103 gave 1 ,4-dioxides 104 and 105, respectively.
Scheme 13
Figure imgf000033_0001
Reagents: a) JBuNO2, CH2I2, CuI, THF; b) Allyl alcohol, Pd(OAc)2, nBu4NBr, NaHCO3, DMF; c) Morpholine, NaBH3CN, EtOH; then HOAc; d) CF3CO3H, CF3CO2H, DCM.
Mesylation of 2-indanol (106) and displacement of the mesylate with methylamine gave the indanamine 107 (Scheme 14). Nitration of indanamine 107 with nitric acid in trifluoroacetic acid gave predominantly the 5-nitroindanamine 108 which was reduced by catalytic hydrogenation and subsequent acetylation to give acetamide 109. Nitration of acetamide 109 with nitric acid in trifluoroacetic acid gave a 6:1 mixture of 6-nitro:4- nitroacetamide isomers which was hydrolysed with ethanolic HCI and recrystallised to give pure 6-nitro-5-aniline 110. Treatment of nitroaniline 110 with cyanamide under acidic conditions followed by cyclisation under basic conditions gave amine 111. Diazotisation and chlorination of 111 gave chloride 112. Reaction of chloride 112 with aqueous ethylamine gave 1 -oxide 113, which was oxidised to 1 ,4-dioxide 114. Scheme 14
Figure imgf000034_0001
106 107 108
Figure imgf000034_0002
110 111 112
Figure imgf000034_0003
Reagents: a) MsCI1 JPr2NEt1 DCM; b) aq. HNMe2, DMF; c) CHNO3, CF3CO2H; d) H2, Pd/C, EtOH; e) Ac2O, dioxane; f) CHNO31 CF3CO2H; g) CHCI1 EtOH; h) NH2CN, HCI; then NaOH; i) NaNO2, TFA; j) POCI3, DMF; k) aq. EtNH2, DME;
I) CF3CO3H, DCM.
Strife coupling of chloride 112 with tetraethyltin gave 1 -oxide 115, which was oxidised to 1 ,4-dioxide 116 (Scheme 15).
Scheme 15
Figure imgf000034_0004
Reagents: a) Et4Sn, Pd(PPh3)4, DME; b) CF3CO3H, CF3CO2H, DCM.
Nitration of 1,2-bis(bromomethyl)benzene (117) gave 4-nitrobenzene 118 (Scheme 16). Condensation of 118 with diethylmalonate gave the acid 119, which was reduced to alcohol 120 with diborane. Catalytic hydrogentation of 120 followed by acetylation with acetic anhydride gave acetamide 121. Nitration of acetamide 121 gave the 5-nitroisomer 122 which was hydrolysed under acidic conditions to give nitroaniline 123. Treatment of nitroaniline 123 with cyanamide under acidic conditions followed by cyclisation under basic conditions gave amine 124. Diazotisation and bromination of 124 gave bromide 125. Reaction of the bromide 125 with aqueous ethylamine gave 1-oxide 126 that was oxidised to 1,4-dioxide 127.
Scheme 16
Figure imgf000035_0001
Reagents: a) KNO3 , CH2SO4; b) NaH, CH2(CO2Et)2, Et2O; c) 2 M NaOH, EtOH; then 1 M HCI; d) Reflux, xylene; e) BH3 DMS1 THF; f) H2, Pd/C, MeOH; g) Ac2O1 Et3N1 DCM; h) CHNO31 CF3CO2H; i) 5 M HCI, MeOH; j) NH2CN, HCI; then NaOH; k) NaNO21 HBr1 DMF; I) aq. EtNH2, DME; m) H2O2, CH3CO2H.
Hydrolysis of 2-indanecarbonitrile (128) (G.M. Ksander et al., J. Med. Chem. 2001, 44, 4677-4687) gave the acid 129 (Scheme 17). Nitration of acid 129 gave a mixture of nitroindanes 119 and 130, which was reduced to a mixture of alcohols 120 and 131 using diborane. Hydrogenation of the mixture of 120 and 131 followed by acetylation with acetic anhydride and subsequent nitration gave acetamide 122. Hydrolysis of acetamide 122 under acidic conditions gave nitroaniline 123. Treatment of nitroaniline 123 with cyanamide under acidic conditions followed by cyclisation under basic conditions gave amine 124. Protection of 124 as the silylether 132 and diazotisation in the presence of diiodomethane and CuI predominantly gave the iodide 133 and lesser amounts of the deaminated product 134. Stille coupling of iodide 133 with tetraethyltin gave 1 -oxide 135 that was oxidised to give 1 ,4-dioxide 136.
Scheme 17
Figure imgf000037_0001
123 124 132
Figure imgf000037_0002
133 134 k
Figure imgf000037_0003
Reagents: a) cHCI, dioxane; b) CHNO31 CF3CO2H; c) BH3 DMS1 THF; d) H2, Pd/C, MeOH; e) Ac2O, Et3N, DCM; f) CHNO31 CF3CO2H; g) 5 M HCI, MeOH; h) NH2CN, HCI; then NaOH; i) TBDMSCI, JPr2NEt, DMF; j) ferf-BuNO2) CH2I2, CuI1 THF; k) Et4Sn, Pd(PPh3).), DME;
I) H2O2, CH3CO2H.
Stille coupling of iodide 133 with allyltributyltin gave alkene 137, which underwent hydroboration with 9-BBN to give alcohol 138 (Scheme 18). Mesylation and displacement of alcohol 138 with morpholine gave 1-oxide 139 that was deprotected to give alcohol 140 and oxidised to give 1 ,4-dioxide 141.
Scheme 18
Figure imgf000038_0001
138 139
Figure imgf000038_0002
Reagents: a) AIIyIBu3Sn, Pd(PPh3)4, DME; b) 9-BBN, THF, 3M NaOAc, 70% H2O2; c) MsCI, JPr2NEt, DCM; d) Morpholine; e) 1 M HCI, MeOH; f) CF3CO3H, CF3CO2H, DCM.
Hydrolysis of silylether 135 gave alcohol 142 (Scheme 19). Mesylation of alcohol 142 and displacement with morpholine gave 1-oxide 143 that was oxidised to give 1 ,4-dioxide 144.
Scheme 19
Figure imgf000038_0003
135 142
Figure imgf000038_0004
Reagents: a) 1 M HCI, MeOH; b) MsCI, JPr2NEt, DCM; c) Morpholine; d) CH3CO3H, CH3CO2H, DCM.
Condensation of 1-indanone (145) with glyoxylic acid gave unsaturated acid 146 that was reduced by catalytic hydrogenation to indane acetic acid 147 (Scheme 20) (Nagasawa, et al., Japanese Patent 4338358, 1992). Esterification of acid 147 gave ester 148 which was reduced to alcohol 149 with LiAIH4. Acetylation of alcohol 149 gave acetate 150 that was nitrated to give an inseparable mixture of nitroindanes 151 and 152. The mixture was reduced by catalytic hydrogenation and acetylated with acetic anhydride to give a mixture of acetanilides 153 and 154. The mixture of 153 and 154 was nitrated with cHNO3 in trifluoroacetic acid and a single isomer, nitroacetanilide 155, was isolated by crystallisation. Hydrolysis of nitroacetanilide 155 gave nitroaniline 156. Treatment of nitroaniline 156 with cyanamide under acidic conditions followed by cyclisation under basic conditions gave amine 157. Diazotisation of amine 157 in the presence of iodine and CuI gave iodide 158 that was protected as the tetrahydropyranyl ether 159. Stille coupling of iodide 159 with tetraethyltin gave 1 -oxide 160, which was deprotected to give alcohol 161 and then oxidised to give 1 ,4-dioxide 162.
Scheme 20
Figure imgf000040_0001
145 146 147
Figure imgf000040_0002
158 159
Figure imgf000040_0003
Reagents: a) aq. glyoxylic acid, CH2SO4; b) H2, Pd/C, MeOH, dioxane; c) CH2SO41 EtOH; d) LiAIH41 THF; e) Ac2O, pyridine, DMAP, DCM; f) Ac2O, Cu(NO3)2-3H2O, DCM; g) H2, Pd/C, MeOH; h) Ac2O, dioxane; i) CHNO3, CF3CO2H; j) 5 M HCI, MeOH; k) NH2CN, HCI; then NaOH;
I) tert-BuNO2, I2, CuI, THF; m) Dihydropyran, PPTS, DCM; n) Et4Sn, Pd(PPh3)4, DME; O) MeSO3H, MeOH; p) CF3CO2H, DCM.
Mesylation of alcohol 161 and displacement with morpholine gave 1 -oxide 163 that was oxidised to give 1 ,4-dioxide 164 (Scheme 21).
Scheme 21
Figure imgf000041_0001
Reagents: a) MsCI, NEt3, DCM; b) morpholine; c) CF3CO3H, CF3CO2H, DCM.
Nitration of 1-tetralone (165) followed by reduction and acetylation gave acetamide 166 (Scheme 22). Further nitration gave a mixture of isomers including 157 and 168.
Hydrolysis of 168 gave nitroaniline 169, which was treated with cyanamide under acidic conditions followed by cyclisation under basic conditions to give amine 170. Diazotisation and chlorination of 170 gave chloride 171. Reaction of the chloride 171 with N,N- dimethylethylenediamine gave 1 -oxide 172 which was oxidised to 1,4-dioxide 173.
Scheme 22
Figure imgf000042_0001
Reagents: a) KNO3, CH2SO4; b) H2, Pd/C, EtOH, EtOAc, HCI; c) Ac2O, dioxane; d) KNO3, CH2SO4; e) 6 M HCI; f) NH2CN, HCI; g) NaOH; h) NaNO2, TFA; i) POCI3, DMF; j) NH2CH2CH2NMe2, DME; k) CF3CO3H, CF3CO2H, DCM.
Deprotection of acetamide 167 under acidic conditions gave nitroaniline 174 (Scheme 23). Treatment of nitroaniline 174 with cyanamide under acidic conditions followed by cyclisation under basic conditions gave 1 -oxide 175. Diazotisation and chlorination of 175 gave chloride 176. Reaction of the chloride 176 with /V,Λ/-dimethylethylendiarnine gave 1- oxide 177 which was oxidised to 1 ,4-dioxide 178. Scheme 23
Figure imgf000043_0001
Reagents: a) HCI; b) NH2CN, HCI; then NaOH; c) NaNO21 TFA; d) POCI3, DMF; e) NH2CH2CH2NMe21 DME; f) CF3CO3H, CF3CO2H, DCM.
Similarly, reaction of chloride 176 with 3-(4-morpholinyl)propylamine gave 1 -oxide 179 which was oxidised to 1 ,4-dioxide 180 (Scheme 24).
Scheme 24
Figure imgf000043_0002
Reagents: a) NH2CH2CH2CH2Nmorpholine, Et3N, DME; b) CF3CO3H, CF3CO2H, DCM.
Nitration of 1-benzosuberone (181) followed by reduction and acetylation gave an acetamide which was further nitrated to give nitroacetanilides 182-184 (Scheme 25). Hydrolysis of acetanilide 182 gave nitroaniline 185. Treatment of nitroaniline 185 with cyanamide under acidic conditions followed by cyclisation under basic conditions gave amine 186. Diazotisation and chlorination of 186 gave chloride 187. Reaction of chloride 187 with Λ/,Λ/-dimethylethylendiamine gave 1-oxide 188 which was oxidised to 1,4-dioxide 189. Scheme 25
Figure imgf000044_0001
Reagents: a) fHNO3, CH2SO4; b) H2, Pd/C, EtOH/EtOAc; c) Ac2O, dioxane; d) KNO31 CH2SO4; e) 5 M HCI; f) NH2CN, HCI; then NaOH; g) NaNO21 TFA; h) POCI3, DMF; i) NH2CH2CH2NMe2, DME; j) CF3CO3H, CF3CO2H, DCM.
Friedel-Crafts acylation of 2,3-dihydrobenzofuran (190) gave ketone 191 which was converted to the oxime and underwent Beckmann rearrangement to the acetamide 192 (Scheme 26). Nitration of acetamide 192 gave nitroacetamide 193, which was hydrolysed to give nitroaniline 194. Treatment of nitroaniline 194 with cyanamide under acidic conditions followed by cyclisation under basic conditions gave amine 195. Diazotisation and chlorination of 195 gave chloride 196. Reaction of the chloride 196 with N1N- dimethylethylendiamine gave 1 -oxide 197 which was oxidised to 1 ,4-dioxide 198.
Figure imgf000045_0001
Reagents: a) AICI31 ACCI1 DCM; b) NH2OH HCI, pyridine, MeOH; then Ac2O, HOAc, HCI; c) KNO31 CH2SO4; d) 5 M HCI; e) NH2CN, HCI; f) NaOH; g) NaNO21 TFA; h) POCI3, DMF; i) NH2CH2CH2NMe2, DME; j) CF3CO3H, CF3CO2H, DCM.
Similarly, reaction of chloride 196 with 3-(4-morpholinyl)propylamine gave 1-oxide 199 which was oxidised to 1 ,4-dioxide 200 (Scheme 27).
Scheme 27
Figure imgf000045_0002
Reagents: a) NH2CH2CH2CH2Nmorpholine, DME; b) CF3CO3H, CF3CO2H, DCM. Preparation of 5-nitro-6-aminodihydrobenzofuran (203) was achieved using the method of Schroeder et al., (Schroeder, E et.al., European J. Med. Chem. 1982, 17, 35-42). Thus, diazotisation of nitroaniline 194 and reaction with phosphoric acid gave 6- nitrodihydrobenzofuran 201 (Scheme 28). Reduction of the nitro group over platinum oxide and subsequent acetylation gave acetamide 202. Nitration and deprotection gave 5- nitroaniline 203. Treatment of nitroaniline 203 with cyanamide under acidic conditions followed by cyclisation under basic conditions gave 1 -oxide 204, which was oxidised to 1 ,4-dioxide 205.
Scheme 28
Figure imgf000046_0001
Reagents: a) NaNO2, CH2SO4; b) 50% aq. H3PO2; c) H2, PtO2, EtOH; d) Ac2O, dioxane; e) 70% HNO3, HOAc; f) cHCI, EtOH; g) NH2CN, HCI; then NaOH; h) CF3CO3H, CF3CO2H, DCM.
Diazotisation and chlorination of amine 204 gave chloride 206 (Scheme 29). Reaction of chloride 206 with a variety of amines gave 1 -oxides 207, 209, and 211, which were oxidised to the corresponding 1,4-dioxides 208, 210, and 212.
Scheme 29
Figure imgf000046_0002
Reagents: a) NaNO21 TFA; b) POCI3, DMF; c) Amine, DME; d) CF3CO3H1 CF3CO2H1 DCM.
Figure imgf000047_0002
Diazotisation of amine 204 in the presence of diiodomethane and CuI gave iodide 213 (Scheme 30). Heck coupling of iodide 213 with allyl alcohol gave the unstable aldehyde 214 which underwent reductive amination with morpholine to give 1 -oxide 215. Oxidation of 1 -oxide 215 gave 1 ,4-dioxide 216.
Scheme 30
Figure imgf000047_0001
Reagents: a) tert-BuNO2, CH2I2, CuI, THF; b) allyl alcohol, Pd(OAc)2, nBu4NBr, NaHCO3, DMF; c) morpholine, NaBH3CN, EtOH; then HOAc; d) CF3CO3H, CF3CO2H, DCM.
Nitroaniline 220 was prepared from 3,4-methylendioxyaniline (217) according to the method of Krasso (Krasso, A. & Ramuz, H., US Patent 4599347, 1986). Thus, acetylation of 3,4-methylenedioxyaniline (217) gave acetamide 218 (Scheme 31). Nitration of acetamide 218 gave nitroacetamide 219, which was hydrolysed to give nitroaniline 220. Treatment of nitroaniline 220 with cyanamide under acidic conditions followed by cyclisation under basic conditions gave amine 221. Diazotisation and chlorination of 221 gave chloride 222. Reaction of the chloride 222 with Λ/,Λ/-dimethylethylendiamine gave 1- oxide 223, which was oxidised to 1 ,4-dioxide 224.
Scheme 31
Figure imgf000048_0001
Reagents: a) Ac2O, dioxane; b) CHNO3, HOAc; c) NaOMe, MeOH; d) NH2CN, HCI; then NaOH; e) NaNO21 TFA; f) POCI3, DMF; g) NH2CH2CH2NMe21 DME; h) CF3CO3H, CF3CO2H, DCM.
Nitration of 4-chromanone (225) gave nitrochromanone isomers 226 and 227 (Scheme 32). Reduction of nitrochromanone 227 and acetylation gave acetamide 228. Alternatively, reduction of chromanone 225 gave chroman 229 which underwent Friedel-Crafts acylation to give ketone 230. Reaction of ketone 230 with hydroxylamine gave the oxime which underwent Beckmann rearrangement to give acetamide 228. Further nitration of 228 gave nitroacetamides 231 and 232. Hydrolysis of acetamide 231 gave nitroaniline 233. Treatment of nitroaniline 233 with cyanamide under acidic conditions followed by cyclisation under basic conditions gave amine 234. Diazotisation and chlorination of 234 gave chloride 235. Reaction of chloride 235 with Λ/,Λ/-dimethylethylendiamine gave 1- oxide 236 which was oxidised to 1 ,4-dioxide 237.
Figure imgf000049_0001
Reagents: a) KNO3, CH2SO4; b) H2, Pd/C, EtOH/EtOAc, HCI; c) Ac2O, dioxane; d) Zn, HOAc; e) AICI3, AcCI, DCM; f) NH2OH HCI, pyridine, MeOH; g) Ac2O, HOAc, HCI; h) KNO31 CH2SO4; i) NaOH, aq EtOH; j) NH2CN, HCI; k) NaOH;
1) NaNO2, TFA; m) POCI3, DMF; n) NH2CH2CH2NMe2, DME; o) CF3CO3H, CF3CO2H, DCM.
Hydrolysis of acetamide 232 gave nitroaniline 238 (Scheme 33). Treatment of nitroaniline 238 with cyanamide under acidic conditions followed by cyclisation under basic conditions gave amine 239. Diazotisation and chlorination of 239 gave chloride 240. Reaction of chloride 240 with Λ/,Λ/-dimethylethylendiamine gave 1 -oxide 241 which was oxidised to 1 ,4-dioxide 242. Similarly, reaction of the chloride 240 with 3-(4-morpholinyl)propylamine gave 1 -oxide 243 which was oxidised to 1 ,4-dioxide 244.
Scheme 33
Figure imgf000050_0001
Reagents: a) HCI, aq EtOH; b) NH2CN1 HCI; c) NaOH; d) NaNO21 TFA; e) POCI31 DMF; f) NH2CH2CH2NMe2, DME; g) CF3CO3H, CF3CO2H, DCM; h) NH2CH2CH2CH2Nmorpholine, DME.
Reaction of dibromide 118 with ethylamine gave nitroisoindole 245 (Scheme 34). Catalytic hydrogenation of 245 followed by acetylation gave acetamide 246. Further nitration of 246 gave nitroacetanilide 247 which was hydrolysed to give nitroaniline 248. Treatment of nitroaniline 248 with cyanamide under acidic conditions followed by cyclisation under basic conditions gave amine 249, which was oxidised to 1 ,4-dioxide 250. Scheme 34
Figure imgf000051_0001
Reagents: a) EtNH2, Et3N, DMF; b) H2, Pd/C, MeOH; c) Ac2O, dioxane; d) KNO3, CH2SO4; e) 5 M HCI; f) NH2CN, HCI; then NaOH; g) H2O2, CF3CO2H, DCM.
Reductive alkylation of tetrahydroisoquinoline 251 gave amine 252 (Scheme 35). Catalytic hydrogenation of 252 followed by acetylation gave acetamide 253. Nitration of acetamide 253 gave a mixture of nitroacetamides which was hydrolysed under acidic conditions and purified by chromatography to give 8-nitroaniline 254 and 6-nitroaniline 255. Treatment of nitroaniline 255 with cyanamide under acidic conditions followed by cyclisation under basic conditions gave amine 256. Diazotisation and chlorination of 256 gave chloride 257. Reaction of the chloride 257 with ethylamine gave 1 -oxide 258 which was oxidised to 1 ,4- dioxide 259. Scheme 35
Figure imgf000052_0001
Reagents: a) Ac2O, HCO2H, THF; b) BH3 DMS1 THF; c) H2, Pd/C, EtOH; d) Ac2O, dioxane; e) KNO31 CH2SO4; f) 5 M HCI; g) NH2CN, HCI; then NaOH; h) NaNO21 TFA; i) POCI3, DMF; j) EtNH2, DME; k) CF3CO3H, CF3CO2H, DCM.
Stille coupling of chloride 257 with tetraethyltin gave 1 -oxide 260, which was oxidised to 1 ,4-dioxide 261 (Scheme 36).
Scheme 36
Figure imgf000052_0002
Reagents: a) Et4Sn1 Pd(PPhS)41 DME; b) CF3CO3H1 CF3CO2H1 DCM. Treatment of nitroaniline 254 with cyanamide under acidic conditions followed by cyclisation under basic conditions gave amine 262 (Scheme 37). Diazotisation and chlorination of 262 gave chloride 263. Stille coupling of chloride 263 with tetraethyltin gave 1-oxide 264, which was oxidised to 1,4-dioxide 265.
Scheme 37
Figure imgf000053_0001
Reagents: a) NH2CN, HCI; then NaOH; b) NaNO2, TFA; c) POCI3, DMF; d) Et4Sn, Pd(PPh3)4, DME; e) CF3CO3H, CF3CO2H, DCM.
Two general methods were used to synthesize amine sidechains which coupled to various chlorides described above. In the first method, the addition of an amine to an aqueous solution of glycolonitrile gave a nitrile, which was reduced to the diamine. Thus, reaction of amine 266 with glycolonitrile gave nitrile 267, which was reduced using Raney Nickel and H2 to give diamine 268 (Scheme 38).
Scheme 38
^\^,0Me ,.0Me H2N. ΛMe
HN NC N
Me Me Me
266 267 268
Reagents: a) aq. Glycolonitrile; b) H2, Raney Nickel, cNH3, EtOH. Protection of amine 269 as the carbamate 270, followed by O-alkylation to give ether 271 and deprotection gave amine 272. Reaction of amine 272 with glycolonitrile gave nitrile 273 which was reduced to diamine 274 (Scheme 39).
Scheme 39
Figure imgf000054_0001
d
HΛM.
HN'^-'^OMe - NC^ OMe N "OMe Me Me Me 272 273 274
Reagents: a) Di-ferf-butyl dicarbonate , CHCI3 ) b) KOH, MeI; c) HCI, dioxane; d) aq. Glycolonitrile, Et3N; e) H2, Raney Nickel, CNH3, EtOH.
Reaction of amine 275 with glycolonitrile gave nitrile 276, which was reduced using Raney Nickel and H2 to give diamine 277 (Scheme 40).
Scheme 40 a b
HN' "^- -UMe — "- NC "~-N-Λ
^OMe ^OMe
275 276 277
Reagents: a) aq. Glycolonitrile; b) H2, Raney Nickel, cNH3, EtOH.
Reaction of amine 278 with glycolonitrile gave nitrile 279, which was reduced using Raney Nickel and H2 to give diamine 280 (Scheme 41).
Scheme 41
Figure imgf000054_0002
Reagents: a) aq. Glycolonitrile; b) H2, Raney Nickel, cNH3, EtOH.
Reaction of amine 281 with glycolonitrile gave nitrile 282, which was reduced using Raney Nickel and H2 to give diamine 283 (Scheme 42).
Scheme 42
Figure imgf000055_0001
Reagents: a) aq. Glycolonitrile, Et3N; b) H2, Raney Nickel, cNH3, EtOH.
Reaction of amine 286, prepared by O-alkylation of the carbamate 284, to give ether 285 which was deprotected, gave nitrile 287 which was reduced to diamine 288 (Scheme 43).
Scheme 43
Figure imgf000055_0002
^^OMe ^^OMe ^^OMe
286 287 288 Reagents: a) KOH, MeI, DMSO; b) HCI, dioxane; c) aq. Glycolonitrile; d) H2, Raney Nickel, cNH3, EtOH.
Reaction of azepane (289) with glycolonitrile gave nitrile 290, which was reduced using Raney Nickel and H2 to give diamine 291 (Scheme 44). Scheme 44
Figure imgf000056_0001
Reagents: a) aq. Glycolonitrile; b) H2, Raney Nickel, cNH3, EtOH.
Reaction of oxazepane (292) with glycolonitrile gave nitrile 293, which was reduced using Raney Nickel and H2 to give diamine 294 (Scheme 45).
Scheme 45
HN^0 . NC-N^0 H2N^ x Q
292 293 294
Reagents: a) aq. Glycolonitrile; b) H2, Raney Nickel, cNH3, EtOH.
In the alternative method for synthesizing the amine sidechains the appropriate bromoalkylphthalimide was condensed with a secondary amine and then reduced with hydrazine to give the diamine. Thus, reaction of bromoethylphthalimide with N,N- dipropylamine (295) gave phthalimide 296, which was reduced with hydrazine hydrate in EtOH to give diamine 297 (Scheme 46).
Scheme 46
Figure imgf000056_0002
Reagents: a) Λ/-(2-Bromoethyl)phthalimide, K2CO3, DMF; b) N2H4 H2O1 EtOH.
Similarly, reaction of bromopropylphthalimide with amine (266) gave phthalimide 298, which was reduced with hydrazine hydrate in EtOH to give diamine 299 (Scheme 47). Scheme 47
Figure imgf000057_0001
Reagents: a) Λ/-(2-Bromopropyl)phthalimide, K2CO3, DMF; b) N2H4 H2O1 EtOH.
Similarly, reaction of bromopropylphthalimide with azetidine 275 gave phthalimide 300, which was reduced with hydrazine hydrate in EtOH to give diamine 301 (Scheme 48).
Scheme 48
Figure imgf000057_0002
Reagents: a) Λ/-(2-Bromopropyl)phthaIimide, K2CO3, DMF; b) N2H4 H2O, EtOH.
Similarly, reaction of bromopropylphthalimide with pyrrolidine 302 gave phthalimide 303, which was reduced with hydrazine hydrate in EtOH to give diamine 304 (Scheme 49).
Scheme 49
HNxAcN
Figure imgf000057_0003
302 303 304
Reagents: a) Λ/-(2-Bromopropyl)phthalimide, K2CO3, DMF; b) N2H4 H2O1 EtOH.
Similarly, reaction of bromopropylphthalimide with piperdine 286 gave phthalimide 305, which was reduced with hydrazine hydrate in EtOH to give diamine 306 (Scheme 50). Scheme 50
Figure imgf000058_0001
Reagents: c) Λ/-(2-Bromopropyl)phthalimide, K2CO3, DMF; d) N2H4 H2O, EtOH.
Similarly, reaction of bromobutylphthalimide with morpholine gave phthalimide 307, which was reduced with hydrazine hydrate in EtOH to give diamine 308 (Scheme 51).
Scheme 51
Figure imgf000058_0002
307 308
Reagents: e) Λ/-(2-Bromobυtyl)phthalimide, K2CO3, DMF; f) N2H4 H2O, EtOH.
Reaction of the alcohol 70 with 4-(dimethylamino)butanoic acid in the presence of DCC gave 1 -oxide 309 (Scheme 52). Similarly reaction of alcohol 70 with N-(tert- butoxycarbonyl)-L-valine gave carbamate 311.
Scheme 52
Figure imgf000058_0003
310
Reagents: a) Me2NCH2CH2CH2CO2H, DCC, DCM; b) Λ/BOC-L-valine, DCC1 DCM; It is to be appreciated that many variations and modifications of the reagents and starting materials in the schemes above could be readily brought about by a skilled artisan to make further compounds of Formula I without departing from the scope of the invention as defined. For example the benzo ring of the compounds of Formula I could be substituted with X groups, where X is other than H, by making or obtaining an appropriately substituted nitroaniline compound and where necessary protecting that substituent with appropriate protecting groups throughout the rest of the synthesis to ensure that the desired substitutent is carried through to the compound of Formula I.
Examples of the compounds of the invention
The following examples are representative of the invention and the detailed methods for preparing them; however, the scope of the invention is not to be taken as being limited to these examples.
Analyses were carried out in the Microchemical Laboratory, University of Otago, Dunedin, NZ. Melting points were determined on an Electrothermal 2300 Melting Point Apparatus. NMR spectra were obtained on a Bruker Avance 400 spectrometer at 400 MHz for 1H and 100 MHz for 13C spectra. Spectra were obtained in CDCI3 unless otherwise specified, and were referenced to Me4Si. Chemical shifts and coupling constants were recorded in units of ppm and Hz, respectively. Assignments were determined using COSY, HSQC, and HMBC two-dimensional experiments. Low resolution mass spectra were gathered by direct injection of methanolic solutions into a Surveyor MSQ mass spectrometer using an atmospheric pressure chemical ionization (APCI) mode with a corona voltage of 50 V and a source temperature of 400 0C. Low resolution mass spectra were also determined on a VG-70SE mass spectrometer using an ionizing potential of 70 eV at a nominal resolution of 1000. High-resolution spectra were obtained at nominal resolutions of 3000, 5000, or 10000 as appropriate. All spectra were obtained as electron impact (El) spectra using PFK as the reference unless otherwise stated. Solutions in organic solvents were dried with anhydrous Na2SO4. Solvents were evaporated under reduced pressure on a rotary evaporator. Thin-layer chromatography was carried out on aluminum-backed silica gel plates (Merck 60 F254) with visualization of components by UV light (254 nm) or exposure to I2. Column chromatography was carried out on silica gel (Merck 230-400 mesh). Ac2O refers to acetic anhydride; DCM refers to dichloromethane; DME refers to dimethoxyethane, DMF refers to dry /V,Λ/-dimethylformamide; ether refers to diethyl ether; EtOAc refers to ethyl acetate; EtOH refers to ethanol; HOAc refers to acetic acid; MeOH refers to methanol; pet. ether refers to petroleum ether, boiling range 40-60 0C; TFA refers to trifluoroacetic acid; TFAA refers to trifluoroacetic anhydride;THF refers to tetrahydrofuran dried over sodium benzophenone ketyl.
Example 1
8,9-Dihydro-7/V-indeno[5,4-e][1,2,4]triazin-3-amine 1 -Oxide (4). 6-Nitro-5-indanamine (2) and 4-Nitro-5-indaπamine (3). Ac2O (15.6 mL, 165 mmol) was added dropwise to a stirred solution of 5-aminoindan (1) (10 g, 75.1 mmol) in dioxane (40 mL) at 5 °C and the solution stirred at 20 0C for 16 h. The solution was diluted with water (100 mL) and the precipitate filtered, washed with water (2 x 10 mL) and dried. The solid was dissolved in CH2SO4 (100 mL) and cooled to 5 0C. A solution of KNO3 (8.35 g, 82.6 mmol) in CH2SO4 (15 mL) was added dropwise and the solution stirred at 5 0C for 2 h, then at 20 0C for 2 h. The solution was poured into ice/water (500 mL) and the suspension stirred for 2 h. The precipitate was filtered, washed with water (2 x 20 mL) and dried. The solid was purified by chromatography, eluting with a gradient (20-40%) of EtOAc/pet. ether, to give (i) Λ/-(6-nitro-2,3-dihydro-1H-inden-5-yl)acetamide (3.97 g, 24%) as a colourless solid: mp (EtOAc/pet. ether) 105-108 0C [lit. (Schroeder, E., et al., European J. Med. Chem. 1982, 17, 35) mp 108-109 0C]; (ii) Λ/-(4-nitro-2,3-dihydrσ-1H-inden-5- yl)acetamide (0.92 g, 5%) as a white solid: 1H NMR δ 9.51 (br s, 1 H, NHCO), 8.28 (d, J = 8.3 Hz, 1 H, H-7), 7.41 (d, J = 8.3 Hz, 1 H, H-6), 3.25 (br t, J = 7.5 Hz, 2 H, H-1), 2.96 (br t, J = 7.6 Hz, 2 H, H-3), 2.22 (s, 3 H, CH3), 2.07-2.13 (m, 2 H, H-2); 13C NMR δ 164.1 , 143.3, 142.1, 134.6, 131.9, 130.9, 117.3, 35.5, 32.1, 24.9; and (iii) Λ/-(7-nitro-2,3-dihydro- 1A7-inden-5-yl)acetamide (6.48 g, 39%) as a white solid: 1H NMR δ 7.94 (s, 1 H, H-5), 7.89 (s, 1 H, H-7), 7.44 (br s, 1 H, NHCO), 3.36 (br t, J = 7.5 Hz, 2 H, H-3), 2.92 (br t, J = 7.6 Hz, 2 H, H-1), 2.20 (s, 3 H, CH3), 2.09-2.18 (m, 2 H, H-2).
A suspension of Λ/-(6-nitro-2,3-dihydro-1H-inden-5-yl)acetamide (0.90 g, 4.09 mmol) in 5 M HCI was heated at 100 0C for 16 h. The suspension was cooled to 20 0C, diluted with water (100 mL), filtered, washed with water (3 x 15 mL) and dried to give 6-nitro-5- indanamine 2 (0.69 g, 95%) as an orange solid: 1H NMR δ 7.93 (s, 1 H, H-7), 6.64 (s, 1 H, H-4), 5.99 (br s, 2 H, NH2), 2.79-2.88 (m, 4 H, H-1 , H-3), 2.02-2.10 (m, 2 H, H-2); 13C NMR δ 154.3, 144.2, 134.0, 131.3, 120.8, 113.5, 33.0, 31.4, 25.7. A suspension of Λ/-(4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide (0.90 g, 4.09 mmol) in 5 M HCI was heated at 100 0C for 16 h. The suspension was cooled to 20 0C, diluted with water (100 mL), filtered, washed with water (3 x 15 mL) and dried to give 4-nitro-5- indanamine 3 (Schroeder, E, et al., European J. Med. Chem. 1982, 17, 35) (0.69 g, 95%) as an orange solid: mp (H2O) 105-107 0C; 1H NMR δ 7.17 (d, J = 8.2 Hz, 1 H, H-7), 6.62 (d, J = 8.2 Hz, 1 H, H-6), 5.73 (br s, 2 H, NH2), 3.32 (br t, J = 7.5 Hz, 2 H, H-3), 2.80-2.85 (m, 2 H, H-1), 2.02-2.11 (m, 2 H, H-2). Anal, calcd for C9H10N2O2: C, 60.7; H, 5.7; N, 15.7. Found: C, 60.5; H, 5.5; N, 15.8%.
8,9-Dihydro-7H-indeno[5,4-e][1,2,4]triazin-3-amine 1 -Oxide (4). A mixture of 4-nitro-5- indanamine (3) (0.67 g, 3.8 mmol) and cyanamide (0.63 g, 15.0 mmol) were mixed together at 100 0C, cooled to 50 0C, cHCI (5 ml_) added carefully and the mixture heated at 100 0C for 4 h. The mixture was cooled to 50 0C, 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100 °C for 3 h. The mixture was cooled, diluted with water (100 ml_), filtered, washed with water (3 x 20 ml_), washed with ether (3 x 5 ml_) and dried. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give amine 4 (279 mg, 37%) as a yellow powder: mp (MeOH/DCM) 270-274 0C; 1H NMR [(CD3)2SO] δ 7.56 (d, J = 8.4 Hz, 1 H, H-6), 7.31 (d, J = 8.4 Hz, 1 H, H-5), 6.79 (br s, 2 H1 NH2), 3.55 (br t, J = 7.5 Hz, 2 H, H-9), 2.95 (br t, J = 7.7 Hz, 2 H, H-7), 2.09-2.20 (m, 2 H, H-8); 13C NMR [(CD3)2SO] δ 159.4, 148.7, 140.9, 136.0, 131.6, 128.1 , 123.9, 34.6, 32.1 , 24.1. Anal, calcd for C10H10N4O: C, 59.4; H, 5.0; N, 27.7. Found: C, 59.5; H, 5.0; N, 27.7%.
Example 2 3-Chloro-8,9-dihydro-7H-indeno[5,4-e][1 ,2,4]triazine 1 -Oxide (5). NaNO2 (167 mg, 2.4 mmol) was added in small portions to a stirred solution of amine 4 (244 mg, 1.2 mmol) in TFA (10 ml_) at 5 0C and the solution stirred at 20 0C for 3 h. The solution was poured into ice/water, stirred for 30 minutes, filtered, washed with water (3 x 30 mL) and dried. The solid was suspended in POCI3 (20 mL) and DMF (0.3 mL) and stirred at 100 0C for 1 h. The solution was cooled, poured into ice/water, stirred for 30 minutes, filtered, washed with water (3 x 30 mL) and dried. The solid was suspended in DCM (100 mL), dried and the solvent evaporated. The residue was purified by chromatography, eluting with 5% EtOAc/DCM, to give chloride 5 (215 mg, 80%) as a pale yellow solid: mp (DCM/EtOAc) 162-164 0C; 1H NMR δ 7.81 (d, J = 8.4 Hz, 1 H, H-6), 7.74 (d, J = 8.4 Hz, 1 H, H-5), 3.70 (dd, J = 8.0, 7.3 Hz, 2 H, H-9), 3.11 (dd, J = 8.0, 7.6 Hz, 2 H, H-7), 2.22-2.30 (m, 2 H, H- 8); 13C NMR δ 155.0, 148.4, 146.8, 137.0, 132.8, 131.5, 126.1 , 34.4, 32.9, 24.3. Anal, calcd for C10H8CIN3O: C, 54.2; H, 3.6; N, 19.0. Found: C, 54.2; H, 3.8; N, 18.9%. Example 3
Figure imgf000062_0001
ethanediamine (6). Λ/,Λ/-Dimethyl-1 ,2-ethanediamine (0.28 mL, 2.5 mmol) was added to a stirred solution of chloride 5 (187 mg, 0.8 mmol) in DME (30 mL), and the solution stirred at reflux temperature for 2 h. The solvent was evaporated and the residue was partitioned between DCM (100 ml_) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 6 (201 mg, 88%) as a pale yellow solid: mp (MeOH/EtOAc) 186-190 0C; 1H NMR δ 7.54 (d, J = 8.4 Hz, 1 H, H-6), 7.37 (d, J = 8.4 Hz, 1 H, H-5), 5.80 (br s, 1 H, NH), 3.63 (br t, J = 7.3 Hz, 2 H, H-9), 3.52- 3.57 (m, 2 H, CH2N), 2.96 (br t, J = 7 Hz, 2 H, H-7), 2.57 (t, J = 6.0 Hz, 2 H, CH2N), 2.29 [s, 6 H, N(CHs)2], 2.12-2.21 (m, 2 H, H-8); 13C NMR δ 158.5, 149.0, 142.0, 137.3, 132.2, 129.2, 124.7, 57.6, 45.0 (2), 38.7, 35.3, 32.9, 24.8. Anal, calcd for Ci4H19N5O y4H2O: C, 60.5; H1 7.1; N, 25.2. Found: C, 60.6; H, 6.6; N, 25.4%.
Example 4
Figure imgf000062_0002
ethanediamine (7). H2O2 (70%, 0.33 mL, ca. 6.7 mmol) was added dropwise to a stirred solution of TFAA (0.94 mL, 6.7 mmol) in DCM (10 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to a stirred solution of 1-oxide 6 (182 mg, 0.7 mmol) and TFA (0.10 mL, 1.3 mmol) in CHCI3 (15 mL) at 0 0C. The solution was stirred at 5 0C for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCI3 (4 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 ,4-dioxide 7 (60 mg, 31%) as a red solid: mp (MeOH/EtOAc) 153-156 0C; 1H NMR δ 8.12 (d, J = 8.7 Hz, 1 H, H-5), 7.70 (d, J = 8.7 Hz, 1 H, H-6), 7.37 (br s, 1 H, NH), 3.71 (br t, J = 7.4 Hz, 2 H, H-9), 3.60-3.64 (m, 2 H, CH2N), 3.03 (br t, J = 7.8 Hz, 2 H, H-7), 2.61 (t, J = 6.0 Hz, 2 H, CH2N), 2.30 [s, 6 H, N(CH3)2], 2.17-2.26 (m, 2 H, H-8); 13C NMR δ 149.1 , 144.7, 138.6, 138.4, 132.7, 129.1 , 115.8, 57.6, 45.2 (2), 38.8, 35.1, 32.9, 24.6; MS m/z 289 (M+, 0.5%), 273 (2), 256 (3), 58 (100); HRMS calcd for C14H19N5O2 (M+) m/z 289.1539, found 289.1536.
Example 5
/V1,Λ/1-Diethyl-Λ/2-(1-oxido-8,9-dihydro-7H-indeno[5,4-e][1,2,4]triazin-3-yl)-1,2- ethanediamine (8). Λ/,Λ/-Diethyl-1 ,2-ethanediamine (0.41 mL, 2.9 mmol) was added to a stirred solution of chloride 5 (215 mg, 1.0 mmol) in DME (30 mL) and the solution stirred at reflux temperature for 5 h. The solvent was evaporated and the residue was partitioned between DCM (100 ml_) and dilute aqueous NH3 solution (50 ml_). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 -oxide 8 (271 mg, 93%) as a pale yellow solid: mp (MeOH/EtOAc) 126-130 0C; 1H NMR δ 7.54 (d, J = 8.4 Hz, 1 H, H-6), 7.39 (d, J = 8.4 Hz, 1 H, H-5), 5.93 (br s, 1 H, NH), 3.63 (br dd, J = 7.5, 7.4 Hz, 2 H, H-9), 3.52-3.57 (m, 2 H1 CH2N), 2.97 (br dd, J = 7.8, 7.6 Hz, 2 H, H-7), 2.74 (br t, J = 6.0 Hz, 2 H, CH2N)1 2.63 (q, J = 7.4 Hz, 4 H, 2 x CH2N), 2.16 (br p, J = 7.6 Hz, 2 H, H-8), 1.07 (t, J = 7.1 Hz, 6 H, 2 x CH3); 13C NMR δ 158.4, 149.0, 142.0, 137.3, 132.2, 129.2, 124.6, 51.2, 46.6 (2), 38.5, 35.3, 32.8, 24.8, 11.5 (2). Anal, calcd for C16H23N5Oy4H2O: C, 62.8; H, 7.7; N, 22.9. Found: C, 63.0; H, 7.6; N, 22.9%.
Example 6
Figure imgf000063_0001
,2- ethanediamine (9). H2O2 (70%, 0.37 mL, ca. 7.3 mmol) was added dropwise to a stirred solution of TFAA (1.0 mL, 7.3 mmol) in DCM (10 mL) at 0 0C. The solution was stirred at 0 °C for 5 min, warmed to 20 °C for 10 min, then cooled to 0 0C and added to a stirred solution of 1-oxide 8 (219 mg, 0.7 mmol) and TFA (280 μl_, 3.6 mmol) in DCM (15 mL) at 0 0C. The solution was stirred at 20 0C for 16 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCI3 (4 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 ,4-dioxide 9 (91 mg, 31%) as a red solid: mp (MeOH) 138-141 0C; 1H NMR δ 8.11 (d, J = 8.7 Hz, 1 H, H-5), 7.70 (d, J = 8.7 Hz, 1 H1 H- 6), 7.44 (br s, 1 H, NH), 3.70 (br t, J = 7.4 Hz, 2 H, H-9), 3.58-3.63 (m, 2 H, CH2N), 3.03 (br t, J = 7.7 Hz, 2 H, H-7), 2.77 (br dd, J = 6.0, 5.8 Hz, 2 H, CH2N), 2.63 (q, J = 7.1 Hz, 4 H, 2 x CH2N), 2.22 (br p, J = 7.7 Hz, 2 H, H-8), 1.08 (t, J = 7.1 Hz, 6 H, 2 x CH3); 13C NMR δ 149.0, 144.7, 138.6, 138.3, 132.7, 129.0, 115.7, 51.2, 46.8 (2), 38.8, 35.1, 32.9, 25.6, 11.7 (2). Anal, calcd for C16H23N502-1/zH20: C, 58.9; H1 7.4; N, 21.5. Found: C, 59.2; H, 7.2; N, 21.5%.
Example 7
N1-(1 -Oxido-8,9-dihydro-7H-indeno[5,4-e][1.^triazin-S-yO-Λf.Λ^-dipropyM ,2- ethanediamine (10). Λ/,Λ/-Dipropyl-1 ,2-ethanediamine (297) (0.53 g, 3.7 mmol) was added to a stirred solution of chloride 5 (325 mg, 1.5 mmol) in DME (30 mL) and the solution stirred at reflux temperature for 2 h. The solvent was evaporated and the residue was partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 -oxide 10 (454 mg, 94%) as a pale yellow solid: mp (MeOH) 148-151 0C; 1H NMR δ 7.54 (d, J = 8.4 Hz, 1 H, H-6), 7.40 (d, J = 8.4 Hz, 1 H, H-5), 5.77 (br s, 1 H, NH), 3.63-3.68 (m, 2 H, H-9), 3.48- 3.52 (m, 2 H, CH2N), 2.95-3.00 (m, 2 H, H-7), 2.68 (dd, J = 6.0, 5.8 Hz, 2 H, CH2N), 2.40- 2.45 (m, 4 H, 2 x CH2N), 2.16-2.23 (m, 2 H, H-8), 1.43-1.52 (m, 4 H, 2 x CH2), 0.90 (t, J = 7.3 Hz, 6 H, 2 x CH3); 13C NMR δ 158.5, 149.0, 142.0, 137.3, 132.2, 129.2, 124.7, 55.9 (2), 52.6, 38.9, 35.3, 32.9, 24.8, 20.3 (2), 11.9 (2). Anal, calcd for C18H27N5O: C, 65.6; H, 8.3; N, 21.3. Found: C, 65.7; H, 8.6; N, 21.5%.
Example 8
W1-(1 -Oxido-8,9-dihydro-7H-indeno[5,4-e][1 ,2,4]triazin-3-yl)-Λ/2,Λ/2-dipropyl-1 ,2- ethanediamine (11). H2O2 (70%, 0.53 mL, ca. 10.5 mmol) was added dropwise to a stirred solution of TFAA (1.5 mL, 10.5 mmol) in DCM (10 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 °C for 10 min, then cooled to 0 0C and added to a stirred solution of 1-oxide 10 (364 mg, 1.1 mmol) and TFA (0.40 mL, 5.3 mmol) in DCM (15 mL) at 0 0C. The solution was stirred at 20 0C for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCI3 (4 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 ,4-dioxide 11 (207 mg, 57%) as a red solid: mp (MeOH/EtOAc) 133-135 0C; 1H NMR δ 8.11 (d, J = 8.7 Hz1 1 H, H-5), 7.68 (d, J = 8.7 Hz, 1 H, H-6), 7.48 (br s, 1 H, NH), 3.68 (t, J = 7.5 Hz, 2 H, H-9), 3.58-3.64 (m, 2 H, CH2N), 3.02 (t, J = 7.8 Hz, 2 H, H-7), 2.76-2.81 (m, 2 H, CH2N), 2.46-2.55 (m, 4 H, 2 x CH2N), 2.17-2.25 (m, 2 H, H-8), 1.47-1.58 (m, 4 H, 2 x CH2), 0.92 (t, 6 H, J = 7.4 Hz, 2 x CH3); 13C NMR δ 149.1 , 144.7, 138.6, 138.4, 132.6, 129.0, 115.8, 55.9 (2), 52.5, 38.8, 35.1 , 32.9, 24.6, 20.0 (2), 11.8 (2). Anal, calcd for C18H27N5O2: C, 62.6; H, 7.9; N, 20.3. Found: C, 62.7; H, 8.0; N, 20.4%.
Example 9 /V-[2-(1-Piperϊdinyl)ethyl]-8,9-dihydro-7H-indeno[5,4-e][1,2,4]triazin-3-amine 1 -Oxide (12). 2-(1-Piperidinyl)ethylamine (0.32 mL, 2.2 mmol) was added to a stirred solution of chloride 5 (165 mg, 0.7 mmol) in DME (30 mL) and the solution stirred at reflux temperature for 5 h. The solvent was evaporated and the residue was partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 12 (205 mg, 88%) as a pale yellow solid: mp (MeOH) 152-155 0C; 1H NMR δ 7.53 (d, J = 8.4 Hz, 1 H, H-5), 7.38 (d, J = 8.4 Hz, 1 H, H-6), 5.90 (br s, 1 H, NH), 3.60-3.66 (m, 2 H, H-9), 3.48-3.54 (m, 2 H, CH2N), 2.97 (br t, J = 7.7 Hz, 2 H, H-7), 2.57 (dd, J = 6.1 , 5.9 Hz, 2 H, CH2N), 2.38-2.45 (m, 4 H, 2 x CH2N), 2.17 (br p, J = 7.7 Hz, 2 H, H-8), 1.55-1.61 (m, 4 H, 2 x CH2), 1.41-1.48 (m, 2 H, CH2); 13C NMR δ 158.4, 149.0, 142.0, 137.3, 132.2, 129.1 , 124.6, 56.9, 54.2 (2), 37.9, 35.3, 32.8, 25.9 (2), 24.8, 24.4. Anal, calcd for C17H23N5O: C, 65.2; H, 7.4; N1 22.4. Found: C, 65.1; H, 7.2; N1 22.5%.
Example 10 W-[2-(1-Piperidinyl)ethyl]-8,9-dihydro-7H-indeno[5,4-e][1,2,4]triazin-3-amine 1,4-
Dioxide (13). H2O2 (70%, 0.27 mL, ca. 5.4 mmol) was added dropwise to a stirred solution of TFAA (0.8 mL, 5.4 mmol) in DCM (10 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to a stirred solution of 1-oxide 12 (170 mg, 0.5 mmol) and TFA (0.21 mL, 2.7 mmol) in DCM (15 mL) at 0 0C. The solution was stirred at 20 0C for 16 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCI3 (4 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 ,4-dioxide 13 (89 mg, 50%) as a red solid: mp (MeOH/EtOAc) 138-141 0C; 1H NMR δ 8.12 (d, J = 8.7 Hz, 1 H, H-5), 7.70 (d, J = 8.7 Hz, 1 H, H-6), 7.44 (br s, 1 H, NH), 3.70 (br t, J = 7.6 Hz, 2 H, H-9), 3.60-3.64 (m, 2 H, CH2N), 3.04 (br t, J = 7.7 Hz, 2 H, H-7), 2.64 (br t, J = 6.1 Hz, 2 H, CH2N), 2.43-2.50 (m, 4 H, 2 x CH2), 2.21 (br p, J = 7.7 Hz, 2 H, H-8), 1.59-1.65 (m, 4 H, 2 x CH2), 1.42-1.48 (m, 2 H, CH2); 13C NMR δ 149.1 , 144.7, 138.6, 138.4, 132.7, 129.0, 115.7, 56.9, 54.4 (2), 38.1 , 35.1 , 32.9, 25.9 (2), 24.6, 24.3. Anal, calcd for C17H23N5O2 V2H2O: C, 60.3; H, 7.2; N, 20.7. Found: C, 59.9; H, 7.0; N, 20.3%.
Example 11
/V-[3-(1-Morpholinyl)propyl]-8,9-dihydro-7W-indeno[5,4-e][1,2,4]triazin-3-amine 1- Oxide (14). 3-(1-Morpholinyl)propylamine (0.31 mL, 2.1 mmol) was added to a stirred solution of chloride 5 (158 mg, 0.7 mmol) in DME (30 mL) and the solution stirred at reflux temperature for 5 h. The solvent was evaporated and the residue was partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 14 (212 mg, 91%) as a pale yellow solid: mp (MeOH/EtOAc) 179-181 0C; 1H NMR δ 7.54 (d, J = 8.4 Hz, 1 H, H-5), 7.37 (d, J = 8.4 Hz, 1 H, H-6), 6.11 (br s, 1 H, NH), 3.73-3.78 (m, 4 H, 2 x CH2O), 3.63 (brt, J = 7.6 Hz, 2 H, H-9), 3.55-3.60 (m, 2 H, CH2N), 2.97 (br t, J = 7.7 Hz1 2 H, H-7), 2.43-2.52 (m, 6 H, 3 x CH2N)1 2.18 (br p, J = 7.7 Hz, 2 H, H-8), 1.90-1.96 (m, 2 H, CH2); 13C NMR δ 158.5,
149.0, 142.0, 137.3, 132.2, 129.1 , 124.6, 67.0 (2), 57.2, 53.7 (2), 40.7, 35.3, 32.8, 25.3, 24.8. Anal. CaICcI fOr C17H23N5O-1Z4H2O: C, 61.2; H, 7.1 ; N, 21.0. Found: C, 61.2; H, 7.0; N, 21.0%.
Example 12
N-[Z-Ci -Morpholinyl)propyl]-8,9-dihydro-7H-indeno[5,4-e][1 ,2,4]triazin-3-amine 1 ,4-
Dioxide (15). H2O2 (70%, 0.27 ml_, ca. 5.3 mmol) was added dropwise to a stirred solution of TFAA (0.8 mL, 5.3 mmol) in DCM (10 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to a stirred solution of 1 -oxide 14 (173 mg, 0.5 mmol) and TFA (0.20 mL, 2.6 mmol) in DCM (15 mL) at 0 0C. The solution was stirred at 20 0C for 16 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCI3 (4 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 15 (42 mg, 23%) as a red solid: mp (MeOH) 172-175 0C; 1H NMR δ 8.28 (br s, 1 H, NH), 8.12 (d, J = 8.7 Hz, 1 H, H-5), 7.69 (d, J = 8.7 Hz, 1 H1 H-6), 3.81-3.85 (m, 4 H, 2 x CH2O)1 3.64-3.72 (m, 4 H, CH2N1 H-9), 3.03 (br t, J = 7.7 Hz, 2 H1 H-7), 2.49-2.57 (m, 6 H1 3 x CH2N), 2.22 (br p, J = 7.7 Hz, 2 H, H-8), 1.84-1.91 (m, 2 H, CH2); 13C NMR δ 149.2, 144.6, 138.6, 138.4, 132.6, 128.9, 115.8, 66.9 (2), 57.6, 53.9 (2), 41.4, 35.1, 32.9, 24.6, 24.3. Anal, calcd for C17H23N5O3-1Z4CH3OH: C, 58.6; H, 6.9; N, 19.8. Found: C, 58.6; H, 6.7; N, 19.9%.
Example 13 7,8-Dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-amine 1 -Oxide (19). yV-(2,3-Dihydro-1H-inden-5-yl)acetamide (16). Ac2O (44.6 mL, 473 mmol) was added dropwise to a stirred solution of 5-indanamine (1) (30 g, 225 mmol) in dioxane (120 mL) at 0 0C and the solution stirred at 20 0C for 48 h. The solution was diluted with water (500 mL), stirred 20 min and the precipitate filtered. The solid was washed with water (3 x 30 mL) and air-dried to give acetamide 16 (37.4 g, 95%) as a tan solid: mp 99-101 0C; 1H NMR δ 7.38-7.43 (m, 2 H, H-4, NH), 7.10-7.16 (m, 2 H, H-6, H-7), 2.85 (br q, J = 7.7 Hz, 4 H, H-1 , H-3), 2.13 (s, 3 H, CH3), 2.06 (br, p, J = 7.4 Hz1 2 H1 H-2); 13C NMR δ 168.3,
145.1 , 140.3, 136.0, 124.4, 118.2, 116.6, 33.0, 32.3, 25.6, 24.4.
/V-(6-Nitro-2,3-dihydro-1W-inden-5-yl)acetamide (17) and iV-(4-Nitro-2,3-dihydro-1H- inden-5-yl)acetamide (18). CHNO3 (70%, 40.5 mL, 639 mmol) was added dropwise to a stirred solution of acetamide 16 (37.4 g, 213 mmol) in HOAc (300 mL) at 20 0C and the solution stirred at 20 0C for 16 h. The solution was poured into ice/water (1500 mL) and the mixture stirred for 30 min. The precipitate was filtered, washed with water (3 x 30 mL), and air-dried to give a cream solid that was used directly. The solid was a mixture of 6- nitroacetamide 17 and 4-nitroacetamide 18 in a ratio of 20:1. A sample was separated by chromatography, eluting with 20% EtOAc/pet. ether, to give (i) 6-nitroacetamide 17 as a pale yellow solid: mp 105-108 °C, [lit. (Schroeder, E.; et al., European J. Med. Chem. 1982, 17, 35) mp 108-109 0C], 1H NMR δ 10.36 (s, 1 H, NHCO), 8.57 (s, 1 H, H-7), 8.03 (s, 1 H, H-4), 2.98 (brt, J = 7.5 Hz, 2 H, H-1), 2.93 (brt, J = 7.4 Hz, 2 H, H-3), 2.27 (s, 3 H, CH3), 2.10-2.17 (m, 2 H, H-2); and (ii) 4-nitroacetamide 18 as a tan solid: mp 126-128 0C [lit. (Schroeder, E.; et al., European J. Med. Chem. 1982, 17, 35) mp 128.5 0C]; 1H NMR δ 9.51 (s, 1 H, NHCO), 8.28 (d, J = 8.3 Hz, 1 H, H-7), 7.41 (d, J = 8.3 Hz, 1 H, H-6), 3.25 (br t, J = 7.5 Hz, 2 H, H-1), 2.96 (brt, J = 7.6 Hz, 2 H, H-3), 2.22 (s, 3 H, CH3), 2.07- 2.13 (m, 2 H, H-2); 13C NMR δ 164.1, 143.3, 142.1, 134.6, 131.9, 130.9, 117.3, 35.5, 32.1, 24.9.
6-Nitro-5-indanamine (2). A suspension of the mixture of acetamides 17 and 18 in EtOH (400 mL) and cHCI (180 mL) was stirred at 80 °C for 6 h. The resulting solution was cooled and diluted with water (400 mL) and allowed to stand for 16 h. The precipitate was filtered, washed with water, and air-dried to give amine 2 (27.52 g, 73%, from 16) as an orange powder: mp 129-131 0C [lit. (Schroeder, E.; et al., European J. Med. Chem. 1982, 17, 35) mp (EtOH) 128.5-129.5 0C]; 1H NMR δ 7.93 (s, 1 H, H-7), 6.55 (s, 1 H, H-4), 5.99 (br s, 2 H, NH2), 2.79-2.88 (m, 4 H, H-1, H-3), 2.02-2.10 (m, 2 H, H-2); 13C NMR δ 154.3, 144.2, 134.0, 131.3, 120.8, 113.5, 33.0, 31.4, 25.7.
7,8-Dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-amine 1 -Oxide (19). A mixture of amine 2 (21.67 g, 121.6 mmol), cyanamide (20.45 g, 486 mmol) and Et2O (10 mL) were mixed together at 80 0C, cooled to ca. 50 0C, cHCI (20 mL) added dropwise, during which a vigorous reaction occurred, and the mixture was heated at 80 0C for 1 h. The mixture was cooled to 50 0C, 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100 °C for 8 h. The mixture was cooled, diluted with water (500 mL), and the yellow/green precipitate filtered. The precipitate was washed with water (3 x 50 mL), washed with ether (3 x 30 mL) and dried to give crude material (20.93 g, 85%), which can be used without further purification. The material was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give 1-oxide 19 (16.72 g, 68%) as a yellow powder: mp (MeOH/DCM) 270-272 °C; 1H NMR [(CD3)2SO] δ 7.92 (s, 1 H, H-9), 7.33 (s, 1 H, H-5), 7.11 (br s, 2 H, NH2), 2.91-2.99 (m, 4 H, H-6, H-8), 2.01-2.09 (m, 2 H, H-7); 13C NMR [(CDs)2SO] δ 159.9, 154.0, 148.5, 142.5, 128.7, 119.8, 113.8, 32.4, 31.6, 25.2. Anal, calcd for C10H10N4O: C, 59.4; H, 5.0; N, 27.7. Found: C, 59.4; H, 5.1; N, 27.8%.
Example 14
7,8-Dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-amine 1,4-Dioxide (20). H2O2 (70%, 5.0 mL, ca. 99.4 mmol) was added dropwise to a stirred solution of 1-oxide 19 (2.0 g, 9.9 mmol) in HOAc (30 mL) and the solution was stirred at 50 0C for 96 h. The mixture was cooled to 0 0C, neutralised with dilute aqueous NH3 solution and the mixture stirred vigorously for 30 min, then extracted with CHCI3 (4 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give 1 ,4-dioxide 20 (317 mg, 15%) as a red solid: mp (MeOH/EtOAc) 190-195 0C; 1H NMR [(CD3)2SO] δ 8.01 (s, 1 H, H-9), 7.98 (s, 1 H, H-5), 7.87 (br s, 2 H, NH2), 3.07 (br t, J = 7.4 Hz, 2 H, H-6), 3.01 (br t, J = 7.4 Hz, 2 H, H-8), 2.10 (p, J = 7.4 Hz, 2 H, H-7); 13C NMR [(CD3)2SO] δ 154.3, 150.8, 144.7, 137.8, 129.6, 115.1 , 111.2, 32.6, 31.7, 25.1. Anal, calcd for C10H10N4O2-1Z2CH3OH: C, 53.8; H, 5.2; N, 23.9. Found: C, 53.6; H, 5.2; N, 23.9%.
Example 15 3-Chloro-7,8-dihydro-6H-indeno[5,6-e][1,2,4]trϊazine 1 -Oxide (21). NaNO2 (570 mg, 8.3 mmol) was added in small portions to a stirred solution of 1-oxide 19 (837 mg, 4.1 mmol) in TFA (30 mL) at 0 0C and the solution stirred at 20 0C for 3 h. The solution was poured into ice/water, stirred for 30 min, filtered, washed with water (3 x 30 mL) and dried. The solid was suspended in POCI3 (50 mL) and DMF (0.5 mL) and stirred at 100 0C for 1 h. The solution was cooled, poured into ice/water, stirred for 30 minutes, filtered, washed with water (3 x 30 mL) and dried. The solid was suspended in DCM (150 mL), dried and the solvent evaporated. The residue was purified by chromatography, eluting with 5% EtOAc/DCM, to give chloride 21 (696 mg, 76%) as a pale yellow solid: mp (DCM) 162- 164 0C; 1H NMR δ 8.21 (s, 1 H, H-9), 7.75 (s, 1 H, H-5), 3.11-3.18 (m, 4 H, H-6, H-8), 2.21-2.28 (m, 2 H, H-7); 13C NMR δ 156.4, 156.0, 150.1, 147.3, 132.8, 122.5, 114.5, 33.3, 32.9, 25.7. Anal, calcd for C10H8CIN3O: C, 54.2; H, 3.6; N, 19.0. Found: C, 54.1 ; H, 3.8; N, 18.7%.
Example 16 W1,Λ/1-Dimethyl-Λ/2-(1-oxido-7,8-dihydro-6W-indeno[5,6-e][1,2,4]trlazin-3-yl)-1,2- ethanediamine (22). Λ/,/V-Dimethyl-1 ,2-ethanediamine (0.45 mL, 4.1 mmol) was added to a stirred solution of chloride 21 (305 mg, 1.4 mmol) in DME (30 ml_) and the solution stirred at reflux temperature for 2 h. The solvent was evaporated and the residue was partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 22 (334 mg, 88%) as a yellow solid: mp (MeOH/EtOAc) 122-124 0C; 1H NMR δ 8.06 (s, 1 H, H-9), 7.38 (s, 1 H, H-5), 5.80 (br s, 1 H, NH), 3.50-3.55 (m, 2 H, CH2N), 2.96-3.03 (m, 4 H, H-6, H-8), 2.55 (t, J = 6.0 Hz, 2 H, CH2N)1 2.27 [s, 6 H1 N(CH3)J, 2.09-2.18 (m, 2 H1 H-7); 13C NMR δ 158.8, 154.5, 148.8, 143.2, 129.8, 120.5, 114.6, 57.6, 45.1 (2), 38.8, 33.1 , 32.3, 25.7. Anal, calcd for C14H19N5O y4H2O: C, 60.5; H, 7.1; N, 25.2. Found: C, 60.6; H, 6.8; N, 25.2%.
Example 17 yV1-(1,4-Dioxido-7,8-dihydro-6//-indeno[5,6-e][1)2,4]triazin-3-yl)-/V2,Λ/2-dimethyl-1)2- ethanediamine (23). H2O2 (70%, 0.54 mL, ca. 10.8 mmol) was added dropwise to a stirred solution of TFAA (1.5 mL, 10.8 mmol) in DCM (10 mL) at 0 0C. The solution was stirred at
0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to a stirred solution of 1-oxide 22 (294 mg, 1.1 mmol) and TFA (0.17 mL, 2.2 mmol) in CHCI3 (15 mL) at 0 0C. The solution was stirred at 20 0C for 6 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCI3 (4 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 ,4-dioxide 23 (173 mg, 55%) as a red solid: mp (MeOH/EtOAc) 150-153 0C; 1H NMR δ 8.12 (s, 1 H, H-9), 8.10 (s, 1 H, H-5), 7.40 (br s, 1 H, NH)1 3.62-3.67 (m, 2 H1 CH2N)1 3.03-3.13 (m, 4 H, H-6, H-8), 2.63 (t, J = 6.0 Hz, 2 H, CH2N), 2.31 [s, 6 H, N(CHs)2], 2.17-2.23 (m, 2 H, H-7); 13C NMR δ 155.6, 149.5, 145.8, 138.0, 129.7, 115.7, 111.6, 57.5, 45.2 (2), 38.8, 33.6, 32.4, 25.6; MS m/z 289 (M+, 0.5%), 272 (5), 58 (100); HRMS calcd for C14H19N5O2 (M+) m/z 289.1539, found 289.1536. The hydrochloride salt was crystallised from MeOH/EtOAc. Anal, calcd for C14H20CIN5O2-1Z4CH3OH: C1 49.7; H1 6.8; N, 19.3. Found: C, 49.4; H, 7.0; N, 19.8%.
Example 18
2-[(1 -Oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)amino]ethanol (24). 2-
Aminoethanol (1.80 mL, 30.0 mmol) was added to a stirred solution of chloride 21 (2.21 g, 10.0 mmol) in DME (100 mL) and the solution stirred at reflux temperature for 90 min. The solvent was evaporated and the residue stirred with water (150 mL) at 20 °C for 30 min. The solid was filtered, washed with water several times and dried to give alcohol 24 (2.44 g, 99%) as an orange solid: mp (DME/water) 222-224 0C; 1H NMR [(CDg)2SO] δ 7.92 (s, 1 H, H-9), 7.54 (br t, J = 6.0 Hz, 1 H, NH), 7.36 (s, 1 H, H-5), 4.68 (t, J = 6.0 Hz, 1 H, OH)), 3.56 (q, J = 6.0 Hz, 2 H, CH2O), 3.40 (q, J = 6.0 Hz, 2 H, CH2N), 2.89-3.00 (m, 4 H, H-6, H-8), 2.00-2.08 (m, 2 H, H-7); 13C NMR [(CD3)2SO] δ 158.7, 154.0 148.0, 142.3, 128.8, 120.0, 113.9, 59.3, 43.2, 32.4, 31.6, 25.2. Anal, calcd for C12H14N4O2: C, 58.5; H, 5.7; N, 22.8. Found: C, 58.8; H, 5.9; N, 22.9%.
Example 19 2-[(1,4-Dioxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-yl)amino]ethanol (25).
H2O2 (70%, 0.5 mL, ca. 10 mmol) was added dropwise to a stirred solution of TFAA (1.4 mL, 10 mmol) in DCM (20 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to a stirred solution of 1 -oxide 24 (246 mg, 1.0 mmol) and TFA (0.28 mL, 2.0 mmol) in DCM (20 mL) at 0 0C. The solution was stirred at 0 0C for 1 h and then at 20 0C for 30 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with DCM (5 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-^4%) of MeOH/DCM, to give 1 ,4-dioxide 25 (106 mg, 40%) as a red solid: mp (MeOH/DCM) 187-188 0C; 1H NMR [(CD3)2SO] δ 7.99 (s, 1 H, H-9), 7.92-7.98 (m, 2 H, NH, H-5), 4.84 (t, J = 6.0 Hz, 1 H, OH)), 3.61 (q, J = 6.0 Hz, 2 H, CH2O), 3.46 (q, J = 6.0 Hz, 2 H, CH2N), 2.98-3.10 (m, 4 H, H-6, H-8), 2.05-2.14 (m, 2 H, H-7); 13C NMR [(CDs)2SO] δ 154.5, 149.4 144.9, 137.6, 129.0, 115.0, 110.9, 59.1 , 43.1, 32.6, 31.7, 25.1. Anal, calcd for C12H14N4O3: C, 55.0; H, 5.4; N, 21.4. Found: C, 54.8; H, 5.4; N, 21.1%.
Example 20
/V1-(1 -Oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)-W2,Λ/2-diethyl-1 ,2- ethanediamine (26). Λ/1,Λ/1-Diethyl-1 ,2-ethanediamine (0.50 mL, 3.5 mmol) was added to a stirred solution of chloride 21 (314 mg, 1.4 mmol) in DME (50 mL) and the solution stirred at reflux temperature for 2 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 -oxide 26 (406 mg, 95%) as a yellow solid: mp (MeOH/EtOAc) 109-112 0C; 1H NMR δ 7.93 (s, 1 H, H-9), 7.31 (s, 1 H, H-5), 7.14 (br s, 1 H, NH), 3.97-4.03 (m, 2 H, CH2N), 3.42-3.46 (m, 2 H, CH2N), 3.25-3.33 (m, 4 H, 2 x CH2N), 2.19-2.29 (m, 4 H, H-6, H-8), 2.08-2.14 (m, 2 H, H- I)1 1.45 (t, J = 7.3 Hz, 6 H, 2 x CH3); 13C NMR δ 158.2, 154.6, 148.4, 143.7, 129.8, 120.7, 114.4, 50.8, 47.7 (2), 36.3, 33.1 , 32.3, 25.7, 8.8 (2). Anal. CaICcI fOr C16H23N5O: C, 63.8; H1 7.7; N, 23.2. Found: C, 63.9; H, 7.7; N, 23.3%.
Example 21 Λ/1-(1,4-Dioxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-yl)-Λ/2,/V2-diethyl-1,2- ethanediamine (27). H2O2 (70%, 0.52 mL, ca. 10.4 mmol) was added dropwise to a stirred solution of TFAA (1.5 mL, 10.4 mmol) in DCM (15 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 °C for 10 min, then cooled to 0 °C and added to a stirred solution of 1-oxide 26 (312 mg, 1.0 mmol) and TFA (0.40 mL, 5.2 mmol) in DCM (20 mL) at 0 0C. The solution was stirred at 5 0C for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCI3 (4 \ 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 27 (179 mg, 54%) as a red gum: 1H NMR δ 8.11 (br s, 2 H, H-5, H-9), 7.73 (br s, 1 H, NH), 3.64-3.69 (m, 2 H, CH2N), 3.01-3.10 (m, 4 H, H-6, H-8), 2.81-2.85 (m, 2 H, CH2N), 2.64-2.73 (m, 4 H, 2 x CH2N), 2.14-2.22 (m, 2 H, H-7), 1.09 (t, J = 7.1 Hz, 6 H, 2 x CH3); 13C NMR δ 156.0,
149.5, 145.8, 138.1 , 129.8, 115.7, 111.7, 51.1 , 46.6 (2), 38.5, 33.4, 32.3, 25.6, 11.0 (2); MS (FAB+) m/z 318 (MH+, 70%), 302 (20); HRMS (FAB+) calcd for C16H24N5O2 (MH+) m/z 318.1930, found 318.1933.
Example 22
/V1-(1 -Oxido-7,8-dihydro-6W-indeno[5,6-e][1 ,2,4]triazin-3-yl)-/V2,Λ/2-dipropyl-1 ,2- ethanediamine (28). Λ/1,Λ/1-Dipropyl-1 ,2-ethanediamine (297) (0.27 g, 1.9 mmol) was added to a stirred solution of chloride 21 (298 mg, 1.3 mmol) in DME (50 mL) and the solution stirred at reflux temperature for 2 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 28 (325 mg, 74%) as a yellow powder: mp (MeOH/EtOAc) 95-97 0C; 1H NMR δ 8.07 (s, 1 H, H-9), 7.39 (s, 1 H, H-5), 5.80 (br s, 1 H, NH), 3.46-3.53 (m, 2 H1 CH2N), 2.96-3.03 (m, 4 H, 2 x CH2N), 2.68 (dd, J = 6.0, 5.8 Hz, 2 H, CH2N), 2.38-2.45 (m, 4 H, H-6, H-8), 2.10-2.18 (m, 2 H, H-7), 1.41-1.51 (m, 4 H, 2 x CH2), 0.87 (t, J = 7.1 Hz, 6 H, 2 x CH3); 13C NMR δ 158.7, 154.4, 148.8, 143.0, 129.8, 120.5, 114.7, 55.9 (2), 52.6, 38.9, 31.1 , 32.3, 25.7, 20.3 (2), 11.9 (2). Anal, calcd for C18H27N5O: C, 65.6; H, 8.3; N, 21.3. Found: C, 65.4; H, 8.4; N, 21.3%. Example 23
/V1-(1 ,4-Dioxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)-N2,N2-dipropyl-1 ,2- ethanediamine (29). H2O2 (70%, 0.39 mL, ca. 7.7 mmol) was added dropwise to a stirred solution of TFAA (1.1 mL, 7.7 mmol) in DCM (15 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to a stirred solution of 1 -oxide 28 (253 mg, 0.8 mmol) and TFA (0.30 mL, 3.8 mmol) in DCM (20 mL) at 0 0C. The solution was stirred at 5 0C for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCI3 (4 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 ,4-dioxide 29 (134 mg, 50%) as a red solid: mp (MeOH/EtOAc) 142-145 0C; 1H NMR δ 8.12 (s, 1 H, H-9), 8.10 (s, 1 H, H-5), 7.46 (br s, 1 H, NH), 3.54-3.60 (m, 2 H, CH2N), 3.03-3.11 (m, 4 H, H-6, H-8), 2.74 (dd, J = 6.1, 5.9 Hz, 2 H, CH2N), 2.43-2.47 (m, 4 H, 2 x CH2N), 2.16-2.24 (m, 2 H, H-7), 1.45-1.54 (m, 4 H, 2 x CH2), 0.91 (t, J = 7.4 Hz, 6 H, 2 x CH3); 13C NMR δ 155.5, 149.5, 145.7, 138.0, 129.6, 115.7, 111.6, 56.0 (2), 52.5, 39.1, 33.4, 32.4, 25.6, 20.4 (2), 11.8 (2). Anal, calcd for Ci8H27N5O2: C, 62.6; H, 7.9; N, 20.3. Found: C, 62.3; H, 8.0; N, 20.2%.
Example 24 N1-(1-Oxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-yl)-W2-(2-methoxyethyl)-Λ/2- methy!-1,2-ethanediamine (30). A solution of the chloride 21 (2.0 g, 9.03 mmol) and Λ/1- (2-methoxyethyl)-Λ/1-methyl-1 ,2-ethanediamine (268) (2.38 g, 18.1 mmol) in DME (140 mL) was heated at reflux temperature for 22 h. The solution was cooled to 20 °C, the solvent evaporated and the residue purified by column chromatography, eluting with a gradient (2-16%) of MeOH/DCM, to give 1-oxide 30 (1.89 g, 66%) as a yellow solid: mp 107-110 0C; 1H NMR δ 8.07 (s, 1 H, H-9), 7.40 (s, 1 H, H-5), 5.89 (br s, 1 H, NH), 3.48- 3.56 (m, 4 H, CH2O, CH2N), 3.36 (s, 3 H, OCH3), 3.00 (q, J = 7.6 Hz, 4 H, H-6, H-8), 2.63- 2.71 (m, 4 H, 2 x CH2N), 2.33 (s, 3 H, NCH3), 2.14 (p, J = 7.4 Hz, 2 H, H-7); 13C NMR δ 158.8, 154.4, 148.8, 143.1 , 129.8, 120.5, 114.7, 71.0, 58.8, 56.7, 56.0, 42.4, 38.8, 33.1, 32.3, 25.7; HRMS (FAB+) calcd for C16H24N5O2 (MH+) m/z 318.1930, found 318.1930.
Example 25
/V1-(1,4-Dioxido-7,8-dihydro-6/y-indeno[5,6-e][1,2,4]triazin-3-yl)-/V2-(2-methoxyethyl)- Λ/2-methyl-1,2-ethanediamine (31). H2O2 (70%, 11 x 0.3 mL, ca. 60.72 mmol) was added over a period of 8 h to a solution of the chloride 21 (1.75 g, 5.52 mmol) in TFA (18 mL) and water (1.2 mL) and the solution stirred at 20 0C for 16 h, after which ice/water (100 ml_) and excess Na2CO3 was added. The mixture was extracted with DCM (5 x 75 ml_), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (4-10%) of MeOH/DCM, to give 1 ,4-dioxide 31 (0.14 g, 8%) as a red solid: mp 58-61 0C; 1H NMR δ 8.13 (s, 1 H, H-9), 8.10 (s, 1 H1 H-5), 7.44 (br s, 1 H, NH), 3.63 (t, J = 5.9 Hz, 2 H, CH2O), 3.53 (t, J = 5.7 Hz1 2 H, CH2N), 3.37 (s, 3 H, OCH3), 3.11 (dt, J = 7.4, 1.0 Hz, 2 H, H-8), 3.06 (dt, J = 7.5, 1.1 Hz, 2 H, H-6), 2.75 (t, J = 6.0 Hz1 2 H1 CH2N)1 2.67 (t, J = 5.7 Hz1 2 H1 CH2N), 2.35 (s, 3 H, NCH3), 2.20 (p, J = 7.5 Hz1 2 H1 H-7); 13C NMR δ 155.5, 149.5, 145.7, 138.0, 129.7, 115.8, 111.6, 71.1 , 58.9, 56.6, 56.0, 42.6, 39.0, 33.4, 32.4, 25.6; HRMS (FAB+) calcd for C16H24N5O3 (MH+) m/z 334.1879, found 334.1877.
Example 26
Λ/1-(3-Methoxypropyl)-Λ/1-methyl-W2-(1-°xido-7,8-dihydro-6H-indeno[5,6- e][1,2,4]triazin-3-yl)-1,2-ethanediamine (32). A solution of chloride 21 (1.62 g, 7.3 mmol), Et3N (2.0 ml_, 14.0 mmol) and Λ/1-(3-methoxypropyl)-Λ/1-methyl-1 ,2-ethanediamine (274) (1.24 g, 8.8 mmol) in DME (50 ml.) was heated at reflux temperature for 18 h. The solution was cooled, the solvent evaporated and the residue partitioned between dilute aqueous NH3 solution (50 ml_) and DCM (50 mL). The aqueous layer was extracted with DCM (4 x 120 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-15%) of MeOH/DCM, to give 1 -oxide 32 (1.79 g, 74%) as a yellow solid: mp 41-42 0C; 1H NMR δ 8.07 (s, 1 H1 H-9), 7.39 (s, 1 H1 H-5), 5.83 (br s, 1 H, NH), 3.55 (dt, J = 5.9, 5.5 Hz1 2 H1 NCH2), 3.43 (t, J = 6.3 Hz, 2 H1 OCH2), 3.33 (s, 3 H1 OCH3), 3.01 (t, J ~ IA Hz, 2 H, H-8), 2.99 (t, J = 7.8 Hz, 2 H1 H-6), 2.64 (t, J = 5.9 Hz, 2 H1 NCH2), 2.50 (t, J = 7.2 Hz, 2 H, NCH2), 2.27 (s, 3 H, NCH3), 2.14 (p, J = 7.4 Hz, 2 H, H-7), 1.76 (tt, J = 7.2, 6.4 Hz, 2 H, CH2); 13C NMR δ
158.7, 154.5, 148.8, 143.2, 129.8, 120.5, 114.7, 70.8, 58.6, 55.8, 54.4, 41.6, 38.6, 33.1 , 32.3, 27.4, 25.7; MS (APCI) m/z 332 (MH+, 100%). Anal, calcd for C17H25N5O2: C1 61.6; H1 7.6; N1 21.1. Found: C, 61.4; H, 7.4; N, 21.4%.
Example 27
W1-(1,4-Dioxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-yl)-N2-(3- methoxypropyl)-Λ/2-methyl-1,2-ethanediamine (33). H2O2 (70%, 2.5 mL, ca. 50 mmol) was added dropwise to a stirred solution of TFAA (7.1 mL, 50 mmol) in DCM (50 mL) at 0 0C. The solution was stirred at 20 °C for 10 min, then cooled to 0 0C, added to a solution of 1 -oxide 32 (1.7 g, 5.0 mmol) and TFA (1.9 mL, 25 mmol) in DCM (50 mL) at 0 0C. The solution was stirred at 20 0C for 6 h, diluted with dilute aqueous NH3 solution (80 mL) and extracted with DCM (4 x 125 ml_). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 33 (620 mg, 35%) as a red solid: mp 129-131 0C; 1H NMR δ 8.13 (s, 1 H, H-9), 8.10 (s, 1 H, H-5), 7.39 (br s, 1 H, NH), 3.57-3.66 (m, 2 H, NCH2), 3.46 (t, J = 6.3 Hz, 2 H, OCH2), 3.33 (s, 3 H, OCH3), 3.11 (dt, J ~ IA, 0.9 Hz, 2 H, H-8), 3.06 (dt, J = 7.4, 1.1 Hz, 2 H, H-6), 2.68 (t, J = 6.0 Hz, 2 H, NCH2), 2.52 (t, J = 7.2 Hz, 2 H, NCH2), 2.28 (s, 3 H, NCH3), 2.20 (p, J = 7.4 Hz1 2 H, H-7), 1.77 (tt, J = 7.2, 6.4 Hz, 2 H, CH2); 13C NMR δ 155.6, 149.5, 145.7, 138.0, 129.7, 115.8, 111.6, 70.7, 58.6, 55.8, 54.3, 41.7, 38.8, 33.4, 32.4, 27.4, 25.6; MS (APCI) m/z 348 (MH+, 100%). Anal. calcd for C17H25N5O3: C, 58.8; H, 7.3; N, 20.2. Found: C, 58.8; H, 7.0; N, 20.0%.
Example 28
/V-[2-(3-Methoxy-1-azetidinyl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3- amine 1 -Oxide (34). A solution of chloride 21 (1.32 g, 6.0 mmol), Et3N (1.65 ml_, 11.8 mmol) and 2-(3-methoxy-1-azetidinyl)ethylamine (277) (950 mg, 7.3 mmol) in DME (30 m!_) was heated at reflux temperature for 18 h. The solution was cooled, the solvent evaporated and the residue partitioned between dilute aqueous NH3 solution (50 mL) and DCM (50 mL). The aqueous layer was extracted with DCM (4 x 50 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 -oxide 34 (890 mg, 48%) as a yellow solid: mp 139-141 0C; 1H NMR δ 8.06 (s, 1 H, H-9), 7.38 (s, 1 H, H- 5), 5.67 (br s, 1 H, NH), 4.04 (p, J = 5.8 Hz, 1 H, CHO), 3.63-3.69 (m, 2 H, CH2N), 3.47 (dt, J = 5.9, 5.6 Hz1 2 H1 CH2N), 3.26 (s, 3 H, OCH3), 2.93-3.03 (m, 6 H, H-6, H-8, CH2N), 2.74 (t, J = 5.9 Hz, 2 H, NCH2), 2.14 (p, J = 7.4 Hz1 2 H, H-7); 13C NMR δ 158.7, 154.5, 148.7, 143.3, 129.8, 120.6, 114.6, 70.0, 61.4 (2), 58.0, 56.0, 39.3, 33.1 , 32.3, 25.7; MS (APCI) m/z 316 (MH+, 100%). Anal, calcd for C16H21N5O2 ^H2O: C, 60.1; H, 6.8; N, 21.9. Found: C, 60.0; H, 6.6; N, 21.7%.
Example 29 /V-[2-(3-Methoxy-1 -azetidinyl)ethyl]-7,8-dihydro-6tf-indeno[5,6-e][1 ,2,4]triazin-3- amine 1,4-Dioxide (35). H2O2 (70%, 1.4 mL, ca. 28 mmol) was added dropwise to a stirred solution of TFAA (4.0 mL, 28 mmol) in DCM (30 mL) at 0 0C. The solution was stirred at 20 0C for 10 min, then cooled to 0 0C, added to a solution of 1 -oxide 34 (890 mg, 2.8 mmol) and TFA (1.1 mL, 14 mmol) in DCM (35 mL) at 0 0C. The solution was stirred at 20 0C for 6 h, diluted with dilute aqueous NH3 solution (80 mL) and extracted with DCM (4 x 125 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 ,4-dioxide 35 (390 mg, 42%) as a red solid: mp 152 0C (dec); 1H NMR δ 8.12 (s, 1 H, H-9), 8.10 (s, 1 H, H-5), 7.30 (br s, 1 H, NH), 4.04 (p, J = 5.8 Hz, 1 H, CHO), 3.67-3.72 (m, 2 H1 CH2N), 3.54 (dt, J = 5.9, 5.5 Hz, 2 H, CH2N), 3.25 (s, 3 H, OCH3), 3.11 (dt, J = 7.4, 0.9 Hz, 2 H, H-6), 3.06 (dt, J = 7.4, 1.1 Hz, 2 H, H-8), 2.95-2.99 (m, 2 H, CH2N), 2.78 (t, J = 5.9 Hz, 2 H, CH2N), 2.20 (p, J = 7.5 Hz, 2 H, H-7); 13C NMR δ 155.6, 149.4, 145.8, 138.0, 129.8, 115.8, 111.6, 69.9, 61.5 (2), 58.0, 56.0, 39.5, 33.4, 32.4, 25.6; MS (APCI) m/z 332 (MH+, 100%). Anal, calcd for C16H21N5O3O-ISCH2CI2: C, 56.4; H, 6.2; N, 20.4. Found: C, 56.2; H, 6.1; N, 20.4%.
Example 30
/V-P-li-PiperidinyOethyll-Z.δ-dihydro-βH-indenolδ.e-eJti^^ltriazin-S-amine i -Oxide (36). 2-(1-Piperidinyl)ethylamine (0.67 mL, 4.7 mmol) was added to a stirred solution of chloride 21 (348 mg, 1.6 mmol) in DME (50 mL) and the solution stirred at reflux temperature for 2 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 36 (465 mg, 95%) as a yellow solid: mp (MeOH/EtOAc) 151-153 0C; 1H NMR δ 8.06 (s, 1 H, H-9), 7.39 (s, 1 H, H-5), 5.91 (br s, 1 H, NH), 3.52-3.57 (m, 2 H, CH2N), 2.97-3.03 (m, 4 H, H-6, H-8), 2.58 (t, J = 6.0 Hz, 2 H, CH2N), 2.40-2.47 (m, 4 H, 2 x CH2N), 2.10-2.18 (m, 2 H, H-7), 1.55-1.63 (m, 4 H, 2 x CH2), 1.42-1.48 (m, 2 H, CH2); 13C NMR δ 158.7, 154.5, 148.8, 143.1, 129.7, 120.5, 114.6, 57.0, 54.3 (2), 37.9, 33.1, 32.3, 25.9 (2), 25.7, 24.4. Anal, calcd for C17H23N5O- %H2O: C, 64.2; H, 7.5; N, 22.0. Found: C, 64.6; H, 6.9; N, 22.1%.
Example 31
W-^i-PiperidinyOethyll-T.δ-dihydro-eH-indenoϊS.e-elϊi^.^triazin-S-amine i^- Dioxide (37). H2O2 (70%, 0.63 mL, ca. 12.7 mmol) was added dropwise to a stirred solution of TFAA (1.8 mL, 12.7 mmol) in DCM (15 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to a stirred solution of 1-oxide 36 (397 mg, 1.3 mmol) and TFA (0.20 mL, 2.5 mmol) in DCM (20 mL) at 0 0C. The solution was stirred at 5 0C for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCI3 (4 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 ,4-dioxide 37 (241 mg, 57%) as a red solid: mp (MeOH/EtOAc) 165-168 0C; 1H NMR δ 8.11 (s, 1 H, H-9), 8.08 (s, 1 H, H-5), 7.43 (br s, 1 H, NH), 3.60-3.64 (m, 2 H, CH2N), 3.03-3.11 (m, 4 H, H-6, H-8), 2.62 (t, J = 6.0 Hz, 2 H, CH2N), 2.42-2.47 (m, 4 H, 2 x CH2), 2.15-2.22 (m, 2 H, H-7), 1.57-1.63 (m, 4 H, 2 x CH2), 1.41-1.47 (m, 2 H, CH2); 13C NMR δ 155.6, 149.5, 145.7, 138.0, 129.7, 115.8, 111.6, 56.9, 54.4 (2), 38.2, 33.4, 32.4, 25.9 (2), 25.6, 24.3. Anal, calcd for C17H23N5O2-1Z4H2O: C, 61.2; H, 7.1; N, 21.0. Found: C, 60.7; H, 7.0; N, 21.0%.
Example 32 yV-[2-(2,6-Dimethyl-1-piperidinyl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3- amine 1 -Oxide (38). 2-(2,6-Dimethyl-1-piperidinyl)ethylamine (280) (0.66 g, 4.3 mmol) was added to a stirred solution of chloride 21 (314 mg, 1.4 mmol) in DME (50 ml_) and the solution stirred at reflux temperature for 3 h. The solvent was evaporated and the residue partitioned between DCM (100 ml_) and dilute aqueous NH3 solution (50 ml_). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 -oxide 38 (389 mg, 80%) as a yellow solid: mp (MeOH) 173-175 0C; 1H NMR δ 8.07 (s, 1 H, H-9), 7.38 (s, 1 H, H-5), 5.47 (br s, 1 H, NH), 3.50-3.55 (m, 2 H, CH2N), 2.96-3.03 (m, 4 H, CH2N, CH2), 2.87-2.91 (m, 2 H, CH2), 2.48-2.57 (m, 2 H, CH2N), 2.10-2.18 (m, 2 H, CH2), 1.64- 1.69 (m, 1 H, CH2), 1.53-1.58 (m, 2 H, CH2), 1.33-1.38 (m, 1 H, CH2), 1.24-1.31 (m, 2 H, CH2), 1.20 (d, J = 6.3 Hz, 6 H, 2 x CH3); 13C NMR δ 158.8, 154.5, 148.8, 143.2, 129.8, 120.6, 114.7, 57.2 (2), 47.5, 39.4, 34.3, 33.1 (2), 32.3, 25.8, 24.4, 21.7 (2). Anal, calcd for C19H27N5O: C, 66.8; H, 8.0; N, 20.5. Found: C, 66.8; H, 7.8; N, 20.6%.
Example 33 yV-[2-(2,6-Dimethyl-1-piperidinyl)ethyl]-7,8-dihydro-6W-indeno[5,6-e][1,2,4]triazin-3- amine 1,4-Dioxide (39). H2O2 (70%, 0.46 mL, ca. 9.2 mmol) was added dropwise to a stirred solution of TFAA (1.3 mL, 9.2 mmol) in DCM (20 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to a stirred solution of 1-oxide 38 (314 mg, 0.9 mmol) and TFA (0.35 mL, 4.6 mmol) in DCM (20 mL) at 0 0C. The solution was stirred at 20 0C for 6 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCI3 (4 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 ,4-dioxide 39 (118 mg, 36%) as a red solid: mp (MeOH) 170-172 0C; 1H NMR δ 8.12 (s, 1 H, H-9), 8.10 (s, 1 H, H-5), 7.21 (br s, 1 H, NH), 3.56-3.63 (m, 2 H, CH2N), 3.12 (br dd, J = 7.6, 7.3 Hz, 2 H, CH2), 3.07 (br dd, J = 7.5, 7.4 Hz, 2 H, CH2N), 2.95 (br dd, J = 7.5, 7.1 Hz, 2 H, CH2N), 2.49-2.57 (m, 2 H, CH2N), 2.20 (p, J = 7.5 Hz, 2 H, CH2), 1.65-1.70 (m, 1 H, CH2), 1.53-1.59 (m, 2 H, CH2), 1.25-1.40 (m, 3 H, CH2), 1.18 (d, J = 6.3 Hz, 6 H, 2 x CH3); 13C NMR δ 155.7, 149.4, 145.7, 137.9, 129.7, 115.8, 111.5, 57.1 (2), 47.2, 39.3, 34.2, 33.4 (2), 32.4, 25.6, 24.4, 21.7 (2). Anal, calcd for C19H27N5O2: C, 63.8; H, 7.6; N, 19.6. Found: C, 64.0; H, 7.6; N, 19.8%.
Example 34
/V-p-tS-Methoxy-i-piperidinyOethyll-T.S-dihydro-eH-indenoIS.β-elfi^^ltriazin-S- amine 1 -Oxide (40). A solution of the chloride 21 (2.0 g, 9.0 mmol), 2-(3-methoxy-1- piperidinyl)ethylamine (283) (1.8 g, 11.4 mmol) and Et3N (1.5 ml_, 9.9 mmol) in DME (140 ml_) was stirred at reflux temperature for 22 h. The solution was cooled to 20 0C, the solvent evaporated and the residue purified by chromatography, eluting with 5% MeOH/DCM to give (i) starting material 21 (0.6 g, 30%) and (ii) 1 -oxide 40 (1.9 g, 61%) as a yellow solid: mp 123-124 0C; 1H NMR δ 8.07 (s, 1 H, H-9), 7.39 (s, 1 H, H-5), 5.81 (br s, 1 H, NH), 3.54-3.58 (m, 2 H, CH2N), 3.35 (s, 3 H, OCH3), 3.24-3.31 (m, 1 H, CHO), 2.97- 3.03 (m, 5 H, H-6, H-8, CH2), 2.68-2.74 (m, 1 H, CH2), 2.63 (dt, J = 6.1 , 2.4 Hz, 2 H,
CH2N), 2.14 (p, J = 7.4 Hz, 2 H, H-7), 1.96-2.07 (m, 3 H, CH2), 1.71-1.78 (m, 1 H, CH2), 1.45-1.58 (m, 1 H, CH2), 1.17-1.27 (m, 1 H, CH2); 13C NMR δ 158.6, 154.5, 148.7, 143.2, 129.8, 120.5, 114.6, 76.2, 57.8, 56.5, 56.1 , 53.2, 38.0, 33.1 , 32.3, 29.9, 25.7, 23.2; HRMS (FAB+) calcd for C18H26N5O2 (MH+) m/z 344.2087, found 344.2090.
Example 35
/V-p^S-Methoxy-i-piperidinyOethyll-T.δ-dihydro-βW-indenofδjβ-eJEI^^Jtriazin-S- amine 1,4-Dioxide (41). H2O2 (70%, 2.5 mL, ca. 51 mmol) was added dropwise to a stirred solution of TFAA (7.1 mL, 51 mmol) in DCM (70 mL) at 0 0C. The solution was stirred at 20 0C for 10 min, then cooled to 0 0C, added to a solution of 1 -oxide 40 (1.75 g, 5.1 mmol) and TFA (0.84 mL, 11 mmol) in CHCI3 (70 mL) at 0 0C. The solution was stirred at 20 °C for 5 h, diluted with dilute aqueous NH3 solution until basic and extracted with CHCI3 (3 x 80 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by column chromatography, eluting with a gradient (4-20%) of MeOH/DCM, to give 1 ,4-dioxide 41 (0.15 g, 8%) as a red gum: 1H NMR δ 8.91 (br s, 1 H, NH), 8.05 (s, 2 H, H-5, H-9), 4.09 (t, J = 5.8 Hz, 2 H, CH2N), 3.84 (td, J = 12.8, 1.9 Hz, 1 H, CHO), 3.57-3.66 (m, 4 H, 2 x CH2), 3.57 (s, 3 H, OMe), 3.40 (td, J = 13.3, 3.5 Hz, 1 H, CH2), 3.01-3.12 (m, 5 H, H-6, H-8, CH2), 2.19 (p, J = 7.4 Hz, 2 H, H-7), 2.16-2.23 (m, 1 H, CH2), 2.02-2.08 (m, 1 H, CH2), 1.62-1.72 (m, 1 H, CH2), 1.37-1.48 (m, 1 H, CH2); 13C NMR δ 155.6, 149.4, 146.1, 138.1, 129.7, 115.5, 111.7, 73.2, 69.7, 67.6, 61.4, 56.9, 36.5, 33.3, 32.4, 28.5, 25.6, 20.3; HRMS (FAB+) calcd for C18H26N5O3 (MH+) m/z 360.2036, found 360.2039.
Example 36 /V-[2-(4-Methoxy-1 -piperidinyl)ethyl]-7,8-dihydro-6H-indenol5,6-e][1 ,2,4]triazin-3- amine 1-Oxide (42). Crude 2-(4-methoxy-1~piperidinyl)ethylamine (288) (3.8 g, 23.9 mmol) was added to a stirred solution of chloride 21 (1.77 g, 8.0 mmol) and Et3N (2.2 mL, 16.0 mmol) in DME (80 mL) and the solution stirred at reflux temperature for 6 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-15%) of MeOH/DCM, to give 1-oxide 42 (2.16 g, 79%) as a yellow solid: mp (MeOH/EtOAc) 131- 133 0C; 1H NMR δ 8.07 (s, 1 H, H-9), 7.39 (s, 1 H1 H-5), 5.82 (br s, 1 H, NH), 3.50-3.56 (m, 2 H, CH2N), 3.33 (s, 3 H, OCH3), 3.21-3.26 (m, 1 H, CHO), 2.97-3.03 (m, 4 H, H-6, H- 8), 2.72-2.82 (m, 2 H, CH2N), 2.60 (dd, J = 6.0, 5.8 Hz, 2 H, CH2N), 2.20-2.26 (m, 2 H, CH2N), 2.15 (br p, J = 7.4 Hz, 2 H, H-7), 1.84-1.92 (m, 2 H, CH2), 1.57-1.65 (m, 2 H, CH2); 13C NMR δ 158.7, 154.5, 148.8, 143.2, 129.8, 120.5, 114.7, 76.2, 56.3, 55.5, 50.7 (2), 38.2, 33.1 , 32.3, 30.8 (2), 25.7. Anal, calcd for C18H25N5O2: C, 63.0; H1 7.3; N, 20.4. Found: C, 63.0; H, 7.4; N, 20.4%.
Example 37
/V-[2-(4-Methoxy-1-piperidinyl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3- amine 1,4-Dioxide (43). H2O2 (70%, 3.1 mL, ca. 62.6 mmol) was added dropwise to a stirred solution of TFAA (8.8 mL, 62.6 mmol) in DCM (40 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to a stirred solution of 1-oxide 42 (2.15 g, 6.3 mmol) and TFA (2.4 mL, 31.3 mmol) in DCM (50 mL) at 0 0C. The solution was stirred at 20 0C for 8 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with DCM (4 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-15%) of MeOH/DCM, to give (i) starting material 42 (204 mg, 9%); and (ii) 1,4-dioxide 43 (1.0 g, 44%) as a red solid: mp (MeOH/EtOAc) 148-151 0C; 1H NMR δ 8.11 (s, 1 H, H-9), 8.10 (s, 1 H1 H-5), 7.44 (br s, 1 H1 NH)1 3.61-3.66 (m, 2 H, CH2N)1 3.33 (s, 3 H, OCH3), 3.22-3.29 (m, 1 H, CHO), 3.10 (brt, J = 7.5 Hz, 2 H, H-6), 3.05 (br t, J = 7.5 Hz1 2 H1 H-8), 2.75-2.81 (m, 2 H, CH2N), 2.68 (brt, J = 6.0 Hz1 2 H, CH2N), 2.27-2.34 (m, 2 H, CH2N), 2.20 (p, J = 7.5 Hz, 2 H, H-7), 1.87-1.95 (m, 2 H, CH2), 1.61-1.70 (m, 2 H, CH2); 13C NMR δ 155.6, 149.4, 145.8, 138.0, 129.7, 115.7, 111.6, 75.8, 56.3, 55.5, 50.7 (2), 38.3, 33.4, 32.4, 30.6 (2), 25.6. Anal, calcd for C1BH25N5O3-1ZlH2O: C, 59.4; H, 7.1; N, 19.2. Found: C, 59.2; H, 6.8; N, 19.1%.
Example 38 Λ/-[2-(4-Morpholinyl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-amine 1- Oxide (44). 2-(4-Morpholinyl)ethylamine (3.93 ml_, 30.0 mmol) was added to a stirred solution of chloride 21 (2.21 g, 10.0 mmol) in DME (50 ml.) and the solution stirred at reflux temperature for 3 h. The solvent was evaporated and the residue stirred with water (150 ml.) at room temperature for 30 min. The solid was filtered, washed with water (3 x 10 ml.) and dried to give 1 -oxide 44 (3.08 g, 98%) as an orange solid: mp (water) 178- 179 0C; 1H NMR δ 8.07 (s, 1 H, H-9), 7.39 (s, 1 H, H-5), 5.79 (br s, 1 H, NH), 3.72 (br t, J = 4.6 Hz, 4 H, CH2O), 3.59 (q, J = 5.6 Hz, 2 H, CH2N), 2.97-3.05 (m, 4 H, H-6, H-8), 2.63 ( t, J = 5.9 Hz, 2 H, CH2N), 2.51 (br t, J = 4.6 Hz, 4 H, CH2N), 2.10-2.19 (m, 2 H, H-7); 13C NMR δ 158.6, 154.6, 148.7, 143.3, 129.8, 120.5, 114.6, 66.9 (2), 56.8, 53.3 (2), 37.5, 33.1 , 32.3, 25.7. Anal, calcd for C16H21N5O2: C, 60.9; H, 6.7; N, 22.2. Found: C, 61.0; H, 6.8; N, 22.3%.
Example 39 A/-[2-(4-Morpholinyl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-amine 1,4- Dioxide (45). H2O2 (70%, 0.50 ml_, ca. 10.0 mmol) was added to a stirred solution of 1- oxide 44 (3.00 g, 9.52 mmol) in a mixture of TFA (30 mL) and water (2 mL) at 20 0C. Ten more aliquots of 70% H2O2 (0.5 mL) were added in 30 min intervals and the reaction mixture was stirred at 20 °C for 26 h. Water (100 mL) was added and the mixture made basic with Na2CO3. The mixture was extracted with DCM (4 x 200 mL) and the combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give 1 ,4-dioxide 45 (1.13 g, 36%) as a red solid: 1H NMR 5 8.13 (s, 1 H, H-9), 8.10 (s, 1 H, H-5), 7.38 (br s, 1 H, NH), 3.73 (t, J = 4.5 Hz, 4 H, CH2O), 3.67 (m, 2 H, CH2N), 3.03-3.15 (m, 4 H, H-6, H- 8), 2.68 (t, J = 6.0 Hz, 2 H, CH2N), 2.53 (t, J = 4.5 Hz, 4 H, CH2N), 2.17-2.25 (m, 2 H, H- 7); 13C NMR δ 155.7, 149.4, 145.9, 137.9, 129.7, 115.8, 111.6, 65.9 (2), 56.8, 53.4 (2), 37.7, 33.4, 32.4, 25.6. The hydrochloride salt was crystallised as a red solid: mp (MeOH/DCM) 184-185 0C. Anal, calcd for C16H2IN5O3-3ZiHCI: C, 53.5; H, 6.2; N, 19.5. Found: C, 53.9; H, 6.3; N, 19.6%. Example 40
/V-[2-(1-Azepanyl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-amine 1 -Oxide (46). 2-(1-Azepanyl)ethylamine (289) (0.52 g, 3.6 mmol) was added to a stirred solution of chloride 21 (322 mg, 1.5 mmol) in DME (30 mL) and the solution stirred at reflux temperature for 3 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 -oxide 46 (264 mg, 56%) as a yellow solid: mp (MeOH) 121-123 0C; 1H NMR δ 8.08 (s, 1 H, H-9), 7.40 (s, 1 H, H-5), 5.93 (br s, 1 H, NH), 3.47-3.52 (m, 2 H, CH2N), 2.97-3.03 (m, 4 H, H-6, H-8), 2.74 (dd, J = 6.0, 5.8 Hz, 2 H, CH2N), 2.65-2.68 (m, 4 H, 2 x CH2N), 2.15 (p, J = 7.4 Hz, 2 H1 H-7), 1.58-1.68 (m, 8 H, 4 x CH2); 13C NMR δ 158.8, 154.5, 148.8, 143.1, 129.7, 120.5, 114.6, 55.9, 55.1 (2), 38.8, 33.1, 32.3, 28.4 (2), 26.9 (2), 25.7. Anal, calcd for C18H25N5O: C, 66.0; H, 7.7; N, 21.4. Found: C, 66.0; H, 7.6; N, 21.5%.
Example 41 yV-[2-(1-Azepanyl)ethyl]-7,8-dihydro-6«-indeno[5,6-e][1,2,4]triazin-3-amine 1,4- Dioxide (47). H2O2 (70%, 0.37 mL, ca. 7.3 mmol) was added dropwise to a stirred solution of TFAA (1.0 mL, 7.3 mmol) in DCM (20 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to a stirred solution of 1 -oxide 46 (240 mg, 0.7 mmol) and TFA (0.28 mL, 3.7 mmol) in DCM (20 mL) at 0 0C. The solution was stirred at 20 °C for 6 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCI3 (4 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 47 (146 mg, 61%) as a red solid: mp (MeOH) 181-184 0C; 1H NMR δ 8.13 (s, 1 H, H-9), 8.10 (s, 1 H, H-5), 7.55 (br s, 1 H, NH), 3.56-3.60 (m, 2 H, CH2N), 3.03-3.07 (m, 4 H, H-6, H-8), 2.81 (dd, J = 6.1 , 6.0 Hz, 2 H, CH2N), 2.67-2.72 (m, 4 H, 2 x CH2N), 2.20 (p, J = 7.5 Hz, 2 H, H-7), 1.60-1.71 (m, 8 H, 4 x CH2); 13C NMR δ 155.6, 149.4, 145.7, 138.0, 129.6, 115.7, 111.5, 55.9, 55.1 (2), 39.0, 33.4, 32.3, 28.5 (2), 27.0 (2), 25.5. Anal, calcd for C18H25N5O2: C, 63.0; H, 7.3; N, 20.4. Found: C, 62.9; H, 7.2; N, 20.3%.
Example 42
/V-[2-(1 ,4-Oxazepan-4-yl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]tιϊazin-3-amine 1 - Oxide (48). A solution of chloride 21 (2.0 g, 9.0 mmol), 2-(1,4-oxazepan-4-yl)ethylamine (292) (1.63 g, 11.3 mmol) and Et3N (1.3 mL, 9.9 mmol) in DME (140 mL) was stirred at reflux temperature for 20 h. The solution was cooled to 20 0C, the solvent evaporated and the residue purified by column chromatography, eluting with a gradient (2-6%) of MeOH/DCM, to give (i) starting material 21 (0.5 g, 25%) and (ii) 1-oxide 48 (1.24 g, 42%) as a yellow solid: mp 119-120 0C; 1H NMR δ 8.08 (s, 1 H, H-9), 7.40 (s, 1 H, H-5), 5.82 (br s, 1 H, NH), 3.81 (t, J = 6.1 Hz, 2 H, CH2O), 3.74 (t, J ~ 4.7 Hz, 2 H, CH2), 3.51-3.56 (m, 2 H, CH2), 2.97-3.04 (m, 4 H, H-6, H-8), 2.73-2.80 (m, 6 H, 3 x CH2), 2.15 (p, J = 7.4 Hz, 2 H, H-7), 1.88-1.94 (m, 2 H, CH2); 13C NMR δ 158.7, 154.6, 148.8, 143.3, 129.8, 120.5, 114.7, 69.3, 68.7, 57.5, 55.8, 53.6, 38.7, 33.1 , 32.3, 30.0, 25.7; HRMS (FAB+) calcd for C17H24N5O2 (MH+) m/z 330.1930, found 330.1937.
Example 43 yV-p-li^-Oxazepan^-yOethylJ-T.S-dihydro-e/y-indenotS.β-eJti^^ltriazin-S-amine 1,4-Dioxide (49). H2O2 (70%, 1.25 ml_, ca. 25.8 mmol) was added dropwise to a stirred solution of TFAA (3.6 mL, 25.8 mmol) in DCM (35 ml_) at 0 0C. The solution was stirred at 20 0C for 10 min, then cooled to 0 0C, added to a solution of 1-oxide 48 (0.85 g, 2.58 mmol) and TFA (0.43 mL, 5.50 mmol) in CHCI3 (35 mL) at 0 0C. The solution was stirred at 20 0C for 5 h, diluted with dilute aqueous NH3 solution until basic and extracted with CHCI3 (4 x 60 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (3-6%) of MeOH/DCM, to give 1 ,4-dioxide 49 (0.37 g, 42%) as a red gum: 1H NMR δ 8.13 (s, 1 H1 H- 9), 8.10 (s, 1 H, H-5), 7.45 (br s, 1 H, NH), 3.82 (t, J = 6.1 Hz, 2 H, CH2O), 3.74 (t, J = 4.6 Hz, 2 H, CH2O), 3.54 (q, J = 5.7 Hz, 2 H, NCH2), 2.97-3.04 (m, 4 H, H-6, H-8), 2.73-2.80 (m, 6 H, CH2), 2.15 (p, J = 7.4 Hz, 2 H1 H-7), 1.91 (p, J = 5.9 Hz, 2 H, CH2); 13C NMR δ 158.7, 154.6, 148.8, 143.3, 129.8, 120.5, 114.7, 69.3, 68.7, 57.4, 55.8, 53.6, 38.7, 33.1 , 32.3, 29.9, 25.7; HRMS (FAB+) calcd for C17H24N5O3 (MH+) m/z 346.1879, found 346.1877.
Example 44 3-[(1-Oxido-7,8-dihydro-6W-indeno[5,6-e]|;i,2,4]triazin-3-yl)amino]-1-propanol (50). 3- Aminopropanol (0.99 mL, 12.9 mmol) was added to a stirred solution of chloride 21 (956 mg, 4.3 mmol) in DME (80 mL) and the solution stirred at reflux temperature for 6 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 -oxide 50 (1.09 g, 98%) as a yellow solid: mp (MeOH/DCM) 190- 190.5 °C; 1H NMR δ 8.07 (s, 1 H1 H-9), 7.40 (s, 1 H, H-5), 5.61 (br s, 1 H, NH)1 3.78 (br s, 1 H, OH), 3.67-3.73 (m, 4 H, CH2O, CH2N), 2.97-3.03 (m, 4 H, H-6, H-8), 2.15 (p, J = 7.5 Hz, 2 H, H-7), 1.82-1.88 (m, 2 H, CH2); 13C NMR δ 159.2, 155.0, 147.9, 143.6, 130.0, 120.3, 114.8, 59.0, 37.7, 33.1 , 33.0, 32.3, 25.7. Anal, calcd for C13H16N4O2: C, 60.0; H, 6.2; N, 21.5. Found: C, 59.8; H, 6.2; N, 21.6%.
Example 45
3-[(1 ,4-Dioxido-7,8-dihydro-6Af-indeno[5,6-e][1 ,2,4]trϊazin-3-yl)amino]-1 -propanol (51). TFAA (0.44 ml_, 2.4 mmol) was added to a stirred solution of 1-oxide 50 (486 mg, 2.2 mmol) in DCM (20 ml_) at 0 0C and the solution stirred at 20 0C for 16 h. H2O2 (70%, 1.1 ml_, ca. 21.9 mmol) was added dropwise to a stirred solution of TFAA (3.1 ml_, 21.9 mmol) in DCM (20 ml_) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to the solution of 1-oxide 50 prepared above and the resulting solution was stirred at 20 0C for 16 h. Dilute aqueous NH3 solution (40 mL) was added and the mixture stirred vigorously for 4 h, then the mixture extracted with DCM (4 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 50 (254 mg, 52%); and (ii) 1 ,4-dioxide 51 (166 mg, 27%) as a red solid: mp (MeOH/DCM) 182-184 0C; 1H NMR δ 8.05 (s, 1 H, H-9), 8.03 (s, 1 H, H-5), 7.61 (br t, J = 5.7 Hz, 1 H, NH), 3.82 (br t, J = 5.7 Hz, 2 H, CH2O), 3.78 (br s, 1 H, OH), 3.71- 3.77 (m, 2 H, CH2N), 3.10 (br t, J = 7.5 Hz, 2 H, H-6), 3.04 (br t, J = 7.5 Hz, 2 H, H-8), 2.20 (p, J = 7.5 Hz, 2 H, H-7), 1.97 (br p, J = 6.0 Hz, 2 H, CH2); 13C NMR δ 156.1 , 149.5, 145.8, 137.8, 129.7, 115.7, 111.3, 60.2, 39.1, 33.4, 32.3, 31.5, 25.5. Anal, calcd for C13H16N4O3: C, 56.5; H, 5.8; N, 20.3. Found: C, 56.8; H, 5.9; N, 20.2%.
Example 46
^-(a-NlethoxyethyO-Λ/^methyl-ΛP-li-oxido-T.δ-dihydro-eH-indenoIS.β- e][1,2,4]triazin-3-yl)-1,3-propanediamine (52). A solution of chloride 21 (2.0 g, 9.03 mmol) and Λ/1-(2-methoxyethyl)-Λ/1-methylpropane-1 ,3-diamine (297) (2.0 g, 13.6 mmol) in DME (140 mL) was stirred at 20 0C for 18 h, the solvent evaporated and the residue purified by column chromatography, eluting with a gradient (2-15%) of MeOH/DCM, to give 1-oxide 52 (2.3 g, 79%) as a yellow solid: mp 59-61 0C; 1H NMR [(CH3)2SO] δ 7.94 (s, 1 H, H-9), 7.68 (br s, 1 H, NH), 7.38 (s, 1 H, H-5), 3.24-3.44 (m, 6 H, CH2), 3.23 (s, 3 H, OCH3), 2.92-2.99 (m, 4 H, H-6, H-8), 2.56 (br t, J = 5.8 Hz, 2 H, CH2N), 2.24 (s, 3 H, NCH3), 2.03-2.07 (m, 2 H, H-7), 1.70-1.74 (m, 2 H, CH2); HRMS (FAB+): calcd for C17H26N5O2 (MH+) m/z 332.2087, found, 332.2089. Example 47
^-(i^-Dioxido-T.S-dihydro-βH-indenotS^-elli.a^ltriazin-S-ylJ-Λ^-tZ-methoxyethyl)-
Figure imgf000083_0001
(53). H2O2 (70%, 3.0 ml_, ca. 60.4 mmo!) was added dropwise to a stirred solution of TFAA (8.4 ml_, 60.4 mmol) in DCM (80 mL) at 0 0C. The solution was stirred at 20 0C for 10 min, then cooled to 0 0C, and added to a solution of 1- oxide 52 (2.0 g, 6.04 mmol) and TFA (1.0 mL, 13.0 mmol) in CHCI3 (80 mL) at 0 0C and the solution stirred at 20 0C for 18 h. The solution was made basic with dilute aqueous NH3 solution and extracted with CHCI3 (3 x 100 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (2-18%) of MeOH/DCM, to give 1 ,4-dioxide 53 (99 mg, 5%) as a red solid: mp 77-79 0C; 1H NMR δ 8.12 (s, 1 H, H-9), 8.10 (s, 1 H, H-5), 7.26 (br s, 1 H, NH), 3.66 (t, J = 6.3 Hz, 2 H, CH2), 3.59 (t, J = 5.6 Hz, 2 H, CH2), 3.36 (s, 3 H, OCH3), 3.03-3.12 (m, 4 H, H-6, H-8), 2.66-2.71 (m, 4 H, 2 x CH2), 2.39 (s, 3 H, NCH3), 2.19 (p, J = 7.4 Hz, 2 H, H- 7), 1.91 (p, J = 6.6 Hz, 2 H, CH2); 13C NMR δ 155.6, 149.5, 145.7, 138.0, 129.7, 115.8, 111.6, 70.5, 58.9, 56.8, 55.9, 42.5, 40.5, 33.4, 32.4, 25.9, 25.6; HRMS (FAB+) calcd for C17H26N5O3 (MH+) m/z 348.2036, found 348.2032.
Example 48 yV-[3-(3-Methoxy-1-azetidinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3- amine 1-Oxide (54). A solution of chloride 21 (1.33 g, 6.0 mmol), Et3N (1.7 mL, 12 mmol) and 3-(3-methoxy-1-azetidinyl)propylamine (299) (1.2 g, 8.4 mmol) in DME (30 mL) was heated at reflux temperature for 18 h. The solution was cooled, the solvent evaporated and the residue partitioned between dilute aqueous NH3 solution (50 mL) and DCM (50 mL). The aqueous layer was extracted with DCM (2 x 25 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-15%) of MeOH/DCM, to give 1 -oxide 54 (1.32 g, 66%) as a yellow solid: mp 101-102 0C; 1H NMR δ 8.07 (s, 1 H, H-9), 7.39 (s, 1 H, H-5), 6.18 (br s, 1 H, NH), 4.07 (p, J = 5.9 Hz, 1 H, CHO), 3.65-3.71 (m, 2 H, CH2N), 3.54 (dt, J = 6.2, 5.8 Hz, 2 H, CH2N), 3.26 (s, 3 H, OCH3), 2.94-3.04 (m, 4 H, H-6, H-8), 2.82-2.88 (m, 2 H, CH2N), 2.63 (t, J = 6.4 Hz1 2 H, CH2N), 2.14 (p, J = 7.1 Hz, 2 H, H-7), 1.70 (p, J = 6.4 Hz, 2 H, CH2); 13C NMR δ 158.8, 154.5, 148.8, 143.1 , 129.8, 120.6, 114.7, 69.7, 61.5 (2), 58.6, 56.0, 40.8, 33.1 , 32.3, 26.6, 25.8; MS (APCI) m/z 330 (MH+, 100%). Anal, calcd for Ci7H23N5O2: C, 62.0; H, 7.0; N, 21.3. Found: C, 61.7; H, 7.2; N, 21.2%. Example 49
W-P-lS-Methoxy-i-azetidinylJpropyll-T.δ-dihydro-βH-indenotSjβ-eϊCija^ltriazin-S- amine 1,4-Dioxide (55). H2O2 (70%, 2.0 ml_, ca. 40 mmol) was added dropwise to a stirred solution of TFAA (5.6 mL, 40 mmol) in DCM (50 ml_) at 0 0C. The solution was stirred at 20 0C for 10 min, then cooled to 0 0C, added to a solution of 1 -oxide 54 (1.3 g, 4.0 mmol) and TFA (1.5 mL, 20 mmol) in DCM (50 mL) at 0 0C. The solution was stirred at 20 0C for 26 h, diluted with dilute aqueous NH3 solution (80 mL) and extracted with DCM (4 x 125 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-15%) of MeOH/DCM, to give 1 ,4-dioxide 55 (400 mg, 30%) as a red solid: mp 150-152 0C; 1H NMR δ 8.12 (s, 1 H, H-9), 8.10 (s, 1 H, H-5), 8.06 (br s, 1 H, NH), 4.18 (p, J = 5.9 Hz, 1 H, CHO), 3.91 (br s, 2 H, CH2N), 3.64 (t, J = 6.4 Hz, 2 H, CH2N), 3.28 (s, 3 H, OCH3), 2.98-3.13 (m, 6 H, H-6, H-8, CH2N), 2.80 (t, J = 6.3 Hz, 2 H, CH2N), 2.20 (p, J = 7.5 Hz, 2 H, H-7), 1.82 (p, J = 6.4 Hz, 2 H, CH2); 13C NMR δ 155.7, 149.4, 145.7, 138.0, 129.7, 115.8, 111.6, 69.3, 61.4 (2), 57.3, 56.2, 40.4, 33.4, 32.4, 26.0, 25.6; MS (APCI) m/z 346 (MH+, 100%); HRMS (FAB+) calcd for C17H24N5O3 (MH+) m/z 346.1879, found 346.1878.
Example 50
1 -{3-[(1 -Oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)amino]propyl}-3- pyrrolidinecarbonitrile (56). 1-(3-Aminopropyl)-3-pyrrolidinecarbonitrile (302) (0.36 g, 2.4 mmol) was added to a stirred solution of chloride 21 (402 mg, 1.8 mmol) and Et3N (0.76 mL, 5.4 mmol) in DME (50 mL) and the solution stirred at reflux temperature for 16 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of
MeOH/DCM, to give 1-oxide 56 (476 mg, 78%) as a yellow solid: mp (EtOAc/pet. ether) 111-112 °C; 1H NMR δ 8.07 (s, 1 H, H-9), 7.39 (s, 1 H, H-5), 5.72 (br t, J = 5.3 Hz, 1 H, NH), 3.58 (q, J = 6.4 Hz, 2 H, CH2N), 2.95-3.07 (m, 6 H, H-6, H-8, CH2N), 2.73-2.80 (m, 1 H, CHCN), 2.55-2.68 (m, 4 H, 2 x CH2), 2.23-2.32 (m, 1 H, CH2), 2.10-2.18 (m, 3 H, CH2, H-7), 1.85 (p, J = 6.7 Hz, 2 H, CH2); 13C NMR δ 158.7, 154.6, 148.7, 143.3, 129.8, 122.1, 120.6, 114.6, 57.4, 53.3, 52.9, 40.2, 33.1, 32.3, 29.2, 27.7, 26.3, 25.7. Anal, calcd for C18H22N6O: C, 63.9; H, 6.6; N, 24.8. Found: C, 64.0; H, 6.4; N, 24.8%.
Example 51 1 -{3-[(1 ,4-Dioxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)amino]propyl}-3- pyrrolidinecarbonitrile (57). H2O2 (70%, 0.67 mL, ca. 13.3 mmol) was added dropwise to a stirred solution of TFAA (1.9 mL, 13.3 mmol) in DCM (20 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 °C for 10 min, then cooled to 0 0C and added to a stirred solution of 1-oxide 56 (449 mg, 1.3 mmol) and TFA (0.51 mL, 6.6 mmol) in DCM (20 mL) at 0 0C. The solution was stirred at 20 0C for 8 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with DCM (4 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 56 (198 mg, 44%) and (ii) 1,4-dioxide 57 (70 mg, 15%) as a red gum: 1H NMR δ 8.15 (br t, J = 5.3 Hz, 1 H, NH), 8.12 (s, 1 H, H-9), 8.08 (s, 1 H, H-5), 3.62-3.68 (m, 2 H, CH2N), 3.15-3.23 (m, 2 H, CH2N), 3.11 (brt, J = 7.5 Hz, 2 H, H-6), 3.07 (brt, J = 7.5 Hz, 2 H, H-8), 2.90-2.95 (m, 1 H, CHCN), 2.73 (t, J = 6.3 Hz, 2 H, CH2N), 2.50-2.61 (m, 2 H, CH2N), 2.33-2.43 (m, 1 H, CH2), 2.11-2.24 (m, 3 H, CH2, H-7), 1.91 (p, J = 6.3 Hz, 2 H, CH2); 13C NMR δ 155.7, 149.4, 145.7, 138.0, 129.6, 122.0, 115.8, 111.5, 57.3, 53.5, 52.8, 41.0, 33.4, 32.3, 29.1, 26.9, 26.1, 25.3; MS (FAB+) m/z 355 (MH+, 30%), 339 (10); HRMS (FAB+) calcd for C18H23N6O2 (MH+) m/z 355.1883, found 355.1893.
Example 52 yV-ΪS-t^Methoxy-i-piperidinylJpropyq-Tjβ-dihydro-ΘH-indenoIδ.e-elli^.^triazin-S- amine 1 -Oxide (58). 3-(4-Methoxy-1-piperidinyl)propylamine (304) (0.59 g, 3.4 mmol) was added to a stirred solution of chloride 21 (505 mg, 2.3 mmol) and Et3N (0.64 mL, 2.6 mmol) in DME (50 mL) and the solution stirred at reflux temperature for 16 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 58 (681 mg, 84%) as a yellow solid: mp (EtOAc/pet. ether) 120-121 0C; 1H NMR δ 8.07 (s, 1 H, H-9), 7.38 (s, 1 H, H-5), 6.25 (br s, 1 H, NH), 3.56-3.61 (m, 2 H, CH2N), 3.33 (s, 3 H, OCH3), 3.24-3.30 (m, 1 H, CHO), 2.97-3.03 (m, 4 H, H-6, H-8), 2.71-2.78 (m, 2 H, CH2N)1 2.52 (br t, J = 6.6 Hz, 2 H, CH2N), 2.21-2.30 (m, 2 H, CH2), 2.15 (br p, J = 7.5 Hz, 2 H, H-7), 1.91-1.98 (m, 2 H, CH2), 1.85 (br p, J = 6.5 Hz, 2 H, CH2), 1.65-1.73 (m, 2 H, CH2); 13C NMR δ 158.8, 154.4, 148.8, 143.0, 129.8, 120.5, 114.7, 75.8, 56.8, 55.5, 50.9 (2), 40.9, 33.1, 32.3, 30.5 (2), 25.7 (2). Anal, calcd for C19H27N5O2: C, 63.8; H, 7.6; N, 19.6. Found: C, 63.6; H, 7.6; N, 19.4%.
Example 53 Λ/-[3-(4-Methoxy-1 -piperidinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3- amine 1,4-Dioxide (59). H2O2 (70%, 0.92 mL, ca. 18.3 mmol) was added dropwise to a stirred solution of TFAA (2.6 ml_, 18.3 mmol) in DCM (20 ml_) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 °C for 10 min, then cooled to 0 0C and added to a stirred solution of 1-oxide 58 (655 mg, 1.8 mmol) and TFA (0.71 ml_, 9.2 mmol) in DCM (20 ml_) at 0 0C. The solution was stirred at 20 0C for 8 h, diluted with dilute aqueous NH3 solution (10 ml.) and extracted with DCM (4 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 58 (360 mg, 55%) and (ii) 1 ,4-dioxide 59 (213 mg, 31%) as a red solid: mp (MeOH/EtOAc) 128-130 0C; 1H NMR δ 8.42 (br s, 1 H, NH), 8.11 (s, 1 H, H-9), 8.10 (s, 1 H, H-5), 3.62-3.68 (m, 2 H, CH2N), 3.28-3.36 (m, 4 H, OCH3, CHO), 3.08 (dt, J = 7.5, 1.1 Hz, 2 H, H-6), 3.03 (dt, J = 7.5, 1.1 Hz, 2 H, H-8), 2.69-2.76 (m, 2 H, CH2N), 2.55 (br t, J = 6.2 Hz, 2 H, CH2N), 2.26-2.34 (m, 2 H, CH2N), 2.17 (p, J = 7.5 Hz, 2 H, H-7), 1.94-2.03 (m, 2 H, CH2), 1.88 (p, J = 6.2 Hz, 2 H, CH2), 1.72-1.81 (m, 2 H, CH2); 13C NMR δ 155.4, 149.5, 145.5, 138.1 , 129.5, 115.7, 111.7, 75.8, 57.2, 55.4, 50.8 (2), 41.6, 33.3, 32.3, 30.3 (2), 25.5, 25.1. Anal, calcd for C19H27N5O3 H2O: C, 58.3; H, 7.5; N, 17.9. Found: C, 58.4; H, 6.8; N1 17.6%.
Example 54
Λ/-[3-(4-Morpholinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 -
Oxide (60). 3-(1-Morpholinyl)propylamine (0.76 mL, 5.2 mmol) was added to a stirred solution of chloride 21 (382 mg, 1.7 mmol) in DME (50 mL) and the solution stirred at reflux temperature for 3 h. The solvent was evaporated and the residue was partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 60 (553 mg, 98%) as a yellow solid: mp (MeOH/EtOAc) 139-141 0C; 1H NMR δ 8.06 (s, 1 H, H-9), 7.38 (s, 1 H, H- 5), 6.10 (br s, 1 H, NH), 3.72-3.77 (m, 4 H, 2 x CH2O), 3.55-3.60 (m, 2 H, CH2N), 2.95- 3.02 (m, 4 H, H-6, H-8), 2.45-2.52 (m, 6 H, 3 x CH2N), 2.09-2.17 (m, 2 H, CH2), 1.79- 1.86 (m, 2 H, CH2); 13C NMR δ 158.8, 154.5, 148.8, 143.2, 129.8, 120.5, 114.7, 67.0 (2), 57.3, 53.8 (2), 40.8, 33.1, 32.3, 25.7, 25.3. Anal, calcd for C17H23N5O2: C, 62.0; H, 7.0; N, 21.3. Found: C, 62.2; H1 6.9; N, 21.3%.
Example 55
W-[3-(4-Wlorpholinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 ,4- Dioxide (61). H2O2 (70%, 0.60 mL, ca. 11.9 mmol) was added dropwise to a stirred solution of TFAA (1.7 mL, 11.9 mmol) in DCM (15 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to a stirred solution of 1 -oxide 60 (412 mg, 1.2 mmol) and TFA (0.46 ml_, 6.0 mmol) in DCM (20 ml_) at 0 °C. The solution was stirred at 20 0C for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCI3 (4 x 50 ml_). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 60 (208 mg, 50%) and (ii) 1,4-dioxide 61 (122 mg, 30%) as a red solid: mp (MeOH) 158-160 0C; 1H NMR δ 8.37 (br s, 1 H, NH), 8.11 (s, 1 H, H-5), 8.09 (s, 1 H, H-9), 3.80-3.84 (m, 4 H, 2 x CH2O), 3.64- 3.69 (m, 2 H, CH2N), 3.02-3.10 (m, 4 H, H-6, H-8), 2.56 (dd, J = 6.2, 6.1 Hz, 2 H1 CH2N)1 2.48-2.52 (m, 4 H, 2 x CH2N)1 2.15-2.22 (m, 2 H, H-7), 1.85-1.91 (m, 2 H, CH2); 13C NMR δ 155.5, 149.5, 145.6, 138.0, 129.6, 115.8, 111.6, 66.9 (2), 57.7, 53.8 (2), 41.6, 33.3, 32.3, 25.5, 24.5. Anal, calcd for C17H23N5O3-1Z4CH3OH: C, 58.6; H, 6.9; N1 19.8. Found: C, 58.4; H1 6.7; N, 19.9%.
Example 56 Λ/-[4-(4-Morpholinyl)buty!]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-amine 1-
Oxide (62). 4-(4-Morpholinyl)butylamine (306) (2.02 g, 12.8 mmol) was added to a stirred solution of chloride 21 (1.89 g, 8.5 mmol) and Et3N (1.8 mL, 12.8 mmol) in DME (80 mL) and the solution stirred at reflux temperature for 16 h. The solvent was evaporated and the residue was partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 62 (2.57 g, 88%) as pale yellow solid: mp (MeOH/EtOAc) 151-152 0C; 1H NMR δ 8.07 (s, 1 H, H-9), 7.38 (s, 1 H, H-5), 5.78 (br s, 1 H, NH), 3.78 (br t, J = 4.6 Hz, 4 H, 2 * CH2O)1 3.50 (br dd, J = 6.6, 5.9 Hz1 2 H1 CH2N)1 2.95-3.02 (m, 4 H, H-6, H-8), 2.45 (br t, J = 4.4 Hz1 4 H, 2 x CH2N)1 2.40 (t, J = 7.0 Hz, 2 H, CH2N), 2.15 (p, J = 7.5 Hz, 2 H, H-7), 1.67- 1.74 (m, 2 H, CH2), 1.58-1.64 (m, 2 H, CH2); 13C NMR δ 158.8, 154.5, 148.8, 143.2, 129.8, 120.5, 114.7, 66.9 (2), 58.5, 53.7 (2), 41.3, 33.1 , 32.3, 27.4, 25.7, 24.0. Anal. Calcd for C18H25N5O2: C, 63.0; H, 7.3; N, 20.4. Found: C1 62.9; H, 7.2; N, 20.5%.
Example 57
/V-[4-(4-Morpholinyl)butyl]-7,8-dihydro-6W-indeno[5,6-e][1,2,4]triazin-3-amine 1,4- Dioxide (63). H2O2 (70%, 3.6 mL, ca. 72 mmol) was added dropwise to a stirred solution of TFAA (10.2 mL, 72 mmol) in DCM (25 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to a stirred solution of 1-oxide 62 (2.48" g, 7.2 mmol) and TFA (2.8 mL, 36 mmol) in DCM (25 mL) at 0 0C. The solution was stirred at 20 °C for 16 h, cooled to 0 °C and made basic with dilute aqueous NH3 solution and stirred vigorously for 30 min. The mixture was extracted with CHCI3 (4 x 50 mL), the combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 62 (981 mg, 40%) and (ii) 1,4-dioxide 63 (504 mg, 19%) as a red solid: mp (MeOH) 140-141 0C; 1H NMR δ 8.09 (s, 2 H, H-5, H-9), 7.32 (br s, 1 H1 NH), 3.74 (br t, J = 4.6 Hz, 4 H, 2 x CH2O), 3.57-3.63 (m, 2 H, CH2N), 3.09 (br t, J = 7.5 Hz, 2 H, H-6), 3.05 (br t, J = 7.5 Hz, 2 H, H-8), 2.50-2.55 (m, 4 H, 2 x CH2N), 2.47 (br t, J ~ 7.1 Hz, 2 H, CH2N), 2.20 (p, J = 7.5 Hz, 2 H, H-7), 1.71-1.79 (m, 2 H, CH2), 1.61-1.69 (m, 2 H, CH2); 13C NMR δ 155.9, 149.5, 145.8, 137.9, 129.8, 115.7, 111.6, 66.6 (2), 58.1 , 53.5 (2), 41.2, 33.4, 32.4, 27.1 , 25.5, 23.4; HRMS (FAB+) calcd for C18H26N5O3 (MH+) m/z 360.2036, found 360.2039.
Example 58
7,8-Dihydro-6A/-indeno[5,6-e][1,2,4]trϊazine 1-Oxide (64). fe/τf-Butyl nitrite (90%, 2 mL, 14.8 mmol) was added to a stirred solution of amine 19 (1.0 g, 4.95 mmol) in DMF (50 mL) at 60 0C and the solution stirred at 60 0C for 2 h. The solution was cooled to 20 °C and the solvent evaporated. The residue was partitioned between EtOAc (150 mL) and water (150 mL), the organic fraction was washed with water (2 x 50 mL), washed with brine (50 mL) and dried and the solvent evaporated. The residue was purified by chromatography, eluting with 10% EtOAc/DCM, to give 1-oxide 64 (401 mg, 43%) as a white solid: mp (EtOAc/pet. ether) 130-131 0C; 1H NMR δ 8.91 (s, 1 H, H-3), 8.28 (s, 1 H1 H-9), 7.82 (s, 1 H, H-5), 3.11-3.19 (m, 4 H, H-6, H-8), 2.24 (p, J = 7.5 Hz, 2 H, H-7); 13C NMR δ 154.9, 153.0, 150.0, 147.3, 134.6, 123.2, 114.4, 33.2, 32.9, 25.7. Anal, calcd for C10H9N3O: C, 64.2; H, 4.9; N, 22.5. Found: C, 64.1 ; H, 4.9; N, 22.5%.
Example 59
7,8-Dihydro-6W-indeno[5,6-e][1,2,4]triazine 1,4-Dioxide (65). H2O2 (70%, 1.1 mL, ca. 21 mmol) was added dropwise to a stirred solution of TFAA (3.0 mL, 21 mmol) in DCM (20 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to a solution of 1-oxide 64 (0.40 g, 2.1 mmol) in DCM (20 mL) at 0 0C and the solution was stirred at 20 0C for 4 h. Dilute aqueous NH3 solution (10 mL) was added and the mixture stirred vigorously for 30 min and then extracted with DCM (4 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (10-30%) of EtOAc/DCM, to give (i) starting material 64 (68 mg, 17%) and (ii) 1 ,4-dioxide 65 (213 mg, 49%) as a tan solid: mp (EtOAc/pet. ether) 179-181 0C; 1H NMR δ 8.81 (s, 1 H, H-3), 8.31 (s, 1 H, H-9), 8.28 (S, 1 H, H-5), 3.13-3.22 (m, 4 H1 H-6, H-8), 2.26 (p, J = 7.5 Hz1 2 H, H-7); 13C NMR δ 155.2, 152.0, 141.0, 139.1 , 134.5, 116.1 , 114.1 , 33.4, 33.0, 25.5. Anal, calcd for C10H9N3O2: C1 59.1; H, 4.5; N, 20.7. Found: C, 58.9; H, 4.6; N, 20.5%.
Example 60
3-lodo-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1-Oxide (66). terf-BuNO2 (9.1 mL, 68.8 mmol) was added to a stirred solution of 1 -oxide 19 (4.49 g, 22.2 mmol), diiodomethane (17.9mL, 222 mmol), and CuI (4.44 g, 23.3 mmol) in THF (200 mL) and the mixture was stirred at reflux temperature for 2.5 h. The mixture was cooled to 20 0C1 the solvent was evaporated and the residue purified by chromatography, eluting with a gradient (0-50% EtOAc/pet. ether), to give (i) iodide 66 (4.04 g, 58%) as pale yellow needles: mp (EtOAc/pet. ether) 189-190 0C; 1H NMR δ 8.18 (s, 1 H, H-9), 7.72 (s, 1 H, H- 5), 3.07-3.15 (m, 4 H, H-6, H-8), 2.23 (m, 2 H, H-7); 13C NMR δ 155.9, 150.2, 147.5, 133.4, 122.3, 121.7, 114.4, 33.3, 33.0, 25.6. Anal, calcd for C10H8IN3O: C, 38.4; H, 2.6; N, 13.4. Found: C, 38.6; H, 2.6; N, 13.4%; and (ii) 1 -oxide 64 (0.38 g, 9%) as a white solid: mp 130-131 0C1 spectroscopically identical to the sample prepared above.
Example 61
Ethyl-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1 -Oxide (67). A solution of EtMgBr in Et2O (3 M, 15 mL, 45 mmol) was added to a stirred solution of ZnCI2 Et2O (45% in DCM, 15 mL, 42 mmol) in THF (100 mL) at 0 0C under N2 and the solution stirred at 0 0C for 10 min. Pd(PPh3)4 (578 mg, 0.5 mmol) and iodide 66 (3.15 g, 10.1 mmol) were added and the mixture stirred at 0 °C for 1 h. The mixture was poured into ice/water (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 30%
EtOAc, to give 1-oxide 67 (1.20 g, 56%) as a pale yellow solid: mp (MeOH) 80-81 0C; 1H NMR δ 8.26 (s, 1 H, H-9), 7.26 (s, 1 H, H-5), 3.11 (q, J = 7.2 Hz, 4 H, H-6, H-8), 3.02 (q, J = 7.6 Hz, 2 H, CH2), 2.21 (p, J = 7.2 Hz, 2 H, H-7), 1.43 (t, J = 7.6 Hz, 3 H, CH3); 13C NMR δ 167.0, 154.6, 148.7, 147.6, 132.3, 122.7, 114.3, 33.2, 32.8, 30.6, 25.8, 12.4. Anal, calcd for C12H13N3O-1Z4CH3OH: C, 65.9; H, 6.3; N, 18.8. Found: C, 66.0; H, 6.1; N, 18.5%.
Example 62
Alternative Preparation of Ethyl-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1 -Oxide (67). Pd(dppf)CI2 (130 mg, 0.08 mmol) was added under N2 to a N2-purged solution of chloride 21 (350 mg, 1.6 mmol) and SnEt4 (455 mg, 1.9 mmol) in DME (20 mL) and the mixture was stirred at 85 0C for 16 h. The mixture was cooled, the solvent evaporated and the residue purified by chromatography, eluting with 20% EtOAc/pet. ether, to give (i) starting material 21 (148 mg, 42%) and (ii) 1-oxide 67 (84 mg, 25%) as a yellow solid: mp 79-81 0C, spectroscopically identical to the sample prepared above.
Example 63
3-Ethyl-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1,4-Dioxide (68). H2O2 (70%, 0.15 mL, ca. 2.9 mmol) was added dropwise to a stirred solution of TFAA (0.40 mL, 2.9 mmol) in DCM (5 mL) at 0 0C. The solution was stirred at 20 0C for 10 min, then cooled to 0 0C, and added to a solution of 1-oxide 67 (60 mg, 0.29 mmol) and TFA (0.05 mL, 0.63 mmol) in CHCl3 (5 mL) at 0 0C. Another aliquot of H2O2 (0.15 mL) was added after 24 h, and the solution stirred at 20 0C for another 24 h. The solution was made basic with dilute aqueous NH3 solution and extracted with CHCI3 (3 x 10 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 5% EtOAc/DCM, to give (i) starting material 67 (18 mg, 30%) and (ii) 1,4-dioxide 68 (32 mg, 48%) as a yellow solid: mp 140-142 0C; 1H NMR δ 8.32 (S, 1 H, H-9), 8.27 (s, 1 H, H-5), 3.13-3.23 (m, 6 H, H-6, H-8, CH2), 2.26 (q, J = 7.5 Hz, 2 H, H-7), 1.43 (t, J = 7.5 Hz1 3 H, CH3); 13C NMR 5 155.7, 155.1, 150.6, 139.1, 133.8, 115.9, 113.9, 33.4, 32.8, 25.6, 23.9, 9.31. Anal, calcd for C12Hi3N3O2- V2CH3OH: C, 60.7; H1 6.1; N, 17.0. Found: C, 60.3; H, 5.7; N, 16.8%.
Example 64
3-Allyl-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1 -Oxide (69). Pd(PPh3)4 (0.89 g, 0.77 mmol) was added to a stirred, degassed solution of iodide 66 (4.80 g, 15.3 mmol) and allyltributyltin (5.2 mL, 16.9 mmol) in DME (100 mL), and the mixture stirred at reflux temperature for 8 h. The solvent was evaporated and the residue purified by chromatography, eluting with 10% EtOAc/pet. ether, to give 1-oxide 69 (2.96 g, 85%) as white solid: mp (EtOAc/pet. ether) 60-61 0C; 1H NMR δ 8.26 (s, 1 H, H-9), 7.77 (s, 1 H, H- 5), 6.12-6.23 (m, 1 H, H-2'), 5.29 (dd, J = 17.1, 1.5 Hz, 1 H, H-3'), 5.22 (dd, J = 10.1, 1.3 Hz, 1 H, H-3'), 3.77 (br d, J = 6.9 Hz, 2 H, H-V), 3.08-3.14 (m, 4 H, H-6, H-8), 2.21 (p, J = 7.5 Hz, 2 H, H-7); 13C NMR δ 164.1, 154.8, 149.0, 147.5, 133.0, 132.3, 122.7, 118.2, 114.3, 41.6, 33.2, 32.8, 25.7. Anal, calcd for C13H13N3O: C, 68.7; H, 5.8; N, 18.5. Found: C, 68.7; H, 5.9; N, 18.7%.
Example 65 3-(1 -Oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)-1 -propanol (70). A solution of 9-BBN in THF (31.1 mL, 15.6 mmol) was added dropwise to a stirred solution of alkene (2.95 g, 13.0 mmol) in THF (150 mL) and the solution stirred at 20 0C for 3 h. A solution of NaOH (3M, 6.5 mL, 19.5 mmol) was added carefully, followed by the dropwise addition of 35% aqueous H2O2 (5.8 mL, 58.4 mmol) and the mixture stirred at 20 0C for 1 h. The mixture was diluted with brine (100 mL), extracted with EtOAc (3 x 100 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (20-30%) of EtOAc/pet. ether, to give alcohol 70 (1.77 g, 55%) as a white solid: mp (EtOAc/pet. ether) 131-133 0C; 1H NMR δ 8.24 (s, 1 H, H-9), 7.74 (S1 1 H, H-5), 3.78 (br dt, J = 5.8, 5.5 Hz, 2 H, CH2O), 3.08-3.14 (m, 6 H, H-6, H-8, CH2), 2.36 (br t, J = 5.5 Hz1 1 H, OH)1 2.21 (p, J = 7.4 Hz, 2 H1 H-7), 2.12-2.17 (m, 2 H1 CH2); 13C NMR δ 165.7, 154.9, 149.0, 147.2, 132.3, 122.5, 114.3, 62.1 , 34.0, 33.2, 32.8, 30.5, 25.7. Anal, calcd for C13H15N3O2: C, 63.7; H, 6.2; N, 17.1. Found: C1 63.7; H1 6.2; N, 17.3%.
Example 66 3-(1-Oxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-yl)-1-propanol (70). Pd(OAc)2 (18 mg, 0.08 mmol) was added to a degassed solution of iodide 66 (250 mg, 0.80 mmol), allyl alcohol (0.27 mL, 3.40 mmol), tetrabutylammonium chloride (182 mg, 0.80 mmol) and NaHCO3 (147 mg, 1.76 mmol) in acetonitrile (12.5 mL) and the solution irradiated in a Milestone MicroSYNTH reactor for 15 min at 150 0C (max. 400 watt). After cooling, the mixture was quenched with saturated aqueous NH4CI solution (10 ml) and filtered. The filtrate was extracted with EtOAc (3 x 20 ml), dried and the solvent evaporated. The crude residue was dissolved in MeOH (20 mL), cooled to -40 0C and NaBH4 (2 x 40 mg, 2.12 mmol) in MeOH (20 mL) added to it. The solution was stirred at -40 0C for 1 , then HOAc (0.1 mL) added, warmed to 20 0C and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (80-100%) EtOAc/pet. ether, to give alcohol 70 (89 mg, 45%) as an off-white solid; spectroscopically identical to the sample prepared above.
Example 67 3-(1,4-Dioxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-yl)-1-propanol (71). H2O2 (70%, 1.6 mL, ca. 33 mmol) was added dropwise to a stirred solution of TFAA (4.6 mL, 33 mmol) in DCM (30 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C. The solution was added to a solution of 1 -oxide 70 (0.86 g, 3.3 mmol) in DCM (50 mL) at 0 0C and the solution was stirred at 20 0C for 16 h. Dilute aqueous NH3 solution (30 mL) was added and the mixture stirred vigorously for 30 min and then extracted with DCM (4 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give (i) starting material 70 (283 mg, 33%) and (ii) 1,4- dioxide 71 (347 mg, 40%) as a yellow solid: mp (MeOH/EtOAc) 153-155 0C; 1H NMR δ 8.33 (s, 1 H, H-9), 8.26 (s, 1 H1 H-5), 3.68 (br dt, J = 6.1, 5.7 Hz, 2 H, CH2O), 3.33 (t, J = 6.9 Hz, 2 H, CH2), 3.13-3.20 (m, 4 H, H-6, H-8), 3.09 (brt, J = 6.1 Hz, 1 H, OH), 2.26 (p, J = 7.5 Hz, 2 H, H-7), 2.10-2.18 (m, 2 H, CH2); 13C NMR δ 155.5, 155.0, 150.9, 138.8, 134.0, 115.8, 114.1 , 61.2, 33.4, 32.9, 29.6, 26.8, 25.6. Anal, calcd for C13H15N3O3: C, 59.8; H, 5.8; N, 16.1. Found: C, 60.0; H, 5.7; N, 16.1%.
Example 68
3-(3-(Di-fert-butoxyphosphoryloxy)propyl)-7,8-dihydro-6H-indeno[5,6- e][1,2,4]triazine 1 -Oxide (72). Tetrazole (428 mg, 6.1 mmol) was added to a stirred solution of alcohol 70 (500 mg, 2.0 mmol) and di-ferf-butyldiethylphoshoramidite (0.77 mL, 2.5 mmol) in dry THF (30 mL) and the solution stirred at 20 0C under N2 for 22 h. The solution was cooled to -40 0C (MeCN/dry ice) and a dried solution of MCPBA (985 mg, 2.9 mmol) in DCM (10 mL) was added, and the solution stirred at -40 0C for 15 min. A solution of NaHSO3 (10%, 2 mL) was added and the mixture partitioned between water and DCM. The organic fraction was washed with dilute aqueous NH3 solution (3 x 20 mL), dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-4%) of MeOH/DCM, to give crude phosphate ester 72 (764 mg, 86%) as a thick pale-brown oil: 1H NMR δ 8.25 (s, 1 H, H-9), 7.74 (s, 1 H, H-5), 4.08-4.13 (m, 2 H, CH2O), 3.09-3.14 (m, 6 H, H-6, H-8, CH2), 2.18-2.31 (m, 4 H, H-7, CH2), 1.48 [s, 18 H, 2 x OC(CH3)3]; HRMS (FAB+) calcd for C21H33N3O5P (MH+) m/z 438.2158, found 438.2154.
Example 69
3-(3-(Di-ferf-butoxyphosphoryloxy)propyl)-7,8-dihydro-6W-indeno[5,6- e][1,2,4]triazine 1,4-Dioxide (73). A dried solution of MCPBA (2.29 g, 6.63 mmol) in DCM (25 mL) was added to a mixture of 1-oxide 72 (ca. 70%, 580 mg, 0.928 mmol) and NaHCO3 (557 mg, 6.63 mmol) in DCM (30 mL) and the solution stirred at 20 0C for 16 h. The solution was diluted with DCM (100 mL) and washed with diluted with dilute aqueous NH3 solution (3 x 60 mL) and extracted with DCM (3 \ 20 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 10% MeOH/EtOAc. to give (i) starting material 72 (224 mg, 55%) and (ii) 1 ,4-dioxide 73 (103 mg, 25%) as a yellow solid: mp 129-131 0C; 1H NMR δ 8.31 (s, 1 H, H-9), 8.26 (s, 1 H, H-5), 4.09-4.16 (m, 2 H, CH2O), 3.27-3.31 (m, 2 H, CH2), 3.09-3.19 (m, 4 H, H-6, H-8), 2.20-2.30 (m, 4 H, H-7, CH2), 1.48 [s, 18 H, 2 x OC(CH3)3]; 13C NMR δ 155.1 , 154.0, 150.7, 139.1, 133.9, 115.9, 113.9, 82.2 (d, J = 8.0 Hz, 2), 65.8 (d, J = 6.0 Hz), 33.4, 32.9, 29.9 (d, J = 5.0 Hz, 6), 27.0, 25.6, 25.6. HRMS (FAB+) calcd for C21H33N3O6P (MH+) m/z 454.2107, found 454.2101.
Example 70
3-(1 ,4-Dioxido-7,8-dihydro-6W-indeno[5,6-e][1 ,2,4]triazin-3-yl)propyl Dihydrogen Phosphate (74). TFA (0.16 mL) was added to a stirred solution of phosphate diester 73 (92 mg, 0.20 mmol) in DCM (15 mL) and the solution stirred at 20 0C for 4 h. The solvent was evaporated, the residue dissolved in CHCI3 and filtered. The filtrate was concentrated and freeze dried to give phosphate 74 as a hygroscopic brown gum (77 mg, 100%); 1H NMR δ 8.24 (br s, 1 H, H-9), 8.17 (br s, 1 H, H-5), 4.13 (br m, 2 H, CH2O), 3.36 (br s, 2 H1 2 x OH), 3.12-3.21 (m, 6 H, H-6, H-8, CH2), 2.08-2.27 (m, 4 H, H-7, CH2); HRMS (FAB+) calcd for C13H17N3O6P (MH+) m/z 342.0855, found 342.0854.
Example 71
3-[3-(4-MorphoHnyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 -Oxide (76). Iodide 66 (3.98 g, 12.7 mmol) was added to a degassed solution of altyl alcohol (1.95 g, 33 mmol), Pd(OAc)2 (120 mg, 0.53 mmol), tetrabutylammonium bromide (3.4 g, 11 mmol) and NaHCO3 (2.3 g, 27 mmol) in DMF (70 mL) and the solution was stirred at 50 °C for 24 h. The mixture was quenched with saturated aqueous NH4CI solution (100 ml) and filtered. The filtrate was extracted with EtOAc (5 x 200 mL), dried and the solvent evaporated. The residue was purified by chromatography, eluting with 50% EtOAc/pet. ether, to give a dark oil (2.7 g, 87%) that was used without further purification. Purification of a small sample by chromatography, eluting with a gradient (20-50%) EtOAc/pet. ether, gave 3-(1-oxido-7,8- dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)propanal (75) as an orange solid: mp (EtOAc/pet. ether) 72-74 0C; 1H NMR δ 9.93 (t, J = 0.9 Hz, 1 H, CHO), 8.25 (s, 1 H, H-9), 7.73 (s, 1 H, H-5), 3.35 (t, J = 7.0 Hz, 2 H, CH2), 3.07-3.14 (m, 6 H, H-6, H-8, CH2), 2.21 (p, J = 7.5 Hz, 2 H, H-7); 13C NMR δ 200.4, 163.9, 154.8, 149.1, 147.2, 132.3, 122.7, 114.2, 40.5, 33.1, 32.8, 29.4, 25.7; MS (Cl, CH3OH) m/z 244 (MH+, 100%); HRMS (Cl, CH3OH) calcd for C13Hi4N3O2 (MH+) m/z 244.1086, found 244.1088. Anal, calcd for C13H13N3O2: C, 64.2; H1 5.4; N, 17.3. Found: C, 63.9; H, 5.5; N, 17.0%. Morpholine (3.9 mL, 44 mmol) was added to a solution of aldehyde (2.7 g, 11.1 mmol) in EtOH (100 mL) at 0 °C and the solution stirred for 20 min. NaCHBH3 (2.1 g, 33 mmol) was added and the mixture stirred at 0 0C for 30 min, then HOAc (0.5 mL) was added and the mixture stirred at 20 0C for 16 h. The solvent was evaporated and the residue partitioned between DCM and water, the organic phase was dried and the solvent evaporated. The residue purified by chromatography, eluting with 10% MeOH/EtOAc, to give 1 -oxide 76 (1.8 g, 52%) as a pale yellow oil: 1H NMR δ 8.25 (s, 1 H, H-9), 7.73 (s, 1 H, H-5), 3.58 (br t, J = 4.6 Hz, 4 H, 2 x CH2O), 3.09-3.15 (m, 4 H, H-6, H-8), 3.04 (br t, J = 7.4 Hz, 2 H, CH2), 2.48 (br dd, J = 7.3, 7.0 Hz, 2 H, CH2N), 2.43 (br t, J = 4.6 Hz, 4 H, 2 x CH2N), 2.22 (p, J = 7.4 Hz, 2 H, H-7), 2.06-2.14 (m, 2 H, CH2). Formation of the hydrochloride salt gave a tan solid: mp (MeOH/EtOAc) 193-195 0C; 1H NMR [(CD3)2SO] δ 11.16 (br s, 1 H, NH+CI ), 8.19 (s, 1 H1 H-9), 7.83 (s, 1 H, H-5), 3.75-3.90 (m, 4 H, 2 x CH2O), 3.25-3.35 (m, 4 H, 2 x CH2N), 3.05-3.15 (m, 6 H, H-6, H-8, CH2N), 3.00 (t, J = 7.4 Hz, 2 H, CH2), 2.19-2.28 (m, 2 H, CH2), 2.12 (p, J = 7.5 Hz, 2 H, H-7); 13C NMR [(CD3)2SO] δ 163.8, 154.7, 148.9, 146.6, 131.8, 122.3, 113.6, 63.2 (2), 55.1, 51.0 (2), 33.2, 32.5, 32.2, 25.3, 21.0. Anal, calcd for C17H23CIN4O2-1Z2H2O: C, 56.7; H, 6.7; N, 15.6. Found: C, 56.6; H, 6.7; N, 15.4%.
Example 72
3-[3-(4-Morpholinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 ,4-Dioxide (77). H2O2 (70%, 2.8 ml_, ca. 56 mmol) was added dropwise to a stirred solution of TFAA (7.9 mL, 56 mmol) in DCM (20 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C. The solution was added to a solution of 1 -oxide 76 (1.76 g, 5.6 mmol) and TFA (2.2 mL, 28 mmol) in DCM (40 mL) at 0 0C and the solution was stirred at 20 0C for 6 h. Dilute aqueous NH3 solution (40 mL) was added and the mixture stirred vigorously for 30 min and then extracted with DCM (4 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 76 (173 mg, 10%); and (ii) 1 ,4-dioxide 77 (868 mg, 47%) as a yellow solid: mp (MeOH/DCM) 109-110 0C; 1H NMR δ 8.30 (s, 1 H, H-9), 8.27 (s, 1 H, H-5), 3.44 (br t, J = 4.4 Hz, 4 H, 2 x CH2O), 3.24 (br t, J = 7.3 Hz, 2 H, CH2), 3.13-3.19 (m, 4 H, H-6, H-8), 2.50 (t, J = 6.5 Hz, 2 H, CH2N), 2.38 (br t, J = 4.3 Hz, 4 H, 2 x CH2N), 2.27 (p, J = 7.5 Hz, 2 H, H-7), 2.06-2.12 (m, 2 H, CH2); 13C NMR δ 155.2, 155.1, 150.5, 139.0, 133.7, 115.8, 113.8, 67.0 (2), 58.0, 53.5 (2), 33.3, 32.8, 28.5, 25.5, 21.8. Anal, calcd for C17H22N4O3: C, 61.8; H, 6.7; N, 17.0. Found: C, 62.0; H, 6.8; N, 17.2%.
Example 73
Λ/,/V-Dimethyl-3-(1 -oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)-1 - propanamine (78). A solution of anhydrous Me2NH (2.4 g, 52 mmol) in MeOH (50 mL) was added to a solution of propanal 75 (1.5 g, 6.2 mmol) in MeOH (50 ml) at 0 0C and the solution stirred for 20 min. NaCNBH3 (1.5 g, 24 mmol) was added and the solution stirred for 30 min, then HOAc (2 ml) was added and the mixture was stirred at 20 0C for 16 h. The solvent was evaporated and the residue was partitioned between DCM (200 mL) and water (200 mL). The aqueous phase was extracted with DCM (2 x 200 ml), the combined organic phase was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 10% MeOH/EtOAc, to give 1 -oxide 78 (930 mg, 55%) as a yellow oil: 1H NMR [(CD3)2SO] δ 8.17 (s, 1 H, H-9), 7.81 (s, 1 H, H-5), 3.06-3.12 (m, 4 H, H-6, H-8), 2.94-3.03 (m, 4 H, 2 x CH2), 2.66 [s, 6 H, N(CH3)2], 2.07-2.18 (m, 4 H, H-7, CH2); 13C NMR δ 164.1 , 155.0, 149.2, 146.8, 131.9, 122.4, 113.7, 56.6, 43.0 (2), 33.3, 32.7, 32.4, 25.4, 22.7; HRMS (FAB+) calcd for C15H21N4O (MH+) m/z 273.1715, found 273.1714.
Example 74 Λ/-[3-(1,4-Dioxido-7,8-dihydro-6W-mdeno[5,6-e][1,2,4]triazin-3-yl)propyl]-Λ/,yV- dimethylamine (79). H2O2 (70%, 0.65 mL, 13 mmol) was added dropwise to a stirred solution of TFAA (1.8 mL, 13 mmol) in DCM (20 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 °C for 10 min, then cooled to 0 0C and added to a stirred solution of 1-oxide 78 (353 mg, 1.3 mmol) and TFA (0.7 mL, 9.1 mmol) in DCM (20 mL) at 0 0C. The solution was stirred at 20 0C for 8 h, diluted with dilute aqueous NH3 solution (12 mL) and extracted with DCM (4 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 79 (154 mg, 41%) as a red solid: 1H NMR δ 8.30 (s, 1 H, H-9), 8.26 (s, 1 H, H-5), 3.25-3.09 (m, 6 H, H-6, H-8, CH2), 2.75 (t, J = 7.3 Hz, 2 H, CH2), 2.70 [s, 6 H, N(CH3)2], 2.29-2.14 (m, 4 H, H-7, CH2); 13C NMR δ 155.2, 153.9, 150.8, 139.1 , 133.9, 115.9, 113.9, 58.0, 44.3 (2), 33.4, 32.9, 27.9, 25.6, 21.7; HRMS (FAB+) calcd for C15H21N4O2 (MH+) m/z 289.1665, found 289.1669.
Example 75 Λ/,/V-Bis(2-methoxyethyl)-3-(1-oxido-7,8-dihydro-6W-indeno[5,6-e][1,2,4]triazin-3-yl)- 1-propanamine (80). Bis-(2-methoxyethyl)amine (3. 0 g, 22.5 mmol) was added to a stirred solution of propanal 75 (1.2 g, 4.9 mmol) in MeOH (100 ml) at 0 °C and the solution stirred for 30 min. NaCNBH3 (1.5 g, 24 mmol) was added and the solution stirred at 0 0C for 30 min and then HOAc (2 mL) was added and the mixture was stirred at 20 0C for 16 h. The solvent was evaporated and the residue was partitioned between DCM (200 mL) and water (200 mL). The aqueous phase was extracted with DCM (2 x 200 ml), the combined organic phase was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 10% MeOH/EtOAc, to give 1-oxide 80 (1.1 g, 50%) as a yellow oil: 1H NMR [(CD3)2SO] δ 8.19 (s, 1 H, H-9), 7.83 (s, 1 H, H-5), 3.61-3.68 (m, 4 H, 2 x CH2O), 3.31-3.38 (m, 4 H, 2 x CH2N), 3.26 (s, 6 H, 2 x OCH3), 3.20-3.14 (m, 4 H, 2 x CH2), 3.07-3.12 (m, 4 H, H-6, H-8), 2.15-2.10 (m, 4 H, H-7, CH2); 13C NMR δ 163.9, 154.7, 149.0, 146.7, 131.8, 122.2, 113.6, 58.0 (2), 57.4 (2), 52.4, 52.3, 32.5, 32.2, 25.3, 23.0 (2), 19.1; HRMS (FAB+) calcd for C19H29N4O3 (MH+) m/z 361.2240, found 361.2243.
Example 76 W-[3-(1,4-Dioxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-yl)propyl]-W,W-bis(2- methoxyethyl)amine (81). H2O2 (70%, 2.0 mL, 39 mmol) was added dropwise to a stirred solution of TFAA (5.4 mL, 39 mmol) in DCM (50 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to a stirred solution of 1-oxide 80 (1.50 g, 4.2 mmol) and TFA (1.5 mL, 1.95 mmol) in DCM (50 mL) at 0 0C. The solution was stirred at 20 0C for 6 h, diluted with dilute aqueous NH3 solution (36 mL) and extracted with DCM (3 x 150 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 ,4-dioxide 81 (533 mg, 35%) as a red gum: 1H NMR δ 8.28 (s, 1 H, H-9), 8.24 (s, 1 H, H-5), 3.78 (br t, J = 4.7 Hz, 4 H, 2 x CH2O), 3.40- 3.45 (m, 6 H, 3 x CH2), 3.33 [s, 6 H, 2 x OCH3), 3.19-3.23 (m, 2 H, CH2), 3.12-3.17 (m, 4 H, H-6, H-8), 2.34-2.38 (m, 2 H, CH2), 2.22-2.28 (m, 2 H, H-7); 13C NMR δ 155.5, 152.5, 151.1, 139.0, 134.0, 115.8, 113.8, 67.2 (2), 58.9 (2), 52.9 (3), 33.4, 32.9, 27.2, 25.5, 18.8; HRMS (FAB+) calcd for C19H29N4O4 (MH+) m/z 377.2189, found 377.2185.
Example 77 3-[3-(3-Methoxy-1-azetidinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1-
Oxide (82). 3-Azetidinyl methyl ether hydrochloride (275) (MacKenzie et al., PCT Int.
Appl. WO 9605193, 1996) (0.60 g, 4.9 mmol) was added to a stirred solution of propanal
75 (1.2 g, 4.9 mmol) in MeOH (100 mL) at 0 0C and the solution stirred for 30 min.
NaCNBH3 (1.5 g, 24 mmol) was added and the solution stirred at 0 0C for 30 min and then HOAc (2 mL) was added and the mixture was stirred at 20 °C for 16 h. The solvent was evaporated and the residue was partitioned between DCM (200 mL) and water (200 mL).
The aqueous phase was extracted with DCM (2 x 200 mL), the combined organic phase was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 10% MeOH/EtOAc, to give 1-oxide 82 (930 mg, 60%) as a yellow oil: 1H NMR δ 8.24 (s, 1 H, H-9), 7.74 (s, 1 H, H-5), 4.27^.39 (m, 3 H, CH2N, CHO), 3.49-3.53 (m, 2
H, CH2N), 3.30 (s, 3 H, OCH3), 3.21-3.27 (m, 2 H, CH2N), 3.09-3.16 (m, 4 H, H-6, H-8), 3.05 (t, J = 7.2 Hz, 2 H, CH2), 2.14-2.26 (m, 4 H, H-7, CH2); 13C NMR δ 163.9, 155.1, 149.3, 147.3, 132.3, 122.7, 144.2, 68.3, 60.9, 58.7, 56.6, 56.5, 33.5, 33.1 , 32.8, 25.7, 23.8; HRMS calcd for C17H22N4O2 (M+) m/z 314.1743, found 314.1742.
Example 78
3-[3-(3-Methoxy-1-azetidinyl)propyl]-7,8-dihydro-6/y-indeno[5,6-e][1,2,4]triazine 1,4- Dioxide (83). H2O2 (70%, 2.0 ml_, 39 mmol) was added dropwise to a stirred solution of TFAA (5.4 ml_, 39 mmol) in DCM (50 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to a stirred solution of 1- oxide 82 (0.93 g, 3.0 mmol) and TFA (1.5 mL, 19.5 mmol) in DCM (50 mL) at 0 0C. The solution was stirred at 20 0C for 8 h, diluted with dilute aqueous NH3 solution (30 mL) and extracted with DCM (3 x 150 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 ,4-dioxide 83 (0.60 g, 60%) as a red gum: 1H NMR δ 8.31 (S1 1 H, H-9), 8.28 (s, 1 H, H-5), 4.60^.70 (m, 2 H, CH2N), 4.33-4.40 (m, 1 H, CHO), 3.60-3.75 (m, 2 H, CH2N), 3.33 (s, 3 H, CH3O), 3.25-3.32 (m, 2 H, CH2N), 3.12-3.25 (m, 6 H, H-6, H-8, CH2), 2.27-2.33 (m, 4 H, H-7, CH2); 13C NMR δ 155.5, 152.3, 151.2, 139.1 , 134.1 , 115.9, 113.9, 67.8, 61.0, 58.9, 56.9, 55.6, 32.9, 32.4, 26.9, 25.6, 22.9; HRMS (FAB+) calcd for C17H23N4O3 (MH+) m/z 331.1770, found 331.1771.
Example 79
3-[3-(1-Pyrrolidinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]tria2ine 1 -Oxide (84). Pyrrolidine (3.0 g, 42 mmol) was added to a stirred solution of propanal 75 (1.5 g, 6.2 mmol) in MeOH (100 mL) at 0 0C and the solution stirred for 30 min. NaCNBH3 (1.5 g, 24 mmol) was added and the solution stirred at 0 0C for 30 min and then HOAc (2 mL) was added and the mixture was stirred at 20 0C for 16 h. The solvent was evaporated and the residue was partitioned between DCM (200 mL) and water (200 mL). The aqueous phase was extracted with DCM (2 x 200 mL), the combined organic phase was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 10% MeOH/EtOAc, to give 1-oxide 84 (1.5 g, 84%) as a yellow oil: 1H NMR [(CDs)2SO] δ 8.25 (s, 1 H, H-9), 7.74 (s, 1 H, H-5), 3.10-3.16 (m, 4 H, H-6, H-8), 3.02-3.09 (m, 2 H, CH2N), 2.80-2.88 (m, 6 H, 3 x CH2), 2.17-2.28 (m, 4 H, H-7, CH2), 1.82-1.90 (m, 4 H, 2 x CH2); 13C NMR δ 165.0, 154.8, 149.2, 147.2, 132.3, 122.7, 114.3, 55.0, 53.4 (2), 34.8, 33.2, 32.8, 25.7, 25.5, 23.4 (2); HRMS calcd for C17H22N4O (M+) m/z 298.1794, found 298.1794. Example 80
S-^i-PyrrolidinyOpropyll-T.S-dihydro-eH-indenotδ.β-elli^^ltriazine i^-Dioxide (85). H2O2 (70%, 2.0 mL, 39 mmol) was added dropwise to a stirred solution of TFAA (5.4 ml_, 39 mmol) in DCM (50 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to a stirred solution of 1 -oxide 84 (1.50 g, 4.6 mmol) and TFA (1.5 mL, 19.5 mmol) in DCM (50 mL) at 0 0C. The solution was stirred at 20 0C for 6 h, diluted with dilute aqueous NH3 solution (30 mL) and extracted with DCM (3 x 150 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 ,4-dioxide 85 (846 mg, 35%) as a red gum: 1H NMR δ 8.25 (s, 1 H, H-9), 8.20 (s, 1 H, H-5), 3.22-3.22 (m, 6 H, 3 x CH2), 3.11-3.20 (m, 4 H, H-6, H-8), 2.80-3.05 (m, 2 H, CH2), 2.33-2.43 (m, 2 H, CH2), 2.21-2.30 (m, 2 H, H-7), 2.13 (br s, 4 H, 2 x CH2); 13C NMR δ 155.4, 152.4, 151.0, 139.0, 133.9, 115.7, 113.7, 54.2, 53.5 (2), 33.3, 32.8, 27.1 , 25.4, 23.8, 23.2 (2); HRMS (FAB+) calcd for Ci7H23N4O2 (MH+) m/z 315.1821 , found 315.1820.
Example 81
3-[3-(1 -Piperidiny l)propyl]-7,8-dihydro-6«-indeno[5,6-e][1 ,2,4]triazine 1 -Oxide (86).
Piperidine (3.0 g, 35 mmol) was added to a stirred solution of propanal 75 (1.5 g, 6.2 mmol) in MeOH (100 mL) at 0 0C and the solution stirred for 30 min. NaCNBH3 (1.5 g, 24 mmol) was added and the solution stirred at 0 0C for 30 min and then HOAc (2 mL) was added and the mixture was stirred at 20 0C for 16 h. The solvent was evaporated and the residue was partitioned between DCM (200 mL) and water (200 mL). The aqueous phase was extracted with DCM (2 x 200 mL), the combined organic phase was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 10%
MeOH/EtOAc, to give 1-oxide 86 (1.33 g, 69%) as a yellow oil: 1H NMR δ 8.24 (s, 1 H, H- 9), 7.74 (s, 1 H, H-5), 3.09-3.15 (m, 4 H, H-6, H-8), 3.02-3.07 (m, 2 H, CH2), 2.82-2.95 (m, 6 H, 3 x CH2), 2.27-2.38 (m, 2 H, CH2), 2.17-2.26 (m, 2 H, H-7), 1.76-1.87 (m, 4 H, 2 x CH2), 1.50-1.60 (m, 2 H, CH2); 13C NMR δ 164.3, 155.0, 149.2, 147.4, 132.3, 122.7, 114.2, 57.1, 53.5 (2), 34.3, 33.2, 32.8, 25.7 (2), 23.7, 22.9, 22.6; HRMS (FAB+) calcd for C18H25N4O (MH+) m/z 313.2025, found 313.2025.
Example 82
3-[3-(1 -Piperidinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 ,4-Dioxide (87). H2O2 (70%, 2.0 mL, 39 mmol) was added dropwise to a stirred solution of TFAA (5.4 mL, 39 mmol) in DCM (50 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to a stirred solution of 1 -oxide 86 (1.33 g, 4.2 mmol) and TFA (1.5 mL, 19.5 mmol) in DCM (50 mL) at 0 0C. The solution was stirred at 0 0C for 4 h, diluted with dilute aqueous NH3 solution (40 mL) and extracted with DCM (3 x 150 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of
MeOH/DCM, to give 1,4-dioxide 87 (1.05 g, 76%) as a red gum: 1H NMR δ 8.30 (s, 1 H, H- 9), 8.26 (s, 1 H, H-5), 3.34-3.40 (m, 4 H, 2 x CH2), 3.27 (t, J = 7.1 Hz, 2 H, CH2N), 3.12- 3.21 (m, 4 H, H-6, H-8), 3.05-3.12 (m, 2 H, CH2), 2.42-2.51 (m, 2 H, CH2), 2.22-2.32 (m, 2 H, H-7), 1.64-1.73 (m, 4 H, 2 x CH2), 1.40-1.51 (m, 2 H, CH2); 13C NMR δ 161.8, 155.2, 150.8, 139.1, 134.0, 115.8, 113.9, 58.9, 53.7, 53.4, 33.4, 32.9, 28.0, 25.6, 24.0 (2), 19.7, 13.6; HRMS (FAB+) calcd for C18H25N4O2 (MH+) m/z 329.1974, found 329.1974.
Example 83 7-Methyl-7,8-dihydro-6W-indeno[5,6-e][1,2,4]triazin-3-amine 1 -Oxide (94). 2-Methyl-6-nitro-1-indanone (89). 2-Methyl-1-indanone (88) (18.74 g, 128 mmol) was added dropwise to stirred fuming HNO3 (100 mL) at -10 0C over 1 h. The mixture was stirred at -10 0C for 10 min then poured into ice/water (1 L) and the mixture stirred for 1 h. The precipitate was filtered and the filtrate extracted with DCM (4 x 80 mL). The combined organic fraction was dried and the solvent evaporated. The combined residue was purified by chromatography, eluting with a gradient (10-20%) of EtOAc/pet. ether, to give (i) 2- methyl-4-nitro-1-indanone (89) (1.89 g, 8%) as a tan solid: mp 61-63 0C [lit. Murray, R. J. & Cromwell, N. H., J. Org. Chem. 1976, 41, 3540) mp (Et2O/pet. ether) 74-75 0C]; 1H NMR δ 8.46 (dd, J = 8.0, 1.1 Hz, 1 H, H-5), 8.08 (br d, J = 7.5 Hz, 1 H, H-7), 7.60 (br dd, J = 8.0, 7.5 Hz, 1 H, H-6), 3.93 (dd, J = 19.2, 8.0 Hz, 1 H, H-3), 3.20 (dd, J = 19.2, 4.0 Hz, 1 H, H-3), 2.76-2.85 (m, 1 H, H-2), 1.37 (d, J = 7.5 Hz, 3 H, CH3); and (ii) 2-methyl-6-nitro- 1-indanone (90) (10.76 g, 44%) as a tan solid: mp 60-61 0C; 1H NMR δ 8.56 (d, J = 2.0 Hz, 1 H, H-7), 8.44 (dd, J = 8.4, 2.2 Hz, 1 H, H-5), 7.63 (d, J = 8.4 Hz, 1 H, H-4), 3.48- 3.54 (m, 1 H, H-2), 2.81-2.90 (m, 2 H1 H-3), 1.36 (d, J = 7.3 Hz, 3 H, CH3). Anal, calcd for C10H9NO3: C, 62.8; H, 4.7; N, 7.3. Found: C, 62.7; H, 4.8; N, 7.4%.
W-(2-MethyI-2,3-dihydro-1H-inden-5-yl)acetamide (91). A solution of nitroindanone 90 (2.08 g, 10.9 mmol) in EtOH (100 mL), water (10 mL) and cHCI (1 mL) with Pd/C (200 mg) was vigorously stirred under H2 (60 psi) for 16 h. The mixture was filtered through Celite and the solvent was evaporated. The residue was partitioned between dilute aqueous NH3 solution and DCM, and the organic fraction dried and the solvent evaporated. The residue was suspended in dioxane (30 mL), and Ac2O (1.6 mL, 17.0 mmol) added dropwise. The mixture was stirred at 20 0C for 16 h, and then quenched with MeOH (20 mL) and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (20-50%) of EtOAc/pet. ether, to give acetamide 91 (1.03 g, 50%) as a white solid: mp (EtOAc/pet. ether) 90-91 0C; 1H NMR δ 7.41 (br d, J = 1.7 Hz, 1 H, H-4), 7.35 (br s, 1 H, NH), 7.15 (br dd, J = 8.0, 1.7 Hz, 1 H, H-6), 7.10 (br d, J = 8.0 Hz, 1 H, H-7), 2.97-3.05 (m, 2 H, CH2), 2.45-2.61 (m, 3 H, H-2, CH2), 2.16 (s, 3 H, COCH3), 1.13 (d, J = 6.4 Hz, 3 H, CH3); 13C NMR δ 168.3, 144.7, 139.9, 136.0, 124.5, 118.2, 116.7, 41.2, 40.6, 34.7, 24.5, 20.7. Anal, calcd for C12H15NO: C, 76.2; H, 8.0; N, 7.4. Found: C, 76.3; H, 7.9; N, 7.4%.
N-(2-WIethyl-6-nitro-2,3-dihydro-1H-inden-5-yl)acetamide (92). A solution of nitric acid (70%, 3.2 mL, 50.3 mmol) in TFA (5 mL) was added dropwise to a stirred solution of acetamide 91 (3.93 g, 16.8 mmol) in TFA (40 mL) and the solution stirred at 20 0C for 2 h. The solution was poured into ice/water (400 mL) and stirred for 30 min. The precipitate was filtered, washed with water (3 x 30 mL), and dried. The solid was purified by chromatography, eluting with 10% EtOAc/pet. ether, to give nitroacetamide 92 (3.79 g, 96%) as a red solid: mp (EtOAc/pet. ether) 99-100 0C; 1H NMR δ 10.41 (br s, 1 H, NH), 8.50 (s, 1 H, H-7), 8.00 (s, 1 H, H-4), 3.03-3.13 (m, 2 H, CH2), 2.51-2.67 (m, 3 H, H-2, CH2), 2.29 (s, 3 H, COCH3), 1.14 (d, J = 6.4 Hz, 3 H, CH3); 13C NMR δ 169.0, 153.9, 139.4, 135.3, 133.7, 121.1, 117.7, 41.6, 40.2, 34.7, 25.6, 20.4. Anal, calcd for C12Hi4N2O3: C, 61.5; H, 6.0; N, 12.0. Found: C, 61.6; H, 6.2; N, 11.5%.
2-Methyl-6-nitro-5-indanamine (93). A suspension of nitroacetamide 92 (3.79 g, 16.2 mmol) in EtOH (100 mL) and cHCI (14 mL) was stirred at reflux temperature for 4 h. The mixture was cooled and the EtOH evaporated. The mixture was diluted with water (100 mL) and the pH adjusted to 9 with cNH3. The mixture was extracted with DCM (3 x 50 mL) and the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with 20% EtOAc/pet. ether, to give nitroaniline 93 (3.01 g, 97%) as a red solid: mp (EtOAc/pet. ether) 100-101 0C; 1H NMR δ 7.89 (s, 1 H, H-7), 6.61 (s, 1 H, H-4), 5.99 (br s, 2 H, NH2), 2.92-2.99 (m, 2 H, CH2), 2.40-2.58 (m, 3 H, H-2, CH2), 1.12 (d, J = 6.5 Hz, 3 H, CH3); 13C NMR δ 153.9, 144.3, 133.6, 131.3, 120.9, 113.6, 41.1, 39.6, 34.8, 20.4. Anal, calcd for C10H12N2O2: C, 62.5; H, 6.3; N, 14.6. Found: C, 62.6; H, 6.3; N, 14.5%.
7-Methyl-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 -Oxide (94). A mixture of nitroaniline 93 (3.0 g, 15.7 mmol) and cyanamide (2.6 g, 62.6 mmol) was mixed together at 80 0C, cHCI (5 ml.) added dropwise and the mixture heated at 100 0C for 3 h. A further three aliquots of cyanamide (0.5 g, 11.9 mmol) and cHCI (0.5 mL) were added over two hours. The mixture was cooled to 50 0C, 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100 0C for 3 h. The mixture was cooled, diluted with water (100 mL), filtered, washed with water (2 x 30 mL), and dried. The residue was purified by chromatography, eluting with a gradient (0-15%) of MeOH/DCM, to give 1- oxide 94 (3.06 g, 90%) as a yellow powder: mp (MeOH/DCM) 275-277 0C; 1H NMR [(CDa)2SO] δ 7.90 (s, 1 H, H-9), 7.31 (s, 1 H1 H-5), 7.10 (br s, 2 H, NH2), 3.05-3.14 (m, 2 H, CH2), 2.48-2.62 (m, 3 H, H-7, CH2), 1.09 (d, J = 6.3 Hz1 3 H, CH3); 13C NMR [(CDa)2SO] δ 159.9, 153.7, 148.6, 142.1, 128.7, 120.0, 113.9, 41.4, 39.6, 34.3, 19.9. Anal, calcd for C11H12N4O: C, 61.1; H, 5.6; N, 25.9. Found: C, 61.3; H, 5.6; N, 26.2%.
Example 84
3-Chloro-7-methyl-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1 -Oxide (95). NaNO2 (0.43 g, 6.2 mmol) was added in small portions to a stirred solution of amine 94 (1.23 g, 5.7 mmol) in TFA (50 mL) at 0 0C and the solution stirred at 20 0C for 1 h. The solution was poured into ice/water (500 mL) and stirred for 30 minutes. The solvent was evaporated and the residue dried. The solid was suspended in POCI3 (40 mL) and DMF (0.4 mL) and stirred at 80 0C for 1 h. The solution was cooled, poured into ice/water, stirred for 30 minutes, filtered, washed with water (3 x 30 mL) and dried. The filtrate was neutralized with cNH3, extracted with CHCI3 (4 x 30 mL), the combined organic fraction dried and the solvent evaporated. The combined residue was purified by chromatography, eluting with 5% EtOAc/DCM, to give chloride 95 (1.06 g, 79%) as a pale yellow solid: mp (DCM/pet. ether) 121-122 0C; 1H NMR δ 8.18 (s, 1 H, H-9), 7.71 (s, 1 H, H-5), 3.21-3.30 (m, 2 H, CH2), 2.65-2.80 (m, 3 H, H-7, CH2), 1.20 (d, J = 6.4 Hz, 3 H, CH3); 13C NMR δ 156.0, 155.9, 149.8, 147.4, 132.8, 122.6, 114.6, 41.3, 40.9, 35.0, 20.2. Anal, calcd for C11H10CIN3O: C, 56.1; H, 4.3; N, 17.8. Found: C, 56.0; H, 4.2; N, 17.8%.
Example 85 ^^^Dimethyl-Λ/^T-methyl-i-oxido-T.δ-dihydro-eH-indenoIS.β-elli^^ltriazin-S-yl)-
1,2-ethanediamine (96). A solution of chloride 95 (240 mg, 0.9 mmol), Λ/1, Λ/1 -dimethyl- 1 ,2-ethanediamine (0.26 mL, 2.4 mmol) and Et3N (0.33 mL, 2.4 mmol) in DME (50 mL) was stirred at reflux temperature for 4 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 -oxide 96 (389 mg, 86%) as a yellow solid: mp (MeOH/EtOAc) 119-121 0C; 1H NMR δ 8.03 (s, 1 H, H-9), 7.35 (s, 1 H, H-5), 5.82 (br s, 1 H, NH), 3.52-3.58 (m, 2 H, CH2N), 3.07-3.17 (m, 2 H, CH2), 2.55-2.67 (m, 5 H, CH, CH2, CH2N), 2.28 [s, 6 H, N(CH3)2], 1.15 (d, J = 6.1 Hz, 3 H, CH3); 13C NMR δ 158.7, 154.2, 148.9, 142.9, 129.8, 120.7, 114.8, 57.6, 45.1 (2), 41.2, 40.4, 38.7, 34.9, 20.2. Anal, calcd for C15H21N5O: C, 62.7; H, 7.4; N, 24.4. Found: C, 62.4; H, 7.1; N, 24.1%.
Example 86 ^.^-Dimethyl-^^T-methyl-i^-dioxido-T.S-dihydro-βH-indenoIS.β-elfi^^ltriazin-S- yl)-1,2-ethanediamine (97). H2O2 (70%, 0.65 ml_, ca. 12.9 mmol) was added dropwise to a stirred solution of TFAA (1.8 mL, 12.9 mmol) in DCM (20 mL) at 0 °C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to a stirred solution of 1-oxide 96 (371 mg, 1.3 mmol) and TFA (0.50 mL, 6.5 mmol) in DCM (20 mL) at 0 0C. The solution was stirred at 20 0C for 6 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCI3 (4 x 30 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 96 (181 mg, 49%) and (ii) 1,4-dioxide 97 (103 mg, 26%) as a red solid: mp (MeOH/DCM) 149-151 0C; 1H NMR δ 8.09 (s, 1 H, H-9), 8.07 (s, 1 H, H-5), 7.52 (br s, 1 H, NH), 3.58-3.64 (m, 2 H, CH2N), 3.14-3.27 (m, 2 H, CH2), 2.63-2.75 (m, 3 H, CH, CH2), 2.59 (br t, J = 6.0 Hz, 2 H, CH2), 2.28 [s, 6 H, N(CH3)2], 1.18 (d, J = 6.2 Hz, 3 H, CH3); 13C NMR δ 155.6, 149.4, 145.5, 138.0, 128.9, 115.8, 111.8, 57.4, 45.0 (2), 41.4, 40.4, 38.7, 34.8, 20.1. Anal, calcd for C15H21N5O2-1Z2CH2CI2: C, 54.6; H, 6.3; N, 19.9. Found: C, 54.4; H, 6.0; N, 19.8%.
Example 87
7-Methyl-/V-[3-(4-morpholinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3- amine 1 -Oxide (98). A solution of chloride 95 (367 mg, 1.6 mmol), 3-(4- morpholinyl)propylamine (0.34 mL, 2.3 mmol) and Et3N (0.33 mL, 2.3 mmol) in DME (50 mL) was stirred at reflux temperature for 8 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 98 (525 mg, 98%) as a yellow solid: mp (MeOH/DCM) 138-140 0C; 1H NMR δ 8.04 (s, 1 H, H-9), 7.35 (s, 1 H, H-5), 6.10 (br t, J = 5.0 Hz, 1 H, NH), 3.75 (br t, J = 4.7 Hz, 4 H, 2 x CH2O), 3.56-3.61 (m, 2 H, CH2N), 3.08-3.18 (m, 2 H, CH2), 2.56-2.65 (m, 3 H, CH, CH2), 2.44- 2.52 (m, 6 H, 3 x CH2N), 1.83 (br p, J = 6.5 Hz, 2 H, CH2), 1.15 (d, J = 6.1 Hz, 3 H, CH3); 13C NMR δ 158.8, 154.2, 148.9, 142.8, 129.8, 120.7, 114.8, 67.0 (2), 57.3, 53.8 (2), 41.2, 40.8, 40.4, 34.9, 25.3, 20.4. Anal, calcd for C18H25N5O2: C, 63.0; H, 7.3; N, 20.4. Found: C, 63.2; H, 7.2; N, 20.4%.
Example 88
7-Methyl-/V-[3-(4-morpholinyl)propyl]-7,8-dihydro-6W-indeno[5,6-e][1J2,4]triazin-3- amine 1,4-Dioxide (99). H2O2 (70%, 0.72 ml_, ca. 14.3 mmol) was added dropwise to a stirred solution of TFAA (2.0 mL, 14.3 mmol) in DCM (20 ml_) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 °C for 10 min, then cooled to 0 0C and added to a stirred solution of 1-oxide 98 (490 mg, 1.4 mmol) and TFA (0.55 mL, 7.1 mmol) in DCM (20 mL) at 0 0C. The solution was stirred at 20 0C for 6 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCI3 (4 x 30 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 98 (280 mg, 57%) and (ii) 1 ,4-dioxide 99 (88 mg, 17%) as a red solid: mp (MeOH/DCM) 161-163 0C; 1H NMR δ 8.30 (br s, 1 H, NH), 8.08 (br s, 2 H, H-5, H-9), 3.82 (br t, J = 4.5 Hz, 4 H, 2 x CH2O), 3.58-3.63 (m, 2 H, CH2N), 3.15-3.25 (m, 2 H, CH2), 2.61-2.74 (m, 3 H, CH, CH2), 2.57 (brt, J = 6.1 Hz, 2 H, CH2N), 2.47-2.53 (m, 4 H, 2 x CH2N), 1.83-1.90 (m, 2 H, CH2), 1.18 (d, J = 6.2 Hz, 3 H1 CH3); 13C NMR δ 155.2, 149.5, 145.2, 138.1 , 129.5, 115.8, 111.7, 66.9 (2), 57.7, 53.8 (2), 41.6, 41.4, 40.4, 34.9, 24.5, 20.2. Anal, calcd for C18H25N5O3: C, 60.2; H, 7.0; N, 19.5. Found: C, 60.6; H, 7.0; N, 18.3%.
Example 89 3-lodo-7-methyl-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1 -Oxide (100). ferf-Butyl nitrite (2.5 mL, 18.6 mmol) was added a stirred mixture of amine 94 (1.30 g, 6.0 mmol), diiodomethane (4.8 mL, 60 mmol) and CuI (1.2 g, 6.3 mmol) in THF (50 mL) and the mixture stirred at reflux temperature for 3 h. The solution was cooled and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (20- 50%) of EtOAc/pet. ether, to give chloride 100 (1.31 g, 67%) as a pale yellow solid: mp (EtOAc/pet. ether) 140-142 0C; 1H NMR δ 8.15 (s, 1 H, H-9), 7.70 (s, 1 H, H-5), 3.20-3.30 (m, 2 H, CH2), 2.65-2.79 (m, 3 H, H-7, CH2), 1.20 (d, J = 6.4 Hz, 3 H, CH3); 13C NMR δ 155.5, 149.9, 147.6, 133.4, 122.5, 121.7, 114.6, 41.3, 41.0, 35.0, 20.2. Anal, calcd for C11H10IN3O: C, 40.4; H, 3.1; N, 12.9. Found: C, 40.6; H, 3.0; N, 12.7%. Example 90 3-(7-Methyl-1-oxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]tria2in-3-yl)propanal (101).
Iodide 100 (1.53 g, 4.7 mmol) was added to a degassed solution of allyl alcohol (0.89 mL, 13.1 mmol), Pd(OAc)2 (52 mg, 0.23 mmol), nBu4NBr (1.35 g, 4.2 mmol) and NaHCO3 (0.86 g, 10.3 mmol) in DMF (40 mL) and the solution was stirred at 50 0C for 24 h under N2. The mixture was quenched with saturated aqueous NH4CI solution (50 mL) and filtered. The filtrate was extracted with EtOAc (5 x 50 mL), dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (20- 50%) of EtOAc/pet. ether, to give (i) starting material 100 (0.86 g, 56%) and (ii) aldehyde 101 as an orange gum: 1H NMR δ 9.93 (s, 1 H, CHO), 8.21 (s, 1 H, H-9), 7.69 (s, 1 H, H- 5), 3.35 (t, J = 7.0 Hz, 2 H, CH2), 3.20-3.27 (m, 2 H, CH2), 3.19 (br dd, J = 7.2, 6.7 Hz, 2 H, CH2), 2.64-2.76 (m, 3 H, H-7, CH2), 1.19 (d, J = 6.4 Hz, 3 H, CH3); 13C NMR δ 200.5, 163.9, 154.5, 148.7, 147.3, 132.4, 122.8, 114.4, 41.2, 40.9, 40.5, 35.0, 29.4, 20.2; MS (FAB+) A77/Z 258 (MH+, 60%), 242 (10); HRMS (FAB+) calcd for C14H16N3O2 (MH+) m/z 258.1243, found 258.1242.
Example 91
7-Methyl-3-[3-(4-morphormyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1- Oxide (102). Morpholine (0.64 mL, 7.3 mmol) was added to a solution of aldehyde 101 (0.47 g, 1.8 mmol) in EtOH (20 mL) at 0 0C and the solution stirred for 30 min. NaCNBH3 (0.35 g, 5.5 mmol) was added and the mixture stirred at 0 °C for 30 min, then HOAc (0.5 mL) was added and the mixture stirred at 20 °C for 30 min. The solvent was evaporated and the residue partitioned between DCM and water, the organic phase was dried, the solvent evaporated and the residue purified by chromatography, eluting with a gradient (0-10%) of MeOH/EtOAc, to give (i) starting material 101 (83 mg, 17%) and (ii) alcohol 103 (134 mg, 28%) as a white solid: mp (MeOH/EtOAc) 70-71 0C; 1H NMR δ 8.21 (s, 1 H, H-9), 7.71 (s, 1 H, H-5), 3.78 (t, J = 6.1 Hz, 2 H, CH2O), 3.20-3.28 (m, 2 H, CH2), 3.15 (t, J = 7.2 Hz, 2 H, CH2), 2.64-2.78 (m, 3 H, H-7, CH2), 2.35 (br s, 1 H, OH), 2.12-2.19 (m, 2 H1 CH2), 1.19 (d, J = 6.4 Hz, 3 H, CH3); 13C NMR 5 165.7, 154.6, 148.7, 147.3, 132.3, 122.6, 114.4, 62.1 , 41.2, 40.9, 35.0, 30.6, 24.7, 20.2. Anal, calcd for C14H17N3O2- %H2O: C, 63.7; H, 6.7; N, 15.9. Found: C, 63.7; H, 6.6; N, 15.9%; and (iii) 1-oxide 102 (331 mg, 55%) as a yellow gum: 1H NMR δ 8.22 (s, 1 H, H-9), 7.70 (s, 1 H, H-5), 3.60 (br t, J = 4.7 Hz, 4 H, 2 x CH2O), 3.21-3.28 (m, 2 H, CH2), 3.05 (br t, J = 7.4 Hz, 2 H, CH2), 2.65-2.77 (m, 3 H, H-7, CH2), 2.47-2.54 (m, 6 H, 3 x CH2N), 2.11 (p, J = 7.3 Hz, 2 H, CH2), 1.19 (d, J = 6.4 Hz, 3 H, CH3); 13C NMR 5 165.7, 154.4, 148.5, 147.5, 132.3, 122.7, 114.4, 66.7 (2), 55.1 , 53.5 (2), 41.2, 40.9, 35.2, 35.0, 24.7, 20.2; MS (FAB+) m/z 392 (MH+, 100%), 311 (20); HRMS (FAB+) calcd for C18H25N4O2 (MH+) m/z 329.1978, found 329.1978.
Example 92 7-Methyl-3-[3-(4-morpholinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 ,4- Dioxide (104). H2O2 (70%, 0.49 mL, ca. 9.7 mmol) was added dropwise to a stirred solution of TFAA (1.4 mL, 9.7 mmol) in DCM (10 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to a stirred solution of 1-oxide 102 (320 mg, 1.0 mmol) and TFA (0.38 mL, 4.9 mmol) in DCM (20 mL) at 0 0C. The solution was stirred at 20 0C for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCI3 (4 x 30 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give 1 ,4-dioxide 104 (148 mg, 44%) as a red solid: mp (MeOH/DCM) 119-121 0C; 1H NMR δ 8.27 (s, 1 H, H-9), 8.23 (s, 1 H, H-5), 3.45 (br t, J = 4.5 Hz, 4 H, 2 x CH2O), 3.21-3.33 (m, 4 H, 2 x CH2), 2.68-2.81 (m, 3 H, H-7, CH2), 2.48 (t, J = 6.5 Hz, 2 H, CH2N), 2.37 (br t, J = 4.5 Hz, 4 H, 2 x CH2N), 2.06-2.13 (m, 2 H, CH2), 1.20 (d, J = 6.4 Hz, 3 H, CH3); 13C NMR δ 155.2, 154.7, 150.2, 139.1 , 133.8, 115.9, 113.9, 67.0 (2), 58.0, 53.5 (2), 41.4, 40.8, 35.0, 28.8, 21.8, 20.1. Anal, calcd for C18H24N4O3-1Z4CH3OH: C, 62.2; H, 7.2; N, 15.9. Found: C, 62.3; H, 7.0; N, 16.0%.
Example 93
S-iT-Methyl-i^-dioxido-T.δ-dihydro-βH-indenotδ.θ-elli^^ltriazin-a-yO-i-propanol (105). H2O2 (70%, 0.25 mL, ca. 5.0 mmol) was added dropwise to a stirred solution of TFAA (0.7 mL, 5.0 mmol) in DCM (10 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to a stirred solution of 1- oxide 103 (130 mg, 0.5 mmol) in DCM (10 mL) at 0 0C. The solution was stirred at 20 °C for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and stirred vigorously for 1 h. The mixture was extracted with CHCI3 (4 x 30 mL) and the combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with EtOAc, to give 1 ,4-dioxide 105 (68 mg, 49%) as a red solid: mp (EtOAc/pet. ether) 130-131 0C; 1H NMR 5 8.30 (s, 1 H, H-9), 8.22 (s, 1 H, H-5), 3.69 (br t, J = 5.8 Hz, 2 H, CH2O), 3.24-3.35 (m, 4 H, 2 x CH2), 3.10 (br s, 1 H, OH), 2.68-2.83 (m, 3 H, H-7, CH2), 2.10-2.17 (m, 2 H, CH2), 1.21 (d, J = 6.5 Hz, 3 H, CH3); 13C NMR δ 155.2, 155.0, 150.5, 138.9, 134.0, 115.9, 114.2, 61.2, 41.4, 40.9, 34.9, 29.6, 26.8, 20.1. Anal, calcd for C14H17N3O3: C, 61.1; H, 6.2; N, 15.3. Found: C, 61.4; H, 6.3; N, 15.0%. Example 94 yV7,/V7-Dimethyl-7,8-dihydro-6W-indeno[5,6-e][1,2,4]triazine-3,7-diamine 1 -Oxide (111). /V,/V-Dimethyl-2-indanamine (107). Methanesulfonyl chloride (11.5 mL, 149 mmol) was added dropwise to a stirred solution of 2-indanol (106) (20 g, 149 mmol) and JPr2NEt (28.6 mL, 164 mmol) in DCM (300 mL) at 0 0C, and the solution stirred at 20 0C for 16 h. The solution was washed with 1 M HCI (80 mL), aqueous saturated NaHCO3 solution (80 mL) and brine (100 mL), dried and the solvent evaporated. The residue was recrystallised from EtOH to give 2,3-dihydro-1/V-inden-2-yl methanesulfonate (31.14 g, 98%) as a white solid. Aqueous HNMe2 (40%, 180 mL, 1.42 mol) was added slowly to a stirred solution of mesylate (30.25 g, 143 mmol) in DMF (200 mL) and the solution stirred at 20 0C for 16 h. The solution was partitioned between EtOAc (400 mL) and water (800 mL) and the organic fraction washed with water (3 x 80 mL), brine (100 mL), dried and the solvent evaporated. The residue was suspended in 1 M HCI (400 mL) and washed with DCM (3 x 80 mL). The pH of the aqueous fraction was adjusted to 14 with NaOH, the mixture chilled at 5 0C for 8 h and the precipitate filtered. The precipitate was washed with water (50 mL) and dried to give amine 107 (21.54 g, 93%) as a light gray solid: 1H NMR δ 7.10-7.17 (m, 4 H, Harom), 3.01-3.08 (m, 3 H, H-2, CH2), 2.82-2.91 (m, 2 H1 CH2), 2.31 [s, 6 H, N(CHa)2].
/V,W-Dimethyl-5-nitro-2-indanamine (108). CHNO3 (70%, 22.6 mL, 357 mmol) was added dropwise to a stirred solution of indane 107 (15.54 g, 95.8 mmol) in TFA (90 mL) and the solution stirred at 20 0C for 48 h. The solution was poured into ice/water (1 L) and the pH adjusted to 10 with cNH3. The mixture was extracted with DCM (4 x 150 mL), the combined organic fraction dried and the solvent evaporated to give crude 5- nitroindanamine 108 containing ca. 5% of the corresponding 4-nitro isomer. A small portion was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give 5-nitroindanamine 108 as an oil: 1H NMR δ 8.03-8.06 (m, 2 H, H-4, H-6), 7.30 (d, J = 8.9 Hz, 1 H, H-7), 3.23-3.30 (m, 1 H, H-2), 3.12-3.20 (m, 2 H, CH2), 2.97-3.03 (m, 2 H, CH2), 2.38 [s, 6 H, N(CH3)2]. The hydrochloride salt crystallised as a tan powder, mp 223- 227 0C. Anal, calcd for C11H15CIN2O2: C, 54.4; H, 6.2; N, 11.5. Found: C, 55.0; H, 6.3; N, 11.4%.
/V-[2-(Dimethylamino)-2,3-dihydro-1A/-inden-5-yl]acetamide (109). A solution of crude nitroindanamine 108 (19.82 g, 95.8 mmol) in EtOH (200 mL) and Pd/C (500 mg) was stirred in 2 x 100 mL batches under H2 (60 psi) for 16 h. The combined batches were filtered through Celite, and washed with warm EtOH (1 L) and then DMF (100 mL). The solvent was evaporated and the residue suspended in dioxane (130 mL), and Ac2O (19 mL, 190 mmol) added dropwise. The mixture was stirred at 20 0C for 16 h, diluted with water (200 mL), the pH adjusted to 10 with cNH3, and the mixture stirred for 30 min. The precipitate was filtered, washed with water (50 mL) and dried to give pure 5-acetamide 109 (15.38 g, 73%) as tan powder: mp 94-96 0C; 1H NMR δ 7.42 (br s, 1 H, NH), 7.08- 7.14 (m, 3 H, H-4, H-6, H-7), 2.97-3.08 (m, 3 H, H-2, CH2), 2.78-2.89 (m, 2 H, CH2), 2.30 [s, 6 H, N(CHs)2], 2.15 (s, 3 H, COCH3); 13C NMR δ 168.3, 142.8, 137.9, 136.3, 124.5, 118.5, 116.6, 68.1, 43.8 (2), 37.7, 37.1, 24.5. Anal, calcd for C13H18N2OH2O: C, 66.1; H, 8.5; N, 11.9. Found: C, 66.1 ; H, 8.5; N, 11.9%.
yV2,Λ/2-Dimethyl-6-nitro-2,5-indanediamine (110). A solution of CHNO3 (70%, 13.4 mL, 211 mmol) in TFA (15 mL) was added dropwise to a stirred solution of acetamide 109 (15.38 g, 70.5 mmol) in TFA (120 mL) and the solution stirred at 20 0C for 16 h. The solution was poured into ice/water (1.2 L) and the pH adjusted to 10 with cNH3. The mixture was extracted with DCM (4 χ 150 mL), the combined organic fraction dried and the solvent evaporated. The residue was filtered through a short column of silica, eluting with a gradient (0-15%) of MeOH/DCM, to give a 6:1 mixture of Λ/-[2-(dimethylamino)-6- nitro-2,3-dihydro-1f/-inden-5-yl]acetamide and Λ/-[2-(dimethylamino)-4-nitro-2,3-dihydro- 1f/-inden-5-yl]acetamide (16.7 g, 90%). A solution of the acetamide mixture (16.7 g, 63.4 mmol) in EtOH (300 mL) and cHCI (70 mL) was stirred at reflux temperature for 4 h. The mixture was cooled and the EtOH evaporated. The mixture was diluted with water (200 mL) and the pH adjusted to 9 with cNH3. The precipitate was filtered, washed with water (40 mL), dried and recrystallised from EtOAc/pet. ether to give pure 6-nitroaniline 110 (8.12 g, 52%) as a red solid: mp 119-121 °C; 1H NMR δ 7.91 (s, 1 H, H-7), 6.61 (s, 1 H, H-4), 6.00 (br s, 2 H, NH2), 2.95-3.06 (m, 3 H, H-2, CH2), 2.74-2.84 (m, 2 H1 CH2), 2.29 [s, 6 H, N(CHa)2]; 13C NMR δ 151.8, 144.4, 131.6, 131.4, 121.0, 113.6, 67.8, 43.8 (2), 37.9, 36.2. Anal, calcd for C11H15N3O2: C, 59.7; H, 6.8; N, 19.0. Found: C, 59.5; H, 6.9; N, 18.9%.
W7,Λ/7-Dimethyl-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine-3,7-diamine 1 -Oxide (111). A mixture of nitroaniline 110 (0.50 g, 2.3 mmol) and cyanamide (0.4 g, 9.0 mmol) were mixed together at 80 0C, cHCI (5 mL) added dropwise and the mixture heated at 100 0C for 3 h. A further aliquot of cyanamide (0.4 g, 9.0 mmol) and cHCI (1 mL) was added and the mixture stirred at 100 0C for 1 h. The mixture was cooled to 50 0C, 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100 0C for 3 h. The mixture was cooled, diluted with water (30 mL), filtered, washed with water (2 x 10 mL), and dried. The residue was filtered through a short plug of silica, eluting with 10% MeOH/DCM, and the solvent evaporated to give 1 -oxide 111 (246 mg, 44%) as a yellow powder: mp (MeOH/DCM) 212-216 0C; 1H NMR [(CD3)2SO] δ 7.93 (s, 1 H, H-9), 7.34 (s, 1 H, H-5), 7.11 (br s, 2 H, NH2), 3.03-3.18 (m, 3 H, H-7, CH2), 2.79-2.89 (m, 2 H, CH2), 2.22 [S, 6 H, N(CHa)2]; 13C NMR [(CD3)2SO] δ 159.9, 152.0, 148.6, 140.5, 128.9, 120.0, 114.1, 67.0, 43.2 (2), 37.0, 36.1. Anal, calcd for C12H15N5O V2H2O: C, 56.7; H, 6.3; N, 27.5. Found: C, 56.9; H, 6.0; N, 27.4%.
Example 95 3-Chloro-W,W-dimethyl-7,8-dihydro-6W-indeno[5,6-e][1,2,4]triazin-7-amine 1 -Oxide (112). NaNO2 (100 mg, 1.4 mmol) was added in small portions to a stirred solution of amine 111 (320 mg, 1.3 mmol) in TFA (10 mL) at 0 0C and the solution stirred at 20 0C for 1 h. The solution was poured into ice/water (50 mL) and stirred for 30 minutes. The solvent was evaporated and the residue dried. The solid was suspended in POCI3 (5 mL) and DMF (3 drops) and stirred at 80 °C for 1 h. The solution was cooled, poured into ice/water, stirred for 30 minutes, filtered, washed with water (3 x 30 mL) and dried. The filtrate was neutralised with cNH3, extracted with CHCI3 (4 x 30 mL), the combined organic fraction dried and the solvent evaporated. The combined residue was purified by chromatography, eluting with 5% MeOH/DCM, to give chloride 112 (245 mg, 71%) as a pale yellow solid: mp (DCM) 160-165 0C; 1H NMR δ 8.19 (s, 1 H, H-9), 7.73 (s, 1 H, H-5), 3.25-3.34 (m, 2 H, CH2), 3.15-3.23 (m, 1 H, H-7), 3.02-3.11 (m, 2 H, CH2), 2.34 [s, 6 H, N(CHs)2]; 13C NMR δ 156.1, 154.0, 147.8, 147.4, 133.0, 122.7, 114.8, 67.5, 43.8 (2), 38.1, 37.7. Anal, calcd for C12H13CIN4O: C, 54.5; H, 5.0; N, 21.2. Found: C, 54.6; H, 4.9; N, 21.3%.
Example 96
Λf-Ethyl-ΛTX-dimethy W7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triaεine-3,7-diamine 1 - Oxide (113). Aqueous ethylamine (70%, 0.35 mL, 4.4 mmol) was added to a stirred solution of chloride 112 (240 mg, 0.9 mmol) in DME (20 mL) and the solution stirred at reflux temperature for 4 h. The solvent was evaporated and the residue purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 -oxide 113 (203 mg, 84%) as a yellow solid: mp (MeOH/EtOAc) 187-190 0C; 1H NMR δ 8.05 (s, 1 H, H-9), 7.37 (s, 1 H, H-5), 5.14 (br s, 1 H, NH), 3.54 (dq, J = 7.2, 1.3 Hz, 2 H, CH2N), 3.06-3.21 (m, 3 H, CH, CH2), 2.89-2.99 (m, 2 H, CH2), 2.32 [s, 6 H, N(CH3)2], 1.28 (t, J = 7.2 Hz, 3 H, CH3); 13C NMR δ 158.7, 152.1, 148.9, 140.9, 130.0, 120.8, 115.0, 67.7, 43.9 (2), 38.0, 37.1 , 36.3, 14.8. Anal, calcd for C14H19N5O: C, 61.5; H, 7.0; N, 25.6. Found: C, 61.3; H, 7.1 ; N, 25.5%. Example 97
Λ^-Ethyl-Λ^ΛT-dimethyl-^δ-dihydro-βH-indenoføe-eHI ,2,4]triazine-3,7-diamine 1 ,4- Dioxide (114). H2O2 (70%, 0.35 mL, ca. 6.9 mmol) was added dropwise to a stirred solution of TFAA (1.0 mL, 6.9 mmol) in DCM (10 mL) at 0 °C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to a stirred solution of 1 -oxide 113 (188 mg, 0.7 mmol) and TFA (0.26 mL, 3.4 mmol) in DCM (10 mL) at 0 0C. The solution was stirred at 20 0C for 6 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCI3 (4 x 30 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 113 (175 mg, 93%) and (ii) 1 ,4-dioxide 114 (8 mg, 4%) as a red gum: 1H NMR δ 8.11 (s, 1 H, H-9), 8.08 (s, 1 H, H-5), 6.98 (br s, 1 H, NH), 3.63 (dq, J = 7.2, 1.0 Hz, 2 H, CH2N), 3.15-3.30 (m, 3 H, CH, CH2), 2.95-3.07 (m, 2 H, CH2), 2.33 [s, 6 H, N(CH3)2], 1.36 (t, J = 7.2 Hz, 3 H, CH3); MS (FAB+) m/z 290 (MH+, 20%), 274 (5); HRMS (FAB+) calcd for C14H20N5O2 (MH+) m/z 290.1617, found 290.1607.
Example 98 7-(Dimethylamino)-3-ethyl-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1 -Oxide (115). Pd(PPh3)4 (240 mg, 0.21 mmol) was added to a N2-purged, stirred solution of chloride 112 (550 mg, 1.9 mmol) and SnEt4 (800 mg, 3.4 mmol) in DME (55 mL), and the mixture stirred at 85 0C under N2 for 16 h. The mixture was cooled, the solvent evaporated and the residue purified by chromatography, eluting with a gradiant (0-10%) of MeOH/DCM, to give 1-oxide 115 (250 mg, 47%) as an unstable brown solid: 1H NMR δ 8.23 (s, 1 H, H-9), 7.73 (s, 1 H, H-5), 3.04-3.33 (m, 5 H, H-6, H-7, H-8) 3.02 (q, J = 7.6 Hz1 2 H, CH2), 2.35 [s, 6 H, N(CHs)2], 1.43 (t, J = 7.6 Hz, 3 H, CH3); 13C NMR δ 167.2, 152.2, 147.6, 146.3, 132.4, 122.9, 114.6, 67.6, 43.8 (2), 38.0, 37.6, 30.6, 12.3; HRMS calcd for C14H18N4O (M+) m/z 258.1481, found 258.1473.
Example 99
7-(Dimethylamino)-3-ethyl-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1,4-Dioxide (116). H2O2 (70%, 0.47 mL, ca. 9.7 mmol) was added dropwise to a stirred solution of TFAA (1.35 mL, 9.7 mmol) in DCM (15 mL) at 0 0C. The solution was stirred at 20 0C for 10 min, then cooled to 0 0C and added to a solution of 1-oxide 115 (250 mg, 0.97 mmol) and TFA (0.16 mL, 2.07 mmol) in CHCI3 (15 mL) at 0 0C. The solution was stirred at 20 0C for 5 h. The solution was made basic with dilute aqueous NH3 solution and extracted with CHCI3 (3 x 30 ml_). The combined organic fraction was dried and the solvent evaporated. The residue was purified by column chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 ,4-dioxide 116 (55 mg, 21%) as an unstable brown solid: 1H NMR δ 8.30 (s, 1 H, H-9), 8.25 (s, 1 H1 H-5), 3.07-3.37 (m, 7 H, H-6, H-7, H-8, CH2), 2.36 [s, 6 H, N(CHa)2], 143 (t, J = 7.5 Hz, 3 H, CH3); HRMS calcd for C14H18N4O2 (M+) m/z 274.1430, found 274.1428.
Example 100 (3-Amino-1-oxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]tria2in-7-yl)methanol (124). 1,2-Bis(brornornethyl)-4-nitrobenzene (118). KNO3 (33.0 g, 330 mmol) was added in small portions, over 1 h, to a stirred solution of 1 ,2-bis(bromomethyl)benzene (117) (72.2 g, 300 mmol) in CH2SO4 (600 ml_) at 0 0C. After the addition was completed, the mixture was stirred at 0 0C for 3 h. The mixture was poured onto ice and stirred at 0 0C for 2 h. The solid was filtered, washed with water several times and dried to give nitrobenzene 118 (63.1g, 68%) as a white solid: mp (EtOAc/pet. ether) 73-74 0C; 1H NMR δ 8.25 (d, J = 2.3 Hz, 1 H, H-3), 8.15 (dd, J = 8.4, 2.3 Hz, 1 H, H-5), 7.56 (d, J = 8.4 Hz, 1 H, H-6), 4.67 (s, 2 H, CH2Br), 4.66 (S, 2 H, CH2Br); 13C NMR δ 148.0, 143.4 138.3, 132.1 , 125.9, 124.1 , 28.0, 27.5. Anal, calcd for C8H7NBr2O2: C, 31.1; H, 2.3; N, 4.5. Found: C, 31.1; H, 2.3; N, 4.5%.
5-Nitro-2-indanecarboxylic Acid (119). Diethyl malonate (9.10 ml_, 60.0 mmol) was added to a stirred suspension of NaH (60% in oil, 3.02 g, 126 mmol) in dry Et2O (500 mL) at 20 0C under N2 and the mixture was stirred for 30 min. 1,2-Bis(bromomethyl)-4- nitrobenzene (118) (18.5 g, 60.0 mmol) was added and the mixture was stirred at 20 0C for 24 h. The reaction was diluted with EtOAc (200 mL) and washed with 1 M HCI. The solvent was evaporated to give a brown oil that was treated with 2 M NaOH (100 mL) in EtOH (100 mL) at 20 °C for 15 h. Most of the solvent was evaporated and DCM (300 mL) was added and the mixture was acidified with 1 M HCI. The organic fraction was dried and the solvent evaporated to give a brown solid that was suspended in xylene (200 mL) and stirred at reflux temperature for 90 min. The solvent was evaporated to give a brown oil which was purified by chromatography, eluting with a gradient (0-20%) of EtOAc/pet. ether, to give acid 119 (2.44 g, 20%) as a pale yellow solid: mp (EtOAc/pet. ether) 115- 117 °C; 1H NMR δ 9.10 (br s, 1 H, CO2H), 8.06-8.11 (m, 2 H, H-4, H-6), 7.36 (d, J = 9.0 Hz, 1 H, H-7), 3.30-3.56 (m, 5 H, H-1 , H-2, H-3); 13C NMR δ 180.0, 149.0, 147.6, 143.1 , 124.8, 122.7, 119.6, 43.3, 35.9, 35.7. Anal, calcd for C10H9NO4: C, 58.0; H, 4.4; N, 6.8. Found: C, 58.2; H, 4.5; N, 6.8%. (5-Nitro-2,3-dihydro-1W-inden-2-yl)methanol (120). BH3 DMS (10 M, 1.30 mL, 13.0 mmol) was added to a stirred solution of acid 119 (2.07 g, 10.0 mmol) in dry THF (30 mL) at 20 0C under N2 and the mixture was stirred at 20 0C for 30 min. The reaction was quenched with MeOH and the solvent evaporated to give a brown oil which was purified by chromatography, eluting with a gradient (0-20%) of EtOAc/pet. ether, to give alcohol 120 (1.13 g, 59%) as an oil: 1H NMR δ 8.01-8.07 (m, 2 H, H-4, H-6), 7.32 (d, J = 8.0 Hz, 1 H, H-7), 3.68 (d, J = 5.8 Hz, 2 H, CH2O), 3.09-3.20 (m, 2 H, CH2), 2.76-2.91 (m, 3 H, CH2, CH); HRMS calcd for C10HnNO3 (M+) m/z 193.0739, found 193.0733.
[5-(Acetylamino)-2,3-dϊhydro-1H-inden-2-yl]methyl Acetate (121). A solution of nitroindanol 120 (0.54 g, 2.77 mmol) in MeOH (70 mL) and 5% Pd/C (100 mg) was stirred under H2 (60 psi) for 16 h. The mixture was filtered through Celite, washed with MeOH and the solvent evaporated to give the corresponding aniline derivative, which was treated with Ac2O (5 mL, 53.0 mmol) and Et3N (5 mL, 36.0 mmol) in DCM (50 mL) at 20 0C for 28 h. The mixture was partitioned between EtOAc and water and the organic fraction was washed with water, dried and the solvent evaporated to give a brown oil which was purified by chromatography, eluting with a gradient (30-50%) of EtOAc/pet. ether, to give acetate 121 (0.38 g, 56%) as an oil: 1H NMR δ 7.44 (s, 1 H, H-4), 7.26 (br s, 1 H, NH), 7.09-7.17 (m, 2 H, H-6, H-7), 4.08 (d, J = 7.0 Hz, 2 H, CH2O), 2.99-3.09 (m, 2 H, CH2), 2.65-2.87 (m, 3 H, CH, CH2), 2.16 (s, 3 H1 COCH3) 2.06 (s, 3 H, CH3); 13C NMR δ 171.2, 168.2, 143.3, 138.4, 136.4, 124.7, 118.5, 116.7, 67.5, 38.5, 36.0, 35.4, 24.5, 20.9; HRMS calcd for C14H17NO3 (M+) m/z 247.1208, found 247.1204.
[5-(Acetylamino)-6-nitro-2,3-dihydro-1A/-inden-2-yl]methyl Acetate (122). CHNO3 (70%, 3.0 mL, 33.3 mmol) was added dropwise (over 20 min) to a stirred solution of 121 (1.45 g, 5.85 mmol) in TFA (30 mL) at 20 °C and the reaction mixture stirred for 15 min at 20 0C. The mixture was poured into ice/water (300 mL), stirred 30 min and extracted with DCM (3 x 100 mL). Evaporation of the solvent gave crude acetate 122 (1.60 g, 94%), containing ca. 8% of the 4-nitro isomer which was removed by recrystallisation from ether, to give acetate 122 as a tan solid: mp (ether) 106-107 0C; 1H NMR δ 10.36 (br s, 1 H, NH), 8.58 (s, 1 H, H-7), 8.03 (s, 1 H, H-4), 4.05^.13 (m, 2 H, CH2O), 3.06-3.22 (m, 2 H, CH2), 2.73-2.94 (m, 3 H, CH2, CH), 2.27 (s, 3 H, COCH3), 2.06 (s, 3 H, COCH3); 13C NMR δ 171.0, 169.0, 152.3, 137.9, 135.5, 134.0, 121.4, 117.8, 66.7, 38.5, 36.5, 35.1 , 25.6, 20.8. Anal, calcd for C14H16N2O5: C, 57.5; H, 5.5; N, 9.6. Found: C, 57.7; H, 5.4; N, 9.7%. (5-Amino-6-nitro-2,3-dihydro-1tf-inden-2-yl)rnethanol (123). A mixture of acetate 122 (5.60 g, 19.2 mmol) and 5 M HC! (80 mL) in MeOH (80 ml.) was stirred at reflux temperature for 30 min. The solvent was evaporated to give the hydrochloride salt of 123 (4.42 g, 94%) as an orange solid: mp (MeOH) 143-145 0C; 1H NMR [(CDa)2SO] δ 7.73 (s, 1 H, H-7), 7.43 (br s, 4 H, NH2, OH, HCI), 6.84 (s, 1 H, H-4), 3.31-3.38 (m, 2 H, CH2O), 2.77-2.90 (m, 2 H, CH2), 2.44-2.64 (m, 3 H, CH2, CH); 13C NMR [(CD3)2SO] δ 153.2, 145.7 131.4, 129.1, 119.8, 113.7, 63.8, 41.5, 35.2, 33.6; HRMS calcd for C10H12N2O3(M+) m/z 208.0848, found 208.0850. Anal, calcd for C10H12N2O3 HCI: C, 49.1 ; H, 5.4; N, 11.5. Found: C, 49.4; H, 5.4; N, 11.5%.
(3-Amino-1-oxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-7-yl)methanol (124).
A mixture of nitroaniline 123 (4.43 g, 17.8 mmol) and cyanamide (3.51 g, 83.6 mmol) were mixed together at 100 0C, cooled to 50 °C, cHCI (8.21 mL) added carefully and the mixture stirred at 65-70 0C for 90 min. A solution of 7.5 M NaOH (72 mL) was added until the mixture was strongly basic and the mixture stirred at 90-98 0C for 45 min. The mixture was cooled, diluted with water (50 mL), filtered, washed with water (3 x 20 mL) and dried to give 1 -oxide 124 (3.67 g, 89%) as a green-yellow solid: mp (DCM/MeOH) 255-257 0C; 1H NMR [(CDa)2SO] δ 7.93 (s, 1 H, H-9), 7.33 (s, 1 H, H-5), 7.10 (s, 2 H, NH2), 4.67 (t, J = 5.2 Hz, 1 H, OH), 3.40 (dd, J = 6.5 Hz, 5.2 Hz, 2 H, CH2O), 2.99-3.10 (m, 2 H1 CH2), 2.73-2.85 (m, 2 H, CH2), 2.52-2.63 (m, 1 H, CH); 13C NMR [(CD3)2SO] δ 159.9, 153.5, 148.6, 141.9, 128.8, 120.1 , 114.1, 63.7, 41.6, 35.3, 34.6. Anal, calcd for C11H12N4O2- V4CH3OH: C, 56.2; H, 5.5; N, 23.3. Found: C, 56.7; H1 5.4; N, 23.2%.
Example 101
(3-Bromo-1-oxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-7-yl)methanol (125).
NaNO2 (23 mg, 0.33 mmol) was added to a stirred mixture of amine 124 (77 mg, 0.33 mmol), HBr (48%, 2 mL) and DMF (2 mL) at 20 0C and the mixture stirred at 20 0C for 1 h. CuBr (57 mg, 0.40 mmol) was added and the reaction mixture stirred at 20 0C for 90 min. The mixture was diluted with EtOAc (50 mL) and washed with water (3 x 20 mL). The organic solution was dried and the solvent evaporated to give an orange oil, that was purified by chromatography, eluting with a gradient (0-30%) of EtOAc/pet. ether, to give bromide 125 (40 mg, 41%) as an oil: 1H NMR δ 8.19 (s, 1 H, H-9), 7.74 (s, 1 H, H-5), 3.72 (d, J = 6.5 Hz, 2 H, CH2O), 3.22-3.33 (m, 2 H, CH2), 2.96-3.08 (m, 2 H, CH2), 2.80-2.89 (m, 1 H, CH), OH not observed; HRMS calcd for C11H10 79BrN3O2 (M+) m/z 294.9956, found 294.9949; calcd for C11H10 81BrN3O2 (M+) m/z 296.9936, found 296.9943. Example 102
[3-(Ethylamino)-1-oxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-7-yl]methanol (126). A mixture of bromide 125 (91 mg, 0.31 mmol), 70% ethylamine (0.5 mL) and DME (3 mL) was stirred at 20 0C for 3 h. The mixture was partitioned between EtOAc and aqueous Na2CO3 solution. The organic layer was separated, dried and the solvent evaporated to give compound 126 (74 mg, 92%) as yellow solid: mp (EtOAc) 150 0C; 1H NMR δ 8.07 (s, 1 H, H-9), 7.40 (s, 1 H1 H-5), 5.07 (br s, 1 H, NH), 3.64-3.72 (m, 2 H, CH2O)1 3.50-3.58 (m, 2 H, CH2N), 3.11-3.21 (m, 2 H, CH2), 2.71-2.93 (m, 3 H, CH2, CH), 1.29 (t, J = 7.2 Hz, 3 H, CH3), OH not observed; HRMS calcd for C13H16 N4O2 (M+) m/z 260.1271 , found 260.1273.
Example 103 [3-(Ethylamino)-1,4-dioxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-7-yl]methanol (127). H2O2 (70%, 1.0 mL, ca. 20.0 mmol) was added dropwise to a stirred solution of 1- oxide 126 (71 mg, 0.27 mmol) in HOAc (3 mL) at 50 0C and the reaction was stirred at 50 0C for 20 h. The mixture was diluted with aqueous NaHCO3 solution and extracted with DCM (5 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-4%) of MeOH/DCM, to give 1 ,4-dioxide 127 (11 mg, 15%) as a red solid: mp (MeOH/DCM) 153- 155 0C; 1H NMR δ 8.10 (s, 1 H, H-9), 8.05 (s, 1 H, H-5), 7.01 (br s, 1 H, NH), 3.69 (d, J = 6.5 Hz, 2 H, CH2O), 3.59-3.67 (m, 2 H, CH2N), 3.15-3.28 (m, 2 H, CH2), 2.90-3.03 (m, 2 H, CH2), 2.72-2.86 (m, 1 H, CH), 1.35 (t, J = 7.2 Hz, 3 H, CH3), OH not observed; HRMS calcd for C13H16 N4O3 (M+) m/z 276.1222, found 276.1222.
Example 104
Alternative Preparation of (3-Amino-1-oxido-7,8-dihydro-6H-mdeno[5,6- e][1,2,4]triazin-7-yl)methanol (124).
2-lndanecarboxylic Acid (129). A mixture of 2-indanecarbonitrile (128) (Ksander, G.M. et al., J. Med. Chem. 2001, 44, 4677) (55.1 g, 0.385 mol), cHCI (100 mL) and dioxane (500 mL) was stirred at 60-70 0C for 41 h. The mixture was cooled and dioxane evaporated to give a residue, which was suspended in 1 M HCI (300 mL) and stirred at 20 0C for 15 h. The solid was filtered, washed with water and dried to give acid 129 (54.1 g, 87%) as a white solid: mp (EtOAc/pet. ether) 128 0C [lit. (Baeyer, A. & Perkin W.H., Chem. Ber. 1884, 17, 122) mp 130.2 0C]; 1H NMR δ 10.50 (br s, 1 H, CO2H), 7.14-7.25 (m, 4 H, H-4, H-5, H-6, H-7), 3.21-3.43 (m, 5 H, H-1 , H-2, H-3). 5-Nitro-2-indanecarboxylic Acid (119) and 4-Nitro-2-indanecarboxylic Acid (130).
70% HNO3 (46 ml_, 798 mmol) was added dropwise (over 2 h 40 min) to a stirred solution of acid 129 (21.6 g, 133 mmol) in TFA (240 mL) at 0 0C and the solution stirred at 0 0C for 2 h 30 min. The mixture was poured onto ice (1.5 L) and stirred for 30 min. The mixture was extracted with DCM (3 x 200 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-30%) of EtOAc/pet. ether, to give a mixture (2.2:1 ratio) of 5-nitroindane 119 and 4- nitroindane 130 isomers (23.4 g, 85%) as a yellow solid. Chromatography of a small sample gave (i) 119 as a yellow solid: spectroscopically identical to the previously reported data (see Example 99); and (ii) 4-nitroindane 130 as needles: mp (EtOAc/pet. ether) 151-153 X; 1H NMR δ 8.04 (dd, J = 8.2 Hz, 0.6 Hz, 1 H, H-5), 7.52 (dd, J = 7.4 Hz, 0.6 Hz, 1 H, H-7), 7.36 (br t, J = 7.8 Hz, 1 H, H-6), 3.72-3.86 (m, 2 H, H-3), 3.31-3.52 (m, 3 H, H-1, H-2), CO2H not observed. Anal, calcd for C10H9NO4: C, 58.0; H, 4.4; N, 6.8. Found: C, 58.1 ; H, 4.4; N, 6.8%.
(5-Nitro-2,3-dihydro-1/V-inden-2-yl)methanol (120) and (4-Nitro-2,3-dihydro-1W-inden- 2-yl)methanol (131). BH3 DMS (10 M, 14.7 mL, 147 mmol) was added dropwise (over 20 min) to a stirred solution of acids 119 and 130 (ratio 2.2:1) (23.4 g, 113 mmol) in THF (150 mL) at 20 0C under N2 and the solution was stirred for 90 min. The reaction was quenched with MeOH (150 mL) and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (10-30%) of EtOAc/pet. ether, to give a mixture (2.0:1 ratio) of alcohols 120 and 131 (20.9 g, 96%) as an oil which was used without further purification.
[5-(Acetylamino)-6-nitro-2,3-dihydro-1W-inden-2-yl]methyl Acetate (122). Two batches of nitroindanes 120 and 131 (20.9 g, 109 mmol) in MeOH (200 mL) were stirred with 5% Pd/C (500 mg) under H2 (60 psi) for 16 h. The mixtures were combined and filtered through Celite, washed with MeOH and the solvent evaporated to give the corresponding aniline derivative, which was treated with Ac2O (103 mL, 1.09 mol) and Et3N (182 mL, 1.31 mol) in DCM (400 mL) at 20 ° C for 25 h. The solvent was evaporated and the residue partitioned between EtOAc and water. The organic fraction was washed with water, dried and the solvent evaporated. The residue was dissolved in TFA (200 mL) and 70% HNO3 (20.0 mL, 222 mmol) was added dropwise (over 1 h) at 0 0C and the reaction mixture was stirred at 20 0C for a further 30 min. The mixture was poured into ice/water (800 mL) and extracted with DCM (3 x 200 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-25%) of EtOAc/pet. ether, to give acetate 122 (16.5 g, 52%) as a tan solid: spectroscopically identical to the sample prepared above (Example 99).
(5-Amino-6-nitro-2,3-dihydro-1H-inden-2-yl)methanol (123). See Example 100.
(3-Amino-1-oxido-7,8-dihydro-6H-indenot5,6-e][1,2,4]triazin-7-yl)methanol (124). See
Example 100.
Example 105
T-tdfert-ButylldimethylJsilylloxylmethylJ-T^-dihydro-βH-indenolS.β-elCi^.^triazin- 3-amine 1 -Oxide (132). JPr2NEt (22.1 mL, 127 mmo!) was added dropwise (over 30 min) to a mixture of alcohol 124 (8.56 g, 36.9 mmol) and TBDMSCI (8.34 g, 55.3 mmol) in DMF (100 mL) at 20 0C and the mixture was stirred at 20 0C for 1 h. The solvent was evaporated, the residue suspended in water (400 mL) and stirred at 0 0C for 1 h. The solid was filtered, washed with water (3 x 50 mL) and dried to give silylether 132 (12.1 g, 94%): mp (MeOH/EtOAc) 169-171 0C; 1H NMR [(CD3)2SO] δ 7.93 (s, 1 H, H-9), 7.34 (s, 1 H, H- 5), 7.10 (s, 2 H, NH2), 3.55-3.63 (m, 2 H1 CH2O), 3.20-3.12 (m, 2 H, CH2), 2.72-2.84 (m, 2 H, CH2), 2.58-2.68 (m, 1 H, H-7), 0.83 [s, 9 H, SiC(CH3)3], 0.02 [s, 6 H, Si(CHg)2]; 13C NMR HCD3)ZSO] 5 159.8, 153.2, 148.6, 141.6, 128.7, 120.1 , 114.1 , 65.2, 41.3, 35.1 , 34.3, 25.6 (3), 17.8, -5.52 (2). Anal, calcd for C17H26N4O2Si: C, 58.9; H, 7.6; N, 16.2. Found: C, 58.7; H, 7.6; N, 16.6%.
Example 106 7-({[fe/t-Butyl(dimethyl)silyl]oxy}methyl)-3-iodo-7,8-dihydro-6H-indeno[5,6- e][1,2,4]triazine 1 -Oxide (133) and 7-({[ferf-Butyl(dimethyl)silyl]oxy}methyl)-7,8- dihydro-6H-indeno[5,6-e][1,2,4]triazine 1 -Oxide (134). te/f-Butyl nitrite (3.26 mL, 27.4 mmol) was added to a stirred suspension of amine 132 (2.82 g, 8.15 mmol) in THF (100 mL) at 20 0C and the mixture stirred for 5 min. Diiodomethane (3.26 mL, 40.4 mmol) and CuI (164 mg, 0.82 mmol) were added and the mixture was stirred at reflux temperature for 95 min. The mixture was cooled and partitioned between EtOAc and water. The organic solution was dried and the solvent evaporated to give a brown oil which was purified by chromatography, eluting with a gradient (0-10%) of EtOAc/pet. ether, to give (i) iodide 133 (2.27 g, 61%) as a yellow solid: mp (EtOAc/pet. ether) 108-109 0C; 1H NMR δ 8.15 (s, 1 H, H-9), 7.70 (s, 1 H, H-5), 3.59-3.67 (m, 2 H, CH2O), 3.13-3.25 (m, 2 H, CH2), 2.93-3.05 (m, 2 H, CH2), 2.73-2.84 (m, 1 H, H-7), 0.86 [s, 9 H, SiC(CH3)3], 0.04 [s, 6 H, Si(CH3)2]; 13C NMR δ 155.2, 149.6, 147.6, 133.5, 122.5, 121.7, 114.6, 65.3, 41.9, 36.0, 35.7, 25.8 (3), 18.2, -5.43 (2). Anal, calcd for C17H24IN3O2Si: C, 44.6; H, 5.3; N, 9.2. Found: C, 45.1; H, 5.4; N, 9.2%; and (ii) 1 -oxide 134 (0.32 g, 12%) as a yellow solid: mp (EtOAc/pet. ether) 120-122 0C; 1H NMR δ 8.91 (s, 1 H, H-3), 8.26 (s, 1 H, H-9), 7.80 (s, 1 H, H-5), 3.61-3.69 (m, 2 H, CH2O), 3.16-3.27 (m, 2 H, CH2), 2.96-3.07 (m, 2 H, CH2), 2.74-2.85 (m, 1 H, H-7), 0.86 [s, 9 H, SiC(CHs)3], 0.04 [s, 6 H, Si(CHa)2]; 13C NMR δ 154.2, 153.0, 149.4, 147.3, 134.6, 123.4, 114.6, 65.3, 41.9, 35.9, 35.6, 25.8 (3), 18.2, -5.43 (2). Anal, calcd for C17H25N3O2Si %H2O: C, 60.8; H, 7.7; N, 12.5. Found: C, 60.8; H, 7.4; N, 12.5%.
Example 107
7-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-3-ethyl-7,8-dihydro-6H-indeno[5,6- e]t1,2,4]triazine 1 -Oxide (135). Et4Sn (1.47 ml_, 7.5 mmol) and Pd(PPh3)4 (154 mg, 0.99 mmol) were added to a N2-purged, stirred solution of iodide 133 (2.27 g, 4.97 mmol) in dry dioxane (30 ml_) at 20 °C and the reaction mixture was stirred at reflux temperature under N2. After 5 h more Et4Sn (1.5 ml_, 7.5 mmol) and Pd(PPh3J4 (150 mg, 0.98 mmol) were added and the mixture stirred at reflux temperature for 5 h. The mixture was cooled and partitioned between EtOAc and water. The organic layer was separated, dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of EtOAc/pet. ether, to give 1 -oxide 135 (1.57 g, 88%) as a yellow solid: mp (EtOAc/pet. ether) 63-65 0C; 1H NMR δ 8.23 (s, 1 H, H-9), 7.72 (s, 1 H, H-5), 3.59-3.66 (m, 2 H, CH2O), 3.14-3.24 (m, 2 H, CH2), 2.92-3.06 (m, 4 H, H-6, H-8), 2.72-2.83 (m, 1 H, H-7), 1.43 (t, J = 7.5 Hz, 3 H, CH3), 0.87 [s, 9 H, SiC(CH3)3], 0.04 [s, 6 H, Si(CH3)2]. Anal, calcd for C19H29N3O2Si: C, 63.5; H, 8.1; N, 11.7. Found: C, 63.3; H, 8.2; N, 11.4%.
Example 108
(3-Ethyl-1,4-dioxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triaEin-7-yl)methanol (136).
H2O2 (70%, 1.5 mL, ca. 30.0 mmol) was added dropwise to a stirred solution of 1 -oxide 135 (273 mg, 0.76 mmol) and HOAc (6 mL) at 50 0C and the reaction was stirred at 80 0C for 20 h. The mixture was cooled, water (50 mL) was added and the mixture was extracted with DCM (5 x 50 mL). The combined organic fraction was dried and the solvent evaporated to give a yellow oil which was treated with Et3N (3 mL) in MeOH (20 mL) at 20 0C for 66 h. The solvent was evaporated and the residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give 1,4-dioxide 136 (35 mg, 18%) as a yellow solid: mp (MeOH/DCM) 157-158 0C; 1H NMR δ 8.31 (s, 1 H, H-9), 8.26 (s, 1 H, H- 5), 3.72 (br d, J = 5.8 Hz, 2 H, CH2O), 3.25-3.35 (m, 2 H, CH2), 3.20 (q, J = 7.5 Hz, 2 H, CH2), 3.00-3.10 (m, 2 H, CH2), 2.81-2.92 (m, 1 H, H-7H), 1.43 (t, J = 7.5 Hz, 3 H, CH3), OH not observed; HRMS calcd for C13H15 N3O3 (M+) m/z 261.1113, found 261.1115. Anal, calcd for C13H15N3O3: C, 59.8; H, 5.8; N.16.1. Found: C, 59.6; H, 5.9; N, 15.9%.
Example 109 3-Allyl-7-({[te/t-butyl(dimethyl)silyl]oxy}methyl)-7,8-dihydro-6W-indeno[5,6- e][1,2,4]triazine 1-0xide (137). Allyltributyltin (4.35 m!_, 14.1 mmol) and Pd(PPh3)4 (0.72 g, 0.64 mmol) were added to a N2-purged, stirred solution of iodide 133 (5.88 g, 12.9 mmol) in DME (80 ml.) at 20 0C and the reaction mixture was stirred at reflux temperature under N2 for 8 h. The reaction mixture was cooled and partitioned between EtOAc and brine. The organic layer was separated, dried, and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of EtOAc/pet. ether, to give alkene 137 (4.75 g, 99%) as a yellow solid: mp (EtOAc/pet. ether) 49-52 0C; 1H NMR δ 8.23 (s, 1 H, H-9), 7.74 (s, 1 H, H-5), 6.17-6.24 (m, 1 H, CH), 5.20-5.34 (m, 2 H, CH2), 3.75-3.80 (m, 2 H, CH2), 3.59-3.67 (m, 2 H, CH2O), 3.13-3.25 (m, 2 H, CH2), 2.92-3.04 (m, 2 H, CH2), 2.72-2.84 (m, 1 H, H-7), 0.87 [s, 9 H, SiC(CH3)3], 0.04 [s, 6 H, Si(CHs)2]; 13C NMR δ 164.1 , 154.1 , 148.3, 147.6, 133.0, 132.4, 123.0, 118.2, 114.5, 65.4, 42.0, 41.7, 35.8, 35.5, 25.8 (3), 18.3, -5.41 (2); HRMS (FAB+) calcd for C20H30N3O2Si (MH+) m/z 372.2107, found 372.2110. Anal, calcd for C20H29N3O2Si-1Z4H2O: C, 63.9; H, 7.9; N, 11.2. Found: C, 63.9; H, 7.7; N, 10.8%.
Example 110
3-[7-({[fert-Butyl(dimethyl)sllyl]oxy}methyl)-1-oxido-7,8-dihydro-6/y-indeno[5,6- e][1,2,4]triazin-3-yl]-1-propanol (138). A solution of 9-BBN (0.5 M, 32.5 mL, 16.3 mmol) in THF was added to a stirred solution of alkene 137 (4.02 g, 10.8 mmol) in THF (50 mL) at
20 0C under N2 and the mixture was stirred at 20 0C for 30 min. The mixture was cooled to 0 0C, a solution of sodium acetate (3 M, 25 mL, 75 mmol) and then H2O2 (70%, 25 mL, 468 mmol) were added carefully and stirred for 10 min. MeOH (100 mL) was added and the mixture stirred at 20 0C for 20 min. The mixture was partitioned between aqueous Na2CO3 solution and EtOAc. The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, using a gradient (50-70%) of EtOAc/pet. ether, to give alcohol 138 (2.08 g, 49%) as a pale yellow solid: mp (EtOAc/pet. ether) 93-94 0C; 1H NMR δ 8.22 (s, 1 H, H-9), 7.72 (s, 1 H, H-5), 3.79 (br q, J = 5.1 Hz, 2 H, CH2O), 3.59-3.67 (m, 2 H, CH2OSi), 3.12-3.24 (m, 4 H, CH2), 2.93-3.03 (m, 2 H, CH2), 2.73-2.84 (m, 1 H, H-7), 2.30 (br s, 1 H, OH), 2.11-2.21 (m, 2 H, CH2), 0.87 [s, 9 H, SiC(CHa)3], 0.04 [s, 6 H, Si(CHa)2]; 13C NMR δ 165.7, 154.2, 148.3, 147.3, 132.3, 122.8, 114.5, 65.4, 62.2, 42.0, 35.8, 35.5, 34.0, 30.6, 25.8 (3), 18.3, -5.41 (2). Anal, calcd for C20H31 N3O3Si ^H2O: C, 61.7; H, 8.0; N, 10.8. Found: C, 61.5; H, 7.8; N, 10.9%.
Example 111 7-({[fert-Butyl(dimethyl)silyl]oxy}methyl)-3-[3-(4-morphormyl)propyl]-7,8-dihydro-6H- indeno[5,6-e][1,2,4]triazine 1 -Oxide (139). Methanesulfonyl chloride (54 μl_, 1.32 mmol) was added dropwise to a stirred solution of alcohol 138 (467 mg, 1.20 mmol), and JPr2NEt (0.42 mL, 2.40 mmol) in DCM (15 mL) at 0 0C, and the solution was stirred at 0 0C for 20 min. Water (15 mL) was added and the mixture extracted with EtOAc (3 x 30 mL). The organic fraction was washed with dilute Na2CO3 solution (30 mL) and water (30 mL). The organic solution was dried and the solvent evaporated to give a brown oil to which morpholine (1.05 mL, 12.0 mmol) in DMF (10 mL) was added and the solution stirred at 20 0C for 70 h. The solution was diluted with EtOAc (200 mL) and washed with Na2CO3 solution (30 mL) and water (30 mL). The organic solution was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-30%) of EtOAc/DCM, to give 1-oxide 139 (492 mg, 67%) as an oil: 1H NMR δ 8.23 (s, 1 H, H-9), 7.70 (s, 1 H, H-5), 3.55-3.67 (m, 6 H, CH2OSi, 2 x CH2O), 3.14-3.24 (m, 2 H, H-8), 2.93- 3.07 (m, 4 H, CH2, H-6), 2.72-2.84 (m, 1 H, H-7), 2.38-2.51 (m, 6 H, 2 x CH2N), 2.03- 2.14 (m, 2 H, CH2), 0.87 [s, 9 H, SiC(CH3)3], 0.04 [s, 6 H, Si(CH3),]; HRMS (FAB+) calcd for C24H39N4O3Si (MH+) m/z 459.2791 , found 459.2784.
Example 112
{3-[3-(4-Morpholinyl)propyl]-1-oxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-7- yl}methanol (140). A solution of silyl ether 139 (488 mg, 1.07 mmol), and 1 M HCI (1.18 mL) in MeOH (30 mL) was stirred at 20 °C for 3 h. The solvent was evaporated and the residue was crystallised from MeOH/EtOAc to give alcohol 140 (357 mg, 88%) as the hydrochloride salt: mp (MeOH/EtOAc) 210-212 0C; 1H NMR [(CD3)2SO] δ 11.19 (s, 1 H, HCI), 8.16 (s, 1 H, H-9), 7.80 (s, 1 H, H-5), 4.70 (br s, 1 H, OH), 3.75-3.99 (m, 4 H, 2 x CH2O), 3.41 (d, J = 6.6 Hz, 2 H, CH2O), 3.33-3.51 (m, 2 H, CH2N), 3.11-3.27 (m, 4 H, CH2N, H-8), 2.87-3.11 (m, 6 H, 2 x CH2N, CH2), 2.59-2.71 (m, 1 H1 H-7), 2.22-2.32 (m, 2 H, CH2); 13C NMR [(CD3)2SO] δ 163.6, 154.2, 148.4, 146.7, 131.8, 122.5, 113.8, 63.5, 63.0 (2), 55.0, 50.9 (2), 41.6, 35.4, 35.1 , 33.1, 20.8. Anal, calcd for C18H24N4O3-HCI y4CH3OH: C, 56.4; H, 6.7; N, 14.4. Found: C, 56.3; H, 6.4; N, 14.6%. Example 113
{3-[3-(4-Wlorpholinyl)propyl]-1,4-dioxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-7- yl}methanol (141). H2O2 (70%, 0.46 ml_, 7.7 mmol) was added drop-wise (over 5 min) to a stirred solution of 1 -oxide 140 (292 mg, 0.77 mmol), TFA (0.32 mL, 3.9 mmol), and TFAA (1.24 mL, 7.7 mmol) in DCM (25 mL) at 20 0C and the mixture stirred at 20 0C for 17 h. Another aliquot of H2O2 (70%, 0.46 mL, 7.7 mmol) and TFAA (1.24 mL, 7.7 mmol) were added and the mixture was stirred for 1 h. Aqueous NH3 solution (2 M, 30 mL) was added at 0 0C and the mixture stirred at 0 0C for 10 min, then stirred at 20 0C for 20 min. The mixture was extracted with DCM (5 x 80 mL), the combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give 1 ,4-dioxide 141 (169 mg, 61%) as a dull orange solid: mp (MeOH/DCM) 112-114 0C; 1H NMR δ 8.30 (s, 1 H, H-9), 8.26 (s, 1 H, H- 5), 3.73 (d, J = 6.4 Hz, 2 H, CH2O), 3.45 (br s, 4 H, 2 x CH2O), 3.21-3.37 (m, 4 H, H-8, CH2), 3.00-3.09 (m, 2 H, CH2,), 2.83-2.92 (m, 1 H, H-7), 2.50 (t, J = 6.4 Hz, 2 H, CH2N), 2.39 (br s, 4 H, 2 x CH2N), 2.07-2.15 (m, 2 H, CH2), OH not observed; 13C NMR
[(CDs)2SO] δ 154.1 , 153.7, 149.3, 138.7, 133.5, 115.3, 113.3, 66.0 (2), 63.4, 57.2, 53.0 (2), 41.5, 35.6, 35.1 , 28.0, 21.0. HRMS (FAB+) calcd for C18H25N4O4 (MH+) m/z 361.1876, found 361.1878.
Example 114
(3-Ethyl-1-oxido-7,8-dihydro-6W-indeno[5,6-e][1,2,4]triazin-7-yl)methanol (142).
A solution of silylether 135 (1.57 g, 4.37 mmol), and 1 N HCI (5 mL) in MeOH (40 mL) was stirred at 20 0C for 1 h. The solution was partitioned between EtOAc and water. The organic layer was dried, the solvent evaporated and the residue was purified by chromatography, eluting with a gradient (0-2%) of MeOH/DCM, to give alcohol 142 (0.84 g, 79%) as a yellow solid: mp (MeOH/EtOAc) 122-123 0C; 1H NMR [(CD3)2SO] δ 8.13 (s, 1 H, H-9), 7.77 (s, 1 H, H-5), 4.71 (t, J = 5.2 Hz, 1 H, OH), 3.42 (dd, J = 6.4 Hz, 5.2 Hz, 2 H, CH2O), 3.11-3.20 (m, 2 H, CH2), 2.86-2.96 (m, 4 H, CH2), 2.59-2.71 (m, 1 H, H-7), 1.32 (t, J = 7.5 Hz, 3 H, CH3); 13C NMR [(CDs)2SO] δ 165.9, 153.9, 148.1 , 146.8, 131.6, 122.5, 113.8, 63.5, 41.6, 35.3, 35.0, 29.6, 11.8. Anal, calcd for C13H15N3O2: C, 63.7; H, 6.2; N, 17.1. Found: C, 63.9; H, 6.2; N, 17.4%.
Example 115
3-Ethyl-7-(4-morpholinylmethyl)-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 -Oxide (143). Methanesulfonyl chloride (0.14 mL, 1.7 mmol) was added drop-wise to a stirred solution of alcohol 142 (347 mg, 1.42 mmol) and JPr2NEt (0.49 mL, 2.84 mmol) in DCM (25 mL) at 00C, and the solution was stirred at 00C for 1 h. Water (25 mL) was added and the mixture extracted with EtOAc (3 x 30 mL). The organic fraction was washed with dilute Na2CO3 solution (25 mL) and water (25 mL). The organic solution was dried and the solvent evaporated to give a yellow solid, which was treated with morpholine (0.37 mL, 4.3 mmol) in DMF (10 mL) at 100-110 0C for 10 h. The solution was diluted with EtOAc (200 mL) and washed with Na2CO3 solution (50 mL) and water (30 mL). The organic solution was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (50-70%) of EtOAc/pet. ether, to give 1 -oxide 143 (398 mg, 89%) as a pale yellow solid: mp (EtOAc) 111-112 0C; 1H NMR δ 8.24 (s, 1 H, H-9), 7.73 (s, 1 H, H-5), 3.73 (t, J = 4.6 Hz, 4 H, 2 x CH2O), 3.19-3.29 (m, 2 H, CH2), 3.02 (q, J = 7.6 Hz, 2 H, CH2), 2.88-2.99 (m, 2 H, CH2), 2.77-2.88 (m, 1 H, H-7), 2.47 (t, J = 4.6 Hz, 4 H, 2 x CH2N), 2.38 (d, J = 7.6 Hz, 2 H, CH2), 1.43 (t, J = 7.6 Hz, 3 H, CH3); 13C NMR δ 167.1 , 153.6, 147.7, 147.6, 132.3, 123.1 , 114.7, 67.0 (2), 63.3, 53.9 (2), 37.6, 37.3, 36.7, 30.6, 12.3. Anal, calcd for C17H22N4O2: C, 65.0; H, 7.1 ; N, 17.8. Found: C, 64.9; H, 7.1 ; N, 17.9%.
Example 116
3-Ethyl-7-(4-morpholinylmethyl)-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 ,4-
Dioxide (144). H2O2 (70%, 0.95 mL, ca 16 mmol) was added drop-wise (over 10 min) to a stirred solution of 1 -oxide 143 (503 mg, 1.6 mmol), TFAA (2.56 mL, 16.0 mmol) and TFA (0.66 mL, 8.0 mmol) in DCM (60 mL) at 20 0C and the mixture was stirred at 20 0C for 7 h. Dilute Na2CO3 solution (40 mL) was added and the mixture was extracted with DCM (5 x 80 mL). The combined organic fraction was dried and the solvent evaporated to give an oil which was purified by chromatography, eluting with a gradient (0-2%) of MeOH/DCM, to give 1 ,4-dioxide 144 (87 mg, 21%) as a yellow solid: mp (MeOH/DCM) 164-165 0C; 1H
NMR δ 8.31 (s, 1 H, H-9), 8.25 (s, 1 H, H-5), 3.72 (t, J = 4.6 Hz, 4 H, 2 x CH2O), 3.17-3.34 (m, 4 H, CH2), 2.80-2.95 (m, 3 H, CH2, H-7), 2.45 (t, J = 4.6 Hz, 4 H, 2 x CH2N), 2.38 (d, J = 7.7 Hz, 2 H, CH2), 1.43 (t, J = 7.5 Hz, 3 H, CH3); 13C NMR δ 155.7, 154.1, 149.5, 139.2, 134.0, 116.3, 114.3, 67.0 (2), 63.1, 53.9 (2), 37.7, 37.2, 36.6, 23.8, 9.2. Anal, calcd for C17H22N4O3: C, 61.8; H, 6.7; N, 17.0. Found: C, 62.1 ; H, 6.7; N, 16.8%.
Example 117
2-(3-Amino-1-oxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-7-yl)ethanol (157). (£)-2-(1-Oxo-1H-inden-2(3W)-ylidene)acetic Acid (146). A mixture of 1-indanone (145) (25 g, 190 mmol), glyoxylic acid (50% aqueous solution, 70 g, 470 mmol), and CH2SO4 (6.25 mL) in dioxane (25 mL) were stirred at reflux temperature for 4 h. The mixture was cooled, the product filtered off, washed with water and dried to give acid 146 (32.8 g, 92%) as a white solid: mp 201-203 0C [lit. (Nagasawa et al., Japanese Patent 04338358, 1992) 205-206 0C]; 1H NMR [(CD3)2SO] δ 12.00 (br s, 1 H, OH), 7.73-7.80 (m, 2 H, H-5, H-7), 7.68 (br d, J = 7.7 Hz, 1 H, H-4), 7.49 (t, J = 7.9 Hz, 1 H, H-6), 6.55 (t, J = 2.4 Hz, 1 H, CHCO2), 4.08 (d, J = 1.8 Hz, 2 H, H-3).
2-(2,3-Dihydro-1W-inden-2-yl)acetic Acid (147). A solution of acid 146 (10.0 g, 53.1 mmol) in MeOH (45 mL) and dioxane (150 ml_) with Pd/C (10%, 1.0 g) was stirred under H2 (40 psi) for 16 h. The mixture was filtered through Celite and the solvent evaporated to give acid 147 as an off-white solid: mp 85-88 0C [lit. (Nagasawa et al., Japanese Patent 04338358, 1992) 89-91 0C]; 1H NMR δ 8.47 (br s, 1 H, OH), 7.08-7.18 (m, 4 H, H-4, H-5, H-6, H-7), 2.99-3.06 (m, 2 H, H-1 , H-3), 2.69-2.74 (m, 1 H, H-2), 2.53-2.60 (m, 2 H, H-1 , H-3), 2.48 (d, J = 7.4 Hz, 2 H, CH2CO2).
Ethyl 2-(2,3-Dihydro-1H-inden-2-yl)acetate (148). A solution of acid 147 (32.0 g, 180 mmol) in dry EtOH (250 mL) and CH2SO4 (2.0 mL) was stirred at reflux temperature under N2 for 16 h. The solvent was evaporated, the residue partitioned between ice/water (200 mL) and DCM (50 mL) and the aqueous layer extracted with DCM (2 x 40 mL). The combined organic layer was washed with saturated aqueous NaHCO3 solution and water, dried and the solvent evaporated to yield ester 148 (33.3 g, 90%) (lit. Tanaka, et.al., J.
Med. Chem. 1994, 37, 2071-2078) as a brown oil: 1H NMR δ 7.10-7.21 (m, 4 H, H-4, H-5, H-6, H-7), 4.15 (q, J = 7.1 Hz, 2 H, CH2),3.10-3.45 (m, 2 H, H-1, H-3), 2.82-2.94 (m, 1 H, H-2), 2.62-2.68 (m, 2 H, H-1, H-3), 4.48 (d, J = 7.4 Hz, 2 H, CH2CO2), 1.27 (t, J = 7.1 Hz, 2 H, CH3).
2-(2,3-Dihydro-1H-inden-2-yl)ethanol (149). A solution of ester 148 (68.8 g, 337 mmol) in dry THF (250 mL) was added to dropwise to a suspension of LiAIH4 (20.0 g, 501 mmol) in dry THF (500 mL) at 0 0C and the resulting mixture was stirred for 1.5 h. EtOAc was added to quench excess LiAIH4 and then aqueous H2SO4 solution (10%, 1 L) was added and the organic fraction separated. The aqueous solution was extracted with EtOAc (3 x 250 mL), and the combined organic fraction dried and the solvent evaporated to give alcohol 149 (54.5 g, 100%) (lit. Tanaka, et.al., J. Med. Chem. 1994, 37, 2071-2078) as a yellow oil: 1H NMR δ 7.16-7.25 (m, 2 H, Harom), 7.09-7.14 (m, 2 H, Harom), 3.74 (t, J = 6.8 Hz, 2 H, CH2O), 3.03-3.10 (m, 2 H, CH2), 2.53-2.66 (m, 3 H, CH2, CH), 1.82 (q, J = 6.8 Hz, 2 H, CH2), OH not observed. 2-(2,3-Dihydro-1H-inden-2-yl)ethyl Acetate (150). Ac2O (47 ml_, 505 mmol) in DCM (50 mL) was added over 1 h to a stirred solution of alcohol 149 (54.5 g, 337 mmol), pyridine (52 mL, 981 mmol) and DMAP (1.65 g, 13 mol) in DCM (400 mL) and the resulting solution was stirred at 20 0C for 16 h. H2O (200 mL) was added, and the mixture stirred for 1 h. The organic fraction was washed with aqueous HCI solution (1 M, 100 mL) and H2O (150 mL), dried and the solvent evaporated to give acetate 150 (68.4 g, 99%) as a pale brown oil: 1H NMR δ 7.16-7.19 (m, 2 H, Harom), 7.09-7.14 (m, 2 H, Harom), 4.16 (t, J = 6.8 Hz, 2 H, CH2O), 3.04-3.10 (m, 2 H, CH2), 2.48-2.66 (m, 3 H, CH2, CH), 2.05 (s, 3 H, COCH3), 1.85 (q, J = 6.8 Hz, 2 H, CH2); 13C NMR δ 171.1 , 143.0 (2), 126.2 (2), 124.4 (2), 63.5, 39.1 (2), 37.0, 34.3, 21.0. Anal calcd for C13H16O2: C, 76.4; H, 7.9. Found: C, 76.6; H, 7.9%.
Mixture of 2-(5-Nitro-2,3-dihydro-1W-inden-2-yl)ethyl Acetate (151) and 2-(4-Nitro-2,3- dihydro-1W-inden-2-yl)ethyl Acetate (152). Cu(NO3)2-3H2O (71 g, 294 mmol) was added in portions to a stirred solution of the acetate 150 (30 g, 147 mmol) in DCM (500 mL) and Ac2O (500 mL) at 0 0C, the resulting mixture allowed to warm to 20 0C and stirred for 16 h. The reaction mixture was poured into ice-water/cNH3 (2.5:1 , 3.5 L) and the layers separated. The aqueous layer was extracted with EtOAc (2 x 500 mL), the combined organic layer dried, the solvent evaporated and the residue was purified by chromatography, eluting with 20% EtOAc/pet. ether, to give an inseparable mixture of 2- (5-nitro-2,3-dihydro-1H-inden-2-yl)ethyl acetate (151) and 2-(4-nitro-2,3-dihydro-1H-inden- 2-yl)ethyl acetate (152) (ratio 151:152 = 3:1) (26.5 g, 72%) as a yellow oil which was used without further purification: Anal, calcd for C13H15NO4: C, 62.6; H, 6.1; N, 5.6. Found: C, 62.9; H, 6.1; N, 5.4%.
Mixture of 2-(5-Acetamido-2,3-dihydro-1H-inden-2-yl)ethyl Acetate (153) and 2-(4- Acetamido-2,3-dihydro-1H-inden-2-yl)ethyl Acetate (154). A solution of the nitrocompounds (151 and 152) (13.0 g, 52 mmol) in EtOH (50 mL) and MeOH (50 mL) with Pd/C (10%, 250 mg) was stirred under H2 (45 psi) for 5 h. The solution was filtered through Celite and the solvent evaporated. The residue was dissolved in dioxane (130 mL), Ac2O (12.3 mL, 130 mmol) added, and the mixture stirred at 20 0C for 16 h. H2O (60 mL) and then aqueous NH3 solution (ca 7 M, ca. 50 mL) was added until the solution was basic. The mixture was extracted with EtOAc (3 x 120 mL), the combined organic layer dried and the solvent evaporated to give an inseparable mixture of acetates 153 and 154 (ratio 153:154 = 3:1) (13.5 g, 99%) as an orange oil which was used without further purification: HRMS (FAB+) calcd for C15H20NO3 (MH+) m/z 262.1443, found 262.1443. 2-(5-Acetamido-6-nitro-2,3-dihydro-1H-inden-2-yl)ethyl Acetate (155). HNO3 (70%, 13.6 ml_, 214 mmol) was added dropwise to a solution of the acetates (153 and 154) (27 g, 103 mmol) in TFA (120 ml_) at 0 0C and the solution allowed to warm to 20 0C over 1.5 h. The mixture was poured into ice/water (500 mL) and made basic with cNH3 (ca. 150 ml_). The mixture was extracted with DCM (3 x 250 mL), the combined organic layer dried and the solvent evaporated. The residue was filtered through a plug of silica, eluting with 50% EtOAc/pet. ether, the solvent evaporated and the residue recrystallised from EtOAc/pet. ether to give acetamide 155 (18.2 g, 55%) as a pale yellow solid: mp 89-91 0C; 1H NMR δ 10.36 (br s, 1 H, NH), 8.55 (s, 1 H, H-4), 8.01 (s, 1 H, H-7), 4.16 (t, J = 6.6 Hz, 2 H, CH2O), 3.06-3.18 (m, 2 H, H-1 , H-3), 2.57-2.73 (m, 3 H, H-1, H-2, H-3), 2.27 (s, 3 H, COCH3), 2.07 (s, 3 H, COCH3), 1.85 (q, J = 6.6 Hz, 2 H, CH2); 13C NMR δ 171.0, 167.0, 153.0, 138.6, 135.4, 133.9, 121.1, 117.6, 63.1 , 39.7, 38.2, 37.4, 34.1 , 25.6, 21.0. Anal calcd for C15H18N2O5: C, 58.8; H, 5.9; N, 9.1. Found: C, 59.2; H, 6.0; N, 8.9%.
2-(5-Amino-6-nitro-2,3-dihydro-1H-inden-2-yl)ethanol (156). Acetamide 155 (24.0 g, 78 mmol) was suspended in MeOH (350 mL), H2O (180 mL) and cHCI (150 mL), and stirred at reflux temperature for 1 h. The resulting orange solution was cooled to 20 °C and the solvent evaporated to give nitroaniline 156 (17.4 g, 100%) as an orange solid: mp 89-91 0C; 1H NMR δ 7.90 (s, 1 H, H-4), 6.62 (s, 1 H, H-7), 6.02 (br s, 2 H, NH2), 3.74 (t, J = 6.6 Hz, 2 H, CH2O), 2.96-3.04 (m, 2 H, H-1 , H-3), 2.49-2.60 (m, 3 H, H-1 , H-2, H-3), 1.77 (q, J = 6.6 Hz, 2 H1 CH2), 1.40 (br s, 1 H, OH); 13C NMR δ 153.4, 144.3, 133.0, 131.2, 120.9, 113.5, 61.7, 39.3, 38.2, 37.7, 37.2. Anal, calcd for C11H14N2O3: C, 59.5; H, 6.4; N, 12.6. Found: C, 59.7; H, 6.3; N, 12.2%.
2-(3-Amino-1 -oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-7-yl)ethanol (157). A mixture of nitroaniline 156 (17.6 g, 79 mmol) and cyanamide (19.8 g, 471 mmol) were melted together at 60 °C and cHCI (35 mL) was added dropwise. The solution was heated to 100 0C, stirred for 1 h, cooled to ca. 50 0C and the mixture made strongly basic with 7.5 M NaOH solution. The mixture was heated to 100 0C for 3 h, cooled to 20 0C and diluted with ice/water. The resulting precipitate was filtered, washed with H2O (100 mL) and Et2O (30 mL), and dried to give 1 -oxide 157 (18.4 g, 94%) as a yellow-green solid: mp 230- 235°C; 1H NMR [(CD3)2SO] δ 7.92 (s, 1 H, H-9), 7.33 (s, 1 H, H-5), 7.11 (br s, 2 H, NH2), 4.45 (br s, 1 H, OH), 3.49 (t, J = 6.6 Hz, 2 H, CH2O), 3.06-3.15 (m, 2 H, H-6, H-8), 2.59- 2.69 (m, 2 H, H-6, H-8), 2.49-2.54 (m, 1 H, H-7), 1.63 (q, J = 6.6 Hz, 2 H, CH2); HRMS calcd for C12H14N4O2 (M+) m/z 246.1117, found 246.1115. Example 118
2-(3-lodo-1 -oxido-7,8-dihydro-6H-indeno[5,6-e|[1 ,2,4]triazin-7-yl)ethanol (158). tert- BuNO2 (4.0 mL, 30.6 mmol) was added to a suspension of amine 157 (2.5 g, 10.2 mmol), CuI (2.04 g, 10.7 mmol) and I2 (1.42 g, 5.6 mmol) in THF (50 mL) and the mixture stirred at reflux temperature for 4 h. The mixture was cooled to 20 0C, filtered and the solvent evaporated. The residue was dissolved in EtOAc (50 mL), washed with aqueous Na2S2O4 (5%, 2 x 25 mL), dried, and the solvent evaporated. The residue was purified by chromatography, eluting with 5% MeOH/DCM, to give iodide 158 (1.49 g, 41%) as a pale yellow solid: mp 96-99 0C; 1H NMR δ 8.15 (s, 1 H, H-9), 7.70 (s, 1 H, H-5), 3.79 (t, J = 6.5 Hz, 2 H, CH2O), 3.25-3.33 (m, 2 H, H-6, H-8), 2.68-2.86 (m, 3 H, H-6, H-7, H-8), 1.84 (q, J = 6.5 Hz, 2 H1 CH2), 1.42 (br s, 1 H, OH); 13C NMR δ 155.1, 149.4, 147.6, 133.5, 122.4, 121.8, 114.5, 61.4, 39.5, 39.2, 37.8, 37.5; HRMS (FAB+) calcd for C12H13IN3O2 (MH+) m/z 358.0053, found 358.0053.
Example 119
3-lodo-7-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-7,8-dihydro-6H-indeno[5,6- e][1,2,4]triazine 1 -Oxide (159). Dihydropyran (2.6 mL, 28.6 mmol) was added dropwise to a solution of alcohol 158 (3.4 g, 9.5 mmol) and PPTS (0.60 g, 2.4 mmol) in DCM (150 mL) and the resulting solution stirred at 20 0C for 1 h. The solvent was evaporated and the residue purified by chromatography, eluting with 50% EtOAc/pet. ether, to give a mixture of diasteroisomers of iodide 159 (4.1 g, 98%) as a pale yellow solid: mp 80-82 0C; 1H NMR δ 8.15 (S, 1 H, H-9), 7.70 (s, 1 H, H-5), 4.58-4.60 (m, 1 H, CHO), 3.84-3.86 (m, 2 H, CH2O), 3.48-3.54 (m, 2 H, CH2O), 3.24-3.29 (m, 2 H, H-6, H-8), 2.72-2.86 (m, 3 H, H-6, H-7, H-8), 1.72-1.88 (m, 4 H, CH2), 1.52-1.61 (m, 4 H, CH2); 13C NMR δ 155.2, 149.6, 147.6, 133.5, 122.41 and 122.40, 121.8, 114.52 and 114.50, 99.1 , 66.0, 62.6, 39.7 and 39.5, 39.4 and 39.2, 38.0, 35.1 , 30.8, 25.4, 19.7; HRMS (FAB+) calcd for C17H21IN3O3 (MH+) m/z 442.0628, found 442.0630.
Example 120
3-Ethyl-7-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-7,8-dihydro-6H-indeno[5,6- e][1,2,4]triazine 1-Oxide (160). Pd(PPh3)4 (0.65 g, 0.57 mmol) was added to a N2-flushed solution of iodide 159 (2.5 g, 5.7 mmol) and SnEt4 (1.7 mL, 8.5 mmol) in DME (150 mL) under N2 and the mixture heated to 85 0C for 16 h. The reaction mixture was cooled, the solvent evaporated and the residue purified by chromatography, eluting with 20% EtOAc/pet. ether, to give to give a mixture of diastereoisomers of 1-oxide 160 (1.56 g, 80%) as a pale green oil: 1H NMR δ 8.22 (s, 1 H, H-9), 7.71 (s, 1 H, H-5), 4.59-4.61 (m, 1 H, CHO), 3.85-3.89 (m, 2 H, OCH2), 3.49-3.53 (m, 2 H, CH2), 3.24-3.31 (m, 2 H, H-6, H- 8), 3.02 (q, J = 7.6 Hz, 2 H, CH2), 2.64-2.87 (m, 3 H1 H-6, H-7, H-8), 1.53-1.87 (m, 8 H, 4 x CH2), 1.43 (t, J = 7.6 Hz, 3 H, CH3); 13C NMR δ 166.5, 153.4, 147.5, 147.1 , 131.7, 122.16 and 122.15, 113.8, 98.5, 65.6, 62.0, 39.0 and 38.9, 38.6 and 38.5, 37.4, 34.6, 30.2, 30.1 , 24.9, 19.2, 11.8.
Example 121 2-(3-Ethyl-1-oxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-7-yl)ethanol (161).
Methanesulfonic acid (3 drops) was added to a stirred solution of tetrahydropyranyl ether 160 (1.1O g, 3.2 mmol) in MeOH (30 mL) and the mixture was stirred at 20 0C for 1 h. The solvent was evaporated and the residue purified by chromatography, eluting with 5% MeOH/DCM, to give 1-oxide 161 (783 mg, 94%) as a yellow solid: mp 96-99 0C; 1H NMR δ 8.23 (S, 1 H, H-9), 7.72 (s, 1 H, H-5), 3.80 (t, J = 6.5 Hz, 2 H, CH2O), 3.25-3.33 (m, 2 H, H-6, H-8), 3.02 (q, J = 7.6 Hz, 2 H, CH2), 2.68-2.86 (m, 3 H, H-6, H-7, H-8), 1.84 (q, J = 6.5 Hz, 2 H, CH2), 1.43 (t, J = 7.6 Hz, 3 H, CH3), 1.40-1.45 (m, 1 H, OH); 13C NMR δ 167.1 , 153.8, 147.9, 147.6, 132.3, 122.7, 114.3, 61.5, 39.4, 39.1 , 37.9, 37.5, 30.6, 12.3; HRMS (FAB+) calcd for C14H18N3O2 (MH+) m/z 260.1399, found 260.1397.
Example 122
2-(3-Ethyl-1,4-dioxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-7-yl)ethanol (162). H2O2 (70%, 0.27 mL, ca. 5.6 mmol) was added dropwise to a stirred solution of TFAA (0.77 mL, 5.6 mmol) in DCM (10 mL) at 0 0C. The solution was stirred at 20 0C for 10 min, then cooled to 0 0C and added to a solution of 1-oxide 161 (144 mg, 0.56 mmol) and TFA (0.1 mL, 1.2 mmol) in CHCI3 (10 mL) at 0 0C. The solution was stirred at 20 0C for 22 h, diluted with dilute aqueous NH3 solution until basic and extracted with CHCI3 (3 x 20 mL). The combined organic fraction was stirred with Et3N for 45 min, dried and the solvent evaporated. The residue was purified by chromatography, eluting with EtOAc/pet. ether, to give (i) starting material 161 (35 mg, 24%) and (ii) 1,4-dioxide 162 (92 mg, 60%) as a yellow solid: mp 152-155 0C; 1H NMR δ 8.29 (s, 1 H, H-9), 8.24 (s, 1 H, H-5), 3.77-3.82 (m, 2 H, CH2O), 3.29-3.38 (m, 2 H, H-6, H-8), 3.20 (q, J = 7.5 Hz, 2 H, CH2), 2.73-2.90 (m, 3 H, H-6, H-7, H-8), 1.84 (q, J = 6.6 Hz, 2 H, CH2), 1.43 (t, J = 7.5 Hz, 3 H, CH3), 1.34 (t, J = 4.9 Hz, 1 H, OH); 13C NMR δ 155.8, 154.3, 149.8, 139.2, 133.8, 115.9, 113.9, 61.3, 39.6, 39.1, 37.8, 37.5, 23.9, 9.3. Anal, calcd for C14H17N3O3: C, 61.1 ; H, 6.2; N, 15.3. Found: C, 60.8; H, 6.3; N, 14.9%. Example 123
3-Ethyl-7-[2-(4-morphormyl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1- Oxide (163). Methanesulfonyl chloride (0.18 ml_, 2.3 mmol) was added to a solution of alcohol 161 (457 mg, 1.76 mmol) and Et3N (0.37 ml_, 2.6 mmol) in DCM (30 mL) at 0 0C, and the mixture was stirred for 1 h. Saturated aqueous KHCO3 solution (20 mL) was added and the aqueous layer extracted with DCM (20 mL). The combined organic layer was dried and the solvent evaporated to give a pale yellow solid (560 mg, 94%) that was used without further purification. The mesylate (560 mg, 1.7 mmol) was dissolved in dry DMF (15 mL), and morpholine (0.22 mL, 2.5 mmol) and Et3N (0.35 mL, 2.5 mmol) added. The solution was stirred at 100 0C for 3.5 h, cooled and the solvent evaporated. The residue was purified by chromatography, eluting with 5% MeOH/DCM, to give 1 -oxide 163 (265 mg, 50%) as a brown oil: 1H NMR δ 8.22 (s, 1 H, H-9), 7.71 (s, 1 H, H-5), 3.73 (t, J = 4.7 Hz, 4 H, 2 x CH2O), 3.23-3.30 (m, 2 H, H-6, H-8), 3.01 (q, J = 7.6 Hz, 2 H, CH2), 2.75-2.84 (m, 2 H, H-6, H-8), 2.58-2.62 (m, 1 H, H-7), 2.43-2.48 (m, 6 H, 3 x CH2N), 1.73-1.79 (m, 2 H, CH2), 1.43 (t, J = 7.6 Hz, 3 H, CH3); 13C NMR δ 167.1 , 153.8, 147.9, 147.6, 132.3, 122.7, 114.4, 66.9 (2), 57.5, 53.8 (2), 39.4, 39.1 , 38.8, 32.0, 30.6, 12.3; HRMS (FAB+) calcd for C18H24N4O2 (MH+) m/z 328.1899, found 328.1899.
Example 124
3-Ethyl-7-[2-(4-morpholinyl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 ,4- Dioxide (164). H2O2 (70%, 0.39 mL, ca. 8.1 mmol) was added dropwise to a stirred solution of TFAA (1.12 mL, 8.1 mmol) in DCM (15 mL) at 0 0C. The solution was stirred at 20 °C for 10 min, then cooled to 0 0C, added to a solution of 1 -oxide 163 (265 mg, 0.81 mmol) and TFA (0.13 mL, 1.7 mmol) in CHCI3 (15 mL) at 0 0C. The solution was stirred at 20 0C for 4.5 h, diluted with dilute aqueous NH3 solution until basic and extracted with CHCI3 (3 x 30 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (1-10%) of MeOH/DCM, to give (i) starting material 163 (62 mg, 23%) and (ii) 1 ,4-dioxide 164 (83 mg, 30%) as a yellow solid which was converted to the hydrochloride salt: mp 131-133 0C; 1H NMR δ 13.40 (br s, 1 H, HCI), 8.30 (s, 1 H, H-9), 8.25 (s, 1 H, H-5), 4.32 (t, J = 12.0 Hz, 2 H, CH2), 4.00 (dd, J = 12.0, 3.0 Hz, 2 H, H-6, H-8), 3.48 (d, J = 12.0 Hz, 2 H, H-6, H-8), 3.32-3.39 (m, 2 H, CH2), 3.20 (q, J = 7.5 Hz, 2 H, CH2), 3.06-3.09 (m, 2 H, CH2), 2.88- 2.94 (m, 4 H, 2 x CH2), 2.67-2.73 (m, 1 H, H-7), 2.25-2.28 (m, 2 H, CH2), 1.43 (t, J = 7.5 Hz, 3 H, CH3); 13C NMR δ 156.0, 152.6, 148.2, 139.3, 133.9, 116.3, 114.3, 63.6 (2), 56.5, T/NZ2006/000064
52.0 (2), 39.1, 38.6, 37.8, 28.5, 23.9, 9.3; HRMS (FAB+) calcd for C18H25N4O3 (MH+) m/z 344.1848, found 344.1846.
Example 125 7,8,9,10-Tetrahydronaphtho[2,1-e][1,2,4]triazin-3-amine 1 -Oxide (170).
Λ/-(5,6,7,8-Tetrahydro-2-naphthalenyl)acetamide (166). fHNO3 (8.6 mL, 144 mmol) in CH2SO4 (50 mL) was added dropwise to a stirred solution of α-tetralone (165) (20 g, 137 mmol) in CH2SO4 (300 mL) at 0 0C and the solution stirred for 1 h. The solution was poured into ice/water (2 L), stirred for 30 min, filtered and washed with water. The solid was dried and purified by chromatography, eluting with 20% EtOAc/pet. ether, to give (i) 5-nitro-3,4-dihydro-1(2H)-naphthalenone (4.1 g, 16%) as a white solid: 1H NMR δ 8.35 (dd, J = 7.8, 1.4 Hz, 1 H, H-6), 8.09 (dd, J = 8.0, 1.4 Hz, 1 H, H-8), 7.48 (br t, J = 7.9 Hz, 1 H, H-7), 3.22 (t, J = 6.1 Hz, 2 H, H-4), 2.74 (dd, J = 6.8, 6.4 Hz, 2 H, H-2), 2.13-2.21 (m, 2 H, H-3); and (ii) 7-nitro-3,4-dihydro-1(2H)-naphthalenone (20.1 g, 77%) as a white solid: 1H NMR δ 8.86 (d, J = 2.5 Hz, 1 H, H-4), 8.30 (dd, J = 8.4, 2.5 Hz, 1 H, H-6), 7.46 (d, J = 8.4 Hz, 1 H, H-5), 3.09 (t, J = 6.1 Hz, 2 H, H-4), 2.74 (dd, J = 7.0, 6.2 Hz, 2 H, H-2), 2.17- 2.25 (m, 2 H, H-3).
A solution of 7-nitro-3,4-dihydro-1 (2H)-naphthalenone (1.67 g, 8.7 mmol) in EtOAc/EtOH (1 :1, 150 mL), water (15 mL) and cHCI (2 mL) with Pd/C (5%, 500 mg) was stirred vigorously under H2 (60 psi) for 16 h. The suspension was filtered through Celite, washed with EtOH (4 x 10 mL) and the organic solvent evaporated. The aqueous residue was partitioned between DCM and dilute aqueous NH3 solution and the organic fraction dried and the solvent evaporated. The residue was dissolved in dioxane (20 mL), and Ac2O (1.8 mL, 19.2 mmol) was added dropwise to the solution at 0 0C. The solution was stirred at 20 0C for 16 h, diluted with water (50 mL), and partitioned between EtOAc and dilute aqueous NH3 solution. The organic fraction was washed with water (3 \ 20 mL), dried and the solvent evaporated to give Λ/-(5,6,7,8-tetrahydro-2-naphthalenyl)acetamide 166 (1.57 g, 95%) as a white solid: 1H NMR δ 7.18-7.25 (m, 2 H, H-1, NH), 7.15 (dd, J = 8.2, 2.1 Hz, 1 H, H-3), 7.00 (d, J = 8.2 Hz, 1 H, H-4), 2.69-2.77 (m, 4 H, 2 x CH2), 2.15 (s, 3 H, CH3), 1.74-1.80 (m, 4 H, 2 x CH2). The procedure was repeated a number of times to give N- (5,6,7, 8-tetrahydro-2-naphthalenyl)acetamide 166 (10.21 g, 88% overall).
Λ/-(3-Nitro-5,6,7,8-tetrahydro-2-naphthalenyl)acetamide (167) and N-(1 -Nitro-5,6,7,8- tetrahydro-2-naphthalenyl)acetamide (168). A solution of KNO3 (5.73 g, 56.6 mmol) in CH2SO4 (25 mL) was added dropwise to a stirred solution of acetanilide 166 (10.21 g, 53.9 mmol) in CH2SO4 (150 mL) at 0 °C and the mixture stirred at 0 0C for 2 h. The mixture was poured into ice/water (1.5 L) and the suspension stirred for 30 min. The precipitate was filtered, washed with water and dried. The solid was purified by chromatography, eluting with a gradient (20-70%) of EtOAc/pet. ether, to give (i) /V-(3-nitro-5,6,7,8-tetrahydro-2- naphthalenyl)acetamide (167) (840 mg, 7%) as a white solid: 1H NMR δ 10.24 (br s, 1 H, NH), 8.44 (s, 1 H, H-4), 7.93 (s, 1 H, H-1), 2.82-2.86 (m, 2 H, CH2), 2.75-2.79 (m, 2 H, CH2), 2.27 (s, 3 H, CH3), 1.78-1.83 (m, 4 H, 2 x CH2); and (ii) Λ/-(1-nitro-5,6,7,8- tetrahydro-2-naphthalenyl)acetamide (168) (1.65, g, 13%) as a white solid: 1H NMR δ 8.04 (br s, 1 H, NH), 7.91 (br d, J = 8.4 Hz, 1 H, H-3), 7.24 (d, J = 8.4 Hz, 1 H, H-4), 2.78-2.82 (m, 2 H, CH2), 2.72-2.76 (m, 2 H, CH2), 2.18 (s, 3 H, CH3), 1.76-1.83 (m, 4 H, 2 x CH2); and (iii) Λ/-(4-nitro-5,6,7,8-tetrahydro-2-naphthalenyl)acetamide (7.58 g, 60%) as a white solid: 1H NMR δ 7.79 (d, J = 2.0 Hz, 1 H, H-3), 7.56 (d, J = 2.0 Hz, 1 H, H-1), 7.22 (br s, 1 H, NH), 2.87-2.93 (m, 2 H, CH2), 2.80-2.84 (m, 2 H, CH2), 2.20 (s, 3 H1 CH3), 1.76-1.83 (m, 4 H, 2 x CH2).
1-Nitro-5,6,7,8-tetrahydro-2-naphthalenamine (169). A suspension of acetamide 168 (835 mg, 4.4 mmol) in 6 M HCI (50 mL) was stirred at 100 0C for 16 h. The suspension was cooled to 20 CC, diluted with water (50 mL) and the pH adjusted to 8 with dilute aqueous NH3 solution. The mixture was extracted with DCM (3 x 50 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with 20% EtOAc/pet. ether, to give amine 169 (755 mg, 56%) as an orange solid: mp (EtOAc/pet. ether) 76-78 0C; 1H NMR δ 6.98 (d, J = 8.4 Hz, 1 H, H-4), 6.58 (d, J = 8.4 Hz, 1 H, H-3), 4.73 (br s, 2 H, NH2), 2.76-2.81 (m, 2 H1 CH2), 2.65-2.69 (m, 2 H, CH2), 1.69-1.78 (m, 2 H1 CH2). Anal, calcd for C10H12N2O2: C, 62.5; H, 6.3; N, 14.6. Found: C, 62.8; H, 6.1 ; N, 14.6%.
7,8,9,10-Tetrahydronaphtho[2,1-e][1,2,4]triazin-3-amine 1 -Oxide (170). A mixture of nitroaniline 169 (0.73 g, 3.8 mmol) and cyanamide (0.63 g, 15.1 mmol) were mixed together at 100 °C, cooled to 50 0C, cHCI (5 mL) added carefully and the mixture heated at 100 0C for 2 h. The mixture was cooled to 50 "C, 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100 0C for 3 h. The mixture was cooled, diluted with water (50 mL), filtered, washed with water (2 x 25 mL) and dried. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give amine 170 (124 mg, 15%) as a yellow powder: mp (MeOH) 271 0C (dec); 1H NMR [(CDa)2SO] δ 7.43 (d, J = 8.6 Hz, 1 H, H-6), 7.26 (d, J = 8.6 Hz, 1 H, H-5), 7.00 (br s, 2 H, NH2), 3.36-3.40 (m, 2 H, CH2), 2.75-2.80 (m, 2 H, CH2), 1.67-1.75 (m, 4 H, 2 x CH2); 13C NMR [(CDa)2SO] δ 159.5, 149.5, 137.3, 133.8, 131.1, 129.9, 123.0, 29.8, 28.7, 22.5, 21.0. Anal, calcd for C11H12N4O: C, 61.1; H, 5.6; N, 25.9. Found: C, 61.0; H, 5.6; N, 26.0%.
Example 126 3-Chloro-7,8,9,10-tetrahydronaphtho[2,1-e][1,2,4]triazine 1 -Oxide (171). NaNO2 (73 mg, 1.0 mmol) was added in small portions to a stirred solution of amine 170 (114 mg, 0.5 mmol) in TFA (5 ml_) at 0 0C and the solution stirred at 20 0C for 3 h. The solution was poured into ice/water, stirred 30 minutes, filtered, washed with water (3 x 30 mL) and dried. The solid was suspended in POCI3 (10 mL) and DMF (0.2 mL) and stirred at 100 °C for 1 h. The solution was cooled, poured into ice/water, stirred for 30 minutes, filtered, washed with water (3 x 30 mL) and dried. The solid was suspended in DCM (100 mL), dried and the solvent evaporated. The residue was purified by chromatography, eluting with 5% EtOAc/DCM, to give chloride 171 (95 mg, 76%) as a pale yellow solid: mp (MeOH) 165-167 0C; 1H NMR δ 7.68 (d, J = 8.6 Hz, 1 H, H-5), 7.63 (d, J = 8.6 Hz, 1 H, H- 6), 3.48-3.53 (m, 2 H, CH2), 2.92-2.97 (m, 2 H, CH2), 1.80-1.88 (m, 4 H, 2 x CH2); 13C NMR δ 155.6, 148.3, 141.3, 138.6, 133.9, 132.8, 125.0, 31.1 , 29.0, 22.6, 21.1. Anal, calcd for C11H10CIN3O2: C, 56.0; H, 4.3; N, 17.8. Found: C, 56.3; H, 4.4; N, 17.6%.
Example 127 W1,Λ/1-Dimethyl-W2-(1-oxido-7,8,9,10-tetrahydronaphtho[2,1-e][1,2,4]triazin-3-yl)-1,2- ethanediamine (172). Λ/,Λ/-Dimethyl-1,2-ethanediamine (0.12 mL, 1.0 mmol) was added to a stirred solution of chloride 171 (83 mg, 0.4 mmol) in DME (20 mL) and the solution stirred at reflux temperature for 3 h. The solvent was evaporated and the residue partitioned between DCM (50 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 -oxide 172 (84 mg, 84%) as a yellow solid: mp (MeOH) 151-153 0C; 1H NMR δ 7.31-7.36 (m, 2 H1 H-5, H-6), 5.75 (br s, 1 H, NH), 3.51-3.55 (m, 2 H, CH2N), 3.45-3.49 (m, 2 H, CH2), 2.72-2.83 (m, 2 H, CH2), 2.57 (br dd, J = 6.0, 5.8 Hz, 2 H, CH2N), 2.29 [s, 6 H, N(CH3)2], 1.75-1.82 (m, 4 H, 2 x CH2); 13C NMR δ 158.4, 149.8, 137.4, 134.7, 132.4, 129.1, 123.5, 57.7, 45.0 (2), 38.6, 30.7, 29.3, 23.1 , 21.6. Anal, calcd for C15H21N5O y2CH3OH: C, 61.4; H, 7.6; N, 23.1. Found: C, 61.2; H, 7.4; N, 23.4%.
Example 128 Λ/1-(1,4-Dioxido-7,8,9,10-tetrahydronaphtho[2,1-e][1,2,4]triazin-3-yl)-Λ/2,Λ/2-dimethyl-
1,2-ethanediamine (173). H2O2 (70%, 0.12 mL, ca. 2.4 mmol) was added dropwise to a stirred solution of TFAA (0.34 ml_, 2.4 mmol) in DCM (10 ml_) at 0 0C. The solution was stirred at
0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to a stirred solution of 1 -oxide 172 (70 mg, 0.2 mmol) and TFA (95 μl_, 1.2 mmol) in DCM (10 mL) at 0 0C. The solution was stirred at 20 0C for 6 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCI3 (4 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 ,4-dioxide 173 (38 mg, 52%) as a red solid: mp (MeOH/EtOAc) 139-142 0C; 1H NMR δ 8.06 (d, J = 8.9 Hz, 1 H, H-5), 7.51 (d, J = 8.9 Hz, 1 H1 H-6), 7.38 (br s, 1 H, NH), 3.59-3.66 (m, 2 H, CH2N)1 3.49-3.55 (m, 2 H, CH2), 2.83- 2.92 (m, 2 H, CH2), 2.61-2.65 (m, 2 H, CH2N), 2.32 [s, 6 H, N(CH3)2], 1.80-1.88 (m, 4 H, 2 x CH2).
Example 129 6,7,8,9-Tetrahydronaphtho[2,3-e][1 ,2,4]triazin-3-amine 1 -Oxide (175).
3-Nitro-5,6,7,8-tetrahydro-2-naphthalenamine (174). A suspension of nitroacetamide 167 (151 mg, 0.65 mmol) in 6 M HCI (30 mL) was stirred at 100 0C for 6 h. The suspension was cooled to 20 0C, diluted with water (50 mL) and the pH adjusted to 8 with aqueous NH3 solution. The mixture was extracted with DCM (3 x 50 mL), the combined organic fraction dried, and the solvent evaporated to give amine 174 (113 mg, 100%) as an orange solid: 1H NMR δ 7.83 (s, 1 H, H-4), 7.50 (s, 1 H, H-1), 5.79 (s, 2 H, NH2), 2.67- 2.73 (m, 4 H, 2 x CH2), 1.78-1.83 (m, 4 H, 2 x CH2).
6,7,8,9-Tetrahydronaphtho[2,3-e][1,2,4]triazin-3-amine 1 -Oxide (175). A mixture of nitroaniline 174 (0.77 g, 4.0 mmol) and cyanamide (0.68 g, 16.0 mmol) were mixed together at 100 0C, cooled to 50 0C, cHCI (5 mL) added carefully and the mixture heated at 100 0C for 4 h. The mixture was cooled to 50 0C, 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100 0C for 3 h. The mixture was cooled, diluted with water (100 mL) and filtered. The precipitate was washed with water (3 x 20 mL), washed with ether (10 mL) and dried. The residue was purified by chromatography, eluting with 5% MeOH/DCM, to give amine 175 (0.30 g, 35%) as a yellow powder: mp (MeOH/DCM) 270-274 0C; 1H NMR [(CD3)2SO] δ 7.83 (s, 1 H, H-10), 7.23 (s, 1 H, H-5), 7.11 (br s, 2 H, NH2), 2.82-2.89 (m, 4 H, H-6, H-9), 1.72-1.77 (m, 4 H, H-7, H-8); 13C NMR [(CD3)2SO] δ 159.8, 146.9, 146.8, 136.2, 128.0, 124.0, 118.1 , 29.1 , 28.5, 22.0, 21.8. Anal, calcd for C11 H12N4O- 1/4H2O: C, 59.9; H, 5.7; N, 25.4. Found: C, 60.4; H, 5.5; N, 25.5%. Example 130
3-Chloro-6J,8,9-tetrahydronaphtho[2,3-e][1,2,4]triazine 1-Oxide (176). NaNO2 (181 mg, 2.6 mmol) was added in small portions to a stirred solution of amine 175 (284 mg, 1.3 mmol) in TFA (10 mL) at 0 0C and the solution stirred at 20 0C for 2 h. The solution was poured into ice/water, stirred 30 minutes, filtered, washed with water (3 x 10 mL) and dried. The solid was suspended in POCI3 (10 mL) and DMF (0.1 mL), and stirred at 100 0C for 1 h. The solution was cooled, poured into ice/water, stirred for 30 min, filtered, washed with water (3 x 10 mL) and dried. The solid was suspended in DCM (50 mL), dried and the solvent evaporated. The residue was purified by chromatography, eluting with 5% EtOAc/DCM, to give chloride 176 (173 mg, 56%) as a pale yellow solid: mp (EtOAc/DCM) 104-106 0C; 1H NMR δ 8.10 (s, 1 H, H-10), 7.65 (s, 1 H, H-5), 2.98-3.05 (m, 4 H, H-6, H-9), 1.86-1.93 (m, 4 H, H-7, H-8); 13C NMR δ 155.9, 149.5, 145.5, 143.1, 131.8, 126.9, 118.8, 30.2, 29.9, 22.2, 22.0. Anal, calcd for C1IH10CIN3O: C, 56.0; H, 4.3; N, 17.8. Found: C, 56.2; H, 4.3; N, 17.8%.
Example 131
^-(i-Oxido-ej.δ.θ-tetrahydronaphthop.S-elli.a.^triazin-S-ylJ-^.N^dimethyl-i.a- ethanedϊamine (177). Λ/,N-Dimethylethanediamine (0.22 mL, 2.0 mmol) was added to a stirred solution of chloride 176 (157 mg, 0.7 mmol) in DME (30 mL) and the solution stirred at reflux temperature for 2 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 -oxide 177 (167 mg, 87%) as a yellow solid: mp (MeOH) 149-151 0C; 1H NMR δ 7.96 (s, 1 H, H-10), 7.29 (s, 1 H, H-5), 5.81 (br s, 1 H, NH), 3.50-3.55 (m, 2 H, CH2N), 2.85-2.92 (m, 4 H, H-6, H- 9), 2.56 (br t, J = 6.0 Hz, 2 H, CH2N), 2.28 [s, 6 H, N(CH3)2], 1.81-1.85 (m, 4 H, H-7, H-8); 13C NMR 5 158.7, 147.5, 147.0, 136.0, 129.1 , 124.9, 119.0, 57.6, 45.1 (2), 38.7, 30.0, 29.3, 22.7, 22.5. Anal, calcd for C15H21N5O: C, 62.7; H, 7.4; N, 24.4. Found: C, 62.5; H, 7.2; N, 24.3%.
Example 132
Λ/1-(1,4-Dioxido-6,7,8,9-tetrahydronaphtho[2,3-e][1,2,4]triazin-3-yl)-/V2,W2-dimethyl- 1,2-ethanediamine (178). H2O2 (70%, 0.27 mL, ca. 5.3 mmol) was added dropwise to a stirred solution of TFAA (0.8 mL, 5.3 mmol) in DCM (10 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to a stirred solution of 1 -oxide 177 (153 mg, 0.5 mmol) and TFA (0.20 mL, 2.7 mmol) in DCM (10 mL) at 0 0C. The solution was stirred at 20 0C for 16 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCI3 (4 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 177 (37 mg, 24%) and (ii) 1 ,4-dioxide 178 (47 mg, 29%) as a red solid: mp (MeOH) 148-151 0C; 1H NMR δ 8.02 (s, 1 H, H-10), 7.98 (s, 1 H, H-5), 7.35 (br s, 1 H, NH), 3.63 (br t, J = 6.0 Hz, 2 H, CH2N), 2.98-3.04 (m, 2 H, CH2), 2.91-2.96 (m, 2 H, CH2), 2.61 (br t, J - 6.0 Hz, 2 H, CH2N), 2.30 [s, 6 H, N(CH3)2], 1.83-1.92 (m, 4 H, H-7, H-8); 13C NMR δ 149.4, 148.7, 138.8, 136.5, 128.9, 120.1 , 115.8, 57.6, 45.2 (2), 38.9, 30.3, 29.4, 22.3, 22.0. Anal, calcd for C15H21N5O2-Iy2H2O: C, 54.5; H, 7.3; N, 21.2. Found: C, 54.4; H, 6.3; N, 20.7%.
Example 133
Λ/-[3-(4-Morpholinyl)propyl]-6,7,8,9-tetrahydronaphtho[2,3-e][1 ,2,4]triazin-3-amine 1 - Oxide (179). 3-(4-Morpholinyl)propylamine (314 mg, 2.18 mmol) was added to a stirred solution of chloride 176 (171 mg, 0.73 mmol) in DME (8 mL) and the solution stirred at reflux temperature for 30 min. The solution was cooled and partitioned in between EtOAc and aqueous Na2CO3 solution. The organic fraction was washed with water, dried and the solvent evaporated to give 1 -oxide 179 (250 mg, 100%) as an orange solid: mp (EtOAc) 115-116 0C; 1H NMR 5 7.97 (s, 1 H, H-10), 7.29 (s, 1 H, H-5), 6.14 (br s, 1 H, NH), 3.75 ( t, J = 4.6 Hz, 4 H, 2 x CH2O), 3.60 (q, J = 6.2 Hz, 2 H, CH2N), 2.86-2.95 (m, 4 H, H-6, H- 9), 2.45-2.56 ( m, 6 H, 3 x CH2N), 1.80-1.88 (m, 6 H, H-7, H-8, CH2); 13C NMR δ 158.7, 147.5 147.0, 136.0, 129.1 , 124.9, 119.0, 67.0 (2), 57.3, 53.8 (2), 40.8, 30.0, 29.3, 25.3, 22.7, 22.5. Anal, calcd for C18H25N5O2: C, 63.0; H, 7.3; N, 20.4. Found: C, 62.8; H, 7.4; N, 20.3%.
Example 134 yV-[3-(4-Morpholinyl)propyl]-6,7,8,9-tetrahydronaphtho[2,3-e][1,2,4]triazin-3-amine 1,4-Dioxide (180). H2O2 (70%, 0.36 mL, ca. 6.0 mmol) was added dropwise to a stirred solution of TFAA (0.96 mL, 6.0 mmol) in DCM (5 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then added to a stirred solution of 1 -oxide 179 (204 mg, 0.60 mmol) and TFA (0.24 mL, 3.0 mmol) in DCM (5 mL) at 0 0C. The solution was stirred at 20 °C for 8 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with DCM (5 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-2%) of MeOH/DCM, to give 1 ,4-dioxide 180 (28 mg, 13%) as a red solid which was converted to the hydrochloride salt: mp (MeOH/DCM) 182-185 0C; 1H NMR [(CD3)2SO] δ 10.29 (s, 1 H, HCI), 8.35 (br s, 1 H, NH), 7.95 (s, 1 H, H-10), 7.87 (s, 1 H, H-5), 3.92-4.01 (m, 2 H, CH2O)1 3.37 (m, 4 H, CH2N, CH2O), 2.88-3.22 (m, 8 H, 2 x CH2N, H-6, H-9), 2.53 (t, J = 5.6 Hz, 2 H, CH2N), 2.00-2.09 (m, 2 H, CH2N), 1.74-1.83 (m, 4 H, H-7, H-8); 13C NMR [(CDs)2SO] δ 149.2, 147.8, 138.0, 136.1 , 128.5, 119.4, 115.0, 63.0 (2), 53.5, 50.9 (2), 37.9, 29.4, 28.5, 22.7, 21.7, 21.6. Anal, calcd for Ci8H25N5O3-2HCI-2H2O: C, 46.2; H, 6.7; N, 15.0. Found: C, 46.3; H, 6.4; N, 15.0%.
Example 135 T^^IO-Tetrahydro-βW-cycloheptatgHi^^benzotriazin-S-amine 1-0xide (186). 3-Nitro-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-2-amine (185). A solution of fHNO3 (7.5 mL) in CH2SO4 (50 ml.) was added dropwise to a stirred suspension of 1- benzosuberone (181) (20 g, 124.8 mmol) in CH2SO4 (400 mL) at 0 0C. The mixture was stirred a further 30 min and poured into ice/water. The slurry was extracted with ether (2 x 200 mL), the combined organic fraction dried, and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (10-30%) of EtOAc/pet. ether, to give 3-nitro-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one (14.75 g, 58%) as a tan powder: mp (EtOAc/pet. ether) 81-82 0C; 1H NMR δ 8.56 (d, J = 2.5 Hz, 1 H, H-4), 8.26 (dd, J = 8.3, 2.5 Hz, 1 H, H-2), 7.40 (d, J = 8.3 Hz, 1 H, H-1), 3.02-3.08 (m, 2 H, H-9), 2.78-2.82 (m, 2 H, H-6), 1.92-1.99 (m, 2 H, H-8), 1.83-1.90 (m, 2 H, H-7). A solution of ketone (14.7 g, 71.6 mmol) in EtOAc/EtOH (1:1 , 100 mL) and 20% HCI (50 mL) was stirred vigorously under H2 (60 psi) for 5 days. The suspension was filtered through Celite, washed with EtOH (4 x 20 mL) and the solvent evaporated. The residue was dissolved in DCM, washed with dilute NH3, dried, and the solvent evaporated. The residue was dissolved in dioxane (300 mL), cooled to 0 0C, and Ac2O (13.5 mL, 143.2 mmol) added dropwise. The solution was stirred at 20 0C for 16 h, diluted with water (500 mL) and the suspension filtered. The filtrate was extracted with EtOAc (2 x 100 mL); the combined organic fraction washed with water (50 mL) and dilute aqueous NH3 solution (2 x 50 mL), dried, and the solvent evaporated. The combined solids were purified by chromatography, eluting with 50% EtOAc/pet. ether, to give Λ/-(6,7,8,9-tetrahydro-5AV-benzo[a]cyclohepten- 2-yl)acetamide (10.89 g, 75%) as a tan powder: mp 112-114 0C; 1H NMR δ 7.20 (d, J = 2.2 Hz, 1 H, H-1), 7.15-7.21 (m, 2 H, H-3, NH), 7.02 (d, J = 8.0 Hz, 1 H, H-4), 2.71-2.77 (m, 4 H, H-5, H-9), 2.15 (s, 3 H, CH3), 1.78-1.86 (m, 2 H, H-7), 1.56-1.66 (m, 4 H, H-6, H- 8). A solution of KNO3 (5.96 g, 58.9 mmol) in CH2SO4 (25 mL) was added dropwise to a stirred suspension of amide (10.89 g, 53.6 mmol) in CH2SO4 (160 mL) at 0 0C and the mixture stirred at 0-5 0C for 2 h. The mixture was poured into ice/water, stirred 30 min, filtered, washed with water (3 x 30 mL) and dried. The solid was purified by chromatography, eluting with a gradient (20-50%) of EtOAc/pet. ether, to give (i) /V-(3- nitro-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-2-yl)acetamide (182) (2.62 g, 20%) as a white solid: 1H NMR δ 10.32 (br s, 1 H, NH), 8.52 (s, 1 H, H-4), 7.94 (s, 1 H, H-1), 2.84- 2.88 (m, 2 H, H-5), 2.78-2.82 (m, 2 H, H-9), 2.27 (s, 3 H, CH3), 1.80-1.87 (m, 2 H, H-7), 1.61-1.69 (m, 4 H, H-6, H-8); (ii) /V-(1-nitro-6,7,8,9-tetrahydro-5H-ben∑o[a]cyclohepten-2- yl)acetamide (183) (0.85 g, 6%) as a white solid: 1H NMR δ 7.81 (br d, J = 8.4 Hz, 1 H, H- 4), 7.77 (br s, 1 H, NH), 7.23 (d, J = 8.4 Hz, 1 H, H-3), 2.82-2.86 (m, 2 H, H-5), 2.65-2.69 (m, 2 H, H-9), 2.27 (s, 3 H, CH3), 1.80-1.88 (m, 2 H, H-7), 1.61-1.73 (m, 4 H, H-6, H-8); and (iii) Λ/-(4-nitro-6,7,8,9-tetrahydro-5/-/-benzo[a]cyclohepten-2-yl)acetamide (184) (6.91 g, 52%) as a white solid: 1H NMR δ 7.69 (br d, J = 1.9 Hz, 1 H, H-3), 7.45 (d, J = 1.9 Hz, 1 H, H-1), 7.24 (br s, 1 H, NH), 2.84-2.88 (m, 2 H, H-5), 2.78-2.81 (m, 2 H, H-9), 2.19 (s, 3 H, CH3), 1.81-1.87 (m, 2 H, H-7), 1.61-1.72 (m, 4 H, H-6, H-8). A suspension of 3-nitroacetamide 182 (2.62 g, 10.6 mmol) in 5 M HCI (100 mL) was stirred at reflux temperature for 16 h. The suspension was cooled, diluted with water (100 mL), filtered, washed with water (3 x 10 mL) and dried to give nitroaniline 185 (1.96 g, 90%) as a yellow powder, mp 137-139 0C; 1H NMR δ 7.83 (s, 1 H, H-4), 6.55 (s, 1 H, H- 1), 5.96 (br s, 2 H, NH2), 2.67-2.73 (m, 4 H, H-5, H-9), 1.76-1.81 (m, 2 H, H-7), 1.59-1.67 (m, 4 H, H-6, H-8); 13C NMR δ 153.1 , 143.2, 133.0, 129.8, 125.1 , 118.5, 36.6, 35.4, 32.1 , 28.8, 28.2. Anal, calcd for C11H14N2O2: C, 64.1 ; H, 6.8; N, 13.6. Found: C, 64.0; H, 6.5; N, 13.5%.
7,8,9,10-Tetrahydro-6H-cyclohepta[g][1,2,4]benzotriazin-3-amine 1 -Oxide (186). A mixture of nitroaniline 185 (2.26 g, 11.0 mmol) and cyanamide (1.84 g, 43.8 mmol) were mixed together at 100 0C, cooled to 50 0C, cHCI (10 mL) added carefully and the mixture heated at 100 0C for 4 h. The mixture was cooled to 50 0C, 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100 0C for 3 h. The mixture was cooled, diluted with water (100 mL), filtered, washed with water (3 x 20 mL), washed with ether (10 mL) and dried. The residue as purified by chromatography, eluting with 5% MeOH/DCM, to give amine 186 (0.26 g, 10%) as a yellow powder: mp (MeOH) 261-265 0C; 1H NMR [(CD3)2SO] δ 7.86 (s, 1 H, H-11), 7.29 (s, 1 H, H-5), 7.13 (br s, 2 H, NH2), 2.84-2.90 (m, 4 H, H-6, H-10), 1.74-1.80 (m, 2 H, H-8), 1.58-1.67 (m, 4 H, H-7, H-9); 13C NMR [(CDs)2SO] δ 160.2, 152.8, 147.8, 141.2, 127.9, 124.3, 117.8, 35.6, 35.1 , 31.3, 29.3, 28.0. Anal, calcd for C12H14N4O: C, 62.6; H, 6.1 ; N, 24.3. Found: C, 62.9; H, 6.2; N, 24.6%. Example 136 S-Chloro-Tjβjθ^O-tetrahydro-βH-cycloheptalglti.a^lbenzotriazine i -Oxide (187).
NaNO2 (151 mg, 2.2 mmol) was added in small portions to a stirred solution of amine 186 (252 mg, 1.1 mmol) in TFA (10 mL) at 0 0C and the solution stirred at 20 0C for 2 h. The solution was poured into ice/water, stirred for 30 min, filtered, washed with water (3 x 10 mL) and dried. The solid was suspended in POCI3 (10 mL) and DMF (0.1 mL) and stirred at 100 0C for 1 h. The solution was cooled, poured into ice/water, stirred for 30 minutes, filtered, washed with water (3 x 5 mL) and dried. The solid was suspended in DCM (50 mL), dried and the solvent evaporated. The residue was purified by chromatography, eluting with 5% EtOAc/DCM, to give chloride 187 (204 mg, 75%) as a pale yellow solid: mp (EtOAc/DCM) 146-148 0C; 1H NMR δ 8.11 (s, 1 H, H-11), 7.67 (s, 1 H, H-5), 2.97- 3.03 (m, 4 H, H-6, H-10), 1.85-1.91 (m, 2 H, H-8), 1.70-1.76 (m, 4 H, H-7, H-9); 13C NMR δ 156.3, 155.2, 148.9, 146.7, 132.0, 126.8, 118.5, 36.9, 36.7, 31.9, 28.2, 28.1. Anal, calcd for C12H12CIN3O: C, 57.7; H, 4.8; N, 16.8. Found: C, 57.6; H, 4.9; N, 16.9%.
Example 137
Figure imgf000135_0001
3-yl)-1,2-ethanediamine (188). Λ/,/V-Dimethyl-1 ,2-ethanediamine (0.23 mL, 2.1 mmol) was added to a stirred solution of chloride 187 (178 mg, 0.7 mmol) in DME (30 mL) and the solution stirred at reflux temperature for 2 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 -oxide 188 (204 mg, 95%) as a yellow solid: mp (MeOH) 149-152 0C; 1H NMR δ 7.96 (s, 1 H, H-11), 7.31 (s, 1 H, H-5), 5.84 (br s, 1 H, NH), 3.52-3.57 (m, 2 H, CH2N), 2.85-2.90 (m, 4 H, H-6, H- 10), 2.58 (br t, J = 6.0 Hz, 2 H, CH2N), 2.28 [s, 6 H, N(CH3)2], 1.79-1.85 (m, 2 H, H-8), 1.65-1.74 (m, 4 H, H-7, H-9); 13C NMR δ 159.0, 153.4, 148.0, 142.1 , 129.0, 125.0, 118.8, 57.6, 45.1 (2), 38.7, 36.8, 36.2, 32.0, 28.7, 28.4. Anal, calcd for C16H23N5O y2H2O: C, 61.9; H, 7.8; N, 22.6. Found: C, 62.0; H, 7.8; N, 22.4%.
Example 138
^-(i^-Dioxido^.δ.θ.iO-tetrahydro-ΘH-cycloheptatglli.Z^lbenzotriazin-S-yO-Λ/2,^2- dimethyl-1,2-ethanediamine (189). H2O2 (70%, 0.31 mL, ca. 6.2 mmol) was added dropwise to a stirred solution of TFAA (0.9 mL, 6.2 mmol) in DCM (10 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to a stirred solution of 1 -oxide 188 (186 mg, 0.6 mmol) and TFA (0.24 mL, 3.1 mmol) in DCM (10 mL) at O 0C. The solution was stirred at 20 0C for 16 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCI3 (4 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 188 (43 mg, 23%) and (ii) 1 ,4-dioxide 189 (82 mg, 42%) as a red solid: mp (MeOH) 131-133 0C; 1H NMR δ 8.03 (s, 1 H, H-11), 7.99 (s, 1 H1 H-5), 7.36 (br s, 1 H, NH), 3.63 (br t, J = 6.0 Hz, 2 H, CH2N), 2.98-3.03 (m, 2 H, CH2), 2.91-2.95 (m, 2 H, CH2), 2.60 (br t, J = 6.0 Hz, 2 H, CH2N), 2.30 [s, 6 H, N(CH3)2], 1.82-1.89 (m, 2 H, H-8), 1.68- 1.76 (m, 4 H, H-7, H-9); 13C NMR δ 154.4, 149.7, 144.7, 137.1 , 128.7, 119.8, 115.9, 57.5, 45.2 (2), 38.9, 37.0, 36.2, 31.8, 28.4, 28.2. Anal, calcd for C16H23N5O2 -V4CH3OH: C, 60.0; H, 7.4; N, 21.5. Found: C, 59.9; H, 7.0; N, 21.5%.
Example 139 6,7-Dihydrofuro[3,2-g][1,2,4]benzotriazin-3-amine 1 -Oxide (195). 1-(2,3-Dihydro-1-benzofuran-5-yl)ethanone (191). AICI3 (12.4 g, 93.0 mmol) was added in small portions to a stirred solution of AcCI (12.6 mL, 177.7 mmol) in dry DCM (100 mL) at -10 0C and the mixture stirred until homogeneous (15 min). The solution was added, via a cannula, to a stirred solution of 2,3-dihydro-1-benzofuran (190) (11.2 g, 93.0 mmol) in dry DCM (100 mL) at -10 0C and the solution stirred for 30 min at -10 0C, and then poured into ice/cHCI (5:1 v/v, 1 L). The mixture was stirred for 2 h, extracted with DCM (3 x 100 mL), the combined organic fraction dried, and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (10-20%) of EtOAc/pet. ether, to give ketone 191 (14.23 g, 94%) as a white solid: mp 59-60 0C [lit. (Dun, J. P., et al., J. Med. Chem 1986, 29, 2326-2329.) mp 60 0C]; 1H NMR δ 7.85 (d, J = 1.9 Hz, 1 H, H-4), 7.79 (dd, J = 8.5, 1.9 Hz, 1 H, H-6), 6.80 (d, J = 8.5 Hz, 1 H, H-7), 4.65 (t, J = 8.7 Hz, 2 H, H-2), 3.18 (br t, J = 8.7 Hz, 2 H, H-3), 2.13 (s, 3 H, CH3).
W-(2,3-Dihydro-1-benzofuran-5-yl)acetamide (192). NH2OH HCI (7.3 g, 105 mmol) was added to a stirred solution of ketone 191 (14.2 g, 87.7 mmol) and pyridine (9.2 mL, 114 mmol) in MeOH (100 mL) and the mixture stirred at 20 0C for 16 h. The solvent was evaporated and the residue partitioned between brine and EtOAc. The organic fraction was dried and the solvent evaporated to give crude 1-(2,3-dihydro-1-benzofuran-5- yl)ethanone oxime (15.3 g, 99%). HCI gas was bubbled through a solution of the oxime (15.3 g, 86.5 mmol) in Ac2O (16.3 mL, 173 mmol) and HOAc (54 mL, 865 mmol), and the solution stood at 20 0C for 24 h. The precipitate was poured into ice/water, stirred for 2 h, the solid filtered and washed with water and dried. The aqueous fraction was extracted with DCM (2 x 50 ml_), the combined organic extract dried and the solvent evaporated. The slurry was treated with water (20 mL) and evaporated several times to remove Ac2O. The combined solids were purified by chromatography, eluting with a gradient (50-100%) of EtOAc/pet. ether, to give acetamide 192 (7.94 g, 52%) as a white solid: mp 92-93 0C [lit. (Blade-Font, A.; de Mas Rocabayera, T. J. Chem. Soc. P1, 1982, 814-848) mp 93 0C]; 1H NMR δ 7.47 (br s, 1 H, H-4), 7.21 (br s, 1 H, NH), 6.99 (dd, J = 8.5, 2.1 Hz, 1 H, H-6), 6.69 (d, J = 8.5 Hz, 1 H, H-7), 4.55 (t, J = 8.7 Hz, 2 H, H-2), 3.18 (br t, J = 8.7 Hz, 2 H, H- 3), 2.13 (S1 3 H1 CH3).
N-(6-Nitro-2,3-dihydro-1-ben2θfuran-5-yl)acetamide (193). A solution of fHNO3 (2.1 mL, 52.0 mmol) in HOAc (10 mL) was added dropwise to a stirred solution of acetamide 192 (6.58 g, 37.1 mmol) in HOAc (100 mL) at 15 °C. The mixture was stirred at 15 0C for 1 h, then poured into ice/water (800 mL) and stirred for 30 min. The precipitate was filtered, washed with water (3 x 30 mL) and dried. The solid was purified by chromatography, eluting with a gradient (50-100%) of EtOAc/pet. ether, to give acetamide 193 (7.52 g, 91%) as a white solid: mp (EtOAc) 139-140 0C [lit. (Schroeder, E.; Lehman, M.; Clemens, R. US Patent 4,411,910, 1983.) mp 141-142 0C]; 1H NMR δ 10.19 (br s, 1 H1 NH), 8.56 (s, 1 H, H-7), 7.53 (s, 1 H, H-4), 4.65 (t, J = 8.7 Hz, 2 H, H-2), 3.30 (dt, J = 8.7, 1.1 Hz, 2 H, H-3), 2.26 (s, 3 H, CH3). Anal, calcd for C10H10N2O4: C, 54.0; H, 4.5; N, 12.6. Found: C, 54.2; H, 4.6; N, 12.6%.
6-Nitro-2,3-dihydro-1-benzofuran-5-ylamϊne (194). A suspension of acetamide 193 (8.98 g, 40.4 mmol) and cHCI (50 mL) in EtOH (100 mL) was heated at reflux temperature for 2 h. The solution was cooled, carefully neutralized with aqueous NH3 solution, and the resulting precipitate filtered and dried to give nitroaniline 194 (7.27 g, 100%) as an orange solid: mp (H2O) 148-149 °C; 1H NMR δ 7.44 (s, 1 H, H-7), 6.68 (t, J = 1.2 Hz, 1 H, H-4), 5.92 (br s, 2 H, NH2), 4.54 (t, J = 8.4 Hz, 2 H, H-2), 3.18 (dt, J = 8.4, 1.2 Hz, 2 H, H-3); 13C NMR δ 151.8, 140.8, 139.0, 131.2, 114.4, 103.4, 71.2, 30.0. Anal, calcd for C8H8N2O3: C, 53.3; H, 4.5; N, 15.6. Found: C, 53.2; H, 4.5; N, 15.6%.
6,7-Dihydrofuro[3,2-g][1,2,4]benzotrϊazin-3-amine 1 -Oxide (195). A mixture of nitroaniline 194 (7.27 g, 40.4 mmol) and cyanamide (6.79 g, 162 mmol) were mixed together at 100 °C, cooled to 50 0C, cHCI (15 mL) added carefully and the mixture heated at 100 0C for 4 h. The mixture was cooled to 50 °C, 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100 0C for 3 h. The mixture was cooled, diluted with water (200 mL), filtered, washed with water (3 x 50 mL) and dried. The aqueous fraction was extracted with CHCI3 (3 x 50 mL), dried and the solvent evaporated. The combined solids were purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give crude amine 195 (1.87 g, 23%) as a yellow powder: mp (MeOH/DCM) 241-246 0C. Anal, calcd for C9H8N4O2: C, 52.9; H, 4.0; N1 27.4. Found: C, 53.3; H, 3.8; N, 26.4%.
Example 140
3-Chloro-6,7-dihydrofuro[3,2-fir][1,2,4]benzotriazine 1-Oxide (196). NaNO2 (310 mg,
4.4 mmol) was added in small portions to a stirred solution of amine 195 (825 mg, 4.0 mmol) in TFA (20 mL) at 0 0C and the solution stirred at 0 0C for 1 h. The solution was poured into ice/water, stirred for 30 minutes, filtered, washed with water (3 x 10 mL) and dried. The solid was suspended in POCI3 (20 mL) and DMF (0.2 mL) and stirred at 100 0C for 1 h. The solution was cooled, poured into ice/water, stirred for 30 minutes, filtered, washed with water (3 x 20 mL) and dried. The solid was suspended in DCM (150 mL), dried and the solvent evaporated. The aqueous fraction was extracted with EtOAc (3 x 40 mL), the combined organic fraction dried and the solvent evaporated. The combined solid was purified by chromatography, eluting with 5% EtOAc/DCM, to give chloride 196 (283 mg, 31 %) as a pale yellow solid: mp (EtOAc/DCM) 223-224 0C; 1H NMR δ 7.75 (br t, J = 1.4 Hz, 1 H, H-5), 7.58 (s, 1 H, H-9), 4.81 (t, J = 8.4 Hz1 2 H, H-7), 3.49 (dt, J = 8.4, 1.4 Hz1 2 H, H-6); 13C NMR δ 162.8, 154.9, 154.3, 144.4, 142.3, 123.8, 96.4, 72.9, 29.5. Anal, calcd for C9H6CIN3O2: C1 48.3; H, 2.7; N, 18.8. Found: C, 48.5; H, 2.7; N, 18.9%.
Example 141 ^.yV^Dimethyl-yV^fi-oxido-ej-dihydrofuroCS^-glti.Z^lbenzotriazin-S-yO-i^- ethanediamine (197). Λ/,Λ/-Dimethyl-1 ,2-ethanediamine (0.40 mL, 3.6 mmol) was added to a stirred solution of chloride 196 (270 mg, 1.2 mmol) in DME (30 mL) and the solution stirred at reflux temperature for 4 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 197 (216 mg, 65%) as a yellow solid: mp (MeOH/EtOAc) 153-157 0C; 1H NMR δ 7.50 (s, 1 H, H-9), 7.40 (t, J = 1.4 Hz, 1 H, H-5), 5.73 (br s, 1 H, NH)1 4.67 (t, J = 8.3 Hz, 2 H, H-7), 3.48-3.53 (m, 2 H1 CH2N)1 3.53 (dt, J = 8.3, 1.4 Hz1 2 H, H-6), 2.55 (dd, J = 6.1 , 5.9 Hz, 2 H1 CH2N), 2.28 [S1 6 H1 N(CHa)2]; 13C NMR δ 158.3, 158.2, 146.1 , 140.6, 130.6, 121.8, 96.6, 71.9, 57.7, 45.1 (2), 38:8, 29.7. Anal, calcd for C13H17N5O2 Y4CH3OH: C, 56.2; H, 6.4; N1 24.7. Found: C1 56.1 ; H1 6.2; N1 25.0%. Example 142
/^-(1 ,4-Dioxido-6,7-dihydrofuro[3,2-g][1.^ibenzotriazin-S-yO-ΛfW-dimethyM ,2- ethanediamine (198). H2O2 (70%, 0.66 ml_, ca. 13.2 mmol) was added dropwise to a stirred solution of TFAA (1.9 mL, 13.2 mmol) in DCM (10 mL) at 0 0C. The solution was stirred at
0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to a stirred solution of 1 -oxide 197 (363 mg, 1.3 mmol) and TFA (0.51 mL, 6.6 mmol) in DCM (15 mL) at 0 0C. The solution was stirred at 20 0C for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCI3 (4 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 ,4-dioxide 198 (98 mg, 25%) as a red solid: mp (MeOH/EtOAc) 149-151 0C; 1H NMR δ 8.12 (s, 1 H, H-5), 7.54 (s, 1 H, H-9), 7.27 (br s, 1 H, NH), 4.75 (t, J = 8.3 Hz, 2 H, H-7), 3.58-3.64 (m, 2 H, CH2N), 3.43 (t, J = 8.2 Hz, 2 H, H-6), 2.62 (t, J = 6.0 Hz, 2 H, CH2N), 2.31 [s, 6 H, N(CHa)2]; 13C NMR δ 159.9, 148.9, 141.6, 135.2, 130.9, 113.1, 97.4, 72.4, 57.5, 45.1 (2), 38.8, 29.7. Anal, calcd for C13H17N5O3-1^H2O: C, 52.8; H, 6.0; N1 23.7. Found: C, 52.8; H, 5.7; N, 23.5%.
Example 143 W-[3-(4-Morpholinyl)propyl]-6,7-dihydrofuro[3,2-g][1,2,4]benzotriazin-3-amine 1- Oxide (199). A solution of chloride 196 (850 mg, 3.8 mmol) and 3-(4- morpholinyl)propylamine (1.7 mL, 11.5 mmol) in DME (30 mL) was stirred at reflux temperature for 18 h. The solution was cooled, the solvent evaporated and the residue partitioned between dilute aqueous NH3 solution (50 mL) and DCM (50 mL). The aqueous layer was extracted with DCM (2 x 25 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (2-10%) of MeOH/DCM, to give 1-oxide 199 (1.08 g, 85%) as a yellow solid: mp 142-144 0C; 1H NMR δ 7.52 (s, 1 H, H-9), 7.41 (s, 1 H, H-5), 5.97 (br s, 1 H, NH), 4.67 (t, J = 8.3 Hz, 2 H, H-7), 3.75 (t, J = 4.7 Hz, 4 H, 2 x CH2O), 3.56 (dt, J = 6.4, 5.9 Hz, 2 H, CH2N), 3.35 (dt, J = 8.3, 1.2 Hz, 2 H, H-6), 2.42-2.53 (m, 6 H, 2 x CH2N, CH2), 1.83 (p, J = 6.5 Hz, 2 H, CH2); 13C NMR δ 158.3, 151.4, 146.1, 140.5, 128.7, 121.8, 96.7, 71.9, 67.0 (2), 57.3, 53.8 (2), 40.8, 29.7, 25.4; MS (APCI) m/z 332 (MH+, 100%). Anal, calcd for Ci6H21N5O3: C, 58.0; H, 6.4; N, 21.1. Found: C, 58.0; H, 6.0; N, 21.2%.
Example 144 Λ/-[3-(4-Morpholinyl)propyl]-6,7-dihydrofuro[3,2-g][1,2,4]benzotriazin-3-amine 1,4- Dioxide (200). H2O2 (70%, 1.6 m!_, ca. 32 mmol) was added dropwise to a stirred solution of TFAA (4.5 mL, 32 mmol) in DCM (40 mL) at 0 0C. The solution was stirred at 20 0C for 10 min, then cooled to 0 0C, added to a solution of 1 -oxide 199 (1.06 g, 3.2 mmol) and TFA (1.25 mL, 16 mmol) in DCM (40 mL) at 0 0C. The solution was stirred at 20 0C for 4.5 h, diluted with dilute aqueous NH3 solution (50 mL) and extracted with DCM (4 x 125 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM to give 1,4- dioxide 200 (150 mg, 14%) as a red solid: mp 145-148 0C; 1H NMR δ 8.26 (br s, 1 H, NH), 8.14 (s, 1 H, H-9), 7.53 (s, 1 H, H-5), 4.74 (t, J = 8.3 Hz, 2 H, H-7), 3.83 (t, J = 4.6 Hz, 4 H, 2 x CH2O), 3.65 (br q, J = 5.9 Hz, 2 H, CH2N), 3.43 (dt, J = 8.3, 1.2 Hz, 2 H, H-6), 2.58 (br t, J = 6.1 Hz, 2 H, CH2), 2.53 (br s, 4 H, 2 x CH2N), 1.88 (p, J = 6.2 Hz, 2 H, CH2); 13C NMR 5 159.8, 149.0, 141.5, 135.2, 130.8, 113.1 , 97.4, 72.4, 66.8 (2), 57.7, 53.8 (2), 41.6, 29.7, 24.5; MS (APCI) m/z 348 (MH+, 100%); HRMS (FAB+) calcd for C16H22N5O4 (MH+) m/z 348.1672, found 348.1666. Anal, calcd for C16H21N5O4 0.4CH2CI2: C1 51.7; H, 5.8; N, 18.4. Found: C, 51.7; H, 5.4; N, 18.1%.
Example 145
3-Amino-7f 8-dihydrobenzof uro[6,5-e][1 ,2,4]triazine 1 -Oxide (204). 6-Nitro-2,3-dihydro-1-benzofuran (201). NaNO2 (2.66 g, 39 mmol) was added in portions to a solution of nitroaniline 194 (6.5 g, 36 mmol) in water (150 mL) and CH2SO4 (60 mL) at 0 0C. The solution was stirred at 0 0C for 3 h, aqueous H3PO2 solution (50%, 13 mL) was added, and the mixture stood at 0 0C for 16 h and then at 20 0C for 4 d. The mixture was extracted with ether (3 x 300 mL), the combined organic layer washed with water (3 x 200 mL), dried and the solvent evaporated to yield dihydrobenzofuran 201 (4.34 g, 73%) as a red-brown solid: mp 71-72 °C; 1H NMR δ 7.76 (dd, J = 8.1 , 2.1 Hz, 1 H, H-5), 7.57 (d, J = 2.1 Hz, 1 H, H-7), 7.29 (d, J = 8.1 Hz, 1 H, H-4), 4.70 (t, J = 8.1 Hz, 2 H, H-2), 3.30 (t, J = 8.1 Hz, 2 H, H-3). Anal, calcd for C8H7NO3: C, 58.2; H, 4.3; N, 8.5. Found: C, 58.5; H, 4.3; N, 8.5%.
/V-(2,3-Dihydro-1-benzofuran-6-yl)acetamide (202). A mixture of dihydrobenzofuran 201 (4.34 g, 26.3 mmol) and PtO2 (420 mg, 1.9 mmol) in THF (40 mL) and EtOH (200 mL) was stirred vigorously under H2 (30 psi) for 16 h. The mixture was filtered through Celite, washed with THF and the solvent evaporated. The residue was purified by chromatography, eluting with 2% MeOH/DCM, to give 6-amino-2,3-dihydrobenzofuran (2.89 g, 81%), which was dissolved in dioxane (95 mL), Ac2O (4.3 mL, 45.6 mmol) was added dropwise, and the solution stirred at 20 0C for 16 h. Water (200 mL) was added and the mixture extracted with DCM (3 x 120 mL). The combined organic layer was dried and the solvent evaporated to give acetamide 202 (3.56 g, 97%) as a yellow solid: mp 115- 118 0C; 1H NMR δ 7.26 (br s, 1 H, NH)1 7.09 (d, J = 7.9 Hz, 1 H, H-4), 7.04 (s, 1 H, H-7), 6.91 (d, J = 7.9 Hz, 1 H, H-5), 4.56 (t, J = 8.6 Hz, 2 H, H-2), 3.15 (t, J = 8.1 Hz, 2 H, H-3), 2.14 (s, 3 H, COCH3). Anal, calcd for C10H11NO2: C, 67.8; H, 6.3; N, 7.9. Found: C, 67.7; H, 6.4; N, 8.0%.
5-Nitro-2,3-dihydro-1-benzofuran-6-ylamine (203). A solution of cHNO3 (70%, 1.3 mL, 21 mmol) in HOAc (5 mL) was added dropwise to a stirred solution of acetamide 202 (3.56 g, 20 mmol) in HOAc (15 mL) at 20 0C and the solution stirred at 20 0C for 2 h. The solution was poured into ice/water (150 mL) and the mixture stirred for 30 min. The precipitate was filtered, washed with water, and dried to give a pale-brown solid, which was dissolved in a mixture of EtOH (35 mL) and cHCI (16 mL) and stirred at reflux temperature for 2 h. The resulting solution was cooled, the solvent evaporated, the residue diluted with water (40 mL), and then made basic with dilute aqueous NH3 solution. The precipitate was filtered, washed with water, and dried to give nitroaniline 203 (2.08 g, 90%) as a yellow solid, mp 140-142 0C; 1H NMR δ 7.98 (s, 1 H, H-4), 6.25 (br s, 2 H, NH2), 6.11 (s, 1 H, H-7), 4.64 (t, J = 8.0 Hz, 2 H, H-2), 3.13 (t, J = 7.8 Hz, 2 H, H-3); 13C NMR δ 166.6, 147.7, 126.9, 122.8, 118.9, 96.1, 73.2, 27.9. Anal, calcd for C8H8N2O3: C, 53.3; H, 4.5; N, 15.6. Found: C, 53.1; H, 4.6; N, 15.5%.
7,8-Dihydrofuro[2,3-g][1,2,4]benzotriazin-3-amine 1 -Oxide (204). A mixture of nitroaniline 203 (4.0 g, 22.2 mmol) and cyanamide (7.2 g, 171 mmol) were mixed together at 80 0C, cooled to 50 0C, cHCI (8.0 mL) added carefully and the mixture heated at 80 0C for 4 h. The mixture was cooled to 50 °C, 7.5 M NaOH solution added until the mixture was strongly basic, and the mixture stirred at 100 0C for 3 h. The mixture was cooled, diluted with water (20 mL), filtered, washed with water (20 mL) and ether (5 mL), and dried to give 1 -oxide 204 (8.6 g, 96%) as a yellow powder: mp (DCM) 293-296 0C; 1H NMR [(CDs)2SO] δ 7.71 (s, 1 H, H-9), 6.23 (s, 1 H, H-5), 4.59 (t, J = 8.5 Hz, 2 H, H-7), 3.12 (t, J = 8.5 Hz, 2 H, H-8), NH2 not observed; HRMS (FAB+) calcd for C9H9N4O2 (MH+) m/z 205.0726, found 205.0725.
Example 146 7,8-Dihydrofuro[2,3-g][1 ,2,4]benzotriazin-3-amine 1 ,4-Dioxide (205). H2O2 (70%, 1.2 mL, ca. 24.5 mmol) was added dropwise to a stirred solution of 1 -oxide 204 (500 mg, 2.45 mmol) in HOAc (10 mL) and the solution stirred at 50 °C for 24 h. The solution was cooled to 0 0C and the precipitate filtered. The solid was recrystallised from DMF to give 1 ,4- dioxide 205 (199 mg, 37%) as a red solid: mp > 300 °C (235-240 0C dec); 1H NMR [(CDa)2SO] δ 8.06 (t, J = 1.6 Hz, 1 H, H-9), 7.86 (br s, 2 H, NH2), 7.23 (s, 1 H, H-5), 4.77 (t, J - 8.3 Hz, 2 H, H-8), 3.30-3.60 (m, 2 H, H-7); HRMS calcd for C9H8N4O3 (M+) m/z 220.0596, found 220.0601.
Example 147
3-Chloro-7,8-dihydrofuro[2,3-g][1,2,4]benzotriazine 1 -Oxide (206). NaNO2 (3.38 g, 49.0 mmol) was added in small portions to a stirred solution of amine 205 (5.0 g, 24.5 mmol) in TFA (50 mL) at 20 °C and the solution stirred at 20 0C for 1 h. The solution was poured into ice/water, stirred 30 min, filtered, the solid washed with water and dried. The solid was suspended in POCI3 (65 mL) and DMF (0.4 mL) and stirred at 100 0C for 1 h. The solution was cooled, poured into ice/water, stirred for 30 min, filtered, washed with water and dried. The residue was purified by chromatography, eluting with a gradient (0- 3%) of MeOH/DCM, to give chloride 206 (3.76 g, 69%) as a yellow solid: mp (DCM) 203- 205 0C; 1H; 1H NMR [(CD3)2SO] δ 8.23 (t, J = 1.6 Hz, 1 H, H-9), 7.20 (s, 1 H, H-5), 4.23 (t, J - 8.4 Hz, 2 H1 H-7), 3.45 (dt, J = 8.4, 1.6 Hz, 2 H, H-8); 13C NMR δ 167.2, 155.3, 150.0,
137.4, 129.1 , 116.0, 102.7, 73.9, 28.3; HRMS (FAB+) calcd for C9H7 35CIN3O2 (MH+) m/z 224.0227, found 224.0221.
Example 148
^.V-Dimethyl-Λ/Mi-oxido-T.S-dihydrofurop^-glli^^lbenzotriazin-S-yO-i^- ethanediamine (207). A solution of chloride 206 (100 mg, 0.45 mmol) and Λ/1,Λ/1- dimethylethane-1 ,2-diamine (0.2 mL, 1.8 mmol) in DME (10 mL) was stirred at reflux temperature for 1 h, the solvent evaporated and the residue purified by chromatography, eluting with a gradient (5-8%) of MeOH/DCM to give the 1 -oxide 207 (108 mg, 88%) as a yellow solid, mp 163-165 0C; 1H NMR δ 8.09 (t, J = 1.4 Hz, 1 H, H-9), 6.79 (s, 1 H, H-5), 5.83 (br s, 1 H, NH), 4.72 (t, J = 8.3 Hz, 2 H, H-7), 3.52-3.56 (m, 2 H, CH2N), 3.31 (dt, J = 8.3, 1.4 Hz, 2 H, H-8), 2.57 (t, J = 8.3 Hz, 2 H, CH2N), 2.29 [s, 6 H, N(CH3)2]; 13C NMR δ
166.5, 159.3, 151.8, 129.3, 126.4, 116.6, 102.0, 72.9, 57.6, 45.0 (2), 38.6, 28.6. HRMS (FAB+) calcd for C13H18N5O2 (MH+) m/z 276.1461 , found 276.1461.
Example 149 Λ/1-(1 ,4-Dioxido-7,8-dihydrofuro[2,3-g][1 ,2,4]behzotriazin-3-yl)-N2,N2-dimethyl-1 ,2- ethanediamine (208). H2O2 (70%, 0.18 mL, ca. 3.6 mmol) was added dropwise to a stirred solution of TFAA (0.51 mL, 3.6 mmol) in DCM (6 ml_) at 0 0C. The solution was stirred at 20 0C for 10 min, then cooled to 0 0C, added to a solution of 1 -oxide 207 (100 mg, 0.36 mmol) and TFA (0.06 mL, 0.78 mmol) in CHCI3 (6 mL) at 0 0C and the solution stirred at 20 0C for 4.5 h. The solution was cooled to 0 0C, made basic with dilute aqueous NH3 solution and extracted with CHCI3 (3 x 10 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (5-16%) of MeOH/DCM to give 1 ,4-dioxide 208 (56 mg, 53%) as an orange solid: mp 186-189 0C; 1H NMR δ 8.13 (t, J = 1.6 Hz, 1 H, H-9), 7.48 (br s, 2 H, H- 5, NH), 4.81 (t, J = 8.3 Hz, 2 H, H-7), 3.62 (t, J = 6.0 Hz, 2 H, CH2N), 3.37 (dt, J = 8.3, 1.6 Hz, 2 H, H-8), 2.62 (t, J = 8.3 Hz, 2 H, CH2N), 2.30 [s, 6 H, N(CHa)2]; 13C NMR δ 167.2, 149.9, 140.6, 132.0, 117.9, 93.8, 87.9, 73.4, 57.5, 45.2 (2), 38.8, 28.5. HRMS (FAB+) calcd for C13H18N5O3 (MH+) m/z 292.1410, found 292.1409.
Example 150 Λ/1,/V1-Diethyl-iV2-(1-oxido-7,8-dihydrofuro[2,3-g][1,2,4]benzotriazin-3-yl)-1,2- ethanediamine (209). A solution of chloride 206 (250 mg, 1.12 mmol) and Λ/1,Λ/1- diethylethane-1 ,2-diamine (0.63 mL, 4.48 mmol) in DME (25 mL) was stirred at reflux temperature for 2 h, the solvent evaporated and the residue purified by chromatography, eluting with a gradient (5-10%) of MeOH/DCM to give the 1-oxide 209 (255 mg, 75%) as a yellow solid: mp 150-151 0C; 1H NMR δ 8.09 (t, J = 1.6 Hz, 1 H, H-9), 6.79 (s, 1 H, H-5), 5.90 (br s, 1 H, NH), 4.72 (t, J = 8.3 Hz, 2 H, H-7), 3.48-3.54 (m, 2 H1 CH2N), 3.30 (dt, J = 8.3, 1.4 Hz, 2 H, H-8), 2.69-2.72 (m, 2 H, CH2N), 2.59 (q, J = 7.1 Hz, 4 H, 2 x CH2), 1.05 (t, J = 7.1 Hz, 6 H, 2 x CH3); 13C NMR δ 166.5, 159.3, 151.8, 129.3, 126.3, 116.6, 102.1, 72.9, 51.3, 46.7 (2), 38.7, 28.6, 11.7 (2). Anal, calcd for C15H21N5O2 %CH3OH: C, 58.8; H, 7.1; N, 22.5. Found: C, 58.8; H, 6.7; N, 22.8%.
Example 151
W1-(1,4-Dioxido-7,8-dihydrofuro[2,3-g][1,2,4]benzotriazin-3-yl)-N2,N2.diethyl-1,2- ethanediamine (210). H2O2 (70%, 0.38 mL, ca. 2.8 mmol) was added dropwise to a stirred solution of TFAA (1.1 mL, 2.8 mmol) in DCM (15 mL) at 0 0C. The solution was stirred at 20 0C for 10 min, then cooled to 0 0C, added to a solution of 1-oxide 209 (235 mg, 0.78 mmol) and TFA (0.13 mL, 1.7 mmol) in CHCI3 (15 mL) at 0 0C. The solution was stirred at 20 0C for 4 h, diluted with dilute aqueous NH3 solution until basic and extracted with CHCI3 (3 x 25 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (5-10%) of MeOH/DCM, to give 1 ,4-dioxide 210 (95 mg, 38%) as a red solid: mp 187-190 0C; 1H NMR (CD3OD) δ 8.16 (t, J = 1.7 Hz, 1 H, H-9), 7.30 (s, 1 H, H-5), 4.85 (t, J = 8.4 Hz, 2 H, H-7), 3.90-3.94 (m, 2 H, CH2), 3.40-3.49 (m, 4 H, H-8, CH2), 3.36 (q, J = 7.3 Hz, 4 H, CH2), 1.37 (t, J = 7.3 Hz, 6 H, CH3), NH not observed; 13C NMR δ 169.8, 151.5, 142.3, 135.5, 128.2, 119.0, 93.7, 75.6, 51.7, 49.0 (2), 37.3, 29.4, 9.1 (2); HRMS (FAB+) calcd for C15H22N5O3 (MH+) m/z 320.1723, found 320.1726.
Example 152
/V-[3-(4-Morpholinyl)propyl]-7,8-dihydrofuro[2,3-g][1,2,4]benzotriazin-3-amine 1- Oxide (211). A solution of chloride 206 (250 mg, 1.1 mmol) and 3-(4- morpholinyOpropylamine (0.65 ml_, 4.5 mmol) in DME (25 ml_) was stirred at reflux temperature for 2 h, the solvent evaporated and the residue purified by chromatography, eluting with a gradient (2-5%) of MeOH/DCM, to give 1 -oxide 211 (340 mg, 92%) as a yellow solid: mp 152-154 0C; 1H NMR δ 8.10 (t, J = 1.6 Hz, 1 H, H-9), 6.79 (s, 1 H, H-5), 6.09 (br s, 1 H, NH), 4.42 (t, J = 8.3 Hz, 2 H, H-7), 3.75 (t, J = 4.7 Hz, 4 H, 2 x CH2O), 3.55-3.60 (m, 2 H, CH2), 3.30 (dt, J = 8.3, 1.6 Hz, 2 H, H-7), 2.46-2.52 (m, 6 H, 2 x CH2N, CH2), 1.82 (p, J = 6.5 Hz, 2 H, CH2); 13C NMR δ 166.5, 159.4, 151.8, 129.2, 126.4, 116.6, 102.1 , 72.9, 67.0 (2), 57.3, 53.8 (2), 40.8, 28.6, 25.3. Anal, calcd for C16H2I N5O3: C, 58.0; H, 6.4; N, 21.1. Found: C, 57.8; H, 6.2; N, 21.1%.
Example 153
Λ/-[3-(4-Morpholinyl)propyl]-7,8-dihydrofuro[2,3-g][1,2,4]benzotriazin-3-amine 1,4- Dioxide (212). H2O2 (70%, 0.46 ml_, ca. 9.5 mmol) was added dropwise to a stirred solution of TFAA (1.32 ml_, 9.5 mmol) in DCM (20 ml_) at 0 0C. The solution was stirred at 20 0C for 10 min, then cooled to 0 0C, added to a solution of 1 -oxide 211 (313 mg, 0.95 mmol) and TFA (0.16 ml_, 2.0 mmol) in CHCI3 (15 mL) at 0 0C. The solution was stirred at 20 0C for 4 h, diluted with dilute aqueous NH3 solution until basic and extracted with CHCI3 (3 x 25 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (1-12%) of MeOH/DCM, to give (i) starting material 211 (120 mg, 38%) and (ii) 1,4-dioxide 212 (68 mg, 21%) as a dark orange solid: mp 186-189 0C; 1H NMR [(CD3)2SO] δ 8.45 (t, J = 1.4 Hz, 1 H, H-9), 8.05 (s, 1 H, H-5), 7.21 (s, 1 H, NH), 4.77 (t, J = 8.3 Hz, 2 H, H-7), 3.33-3.64 (m, 8 H, 2 x CH2O, H-8, CH2), 2.36-2.45 (m, 6 H, 2 x CH2N, CH2), 1.77 (p, J = 6.6 Hz, 2 H, CH2); HRMS (FAB+) calcd for C16H22N5O4 (MH+) m/z 348.1672, found 348.1671. Example 154
3-lodo-7,8-dihydrobenzofuro[6,5-e][1,2,4]triazine 1-Oxide (213). terf-BuNO2 (90%, 3.8 ml_, 28.8 mmol) was added to a stirred solution of 1-oxide 204 (2.0 g, 9.8 mmol), CH2I2 (3.8 mL, 46.7 mmol) and CuI (1.87 g, 9.8 mmol) in THF (40 ml_), and the mixture was stirred at reflux temperature for 7 h. The mixture was cooled to 20 °C, the solvent was evaporated and the residue purified by chromatography, eluting with a gradient (2-10%) of MeOH/DCM, to give iodide 213 (1.50 g, 49%) as a pale yellow solid: mp 192-194 0C; 1H NMR δ 8.19 (t, J = 1.6 Hz1 1 H, H-9), 7.10 (s, 1 H, H-5), 4.83 (t, J = 8.4 Hz, 2 H, H-7), 3.44 (dt, J = 8.4, 1.6 Hz, 2 H, H-8); 13C NMR 5 167.0, 150.4, 136.2, 123.3, 116.4, 105.8, 103.7, 73.4, 29.0; HRMS calcd for C9H6IN3O2 (M+) m/z 314.9505, found 314.9501.
Example 155
3-(1-Oxido-7,8-dihydrofuro[2,3-g][1,2,4]benzotriazin-3-yl)propanal (214). Pd(OAc)2
(53 mg, 0.24 mmol) was added to a N2-purged solution of iodide 213 (1.50 g, 4.8 mmol), allyl alcohol (0.91 mL, 13.3 mmol), nBu4NBr (1.38 g, 4.3 mmol) and NaHCO3 (880 mg, 10.5 mmol) in dry DMF (40 mL) and the solution was stirred at 60 0C for 24 h under N2. The mixture was quenched with saturated aqueous NH4CI solution (150 mL) and filtered. The filtrate was extracted with EtOAc (5 x 50 mL), dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (20-50%) of EtOAc/pet. ether, to give aldehyde 214 as a dark oil, which was crystallised from MeOH to give a pale purple solid (532 mg, 45%): mp 140-142 0C; 1H NMR δ 9.92 (s, 1 H, CHO), 8.26 (t, J = 1.5 Hz, 1 H, H-9), 7.10 (s, 1 H, H-5), 4.80 (t, J = 8.4 Hz, 2 H, H-7), 3.43 (dt, J = 8.4, 1.5 Hz, 2 H, H-8), 3.29-3.33 (m, 2 H, CH2), 3.06-3.10 (m, 2 H, CH2); 13C NMR δ 200.4, 166.5, 165.0, 150.3, 135.2, 129.0, 116.2, 104.0, 73.1 , 40.5, 29.4, 29.0; HRMS (FAB+) calcd for C12H12N3O3 (MH+) m/z 246.0879, found 246.0881.
Example 156 3-[3-(4-Morpholinyl)propyl]-7,8-dihydrofuro[2,3-g][1,2,4]benzotriazine 1 -Oxide (215).
Morpholine (0.22 mL, 2.52 mmol) was added to a solution of aldehyde 214 (220 mg, 0.90 mmol) in MeOH (10 mL) and DMF (10 ml), and the solution stirred for 30 min. NaCNBH3 (176 mg, 2.80 mmol) was added, followed by HOAc (0.12 mL) and the mixture stirred at 20 °C for 30 min. The solvent was evaporated and the residue partitioned between DCM (40 mL) and water (40 mL). The aqueous phase was extracted with DCM (2 x 40 mL), the combined organic phase was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 10% MeOH/EtOAc, to give 1-oxide 215 (210 mg, 74%) as a pale brown solid, mp 96-99 0C; 1H NMR δ 8.27 (t, J = 1.6 Hz, 1 H, H-9), 7.11 (s, 1 H, H- 5), 4.80 (t, J = 8.4 Hz1 2 H, H-8), 3.59 (t, J = 4.6 Hz, 4 H, 2 x CH2O), 3.43 (dt, J = 8.4, 1.6 Hz, 2 H, H-7), 2.97-3.01 (m, 2 H, CH2), 2.44-2.48 (m, 2 H, CH2), 2.41 (t, J = 4.5 Hz, 4 H, 2 x CH2N), 2.03-2.11 (m, 2 H, CH2); 13C NMR δ 167.1 , 166.4, 150.5, 134.8, 128.9, 116.2, 103.9, 73.0, 67.0 (2), 58.3, 53.5 (2), 53.4, 27.0, 24.9. Anal, calcd for C16H20N4O3: C, 60.8; H, 6.4; N, 17.7. Found: C, 60.7; H, 6.5; N, 17.7%.
Example 157
3-[3-(4-Morpholinyl)propyl]-7,8-dihydrofuro[2,3-g][1,2,4]benzotriazine 1,4-Dioxide (216). H2O2 (70%, 0.31 mL, ca. 6.3 mmol) was added dropwise to a stirred solution of TFAA (0.88 mL, 6.3 mmol) in DCM (12 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C. The solution was added to a solution of 1 -oxide 215 (200 mg, 0.63 mmol) and TFA (0.10 mL, 1.4 mmol) in DCM (12 mL) at 0 0C and the solution was stirred at 20 0C for 2.5 h. Dilute aqueous NH3 solution was added until the mixture was basic and and then the mixture was extracted with CHCI3 (3 x 20 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (1-5%) of MeOH/DCM, to give 1 ,4-dioxide 216 (88 mg, 43%) as a dark yellow solid: mp 150-154 0C; 1H NMR δ 8.28 (t, J = 1.6 Hz, 1 H, H-9), 7.68 (s, 1 H, H-5), 4.87 (t, J = 8.5 Hz, 2 H, H-7), 3.48 (dt, J = 8.5, 1.5 Hz, 2 H, H-8), 3.44 (t, J = 4.4 Hz, 4 H, 2 x CH2O), 3.22 (t, J = 7.2 Hz, 2 H, CH2), 2.49 (t, J = 6.5 Hz, 2 H, CH2), 2.38 (t, J = 4.4 Hz, 4 H, 2 x CH2N), 2.06-2.13 (m, 2 H, CH2); 13C NMR δ 166.7, 156.1, 141.7, 136.3, 130.2, 117.8, 96.1 , 73.5, 67.0 (2), 58.0, 53.5 (2), 29.0, 28.8, 21.8. Anal, calcd for C16H20N4O4: C, 57.8; H, 6.1 ; N, 16.9. Found: C, 57.8; H, 6.1 ; N, 16.6%.
Example 158
[1,3]Dioxolo[4,5-g][1,2,4]benzotriazin-3-amine 1 -Oxide (221). yV-(1,3-Benzodioxol-5-yl)acetamide (218). Ac2O (21.4 mL, 226 mmol) was added dropwise to a stirred solution of 3,4-methylendioxyaniline (217) (25.87 g, 189 mmol) in dioxane (200 mL) at 0 0C and the mixture was stirred at 16 0C for 16 h. MeOH (10 mL) was added to decompose excess Ac2O and the solvent evaporated. The residue was dissolved in EtOAc (200 mL), dried and the solvent evaporated. The residue was filtered through a short column of silica, eluting with a gradient (50-100%) of EtOAc/pet. ether, to give acetamide 218 (29.17 g, 86%) as a white solid: mp 133-135 0C [lit (Krasso, A. & Ramuz, H., US Patent 4599347, 1986) mp (toluene) 138-139 0C]; 1H NMR δ 7.09 (d, J = 1.8 Hz, 1 H, H-4), 7.06 (br s, 1 H, NH), 6.77 (dd, J = 8.3, 1.8 Hz, 1 H, H-6), 6.72 (d, J = 8.3 Hz, 1 H, H-7), 5.94 (s, 2 H1 H-2), 2.14 (s, 3 H, CH3). W-(6-Nitro-1,3-benzodioxol-5-yl)acetamide (219). A solution of 70% HNO3 (15.5 mL, 244 mmol) in HOAc (40 mL) was added dropwise to a stirred solution of acetamide 218 (29.17 g, 163 mmol) in HOAc (150 mL) at 15-20 0C and the mixture stirred at 20 0C for 16 h. The precipitate was filtered, washed with water and dried to give nitroacetamide 219 (36.0 g, 99%) as a yellow powder: mp 207-208 0C (Krasso, A. & Ramuz, H., US Patent 4599347, 1986) mp 212-213 0C]; 1H NMR δ 10.78 (br s, 1 H, NH), 8.36 (s, 1 H, H-7), 7.66 (s, 1 H, H-4), 6.10 (s, 2 H, H-2), 2.27 (s, 3 H, CH3).
6-Nitro-1,3-benzodioxol-5-amine (220). NaOMe (4.82 g, 89.2 mmol) was added to a stirred solution of nitroacetamide 219 (5.0 g, 22.3 mmol) in MeOH (100 mL) at reflux temperature and the mixture stirred at reflux temperature for 15 min. HOAc (25 mL, 446 mmol) was added to quench the reaction and the solvent evaporated. Toluene (2 x 50 mL) was added and the azeotrope evaporated. The residue was dissolved in DCM (100 mL) and filtered through a short column of silica to give nitroaniline 220 (3.25 g, 80%) as an orange solid: mp 199-201 0C [lit (Krasso, A. & Ramuz, H., US Patent 4599347, 1986) mp (/PrOH) 203-204 0C]; 1H NMR δ 7.53 (s, 1 H, H-7), 6.30 (br s, 2 H, NH2), 6.22 (s, 1 H, H-4), 5.98 (s, 2 H, H-2).
[1 ,3]Dioxolo[4,5~g][1 ,2,4]benzotriazin-3~amine 1 -Oxide (221 ). A mixture of nitroaniline 220 (5.55 g, 30.5 mmol) and cyanamide (5.37 g, 122 mmol) were melted together at 100 0C, cooled to 50 °C, cHCI (15 mL) added dropwise and the mixture heated at 100 0C for 4 h. The mixture was cooled to 50 °C, 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100 0C for 3 h. The mixture was cooled, diluted with water (200 mL), filtered, washed with water (3 x 30 mL), washed with ether (3 x 5 mL) and dried to give 1 -oxide 221 (3.24 g, 51%) as a yellow powder: mp (MeOH/DCM) 290-295 °C; 1H NMR [(CD3)2SO] δ 7.45 (s, 1 H, H-9), 7.00 (br s, 2 H, NH2), 6.94 (s, 1 H1 H-5), 6.23 (s, 2 H, H-7); 13C NMR [(CD3)2SO] δ 160.0, 155.1 , 149.0, 147.0, 125.3, 103.1 , 101.3, 95.8. Anal, calcd for C8H6N4O3: C, 46.6; H, 2.9; N, 27.2. Found: C, 46.7; H, 2.9; N, 27.3%.
Example 159
3-Chloro[1,3]dioxolo[4,5-g][1,2,4]benzotriazine 1 -Oxide (222). NaNO2 (620 mg, 8.9 mmol) was added in small portions to a stirred solution of amine 221 (1.75 g, 8.5 mmol) in TFA (25 mL) at 0 0C and the solution stirred at 20 0C for 1 h. The solution was poured into ice/water, stirred 30 minutes, filtered, the precipitate was washed with water (3 x 30 mL) and dried. The solid was suspended in POCI3 (50 mL) and DMF (0.5 mL) and stirred at 100 0C for 1 h. The solution was cooled, poured into ice/water, stirred for for 30 min, filtered, washed with water (3 x 30 mL) and dried. The solid was suspended in DCM (150 mL), dried and the solvent evaporated. The residue was purified by chromatography, eluting with 5% EtOAc/DCM, to give chloride 222 (753 mg, 39%) as a pale yellow solid: mp (DCM) 253-255 0C; 1H NMR δ 7.69 (s, 1 H, H-9), 7.45 (s, 1 H, H-5), 6.42 (s, 2 H, H-7); 13C NMR δ 156.6, 154.2, 152.0, 147.8, 130.6, 104.7, 103.1 , 95.7. Anal, calcd for C8H4CIN3O3: C, 42.6; H, 1.8; N, 18.6. Found: C, 42.7; H, 1.7; N, 18.5%.
Example 160
Λ/1,W1-Dimethyl-Λ/2-(1-oxido[1,3]dioxolo[4,5-g][1,2,4]benzotriazin-3-yl)-1,2- ethanediamine (223). Λ/,Λ/-Dimethyl-1,2-ethanediamine (0.52 mL, 4.8 mmol) was added to a stirred solution of chloride 222 (359 mg, 1.6 mmol) in DME (40 mL) and the solution stirred at reflux temperature for 2 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-15%) of MeOH/DCM, to give 1-oxide 223 (390 mg, 88%) as a yellow solid: mp (MeOH/DCM) 192-194 0C; 1H NMR δ 7.45 (s, 1 H, H-9), 7.35 (br s, 1 H, NH), 6.96 (s, 1 H, H-5), 6.23 (s, 2 H, H-7), 3.35-3.39 (m, 2 H, CH2N), 2.42 (t, J = 6.7 Hz, 2 H, CH2N), 2.18 [s, 6 H, N(CH3)2]; 13C NMR δ 158.9, 155.2, 148.7, 146.9, 125.3, 103.2, 101.6, 95.9, 57.8, 45.2 (2), 38.6. Anal, calcd for C12H15N5O3: C, 52.0; H, 5.5; N, 25.3. Found: C, 52.1 ; H, 5.5; N, 25.3%.
Example 161 /V1-(1,4-Dioxido[1,3]dioxolo[4,5-g][1,2,4]benzotriazin-3-yl)-W2,W2-dimethyl-1,2- ethanediamine (224). H2O2 (70%, 0.67 mL, ca. 13.5 mmol) was added dropwise to a stirred solution of TFAA (1.9 mL, 13.5 mmol) in DCM (20 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to a stirred solution of 1-oxide 223 (374 mg, 1.4 mmol) and TFA (0.52 mL, 6.7 mmol) in DCM (15 mL) at 0 0C. The solution was stirred at 20 °C for 8 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCI3 (4 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-20%) of MeOH/DCM, to give 1 ,4-dioxide 224 (52 mg, 13%) as a red solid: mp (MeOH/EtOAc) 175-179 0C; 1H NMR δ 7.60 (s, 1 H, H-9), 7.59 (s, 1 H, H-5), 7.35 (br s, 1 H, NH), 6.21 (s, 2 H, H-7), 3.61 (br t, J = 6.0 Hz, 2 H, CH2N), 2.62 (br t, J = 6.0 Hz, 2 H, CH2N), 2.31 [s, 6 H, N(CH3J2]; 13C NMR δ 155.9, 149.7, 148.9, 137.8, 126.7, 103.5, 97.9, 94.1, 57.4, 45.1 (2), 38.8. Anal, calcd for Ci2H15N5O4-1Z2CH3OH: C, 48.5; H, 5.5; N, 22.6. Found: C, 48.7; H, 5.3; N, 22.6%.
Example 162
9,10-Dihydro-8W-chromeno[6,5-e][1,2,4]triazin-3-amine 1 -Oxide (234). /V-(3,4-Dihydro-2W-chromen-6-yl)acetamide (228). A solution of KNO3 (2.25 g, 22.3 mmol) in CH2SO4 (10 mL) was added dropwise to a stirred solution of 4-chromanone (225) (3.0 g, 20.2 mmol) in CH2SO4 (50 mL) at 0 0C and the mixture stirred at 0 0C for 2 h. The mixture was poured into ice/water (500 mL), stirred 30 min and the precipitate filtered. The solid was washed with water (3 x 10 mL) and dried. The solid was purified by chromatography, eluting with 20% EtOAc/pet. ether, to give (i) 8-nitro-2,3-dihydro-4/-/- chromen-4-one (226) (369 mg, 9%) as a white solid: mp (EtOAc/pet. ether) 120-121 0C; 1H NMR δ 8.17 (dd, J = 7.8, 1.8 Hz, 1 H, H-7), 8.10 (dd, J = 8.0, 1.8 Hz, 1 H, H-5), 7.12 (dd, J = 8.0, 7.8 Hz, 1 H, H-6), 4.73 (dd, J = 6.5, 6.4 Hz, 2 H, H-2), 2.95 (br t, J = 6.5 Hz, 2 H, H-3). Anal, calcd for C9H7NO4: C, 56.0; H, 3.7; N, 7.3. Found: C, 56.1; H, 3.7; N, 7.3%; and (ii) 6-nitro-2,3-dihydro-4/-/-chromen-4-one (227) (3.17 g, 81%) as a white solid: mp (EtOAc/pet. ether) 169-171 0C; 1H NMR δ 8.78 (d, J = 2.8 Hz, 1 H, H-5), 8.32 (dd, J = 9.1, 2.8 Hz, 1 H, H-7), 7.11 (d, J = 9.1 Hz, 1 H, H-8), 4.67 (dd, J = 6.6, 6.4 Hz, 2 H, H-2), 2.91 (dd, J = 6.6, 6.4 Hz, 2 H, H-3); 13C NMR δ 189.4, 165.7, 142.1, 130.3, 123.7, 120.8, 119.3, 67.6, 37.1. Anal, calcd for C9H7NO4: C, 56.0; H, 3.7; N, 7.3. Found: C, 56.1; H, 3.7; N, 7.4%.
A mixture of nitrochromanone 227 (2.0 g, 13.4 mmol) and Pd/C (5%, 100 mg) in EtOH/EtOAc (4:1, 150 mL), water (10 mL), and cHCI (1 mL) was stirred under H2 (60 psi) for 16 h. The mixture was filtered through celite, washed with EtOH (3 x 25 mL) and the solvent evaporated. The residue was partitioned between dilute aqueous NH3 solution and DCM, the organic fraction dried, and the solvent evaporated. The residue was dissolved in dry dioxane (100 mL) and Ac2O (2.8 mL, 29.4 mmol) added dropwise. The solution was stirred at 20 0C for 16 h, diluted with water and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (50-100%) of EtOAc/pet. ether, to give acetamide 228 (2.09 g, 70%) as a white solid: mp 111-113 0C [lit. (Hach, V. Coll. Czech. Chem. Commun. 1959, 24, 3136-3140) mp (EtOH) 118 0C]; 1H NMR δ 7.28 (d, J = 2.2 Hz, 1 H, H-5), 7.02 (dd, J = 8.6, 2.2 Hz, 1 H, H-7), 6.72 (d, J = 8.6 Hz, 1 H, H-8), 4.15 (br dd, J = 5.2, 5.0 Hz, 2 H, H-2), 2.77 (br t, J = 6.5 Hz, 2 H, H-4), 2.13 (s, 3 H, CH3), 1.95- 2.02 (m, 2 H, H-3). Alternative Preparation of Λ/-(3,4-Dihydro-2/Y-chromen-6-yl)acetamide (228). A solution of 4-chromanone (225) (14.82 g, 0.1 mol) in HOAc (50 mL) was added to a stirred suspension of Zn dust (10 eq. w/w, 148 g) in HOAc (200 mL) and the mixture stirred at 100 0C for 16 h. The mixture was cooled, filtered, washed with HOAc (3 x 100 mL) and the solvent from the combined filtrate evaporated. The residue was suspended in water (200 mL) and the suspension made basic with NaOH1 extracted with EtOAc (3 x 100 mL), the combined extracts dried and the solvent evaporated to give chroman (229) (11.83 g, 88%) as a white solid. AICI3 (11.8 g, 88.2 mmol) was added in small portions to a stirred solution of AcCI (11.9 mL, 167.5 mmol) in dry DCM (250 mL) at -10 0C and the mixture stirred until homogeneous (15 min). The solution was added, via a cannula, to a stirred solution of chroman (229) (11.8 g, 88.2 mmol) in dry DCM (200 mL) at -10 0C and the solution stirred for 30 min at -10 °C and then poured into ice/cHCI (5:1 v/v, 1.5 L). The mixture was stirred for 2 h, extracted with DCM (3 x 100 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (10-20%) of EtOAc/pet. ether, to give 1-(3,4-dihydro-2f/-chromen-6-yl)ethanone (230) (12.45 g, 80%) as a white solid: 1H NMR δ 7.68-7.22 (m, 2 H, H-5, H-7), 6.82 (d, J = 9.2 Hz, 1 H, H-8), 4.24 (br dd, J = 5.3, 5.2 Hz, 2 H, H 2), 2.83 (br t, J = 6.5 Hz, 2 H, H-4), 2.53 (s, 3 H, CH3), 2.00-2.06 (m, 2 H, H-3). Hydroxylamine HCI (2.9 g, 41.9 mmol) was added to a stirred solution of ketone 230 (6.15 g, 34.9 mmol) and pyridine (3.7 mL, 45.4 mmol) in MeOH (30 mL) and the mixture stirred at 20 0C for 16 h. The solvent was evaporated and the residue partitioned between brine and EtOAc. The organic fraction was dried and the solvent evaporated to give crude 1- (3,4-dihydro-2/7-chromen-6-yl)ethanone oxime (6.3 g, 94%). HCI gas was bubbled through a solution of oxime (6.3 g, 32.5 mmol) in Ac2O (6.1 mL, 65 mmol) and HOAc (40 mL, 650 mmol), and the solution stood at 20 0C for 24 h. The precipitate was poured into ice/water, stirred for 2 h, the solid filtered and washed with water and dried. The aqueous fraction was extracted with DCM (2 x 50 mL), the combined extract dried and the solvent evaporated. The slurry was treated with water (20 mL) and evaporated several times to remove Ac2O. The combined solids were purified by chromatography, eluting with a gradient (50-100%) of EtOAc/pet. ether, to give acetamide 228 (3.74 g, 59%) as a white solid: spectroscopically identical to the sample prepared above.
yV-(7-Nitro-3,4-dihydro-2W-chromen-6-yl)acetamide (232) and /V-(5-Nitro-3,4-dihydro- 2tf-chromen-6-yl)acetamide (231 ). A solution of fHNO3 (2.5 mL, 63.2 mmol) in HOAc (10 mL) was added dropwise to a stirred solution of acetamide 228 (8.63 g, 45.1 mmol) in HOAc (100 mL) at 15 0C. The mixture was stirred at 15 0C for 1 h, then poured into ice/water (800 mL) and stirred for 30 min. The precipitate was filtered, washed with water (3 x 30 mL) and dried. The solid was purified by chromatography, eluting with a gradient (30-100%) of EtOAc/pet. ether, to give (i) 7-nitro-6-acetamide 232 (2.49 g, 23%) as a white solid: mp (EtOAc) 141-143 0C [lit. (Brancaccio, G.; Lotteiri, G.; Viterbo, R. J. Het. Chem. 1973, 10, 623-629.) mp (EtOH) 139-142 0C]; 1H NMR δ 10.0 (br s, 1 H, NH), 8.40 (s, 1 H, H-8), 7.61 (s, 1 H, H-5), 4.21 (br t, J = 5.2 Hz, 2 H, H-2), 2.87 (br t, J = 6.5 Hz, 2 H, H-4), 2.24 (s, 3 H, CH3), 2.00-2.06 (m, 2 H, H-3); and (ii) 5-nitro-6-acetamide 231 (2.08 g, 19%) as a white solid: mp (EtOAc) 191-192 0C [lit. (Brancaccio, G.; Lotteiri, G.; Viterbo, R. J. Het Chem. 1973, 10, 623-629.) mp (EtOH) 177-180 0C]; 1H NMR δ 8.07 (br s, 1 H, NH), 7.83 (br d, J = 9.1 Hz, 1 H, H-7), 6.99 (d, J = 9.1 Hz, 1 H, H-8), 4.20 (br t, J = 5.2 Hz, 2 H, H-2), 2.80 (brt, J = 6.5 Hz, 2 H, H-4), 2.16 (s, 3 H, CH3); 1.96-2.02 (m, 2 H, H-3); and (iii) Λ/-(8-nitro-3,4-dihydro-2H-chromen-6-yl)acetamide (0.85g, 8%), as a white solid: mp (EtOAc) 200-201 °C [lit. (Brancaccio, G.; Lotteiri, G.; Viterbo, R. J. Het. Chem. 1973, 10, 623-629.) mp (EtOH) 188-191 0C]; 1H NMR δ 7.67 (br s, 1 H, H-6), 7.61 (br s, 1 H, H- 5), 7.16 (br s, 1 H, NH), 4.30 (br t, J = 5.2 Hz, 2 H, H-2), 2.86 (br t, J = 6.5 Hz, 2 H, H-4), 2.17 (s, 3 H, CH3); 2.04-2.10 (m, 2 H, H-3).
5-Nitro-3,4-dihydro-2H-chromen-6-ylamine (233). A solution of acetamide 231 (1.24 g, 5.25 mmol) in 95% EtOH (50 mL) and NaOH (0.63 g, 15.7 mmol) was stirred at reflux temperature for 16 h. The mixture was cooled and the solvent evaporated. The residue was partitioned between Et2O and water, the organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with 20% EtOAc/pet. ether, to give nitroaniline 233 (1.54 g, 85%) as red oil: 1H NMR δ 6.85 (d, J = 9.0 Hz, 1 H, H-8), 6.60 (d, J = 9.0 Hz, 1 H, H-7), 4.90 (br s, 2 H, NH2), 4.13 (dd, J = 5.3, 5.1 Hz, 2 H, H- 2), 2.90 (br t, J = 6.5 Hz, 2 H, H-4), 1.91-1.96 (m, 2 H, H-3).
9,10-Dihydro-8H-chromeno[6,5-e][1,2,4]triazin-3-amine 1 -Oxide (234). A mixture of nitroaniline 233 (1.52 g, 7.8 mmol) and cyanamide (1.32 g, 31.3 mmol) were mixed together at 100 °C, cooled to 50 °C, cHCI (10 mL) added carefully and the mixture heated at 100 °C for 4 h. The mixture was cooled to 50 °C, 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100 0C for 3 h. The mixture was cooled, diluted with water (100 mL), filtered, washed with water (3 \ 20 mL) and dried. The aqueous fraction was extracted with CHCI3 (3 x 50 mL), the combined organic fraction dried and the solvent evaporated. The combined solids were purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give (i) starting nitroaniline 233 (470 mg, 31%) and (ii) amine 234 (246 mg, 14%) as a yellow powder: mp (MeOH/DCM) 275-279 0C (dec); 1H NMR [(CD3)2SO] δ 7.26-7.31 (m, 2 H, H-5, H-6), 6.90 (br s, 2 H, NH2), 4.12-4.17 (m, 2 H, H-8), 3.30-3.33 (m, 2 H, H-10), 1.87-1.93 (m, 2 H, H-9); 13C NMR [(CD3)2SO] δ 159.0, 151.2, 146.3, 129.5, 128.0, 124.6, 113.5, 65.3, 24.4, 21.5. Anal, calcd for C10H10N4O2: C, 55.0; H, 4.6; N, 25.6. Found: C, 55.0; H, 4.6; N, 25.6%.
Example 163 a-Chloro-Θ.IO-dihydro-SH-chromenotβ.S-elli.^triazine 1-Oxide (235). NaNO2 (134 mg, 1.9 mmol) was added in small portions to a stirred solution of amine 234 (231 mg, 1.0 mmol) in TFA (10 ml_) at 0 0C and the solution stirred at 20 0C for 3 h. The solution was poured into ice/water, stirred for 30 min, filtered, washed with water (3 x 10 ml_) and dried. The solid was suspended in POCI3 (20 ml_) and DMF (0.3 mL), and stirred at 100 0C for 1 h. The solution was cooled, poured into ice/water, stirred for 30 min, filtered, washed with water (3 x 20 mL) and dried. The solid was suspended in DCM (100 mL), dried and the solvent evaporated. The aqueous fraction was extracted with EtOAc (3 x 30 mL), the combined organic fraction dried and the solvent evaporated. The combined solids were purified by chromatography, eluting with 5% EtOAc/DCM, to give chloride 235 (63 mg, 27%) as a pale yellow solid: mp (EtOAc) 160-162 0C; 1H NMR δ 7.70 (d, J = 9.2 Hz, 1 H, H-6), 7.47 (d, J = 9.2 Hz, 1 H, H-5), 4.29 (br dd, J = 5.2, 5.2 Hz, 2 H, H-8), 3.54 (t, J = 6.5 Hz1 2 H, H-10), 2.03-2.09 (m, 2 H, H-9); 13C NMR δ 156.6, 154.0, 145.0, 133.9, 129.5, 126.9, 114.0, 66.4, 24.6, 21.6. Anal, calcd for Ci0H8CIN3O2: C, 50.5; H, 3.4; N, 17.7. Found: C, 50.7; H, 3.4; N, 17.8%.
Example 164
^.Λ/^Dimethyl-Λ/Mi-oxido-Θ.IO-dihydro-δH-chromenoie.δ-elϊi^^ltriazin-S-yO-i^- ethanediamine (236). Λ/,Λ/-Dimethyl-1 ,2-ethanediamine (65 μL, 0.6 mmol) was added to a stirred solution of chloride 235 (47 mg, 0.2 mmol) in DME (20 mL) and the solution stirred at reflux temperature for 2 h. The solvent was evaporated and the residue was partitioned between DCM (50 mL) and dilute aqueous NH3 solution (20 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 -oxide 236 (55 mg, 95%) as a pale yellow solid: mp (MeOH/EtOAc) 119-120 0C; 1H NMR δ 7.35 (d, J = 9.2 Hz, 1 H, H-6), 7.23 (d, J = 9.2 Hz, 1 H, H-5), 5.66 (br s, 1 H, NH)1 4.19 (br dd, J = 5.1 , 5.0 Hz, 2 H, H-8), 3.47-3.53 (m, 4 H, H-10, CH2N), 2.54 (brt, J = 6.0 Hz, 2 H, CH2N), 2.27 [s, 6 H, N(CH3J2], 1.97-2.04 (m, 2 H, H-9); 13C NMR δ 158.0, 152.2, 146.7, 130.3, 128.4, 125.2, 114.0, 65.9, 57.7, 45.1 (2), 38.7, 24.9, 22.2. Anal. CaICcI fOr C14H19N5O2-1Z4H2O: C, 57.2; H, 6.7; N, 23.8. Found: C, 57.5; H1 6.6; N, 23.8%.
Example 165 W1-(1 ,4-Dioxido-9,10-dihydro-8H-chromeno[6,5-e][1 ,2,4]triazin-3-yl)-Λ/2,Λ/2-dimethyl- 1,2-ethanediamine (237). H2O2 (70%, 0.16 ml_, ca. 3.2 mmol) was added dropwise to a stirred solution of TFAA (0.45 ml_, 3.2 mmol) in DCM (10 ml_) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to a stirred solution of 1 -oxide 236 (50 mg, 0.17 mmol) and TFA (0.12 ml_, 1.6 mmol) in DCM (15 ml.) at 0 °C. The solution was stirred at 20 °C for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCI3 (4 x 50 ml_). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 237 (28 mg, 54%) as a red gum: 1H NMR δ 8.11 (d, J = 9.5 Hz, 1 H, H-5), 7.36 (d, J = 9.5 Hz, 1 H, H-6), 7.23 (br s, 1 H, NH), 4.21-4.25 (m, 2 H1 H-8), 3.61 (br t, J = 5.8 Hz, 2 H, CH2N), 3.56 (br t, J = 6.5 Hz, 2 H, H- 10), 2.62 (br t, J = 6.0 Hz, 2 H, CH2N), 2.31 [s, 6 H, N(CH3)2], 2.00-2.07 (m, 2 H, H-9); 13C NMR δ 154.0, 148.4, 135.8, 130.6, 128.9, 116.0, 114.9, 66.2, 57.5, 45.1 (2), 38.7, 24.5, 21.9; MS (FAB+) m/z 306 (MH+, 60%), 290 (20), 176 (100); HRMS (FAB+) calcd for C14H20N5O3 (MH+) m/z 306.1566, found 306.1568. Anal, calcd for
C14H19N5O3 Y2H2O y2MeOH: C, 52.7; H, 6.7; N, 21.2. Found: C, 52.8; H, 6.7; N, 21.2%.
Example 166 7,8-Dihydro-6//-chromeno[6,7-e][1,2,4]triazin-3-amine 1 -Oxide (239). 7-Nitro-3,4-dihydro-2H-chromen-6-ylamine (238). A suspension of acetamide 232 (2.49 g, 10.5 mmol) and cHCI (10 mL) in EtOH (50 mL) was heated at reflux temperature for 16 h. The solution was cooled, carefully neutralized with aqueous NH3 solution, extracted with EtOAc (2 x 50 mL), the combined organic fraction dried and the solvent evaporated to give nitroaniline 238 (2.05 g, 100%) as an orange solid: mp (EtOAc) 145-148 0C [lit. (Brancaccio, G.; Lotteiri, G.; Viterbo, R. J. Het Chem. 1973, 10, 623-629) mp (H2O) 139- 140 0C]; 1H NMR δ 7.54 (s, 1 H, H-8), 6.50 (s, 1 H, H-5), 5.62 (br s, 2 H, NH2), 4.14 (br t, J = 5.2 Hz, 2 H, H-2), 2.77 (br t, J = 6.5 Hz, 2 H, H-4), 1.95-2.02 (m, 2 H, H-3).
7,8-Dihydro-6W-chromeno[6,7-e][1,2,4]triazin-3-amine 1 -Oxide (239). A mixture of nitroaniline 238 (2.05 g, 10.6 mmol) and cyanamide (1.78 g, 42.3 mmol) were mixed together at 100 0C, cooled to 50 0C, cHCI (10 mL) added carefully and the mixture heated at 100 0C for 4 h. The mixture was cooled to 50 0C, 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100 0C for 3 h. The mixture was cooled, diluted with water (200 mL), filtered, washed with water (3 x 50 mL) and dried. The aqueous fraction was extracted with CHCI3 (3 x 50 mL), dried and the solvent evaporated. The combined solids were purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give amine 239 (1.30 g, 56%) as a yellow powder: mp (MeOH/DCM) 280-283 0C; 1H NMR [(CD3)2SO] δ 7.32 (s, 1 H, H-10), 7.31 (s, 1 H, H-5), 6.96 (br s, 2 H, NH2), 4.22 (dd, J = 5.3, 5.2 Hz, 2 H1 H-8), 2.95 (br t, J = 6.3 Hz, 2 H, H-6), 1.92-1.98 (m, 2 H, H-7); 13C NMR [(CDg)2SO] δ 159.1 , 152.2, 143.4, 135.8, 128.7, 125.7, 102.6, 66.5, 25.0, 21.0. Anal, calcd for C10H10N4O2: C, 55.0; H, 4.6; N, 25.7. Found: C, 55.1 ; H, 4.6; N, 25.5%.
Example 167
3-Chloro-7,8-dihydro-6H-chromeno[6,7-e][1,2,4]triazine 1 -Oxide (240). NaNO2 (320 mg, 4.6 mmol) was added in small portions to a stirred solution of amine 239 (963 mg, 4.4 mmol) in TFA (20 mL) at 0 0C and the solution stirred at 0 °C for 1 h. The solution was poured into ice/water, stirred for 30 min, filtered, washed with water (3 x 10 mL) and dried. The solid was suspended in POCI3 (20 mL) and DMF (0.2 mL) and stirred at 100 0C for 1 h. The solution was cooled, poured into ice/water, stirred for 30 minutes, filtered, washed with water (3 x 20 mL) and dried. The solid was suspended in DCM (150 mL), dried and the solvent evaporated. The aqueous fraction was extracted with EtOAc (3 x 40 mL), the combined organic fraction dried and the solvent evaporated. The combined solid was purified by chromatography, eluting with 5% EtOAc/DCM, to give chloride 240 (939 mg, 66%) as a pale yellow solid: mp (EtOAc/DCM) 192-195 0C; 1H NMR δ 7.64-7.67 (m, 2 H, H-5, H-10), 4.34^.39 (m, 2 H, H-8), 3.08 (br dd, J = 6.6, 6.1 Hz, 2 H, H-6), 2.09-2.15 (m, 2 H, H-7); 13C NMR δ 157.6, 154.1 , 141.9, 136.7, 133.2, 128.3, 104.0, 67.4, 26.0, 21.1. Anal, calcd for C10H8CIN3O2: C, 50.5; H, 3.4; N, 17.7. Found: C, 50.8; H, 3.3; N, 17.7%.
Example 168 /V1,/V1-Dimethyl-W2-(1-ox«do-7,8-dihydro-6W-chromeno[6,7-e][1,2,4]triazin-3-yl)-1,2- ethanediamine (241). Λ/,Λ/-Dimethyl-1 ,2-ethanediamine (0.47 mL, 4.3 mmol) was added to a stirred solution of chloride 240 (341 mg, 1.4 mmol) in DME (30 mL) and the solution stirred at reflux temperature for 4 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 -oxide 241 (343 mg, 83%) as a yellow solid: mp (MeOH/EtOAc) 150-152 °C; 1H NMR δ 7.58 (s, 1 H, H- 10), 7.30 (s, 1 H, H-5), 5.79 (br s, 1 H1 NH), 4.25 (br dd, J = 5.3, 5.2 Hz, 2 H, H-8), 3.51- 3.56 (m, 2 H, CH2N), 2.96 (br t, J = 6.0 Hz, 2 H, H-6), 2.60 (br t, J = 6.0 Hz, 2 H, CH2N), 2.31 [s, 6 H, N(CHa)2], 2.02-2.09 (m, 2 H, H-7); 13C NMR δ 158.0, 152.9, 143.6, 135.1 , 130.0, 126.1 , 104.3, 66.9, 57.6, 45.0 (2), 38.7, 25.9, 21.7. Anal, calcd for C14H19N5O2 ^H2O: C, 57.2; H, 6.7; N, 23.8. Found: C, 57.1 ; H, 6.5; N, 23.9%.
Example 169 /V1-(1,4-Dioxido-7,8-dihydro-6W-chromeno[6,7-e][1,2,4]tria2in-3-yl)-Λ/2,Λ/2-dJmethyl- 1,2-ethanediamine (242). H2O2 (70%, 0.47 mL, ca. 9.3 mmol) was added dropwise to a stirred solution of TFAA (1.3 mL, 9.3 mmol) in DCM (10 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 0C for 10 min, then cooled to 0 0C and added to a stirred solution of 1 -oxide 241 (270 mg, 0.9 mmol) and TFA (0.36 mL, 4.7 mmol) in DCM (15 mL) at 0 0C. The solution was stirred at 20 0C for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCI3 (4 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 242 (71 mg, 22%) as a red solid: mp (MeOH/EtOAc) 152-154 0C; 1H NMR δ 7.99 (s, 1 H, H-5), 7.61 (s, 1 H, H- 10), 7.27 (br s, 1 H, NH), 4.30 (br dd, J = 5.3, 5.2 Hz, 2 H, H-8), 3.62 (br t, J = 5.9 Hz, 2 H, CH2N), 3.05 (br t, J = 6.3 Hz, 2 H, H-6), 2.62 (t, J = 6.0 Hz, 2 H, CH2N), 2.31 [s, 6 H, N(CHs)2], 2.05-2.12 (m, 2 H, H-7); 13C NMR δ 154.7, 148.7, 136.2, 133.2, 130.1 , 117.4, 105.2, 67.1, 57.6, 45.1 (2), 38.8, 26.1 , 21.3. Anal, calcd for C14H19N5O3-1/2H2O: C, 52.7; H, 6.5; N, 22.0. Found: C, 53.0; H, 5.9, 21.6%.
Example 170
/V-[3-(4-Morpholinyl)propyl]-7,8-dihydro-6W-chromeno[6,7-e][1,2,4]triazin-3-amine 1- Oxide (243). 3-(4-Morpholinyl)propylamine (0.71 mL, 4.8 mmol) was added to a stirred solution of chloride 240 (380 mg, 1.6 mmol) in DME (40 mL) and the solution stirred at reflux temperature for 4 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 243 (514 mg, 93%) as a yellow solid: mp (MeOH/EtOAc) 151-152 0C; 1H NMR δ 7.60 (s, 1 H, H-10), 7.30 (s, 1 H, H-5), 6.00 (br s, 1 H, NH), 4.26 (br dd, J = 5.3, 5.2 Hz, 2 H, H-8), 3.75 (br t, J = 4.7 Hz, 4 H, 2 x CH2O), 3.55 (dt, J = 6.3, 5.9 Hz, 2 H, CH2N), 2.97 (br t, J = 6.3 Hz, 2 H, H-6), 2.45- 2.52 (m, 6 H, 3 x CH2N), 2.02-2.08 (m, 2 H, H-7), 1.79-1.86 (m, 2 H, CH2); 13C NMR δ 158.1, 152.9, 143.6, 135.1 , 130.0, 126.1 , 104.4, 67.0 (2), 66.9, 57.3 (2), 53.8, 40.7, 25.9, 25.3, 21.7. Anal, calcd for C17H23N5O3: C, 59.1; H1 6.7; N, 20.3. Found: C, 59.4; H, 6.6; N, 20.3%.
Example 171
/V-fS^-MorpholinyOpropylJ-y.S-dihydro-βH-chromenoIβy-elti^^Jtriazin-S-amine 1,4-Dioxide (244). H2O2 (70%, 0.74 mL, ca. 14.7 mmol) was added dropwise to a stirred solution of TFAA (2.1 mL, 14.7 mmol) in DCM (20 mL) at 0 0C. The solution was stirred at 0 0C for 5 min, warmed to 20 °C for 10 min, then cooled to 0 0C and added to a stirred solution of 1 -oxide 243 (509 mg, 1.5 mmol) and TFA (0.57 mL, 7.4 mmol) in DCM (15 mL) at 0 0C. The solution was stirred at 20 0C for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCI3 (4 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 243 (80 mg, 16%) and (ii) 1 ,4-dioxide 244 (75 mg, 16%) as a red solid: mp (MeOH/EtOAc) 173-176 0C; 1H NMR δ 8.33 (br t, J = 4.9 Hz, 1 H, NH), 8.01 (s, 1 H, H-5), 7.62 (s, 1 H, H-10), 4.31 (br dd, J = 5.3, 5.2 Hz, 2 H, H-8), 3.83 (br t, J = 4.6 Hz, 4 H, 2 x CH2O), 3.62-3.68 (m, 2 H, CH2N), 3.03- 3.08 (m, 2 H, H-6), 2.58 (br dd, J = 6.2, 6.0 Hz, 2 H, CH2N), 2.50 (m, 4 H, 2 x CH2N), 2.07-2.13 (m, 2 H, H-7), 1.84-1.91 (m, 2 H, CH2); 13C NMR δ 154.5, 148.7, 136.1, 133.2, 129.9, 117.3, 105.2, 67.1 , 66.9 (2), 57.8, 53.8 (2), 41.6, 26.1, 24.4, 21.3. Anal, calcd for C17H23N5O3-1Z4H2O: C, 55.8; H, 6.5; N, 19.1. Found: C, 55.8; H, 6.5, 18.8%.
Example 172
7-Ethyl-7,8-dihydro-6W-[1 ,2,4]triazino[5,6-f|isoindol-3-amine 1 -Oxide (247). 2-Ethyl-5-nitroisoindoline (245). A mixture of dibromide 118 (9.27 g, 30.0 mmol), ethylamine hydrochloride (2.45 g, 30.0 mmol) and Et3N (21 mL, 150 mmol) in DMF (100 mL) was stirred at 200C for 90 min. The mixture was partitioned between EtOAc and aqueous Na2CO3 solution. The organic fraction was washed with water, dried and the solvent evaporated to give isoindole 245 (3.21 g, 56%) as a dark oil: 1H NMR δ 8.11 (dd, J = 8.1 , 2.1 Hz, 1 H, H-6), 8.05 (d, J = 2.1 Hz, 1 H, H-4), 7.34 (d, J = 8.1 Hz, 1 H, H-7), 3.99 (s, 4 H, H-1 , H-3), 2.82 (q, J = 7.2 Hz, 2 H, CH2), 1.22 (t, J = 7.2 Hz, 3 H, CH3); HRMS (FAB+) calcd for C10H13N2O2 (MH+) m/z 193.0977, found 193.0983.
W-(2-Ethyl-2,3-dihydro-1H-isoindol-5-yl)acetamide (246). A solution of isoindole 245 (3.2Og, 16.7 mmol) in MeOH (100 mL) was stirred with Pd/C (5%, 300 mg) under H2 (60 psi) for 16 h. The solution was filtered through Celite, washed with MeOH (3 x 20 mL) and the solvent evaporated. The residue was dissolved in DCM (130 mL) and Et3N (13 mL, 93 mmol), Ac2O (13 mL, 138 mmol) was added dropwise and the solution stirred at 200C for 15 h. The mixture was partitioned between DCM and aqueous Na2CO3 solution. The organic solution was washed with water, dried and the solvent was evaporated to give acetamide 246 (3.00 g, 88%) as a dark oil: 1H NMR δ 7.45 (br s, 1 H, H-4), 7.30 (br s, 1 H, NH), 7.18 (br d, J = 8.0 Hz, 1 H, H-6), 7.12 (d, J = 8.0 Hz, 1 H, H-7), 3.90 (s, 2 H, H-1), 3.87 (s, 2 H, H-3), 2.76 (q, J = 7.2 Hz, 2 H, CH2), 2.15 (s, 3 H, COCH3) 1.19 (t, J = 7.2 Hz1 3 H, CH3); HRMS (FAB+) calcd for C12H17N2O (MH+) m/z 203.1184, found 203.1188.
/V-(2-Ethyl-6-nitro-2,3-dihydro-1H-isoindol-5-yl)acetamide (247). KNO3 (1.33 g, 13.2 mmol) was added in small portions, over 10 min, to a stirred solution of acetamide 246 (2.45 g, 12.0 mmol) in CH2SO4 (50 mL) at 0 0C and the reaction mixture was stirred at 0 0C for a further 45 min. The mixture was poured onto ice, made basic with cNH3 and extracted with DCM (3 x 100 mL). The solvent was evaporated to give a brown oil which was purified by chromatography on neutral AI2O3, eluting with a gradient (0-20%) of EtOAc/pet. ether, to give nitroacetamide 247 (1.49 g, 50%) as a yellow solid: mp EtOAc/pet. ether) 85-87 0C; 1H NMR δ 10.43 (br s, 1 H, NH), 8.62 (s, 1 H, H-7), 8.03 (s, 1 H, H-4), 3.96 (s, 2 H, CH2N), 3.92 (s, 2 H, CH2N), 2.79 (q, J = 7.2 Hz, 2 H, CH2N), 2.28 (s, 3 H, COCH3), 1.21 (t, J = 7.2 Hz, 3 H, CH3); HRMS (FAB+) calcd for C12H16N3O3 (MH+) m/z 250.1192, found 250.1195. Anal, calcd for C12H15N3O3: C, 57.8; H, 6.0; N, 16.9. Found: C, 57.9; H, 5.9; N, 16.7%.
2-Ethyl-6-nitro-5-isoindolinamine (246). A mixture of nitroacetamide 247 (1.52 g, 6.1 mmol) and 5 M HCI (12 mL) was stirred at reflux temperature for 20 min. The suspension was diluted with water (40 mL), cooled to 0 0C, and made basic with CNH3. The precipitate was filtered, washed with water and dried to give nitroaniline 248 (1.13 g, 89%); mp 121-123 0C; 1H NMR δ 7.94 (s, 1 H, H-7), 6.64 (s, 1 H, H-4), 6.06 (br s, 2 H, NH2), 3.83 (br s, 2 H, CH2N), 3.81 (br s, 2 H, CH2N), 2.75 (q, J = 7.2 Hz, 2 H, CH2N), 1.19 (t, J = 7.2 Hz, 3 H, CH3); 13C NMR δ 149.7, 144.6, 131.5, 130.0, 119.3, 111.7, 58.4, 57.3, 49.9, 13.9. Anal, calcd for C10H13N3O2: C, 58.0; H, 6.2; N, 20.3. Found: C, 57.8; H, 6.2; N, 20.0%.
7-Ethyl-7,8-dihydro-6W-[1,2,4]triazino[5,6-/]isoindol-3-amine 1 -Oxide (249). A mixture of nitroaniline 248 (414 mg, 2.0 mmol) and cyanamide (336 mg, 8.0 mmol) were mixed together at 100 0C, cooled to 50 0C, cHCI (0.78 mL) added carefully and the mixture stirred at 70-80 0C for 45 min. The mixture was cooled to ca. 50 0C and 7.5 M NaOH solution (5 ml.) added until the mixture was strongly basic and the mixture stirred at 80-90 0C for 15 min. The mixture was cooled, diluted with water (100 ml_), filtered, washed with water (3 x 20 ml_) and dried to give 1 -oxide 249 (404 mg, 87%) as a greenish-yellow solid: mp 218 0C; 1H NMR [(CD3)2SO] δ 7.98 (s, 1 H, H-9), 7.38 (s, 1 H, H-5), 7.18 (s, 2 H, NH2), 3.89 (s, 2 H, CH2N), 3.86 (s, 2 H, CH2N), 2.70 (q, J = 7.2 Hz, 2 H, CH2N), 1.11 (t, J = 7.2 Hz, 3 H, CH3); 13C NMR [(CD3)2SO] δ 160.0, 149.8, 148.7, 138.5, 128.9, 118.2, 112.5, 57.5, 57.0, 49.0, 13.5. Anal, calcd for CnH13N5O: C, 57.1; H, 5.7; N, 30.3. Found: C, 57.1; H, 5.6; N, 30.3%.
Example 173
7-Ethyl-7,8-dihydro-6H-[1,2,4]triazino[5,6-fIisoindol-3-amine 1r4-Dioxide (250).
H2O2 (70%, 0.50 ml_, ca. 10 mmol) was added dropwise to a stirred mixture of 1 -oxide 249 (328 mg, 1.4 mmol), TFA (4 mL) and water (0.3 mL) at 0 0C and the mixture was stirred at 20 0C. Two more aliquots of H2O2 (70%, 0.50 mL, ca. 10 mmol) were added at 3 h and 20 h. After 28 h at 20 0C, the mixture was diluted with aqueous NH3 solution (20 mL) and extracted with DCM (5 x 50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1 ,4-dioxide 250 (68 mg, 19%) as a red solid which was crystallised as the hydrochloride salt: mp (MeOH/DCM) 230 0C; 1H NMR [(CD3)2SO] δ 11.84 (br s, 1 H, HCI), 8.27 (s, 1 H, H-9), 8.20 (s, 1 H, H-5), 8.14 (br s, 2 H, NH2), 4.88-5.05 (m, 2 H, CH2N), 4.50-4.73 (m, 2 H, CH2N), 3.42 (q, J = 7.2 Hz, 2 H, CH2N), 1.32 (t, J = 7.2 Hz, 3 H, CH3); 13C NMR [(CD3)2SO] 5 151.4, 143.0, 138.5, 134.0, 130.6, 115.6, 111.4, 56.5, 56.1 , 49.1, 10.3; HRMS (FAB+) calcd for C11H14N5O2 (MH+) m/z 248.1148, found 248.1154.
Example 174
7-Methyl-6,7,8,9-tetrahydro[1 ,2,4]triazino[6,5-g]isoquinolin-3-amine 1 -Oxide (256). 2-Methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (252). Formic acid (9.4 mL, 250 mmol) was added dropwise to Ac2O (19 mL, 202 mmol) at 0 0C. The solution was stirred at 50 0C for 45 min, then cooled to -18 0C, diluted with THF (100 mL) and a solution of 7-nitro- 1 ,2,3,4-tetrahydroisoquinoline [(a) Tercel, M.; et al., J. Med. Chem. 1996, 39, 1084-1094; (b) Zhu, Z., et al., J. Med. Chem. 2003, 46, 831-837] (251) (13.8 g, 5.0 mmol) in THF (100 mL) was added and stirred at -15 to -18 0C for 30 min. The solution was warmed to 20 0C, the solvent evaporated and the residue partitioned between saturated aqueous NaHCO3 solution (250 mL) and EtOAc (250 mL). The aqueous fraction was extracted with EtOAc (3 x 250 mL), dried and the solvent evaporated. The residue was dissolved in THF (200 mL), cooled to 10 0C and BH3 DMS solution (10 M, 19.4 mL, 194 mmol) was added. The solution was stirred at 20 0C for 1 h, diluted with MeOH (30 mL) and acidified with HCI solution (1 M, 45 mL). The solution was stirred at 40 0C for 15 min, the solvent evaporated and the residue partitioned between saturated aqueous NaHCO3 solution (250 mL) and EtOAc (250 mL). The aqueous fraction was extracted with EtOAc (3 x 250 mL), dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (2-5%) of MeOH/DCM, to give isoquinoline 252 (12.6 g, 85%) as an orange solid: 1H NMR δ 8.09 (dd, J = 8.4, 2.3 Hz, 1 H, H-6), 7.95 (d, J = 2.3 Hz, 1 H, H-8), 7.37 (d, J = 8.4 Hz, 1 H, H-5), 4.27 (d, J = 16.1 Hz1 1 H, H-1), 3.94 (d, J = 16.1 Hz, 1 H, H-1), 3.23-3.34 (m, 2 H, CH2), 2.99-3.18 (m, 2 H, CH2), 2.17 (s, 3 H, NCH3); MS (APCI) m/z 193 (MH+, 100%).
Λ/-(2-Methyl-1,2,3.4-tetrahydro-7-isoquinolinyl)acetamide (253). A solution of isoquinoline 252 (2.5 g, 13.0 mmol) in EtOH (200 mL) was stirred with Pd/C (5%, 200 mg) under H2 (35 psi) for 4 h. The solution was filtered through Celite, washed with EtOH (50 mL) and the solvent was evaporated. The residue was dissolved in dioxane (50 mL), Ac2O (2.7 mL, 28.6 mmol) was added and the solution stirred at 20 0C for 16 h. The solvent was evaporated and the residue was partitioned between dilute aqueous NH3 solution (50 mL) and DCM (50 mL). The aqueous layer was extracted with DCM (4 x 125 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with 5% MeOH/DCM, to give acetamide 253 (2.1 g, 77%) as a brown solid: mp 157-159 0C; 1H NMR δ 7.29 (br s, 1 H, H-8), 7.27 (br s, 1 H, H-6), 7.22 (br s, 1 H, NH), 7.12 (br d, J = 8.1 Hz, 1 H, H-5), 4.18 (d, J = 16.2 Hz, 1 H, H-1 ), 3.82 (d, J = 16.1 Hz, 1 H, H-1), 3.11-3.25 (m, 2 H, H-3), 2.91-3.00 (m, 2 H, H-4), 2.61 (s, 3 H, NCH3), 2.16 (s, 3 H, COCH3); 13C NMR δ 168.3, 136.6, 131.0, 129.2, 126.6, 119.2, 118.1 , 61.5, 56.6, 47.3, 24.5, 24.0; MS (APCI) m/z 205 (MH+, 100%). Anal, calcd for C12H16N2O y2CH3OH y2H2O: C, 65.5; H, 8.4; N, 12.2. Found: C, 65.8; H, 8.8; N, 12.6%.
2-Methyl-8-nitro-1,2,3,4-tetrahydro-7-isoquinolinamine (254) and 2-Methyl-6-nitro- 1,2,3,4-tetrahydro-7-isoquinolinamine (255). A solution of KNO3 (7.9 g, 78.4 mmol) in CH2SO4 (30 mL) was added dropwise to a stirred solution of acetamide 253 (14.6 g, 71.3 mmol) in CH2SO4 (200 mL) at 0 0C. The solution was stirred at 0 "C for 90 min, then poured into ice/water (1 L), the pH adjusted to 10 with cNH3 and the mixture extracted with DCM (4 x 250 mL). The solvent was evaporated, the residue dissolved in HCI (5 M, 150 mL) and heated at reflux temperature for 3 h. The solution was cooled and partitioned between cNH3 (70 mL) and DCM (250 mL). The aqueous layer was extracted with DCM (3 x 250 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (5-20%) of MeOH/DCM, to give (i) 8-nitroaniline 254 (1.9 g, 12%) as an orange solid: mp 122-123 0C, 1H NMR δ 7.05 (d, J - 8.5 Hz1 1 H, H-6), 6.64 (d, J = 8.5 Hz, 1 H, H-5), 5.24 (br s, 2 H, NH2), 3.69 (s, 2 H, H-1), 2.84 (t, J = 6.0 Hz, 2 H1 H-3), 2.66 (t, J = 6.0 Hz, 2 H, H-4), 2.46 (s, 3 H, NCH3); 13C NMR 5 141.5, 134.5, 134.0, 131.6, 124.6, 116.6, 56.3, 51.9, 46.0, 28.7; MS (APCI) m/z 208 (MH+, 100%). Anal, calcd for C10H13N3O2-1^H2O: C1 56.7; H, 6.4; N, 19.9. Found: C, 56.5; H, 6.8; N, 20.0%; and (ii) 6-nitroaniline 255 (2.8 g, 18%) as an orange solid: mp 171-172 0C, 1H NMR δ 7.89 (s, 1 H, H-5), 6.46 (s, 1 H, H-8), 5.85 (br s, 2 H, NH2), 3.50 (s, 2 H, H- 1), 2.84 (t, J = 6.0 Hz, 2 H, H-3), 2.66 (t, J = 6.0 Hz, 2 H, H-4), 2.43 (s, 3 H, NCH3); 13C NMR δ 144.0, 142.5, 131.4, 125.5, 123.5, 115.4, 57.7, 52.8, 45.8, 28.0; MS (APCI) m/z 208 (MH+, 100%). Anal, calcd for C10H13N3O2: C, 58.0; H, 6.3; N, 20.3. Found: C, 57.9; H, 6.3; N, 20.4%.
7-Methyl-6,7,8,9-tetrahydro[1 ,2,4]triazino[6,5-g]isoquinolin-3-amine 1 -Oxide (256). A mixture of 6-nitroaniline 255 (2.3 g, 10.7 mmol) and cyanamide (2.0 g, 46.6 mmol) was melted at 100 0C. The mixture was cooled to 60 0C and cHCI (5 mL) was slowly added. The solution was heated at 100 0C for 90 min, then a further three aliquots of cyanamide (2.1 g) and cHCI (5 mL) were added over 3 h. The solution was cooled to 50 0C and made basic with NaOH solution (7.5 M, 20 mL). The solution was heated at 100 0C for another 90 min, cooled and diluted with water (50 mL). The solid was filtered and washed with water to give 1-oxide 256 (1.70 g, 66%) as a brown solid: mp 170-175 0C; 1H NMR [(CDa)2SO] δ 7.90 (s, 1 H, H-10), 7.25 (s, 1 H, H-5), 7.15 (br s, 2 H, NH2), 3.62 (s, 2 H, H- 6), 2.96 (t, J = 5.9 Hz, 2 H, H-8), 2.62 (t, J = 5.9 Hz, 2 H, H-9), 2.35 (s, 3 H, NCH3); 13C NMR δ 159.8, 146.8, 144.3, 132.0, 128.4, 121.9, 118.3, 57.3, 51.9, 45.4, 28.3; MS (APCI) m/z 232 (MH+, 100%). Anal, calcd for C11H13N5O V2H2O: C, 55.0; H, 5.9; N, 29.1. Found: C, 55.6; H1 5.5; N, 28.7%.
Example 175 3-Chloro-7-methyl-6,7,8,9-tetrahydro[1 ,2,4]triazino[6,5-g]isoquinoline 1 -Oxide (257).
NaNO2 (570 mg, 8.2 mmol) was added in portions to a solution of 1-oxide 256 (1.8 g, 7.8 mmol) in TFA (20 mL) and the mixture was stirred at 0 °C for 4 h. The solution was poured into ice/water (100 mL), made basic with dilute aqueous NH3 solution (50 mL) and extracted with DCM (150 mL). The aqueous fraction was concentrated and the residue dried. The residue was dissolved in POCI3 (40 mL) and DMF (3 drops) and heated at 100 0C for 3 h. The solution was cooled, poured into ice/water (400 mL), basified with dilute aqueous NH3 solution (50 ml_) and the aqueous layer was extracted with DCM (3 x 200 ml_). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 5% MeOH/DCM, to give chloride 257 (1.47 g, 75%) as a yellow solid: mp 179 0C (dec); 1H NMR δ 8.17 (s, 1 H, H-10), 7.63 (s, 1 H, H- 5), 3.80 (s, 2 H, H-6), 3.17 (t, J = 6.0 Hz, 2 H, H-8), 2.77 (t, J = 5.9 Hz, 2 H, H-9), 2.51 (s, 3 H, NCH3); 13C NMR δ 156.2, 146.3, 145.5, 139.7, 128.0, 124.8, 119.0, 58.0, 52.0, 45.8, 29.7; MS (APCI) m/z 251 (MH+, 100%), 253 (MH+, 30%). Anal, calcd for C11H11CIN4O: C, 52.7; H, 4.4; N, 22.4; Cl, 14.1. Found: C, 52.7; H, 4.4; N, 22.3; Cl, 14.2%.
Example 176
Λ/-Ethyl-7-methyl-6,7,8,9-tetrahydro[1 ,2,4]triazino[6,5-g]isoquinolin-3-amine 1 -Oxide (258). A solution of chloride 257 (500 mg, 2.0 mmol) and ethylamine (0.4 mL, 6.0 mmol) in DME (15 mL) was heated at 60 0C for 4 h in a sealed pressure tube. The solution was cooled to 20 0C, the solid filtered off and solvent evaporated. The combined residue was purified by chromatography, eluting with a gradient (2^4%) of MeOH/DCM, to give 1 -oxide 258 (460 mg, 88%) as a yellow solid: mp 193-196 0C; 1H NMR δ 8.03 (s, 1 H, H-10), 7.27 (s, 1 H, H-5), 5.07 (br s, 1 H, NH), 3.69 (s, 2 H1 H-6), 3.53 (dq, J = 7.2, 5.8 Hz, 2 H, CH2N), 3.05 (t, J = 6.0 Hz, 2 H, H-8), 2.72 (t, J = 6.0 Hz, 2 H, H-9), 2.48 (s, 3 H, NCH3), 1.29 (t, J = 7.2 Hz, 3 H, CH3); 13C NMR δ 158.6, 147.0, 144.4, 132.5, 129.6, 122.8, 119.3, 58.2, 52.6, 46.0, 36.3, 29.1 , 14.8; MS (APCI) m/z 260 (MH+, 100%). Anal, calcd for C13H17N5O: C, 60.2; H, 6.6; N, 27.0. Found: C, 59.9; H, 6.6; N, 26.9%.
Example 177
Λf-Ethyl-7-methyl-6,7,8,9-tetrahydro[1 ,2,4]triazino[6,5-g]isoquinolin-3-amine 1 ,4- Dioxide (259). H2O2 (70%, 1.7 mL, ca. 17 mmol) was added dropwise to a stirred solution of TFAA (2.4 mL, 17 mmol) in DCM (15 mL) at 0 0C. The solution was stirred at 20 °C for 10 min, then cooled to 0 0C, added to a solution of 1 -oxide 258 (440 mg, 1.7 mmol) and TFA (0.66 mL, 8.5 mmol) in DCM (15 mL) at 0 0C. The solution was stirred at 20 0C for 4 h, diluted with dilute aqueous NH3 solution (80 mL) and extracted with DCM (4 x 125 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (1-10%) of MeOH/DCM, to give 1,4- dioxide 259 (35 mg, 8%) as a red solid: mp 120-124 0C; 1H NMR δ 8.10 (s, 1 H, H-10), 7.96 (s, 1 H, H-5), 6.95 (br s, 1 H, NH), 3.78 (s, 2 H, H-6), 3.63 (dq, J = 7.2, 6.0 Hz, 2 H, CH2N), 3.10 (t, J = 6.0 Hz, 2 H, H-8), 2.75 (t, J = 6.0 Hz, 2 H, H-9), 2.50 (s, 3 H, NCH3), 1.36 (t, J = 7.2 Hz, 3 H, CH3); 13C NMR δ 149.3, 145.5, 136.5, 135.3, 129.3, 120.5, 113.9, 58.1 , 52.1 , 45.8, 36.5, 29.1 , 14.8; MS (APCI) m/z 276 (MH+, 100%); HRMS (FAB+) calcd for C13H18N5O2 (MH+) m/z 276.1461 , found 276.1456.
Example 178 3-Ethyl-7-methyl-6,7,8,9-tetrahydro[1,2,4]triazino[6,5-g]isoquinoline 1 -Oxide (260).
Pd(PPh3)4 (350 mg, 0.3 mmol) was added to a N2-purged, stirred solution of chloride 257 (750 mg, 3.0 mmol) and Et4Sn (1.2 mL, 6.0 mmol) in DME (35 ml_), and the mixture was stirred at 85 0C for 18 h under N2. The solution was cooled to 20 0C and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (2-5%) of MeOH/DCM, to give 1 -oxide 260 (590 mg, 81%) as a brown solid: mp 129-131 0C; 1H NMR δ 8.21 (s, 1 H1 H-10), 7.63 (s, 1 H, H-5), 3.79 (s, 2 H, H-6), 3.16 (t, J = 6.0 Hz, 2 H, H-8), 3.02 (q, J = 7.6 Hz, 2 H, CH2), 2.77 (t, J = 6.0 Hz, 2 H, H-9), 2.51 (s, 3 H, NCH3), 1.43 (t, J = 7.6 Hz, 3 H, CH3); 13C NMR 8 167.3, 145.8, 144.6, 138.2, 131.7, 125.0, 118.8, 58.1 , 52.3, 45.9, 30.7, 29.6, 12.2; MS (APCI) m/z 245 (MH+, 100%). Anal, calcd for Ci3H16N4O y4H2O: C, 62.5; H, 6.7; N, 22.4. Found: C, 62.6; H, 6.6; N, 22.4%.
Example 179
3-Ethyl-7-methyl-6,7,8,9-tetrahydro[1 ,2,4]triazino[6,5-g]isoquinoline 1 ,4-Dioxide
(261). H2O2 (70%, 2.4 mL, ca. 25 mmol) was added dropwise to a stirred solution of TFAA (3.5 mL, 25 mmol) in DCM (20 mL) at 0 °C. The solution was stirred at 20 0C for 10 min, then cooled to 0 0C, added to a solution of 1 -oxide 260 (590 mg, 2.4 mmol) and TFA (0.96 mL, 12.2 mmol) in DCM (20 mL) at 0 0C. The solution was stirred at 20 0C for 4 h, diluted with dilute aqueous NH3 solution (80 mL) and extracted with DCM (4 x 150 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (2-5%) of MeOH/DCM, to give 1 ,4-dioxide 261 (107 mg, 17%) as a yellow solid: mp 124-128 0C; 1H NMR δ 8.23 (s, 1 H, H-10), 8.18 (s, 1 H, H-5), 3.83 (s, 2 H, H-6), 3.15-3.24 (m, 4 H, CH2, H-8), 2.78 (t, J = 6.0 Hz, 2 H, H-9), 2.51 (s, 3 H, NCH3), 1.43 (t, J = 7.5 Hz, 3 H, CH3); 13C NMR δ 149.3, 145.5, 136.5, 135.3, 129.3, 120.5, 116.3, 58.1, 51.9, 45.8, 29.6, 23.9, 9.3; MS (APCI) m/z 261 (MH+, 100%). Anal, calcd for C13H16N4O2-1Z4CH2CI2: C, 56.5; H, 5.9; N, 19.9. Found: C, 56.6; H, 5.9; N, 19.7%.
Example 180 9-Methyl-7,8,9,10-tetrahydro[1,2,4]triazino[5,6-/7]isoquinolin-3-amine 1 -Oxide (262). A mixture of 8-nitroaniline 254 (510 mg, 2.5 mmol) and cyanamide (460 mg, 10.9 mmol) was melted at 100 0C. The mixture was cooled to 60 0C and cHCI (4 mL) was added slowly. The solution was heated at 100 0C for 1 h, then three more aliquots of cyanamide (460 mg, 10.9 mmol) and cHCI (5 ml.) were added over 3 h. The solution was cooled to 60 0C and the solution made basic with NaOH solution (7.5 M, 10 ml_). The solution was heated at 100 0C for another 1 h, cooled and diluted with water (50 mL). The solid was filtered and washed with water (30 mL) to give 1 -oxide 262 (360 mg, 63%) as a brown solid: mp 226-229 0C; 1H NMR [(CDs)2SO] δ 7.50 (d, J = 8.6 Hz, 1 H, H-5), 7.32 (d, J = 8.6 Hz, 1 H, H-6), 7.09 (br s, 2 H, NH2), 4.09 (s, 2 H, H-10), 2.88 (t, J = 5.7 Hz, 2 H, H-7), 2.58 (t, J = 5.7 Hz1 2 H, H-8), 2.40 (s, 3 H1 NCH3); MS (APCI) m/z 232 (MH+, 100%). Anal, calcd for C11H13N5O y4CH3OH: C, 56.5; H, 5.9; N, 29.3. Found: C, 56.6; H, 5.6; N, 29.1%.
Example 181
3-Chloro-9-methyl-7, 8,9,10-tetrahydro[1 ,2,4]triazino[5,6-ft]isoquinoline 1 -Oxide (263). NaNO2 (105 mg, 1.5 mmol) was added to a stirred solution of 1 -oxide 262 (295 mg, 1.3 mmol) in TFA (10 mL) and the mixture stirred at 0 0C for 3 h. The solution was poured into ice/water (50 mL), concentrated and the residue dried. The residue was dissolved in POCI3 (10 mL) and DMF (2 drops) and heated at 100 0C for 4 h. The solution was cooled, poured into ice/water (100 mL), and made basic with dilute aqueous NH3 solution (20 mL). The mixture was extracted with DCM (3 x 200 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (3-5%) of MeOH/DCM, to give chloride 263 (240 mg, 75%) as a yellow solid: mp 200-205 0C; 1H NMR δ 7.75 (d, J = 8.6 Hz, 1 H, H-5), 7.69 (d, J = 8.6 Hz, 1 H, H-6), 4.32 (s, 2 H, H-10), 3.07-3.13 (m, 2 H, H-7), 2.74 (t, J = 5.9 Hz, 2 H, H-8), 2.57 (s, 3 H, NCH3); 13C NMR δ 155.9, 148.1 , 138.7, 138.1, 132.5, 130.4, 125.7, 57.2, 50.3, 45.8, 30.9; MS (APCI) m/z 251 (MH+, 100%), 253 (MH+, 35%). Anal, calcd for C11H11CIN4O: C, 52.7; H, 4.4; N, 22.4; Cl, 14.1. Found: C, 52.7; H, 4.4; N, 22.2; Cl, 14.4%.
Example 182
3-Ethyl-9-methyl-7,8,9,10-tetrahydro[1 ,2,4]triazino[5,6-h]isoquinoline 1 -Oxide (264).
Pd(PPh3J4 (108 mg, 0.09 mmol) was added to a N2-purged, stirred solution of chloride 263 (225 mg, 0.9 mmol) and Et4Sn (0.36 mL, 1.8 mmol) in DME (15 mL) and the mixture was stirred at 85 °C for 18 h under N2. The solution was cooled to 20 °C and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (2-10%) of MeOH/DCM, to give 1 -oxide 264 (130 mg, 60%) as a brown solid: mp 99-102 0C; 1H NMR δ 7.75 (d, J = 8.6 Hz, 1 H, H-5), 7.62 (d, J - 8.6 Hz, 1 H, H-6), 4.38 (s, 2 H, H-10), 3.05-3.11 (m, 2 H, H-7), 2.98 (q, J = 7.6 Hz, 2 H, CH2), 2.73 (t, J = 5.9 Hz, 2 H, H-8), 2.57 (s, 3 H, NCH3), 1.42 (t, J = 7.6 Hz, 3 H, CH3); 13C NMR δ 167.1 , 148.4, 137.1 , 136.9, 136.3, 129.7, 126.1, 57.4, 50.5, 45.9, 30.7, 30.2, 12.2; MS (APCI) m/z (MH+, 100%). HRMS (FAB+) calcd for C13H17N4O (MH+) m/z 245.1402, found 245.1403.
Example 183 3-Ethyl-9-methyl-7, 8,9,10-tetrahydro[1,2,4]triazino[5,6-/7]isoquinoline 1,4-Dioxide (265). H2O2 (70%, 0.5 mL, ca. 5 mmol) was added dropwise to a stirred solution of TFAA (0.7 mL, 5 mmol) in DCM (10 mL) at 0 °C. The solution was stirred at 20 0C for 10 min, then cooled to 0 0C, added to a solution of 1 -oxide 264 (120 mg, 0.5 mmol) and TFA (0.19 mL, 2.5 mmol) in DCM (10 mL) at 0 0C. The solution was stirred at 20 0C for 4 h, diluted with dilute aqueous NH3 solution (20 mL) and extracted with DCM (4 x 100 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (2-8%) of MeOH/DCM, to give 1 ,4-dioxide 265 (24 mg, 19%) as a red solid: mp 117-121 0C; 1H NMR δ 8.35 (d, J = 8.8 Hz, 1 H, H-5), 7.70 (d, J = 8.8 Hz, 1 H, H-6), 4.41 (s, 2 H, H-10), 3.18 (q, J = 7.5 Hz, 2 H, CH2), 3.12 (br t, J = 5.8 Hz, 2 H, H-7), 2.74 (t, J = 5.8 Hz, 2 H, H-8), 2.58 (s, 3 H, NCH3), 1.42 (t, J = 7.5 Hz, 3 H, CH3); MS (APCI) m/z 261 (MH+, 100%); HRMS (FAB+) calcd for C13H17N4O2 (MH+) m/z 261.1352, found: 261.1354.
Example 184 Synthesis of amine sidechains
Λ/1-(2-Methoxyethyl)-Λ/1-methyl-1,2-ethanediamine (268).
[(2-Methoxyethyl)(methyl)amino]acetonitrile (267). 2-Methoxy-Λ/-methylethanamine 266 (10.0 g, 112 mmol) was added dropwise to a stirred aqueous solution of glycolonitrile (55%, 12.0 mL, 123 mmol) at 0 0C and the mixture stirred at 70 0C for 1 h. The solution was cooled to 20 0C, and Et2O (150 mL) and water (100 mL) were added. The aqueous layer was extracted with Et2O (3 x 40 mL), the combined organic fraction dried and the solvent evaporated to give nitrile 267 (6.46 g, 45%) as a colourless oil: 1H NMR [(CDs)2SO] δ 3.63 (s, 2 H, CH2CN), 3.50 (t, J = 5.1 Hz, 2 H, CH2O), 3.37 (s, 3 H, OCH3), 2.69 (t, J = 5.1 Hz, 2 H, CH2N), 2.42 (s, 3 H, NCH3); HRMS calcd for C6H12N2O (M+) m/z 128.0947, found 128.0946.
Λ/1-(2-Methoxyethyl)-/V1-methylethane-1,2-diamine (268). A mixture of nitrile 267 (3.06 g, 23.4 mmol) and Raney-Nickel (50% slurry in water, 15 g) in EtOH (100 mL) and cNH3 (10 mL) was stirred vigorously under H2 (60 psi) for 5 h. The mixture was filtered through Celite, washed with EtOH (60 mL) and the solvent evaporated, keeping the bath temperature below 35 0C to give crude diamine 268 (Pasini, C; et al., Farmaco, Edizione Scientifica 1965, 20, 673-685) (2.45 g, 79%) as a colourless oil, which was used without further purification: 1H NMR [(CDs)2SO] δ 3.39 (t, J = 6.0 Hz, 2 H, CH2O), 3.22 (s, 3 H, OCH3), 2.61 (br s, 2 H, CH2N), 2.49 (t, J = 6.0 Hz, 2 H, CH2N), 2.36 (t, J = 6.7 Hz, 2 H, CH2N), 2.17 (s, 3 H, NCH3), NH2 not observed; 13C NMR δ 59.4, 57.9, 56.3, 42.4, 38.6, 20.2.
Λ/1-(3-Methoxypropyl)-Λ/1-methyl-1 ,2-ethanediamine (274). fe/f-Butyl 3-Methoxypropylcarbamate (270). A solution of 3-methoxy-1-propanamine (269) (20 mL, 195 mmol) and di-tert-butyldicarbonate (43.5 g, 199 mmol) in CHCI3 (400 mL) was heated at reflux temperature for 16 h. The solution was cooled, the solvent evaporated and the residue dried to give carbamate 270 (42.3 g, quant.) as a colourless oil: 1H NMR δ 4.81 (br s, 1 H, NH), 3.44 (t, J = 6.0 Hz1 2 H, CH2N), 3.33 (s, 3 H, OCH3), 3.18-3.25 (m, 2 H, OCH2), 1.75 (p, J = 6.3 Hz, 2 H, CH2), 1.44 [s, 9 H, C(CHa)3].
ferf-Butyl 3-Methoxypropyl(methyl)carbamate (271 ). A suspension of carbamate 270 (5.0 g, 26.4 mmol), crushed KOH (3.8 g, 67.7 mmol) in MeI (15 mL) was stirred at 20 0C for 72 h under N2. The solution was filtered through Celite, washed with DCM (2 x 50 mL) and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (30-50%) of EtOAc/pet. ether, to give carbamate 271 (2.0 g, 37%) as a colourless oil: 1H NMR δ 3.38 (t, J = 6.3 Hz, 2 H, CH2N), 3.33 (s, 3 H, OCH3), 3.28 (t, J = 7.0 Hz, 2 H, CH2O), 2.85 (s, 3 H, NCH3), 1.78 (tt, J = 7.0, 6.3 Hz, 2 H, CH2), 1.46 [s, 9 H, C(CHa)3]; MS (APCI) m/z 104 (MHMBuCO2, 100%); HRMS (FAB+) calcd for C10H22NO3 (MH+) m/z 204.1600, found 204.1605.
Λ/-(3-Methoxypropyl)-/V-methylamine (272). A solution of HCI in dioxane (4 M, 15 mL, 60 mmol) was added to a solution of carbamate 271 (3.8 g, 18.7 mmol) in dioxane (50 mL) was stirred at 20 0C for 24 h. The solvent was evaporated to give crude amine 272 as the HCI salt: (2.6 g, quant.) as a colourless oil; 1H NMR δ 9.39 (br s, 2 H, NH2 +CI"), 3.54 (t, J = 5.7 Hz, 2 H, CH2N), 3.36 (s, 3 H, OCH3), 3.10 (tt, J = 7.1 , 6.8 Hz, 2 H, CH2), 2.71 (t, J = 5.6 Hz, 3 H, NCH3), 2.12 (tt, J = 7.0, 6.0 Hz, 2 H, CH2); MS (APCI) m/z 104 (MH+, 100%); HRMS calcd for C5H13NO (M+) m/z 103.0997, found 103.0996.
[(3-Methoxypropyl)(methyl)amino]acetonitrile (273). A solution of amine hydrochloride 272 (2.6 g, 18.7 mmol), aqueous glycolonitrile (55%, 2.4 mL, 24.7 mmol) and Et3N (4.0 mL, 28.1 mmol) was stirred at 50 0C for 3 h. The solution was cooled and partitioned between water (50 mL) and Et2O (50 mL). The organic fraction was washed with water (2 x 50 mL) and brine (50 mL), dried and the solvent evaporated to give nitrile 273 (1.94 g, 73%) as a colourless oil; 1H NMR δ 3.53 (s, 2 H, CH2CN), 3.42 (t, J = 6.3 Hz1 2 H, CH2N), 3.33 (s, 3 H1 OCH3), 2.54 (t, J = 7.1 Hz, 2 H, CH2), 2.36 (s, 3 H1 NCH3), 1.73 (tt, J = 7.1 , 6.3 Hz, 2 H, CH2); MS (APCI) m/z 143 (MH+, 100%).
/V1-(3-Methoxypropyl)-yV1-methyl-1,2-ethanediamine (274). A mixture of nitrile 273 (1.94 g, 14.0 mmol), cNH3 (8 mL) and Raney Nickel (50% slurry in water, 5.3 g) in EtOH (100 mL) was stirred under H2 (60 psi) for 4 h. The mixture was filtered through Celite, washed with EtOH (50 mL) and the solvent was evaporated to give crude diamine 274 (1.65 g, 83%) as a yellow oil, which was used without further purification: 1H NMR δ 3.42 (t, J - 6.4 Hz, 2 H, CH2N)1 3.33 (s, 3 H, OCH3), 2.76 (t, J = 6.1 Hz, 2 H, CH2), 2.43 (t, J = 7.2 Hz, 2 H1 CH2), 2.40 (t, J = 6.2 Hz, 2 H, CH2), 2.21 (s, 3 H, NCH3), 1.74 (tt, J = 7.2, 6.2 Hz, 2 H1 CH2), NH2 not observed; MS (APCI) m/z 147 (MH+, 100%); HRMS calcd for C7H18N2O (M+) m/z 146.1419, found 146.1424.
2-(3-Methoxy-1 -azetidinyl)ethylamine (277).
(3-Methoxy-1-azetidinyl)acetonitrile (276). A solution of 3-methoxyazetidine hydrochloride (275) (MacKenzie et al., PCT Int. Appl. WO 9605193, 1996) (3.0 g, 24.4 mmol), aqueous glycolonitrile (55%, 3.4 mL, 34.3 mmol) and Et3N (5.2 mL, 37.3 mmol) was stirred at 20 0C for 3 h, then heated at 50 0C for 1 h. The solution was cooled and partitioned between water (50 mL) and Et2O (50 mL). The organic fraction was washed with water (2 x 50 mL) and brine (50 mL), dried and the solvent evaporated to give nitrile 276 (1.76 g, 57%) as a colourless oil: 1H NMR 54.06 (p, J = 5.7 Hz, 1 H, CHO), 3.61-3.66 (m, 2 H, CH2N)1 3.49 (s, 2 H, CH2CN), 3.28 (s, 3 H, OCH3), 3.22-3.27 (m, 2 H, CH2N); MS (APCI) m/z 127 (MH+, 100%).
2-(3-Methoxy-1-azetidinyl)ethylamine (277). A mixture of nitrile 276 (1.76 g, 14.0 mmol), CNH3 (7 mL) and Raney Nickel (50% slurry in water, 4.6 g) in EtOH (100 mL) was stirred under H2 (60 psi) for 5 h. The mixture was filtered through Celite, washed with EtOH (50 mL) and the solvent was evaporated to give crude diamine 277 (950 mg, 52%) as a yellow oil, which was used without further purification: 1H NMR δ 4.03 (p, J = 5.8 Hz, 1 H, CHO)1 3.58-3.63 (m, 2 H, CH2N), 3.25 (s, 3 H, OCH3), 2.88-2.93 (m, 2 H1 CH2N), 2.67 (t, J = 6.0 Hz1 2 H, CH2N)1 2.52 (t, J = 6.0 Hz, 2 H, CH2N), NH2 not observed; MS (APCI) m/z 131 (MH+, 100%); HRMS (FAB+) calcd for C6H15N2O (MH+) m/z 131.1184, found 131.1183. 2-(2,6-Dimethyl-1 -piperidinyl)ethylamine (280).
(2,6-Dimethyl-1-piperidinyl)acetonitrile (279). Dimethylpiperidine (278) (5.9 ml_, 43.8 mmol) was added to a stirred aqueous solution of glycolonitrile (55%, 5 g, 48.2 mmol) at 5 0C and the solution stirred at 70 0C for 30 min. The solution was cooled, diluted with ether (50 mL), washed with water (2 x 20 ml_), dried and the solvent evaporated to give nitrile 279 (3.97 g, 60%) as a clear oil: 1H NMR δ 3.78 (s, 2 H, CH2N), 2.41-2.50 (m, 2 H, 2 x CH), 1.65-1.70 (m, 2 H, CH2), 1.25-1.42 (m, 4 H, 2 x CH2), 1.13 (d, J = 6.2 Hz, 6 H, 2 x CH3); MS m/z 153 (MH+, 100%).
2-(2,6-Dimethyl-1-piperidinyl)ethylamine (280). A mixture of nitrile 279 (3.13 g, 20.6 mmol) and Raney Nickel (50% w/w suspension in water, ca. 2 mL) in EtOH (30 mL) and cNH3 (2 mL) was stirred under H2 (60 psi) for 5 h. The suspension was filtered through Celite, washed with EtOH (3 x 10 mL) and the solvent evaporated to give diamine 280 (2.52 g, 78%) as a colourless oil which was used without further purification: 1H NMR δ 2.71-2.76 (m, 2 H, CH2N), 2.63-2.68 (m, 2 H, CH2N), 2.41-2.47 (m, 2 H, 2 x CH), 1.49- 1.55 (m, 2 H, CH2), 1.43 (br s, 2 H, NH2), 1.25-1.42 (m, 4 H, 2 x CH2), 1.11 (d, J = 6.3 Hz, 6 H, 2 x CH3); MS m/z 157 (MH+, 100%).
2-(3-Methoxy-1 -piperidinyl)ethylamine (283). (3-Methoxy-1-piperidinyl)acetonitrile (282). Et3N (7.0 mL, 50 mmol) was added to a suspension of 3-methoxypiperidine hydrochloride (281) (McManus, J. M. et al., J. Med. Chem. 1965, 8, 766-776) (3.80 g, 25.0 mmol) and aqueous glycolonitrile (55%, 2.7 mL, 27.6 mmol), and the resulting solution stirred at 70 0C for 1.5 h. The solution was cooled to 20 0C and diluted with water (40 mL). The aqueous layer was extracted with Et2O (4 x 50 mL), the combined organic fraction dried and the solvent evaporated to give nitrile 282 (3.76 g, 97%) as a colourless oil, which was used without further purification: 1H NMR δ 3.54 (s, 2 H, CH2CN), 3.36-3.40 (m, 1 H, H-3), 3.37 (s, 3 H, OCH3), 2.77 (dd, J = 10.9, 3.2 Hz, 1 H, H-2), 2.44-2.56 (m, 3 H, H-2, H-6), 1.75-1.85 (m, 2 H, H-4, H-5), 1.52-1.57 (m, 2 H, H-4, H-5).
2-(3-Methoxy-1-piperidinyl)ethylamine (283). A mixture of nitrile 282 (3.5 g, 22.7 mmol) and Raney Nickel (50% w/w suspension in water, 8 g) in EtOH (100 mL) and cNH3 (10 mL) was stirred under H2 (60 psi) for 22 h. The mixture was filtered through Celite, the solid washed with EtOH (60 mL) and the solvent evaporated to give diamine 283 as a crude colourless oil (3.48 g, 97%) which was used without further purification: HRMS (FAB+) calcd for C8H19N2O (MH+) m/z 159.14974, found 159.14976. 2-(4-Methoxy-1 -piperidinyl)ethylamine (288).
4-Methoxypiperidine (286). A mixture of terf-butyl 4-hydroxy-1-piperidinecarboxylate (284) (Dailewicz, J. C; et al., J. Med. Chem. 2002, 45, 2432-2453) (19.7 g, 98 mmol), crushed KOH (11.0 g, 196 mmol) and MeI (7.3 mL, 118 mmol) in DMSO (100 mL) was stirred at
20 0C for 16 h under N2. The mixture was poured into water (500 mL) and extracted with Et2O (2 x 150 mL). The combined organic fraction was washed with water (2 x 50 mL), dried and the solvent evaporated to give methyl ether 285 (19.1 g, 91%) as a white solid: 1H NMR δ 3.71-3.78 (m, 2 H, CH2N), 3.31-3.39 (m, 4 H, CHO, OCH3), 3.06-3.12 (m, 2 H, CH2N), 1.80-1.85 (m, 2 H, CH2), 1.45-1.54 (m, 2 H, CH2), 1.43 [s, 9 H, C(CH3)3]. A solution of HCI in dioxane (4 M, 67 mL, 266 mmol) was added to a stirred solution of methyl ether 285 (19.1 g, 88.7 mmol) in dioxane (100 mL) and the mixture stirred at 20 0C for 96 h.The solvent was evaporated and the residue dried to give the amine hydrochoride 286 as a white solid: 1H NMR [(CD3)2SO] δ 8.99 (br s, 2 H, NH.HCI), 3.40-3.46 (m, 1 H, CHO), 3.25 (s, 3 H, OCH3), 3.07-3.12 (m, 2 H, CH2N)1 2.88-2.94 (m, 2 H, CH2N), 1.91- 1.99 (m, 2 H, CH2), 1.63-1.74 (m, 2 H, CH2). The hydrochloride was dissolved in water (50 mL), the pH adjusted to 10 with CNH3 and the mixture extracted with CHCI3 (4 x 50 mL) to give the free base, which was used without further purification.
(4-Methoxy-1-piperidinyl)acetonitrile (287). 4-Methoxypiperidine (286) (10.1 g, 87.6 mmol) was added dropwise to a stirred aqueous solution of glycolonitrile (55%, 10.0 g, 96.4 mmol) at 5 °C and the solution was stirred at 70 0C for 1 h. The solution was cooled, diluted with Et2O (50 mL) and washed with water (2 x 20 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give nitrite 287 (10.25 g, 76%) as a colourless oil: 1H NMR δ 3.51 (s, 2 H, CH2CN), 3.35 (s, 3 H, OCH3), 3.21-3.28 (m, 1 H, CHO), 2.72- 2.78 (m, 2 H1 CH2N)1 2.40-2.46 (m, 2 H, CH2N), 1.90-1.98 (m, 2 H, CH2N)1 1.60-1.69 (m, 2 H, CH2).
2-(4-Methoxy-1-piperidinyl)ethylamine (288). A mixture of nitrile 287 (10.25 g, 66.5 mmol) and Raney Nickel (50% w/w in water, ca. 10 mL) in EtOH (150 mL) and cNH3 (10 mL) was stirred under H2 (60 psi) for 16 h. The mixture was filtered through Celite, washed with EtOH (3 x 10 mL) and the solvent evaporated to give crude diamine 288 as an oil which was used directly. 2-(1-Azepanyl)ethylamine (291).
1-Azepanylacetonitrile (290). Azepane (289) (4.9 ml_, 43.8 mmol) was added dropwise to a stirred aqueous solution of glycolonitrile (55%, 5.0 g, 48.2 mmol) at 5 0C and the solution was stirred at 70 0C for 30 min. The solution was cooled, diluted with water (20 mL), washed with Et2O (3 x 50 ml_). The organic fraction was dried and the solvent evaporated to give nitrile 290 (5.58 g, 92%) as a colourless oil: 1H NMR δ 3.56 (s, 2 H, CH2CN), 2.71 (br dd, J = 5.8, 5.5 Hz, 4 H, 2 x CH2N), 1.67-1.73 (m, 4 H, 2 x CH2), 1.59- 1.64 (m, 4 H, 2 x CH2).
2-(1-Azepanyl)ethylamine (291). A mixture of nitrile 290 (5.58 g, 40.4 mmol) and Raney Nickel (50% w/w in water, ca. 5 mL) in EtOH (50 mL) and cNH3 (4 mL) was stirred under H2 (60 psi) for 16 h. The mixture was filtered through Celite, washed with EtOH (3 x 10 mL) and the solvent evaporated to give crude diamine 291 as an oil (2.03 g, 35%) which was used without further purification: 1H NMR δ 2.72 (t, J = 6.1 Hz, 2 H, CH2N), 2.60-2.68 (m, 4 H, 2 x CH2N), 2.53 (t, J = 6.1 Hz, 2 H, CH2N), 1.55-1.66 (m, 10 H, 4 x CH2, NH2).
2-(1 ,4-Oxazepan-4-yl)ethy lamine (294).
2-(1,4-Oxazepan-4-yl)acetonitrile (293). 1 ,4-Oxazepane (292) (Turner, S. R. et al., PCT
Int. Appl. WO 2000 040561, 2000) (4.95 g, 49.0 mmol) was added dropwise to a stirred aqueous solution of glycolonitrile (55%, 5.3 mL, 53.8 mmol) at 5 0C and stirred at 70 °C for 1 h. More aqueous glycolonitrile (55%, 0.96 mL, 6.13 mmol) was added and the mixture stirred for 30 min, cooled to 20 0C and Et2O (100 mL) and water (50 mL) were added. The aqueous layer was extracted with Et2O (4 x 30 mL), the combined organic fraction dried and the solvent evaporated to give nitrile 293 (3.24 g, 47%) as a pale yellow oil: 1H NMR δ 3.80-3.84 (m, 2 H, H-5), 3.74-3.77 (m, 2 H, H-3), 3.60 (s, 2 H, CH2CN), 2.79-2.84 (m, 4 H, H-2, H-7), 1.92-1.99 (m, 2 H, H-6); HRMS calcd for C7H12N2O (M+) m/z 140.0950, found 140.0947.
2-(1,4-Oxazepan-4-yl)ethanamine (294). A mixture of nitrile 293 (3.2g, 22.8 mmol) and Raney-Nickel (50% w/w in water, ca. 12 g) in EtOH (100 mL) and cNH3 (10 mL) was stirred under H2 (60 psi) for 16 h. The mixture was filtered through Celite, washed with EtOH (3 x 10 mL) and the solvent evaporated to give crude diamine 294 (2.98 g, 91%) as a pale yellow oil, which was used without further purification: 1H NMR [(CD3)2SO] δ 3.64- 3.67 (m, 2 H, H-3), 3.57-3.59 (m, 2 H, H-5), 2.49-2.62 (m, 8 H, H-2, H-7, 2 x CH2), 1.71- 1.80 (m, 2 H, H-6), NH2 not observed; HRMS (FAB+) calcd for C7H17N2O (MH+) m/z 145.13409, found 145.13439. Λ/1,Λ/1-Dipropyl-1 ,2-ethanediamine (297).
2-[2-(Dipropylamino)ethyl]-1H-isoindole-1,3(2H)-dione (296). A mixture of N, N- dipropylamine (295) (12.6 g, 125 mmol), Λ/-(2-bromoethyl)phthalimide (15.8 g, 62.4 mmol) and K2CO3 (10.4 g, 74.9 mmol) in DMF (150 mL) was stirred at 100 0C for 3 h. The solution was cooled and the solvent evaporated. The residue was partitioned between EtOAc (200 mL) and water (200 mL) and the organic fraction extracted with 1 M HCI (200 mL). The acidic fraction was washed with ether (2 x 50 mL), made basic with cNH3 and then extracted with DCM (3 x 100 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with EtOAc, to give phthalamide 296 (10.4 g, 60%) as a colourless oil, which was used without further purification: 1H NMR δ 7.81-7.85 (m, 2 H, Harom), 7.67-7.73 (m, 2 H, Harom), 3.75 (dd, J = 7.1, 6.8 Hz, 2 H, CH2N), 3.69 (dd, J = 7.1 , 6.8 Hz, 2 H, CH2N), 2.39-2.44 (m, 4 H, 2 x CH2N), 1.35-1.45 (m, 4 H, 2 x CH2), 0.81 (t, J = 7.3 Hz, 6 H, 2 x CH3).
/V1,/V1-Dipropyl-1,2-ethanediamine (297). A solution of phthalimide 296 (10.4 g, 37.8 mmol) and N2H4 H2O (3.7 mL, 75.5 mmol) in EtOH (100 mL) was stirred at reflux temperature for 2 h. The solution was cooled to 5 0C for 2 h, the precipitate filtered, washed with EtOH (5 mL) and the filtrate evaporated to half volume. The solution was cooled at 5 0C for a further 2 h, the precipitate filtered, washed with EtOH (5 mL) and the filtrate evaporated. The residue was dissolved in 1 M HCI (50 mL), washed with Et2O (2 x 50 mL) and the pH of the aqueous fraction adjusted to 10 with dilute aqueous NH3 solution. The mixture was extracted with CHCI3 (4 x 50 mL), the combined organic fraction dried and the solvent evaporated to give diamine 297 as a pale yellow oil (4.06 g, 74%) which was used without further purification: 1H NMR δ 2.70 (dd, J = 6.2, 5.9 Hz, 2 H,
CH2N), 2.44 (dd, J = 6.2, 5.9 Hz, 2 H, CH2N), 2.32-2.37 (m, 4 H, 2 x CH2N), 1.50 (br s, 2 H, NH2), 1.38-1.47 (m, 4 H, 2 x CH2), 0.87 (t, J = 7.3 Hz, 6 H, 2 χ CH3).
/V1-(2-Methoxyethyl)-Λ/1-methylpropane-1 ,3-diamine (299). 2-{3-[(2-Methoxyethyl)(methyl)amino]ρropyl}-1 tf-isoindole-1 ,3(2W)-dione (298). A suspension of 2-methoxy-Λ/-methylethanamine (266) (20.0 g, 224 mmol), Λ/-(3- bromopropy)phthalimide (50.1 g, 187 mmol) and K2CO3 (31.0 g, 224 mmol) in DMF (200 mL) was stirred at 100 0C for 3 h. The solution was cooled and the solvent evaporated to give phthalimide 298 (51.7 g, 100%) as a colourless oil, which was used without further purification: 1H NMR δ 7.82-7.86 (m, 2 H, Harom), 7.68-7.73 (m, 2 H, Harom), 3.73 (t, J = 7.2 Hz, 2 H, CH2N), 3.42-3.46 (m, 2 H, CH2O), 3.32 (s, 3 H, OCH3), 2.53-2.56 (m, 2 H, CH2N), 2.44-2.49 (m, 2 H, CH2N), 2.25 (s, 3 H, NCH3), 1.82-1.90 (m, 2 H, CH2); HRMS (Cl+) calcd for C15H21N2O3 (MH+) m/z 277.1552, found 277.1557.
W1-(2-Methoxyethyl)-Λ/1-methylpropane-1,3-dϊamine (299). A solution of phthalimide 298 (50.0 g, 181 mmol) and N2H4 H2O (17.5 ml_, 362 mmol) in EtOH (500 ml_) was stirred at reflux temperature for 2 h. The solution was cooled to 5 0C for 2 h, the precipitate filtered, washed with EtOH (5 mL) and the filtrate evaporated to half volume. The solution was cooled at 5 0C for a further 2 h, the precipitate filtered, washed with EtOH (5 mL) and the filtrate evaporated. The residue was dissolved in 1 M HCI (50 mL), washed with Et2O (2 x 50 mL) and the pH of the aqueous fraction adjusted to 10 with dilute aqueous NH3 solution. The mixture was extracted with CHCI3 (4 x 50 mL), the combined organic fraction dried and the solvent evaporated to give diamine 299 (Sandberg, R., et al., Acta Pharmaceutica Suecica 1979, 16, 386-395) as a pale yellow oil (25.2 g, 95%) which was used without further purification: 1H NMR [(CD3)2SO] δ 3.38 (t, J = 6.0 Hz, 2 H, CH2O), 3.21 (s, 3 H, OCH3), 2.60 (t, J = 6.8 Hz, 2 H, CH2N), 2.46 (t, J = 6.0 Hz, 2 H, CH2N), 2.36 (t, J = 7.0 Hz, 2 H, CH2N), 2.14 (s, 3 H, NCH3), 1.50 (p, J = 7.0 Hz, 2 H, CH2), NH2 not observed; HRMS (Cl+) calcd for C7H17N2O (M-H+) m/z 145.1341 , found 145.1337.
3-(3-Methoxy-1-azetidinyl)propylamine (301). 2-[3-(3-Methoxy-1-azetidinyl)propyl]-1H-isoindole-1,3(2H)-dione (300). A suspension of 3-methoxyazetidine (275) (MacKenzie et al., PCT Int. Appl. WO 9605193, 1996) (1.6 g, 18.8 mmol), 2-(3-bromopropyl)phthalimide (4.8 g, 17.9 mmol) and K2CO3 (3.7 g, 26.9 mmol) in THF (150 mL) was stirred at reflux temperature for 18 h. The solution was cooled, the solvent evaporated and the residue partitioned between water (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (2 x 150 mL), the combined organic fraction washed with water (2 x 100 mL) and brine (100 mL), dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give phthalimide 300 (5.2 g, 65%) as a colourless oil: 1H NMR δ 7.84 (dd, J = 5.4, 3.1 Hz, 2 H, Harom), 7.70 (dd, J = 5.4, 3.1 Hz, 2 H, Harom), 3.95 (p, J = 5.8 Hz, 1 H, CHO), 3.73 (t, J = 7.1 Hz, 2 H, CH2N), 3.55-3.60 (m, 2 H, CH2N), 3.22 (s, 3 H, OCH3), 2.78-2.84 (m, 2 H, CH2N), 2.51 (t, J = 7.1 Hz, 2 H, CH2N), 1.72 (p, J = 7.1 Hz, 2 H, CH2); MS (APCI) m/z 275 (MH+, 100%); HRMS (FAB+) calcd for C15H19N2O3 (MH+) m/z 275.1396, found 275.1391.
3-(3-Methoxy-1-azetidinyl)propylamine (301). A solution of phthalimide 300 (5.2 g, 18.9 mmol) and N2H4 H2O (1.9 g, 37.8 mmol) in EtOH (100 mL) was heated at reflux temperature for 3 h. The solution was cooled to 0 0C, the solid filtered off and washed with cold EtOH (20 mL) and EtOAc (100 ml_). The solvent was evaporated to half volume, stored at -20 0C for 16 h and the suspension filtered. The filtrate was evaporated, the residue was dissolved in Et2O, the solid filtered off and the solvent was evaporated to give crude diamine 301 (1.8 g, 66%) as a yellow oil, which was used without further purification: 1H NMR δ 4.02 (p, J = 5.8 Hz, 1 H, CHO), 3.58-3.63 (m, 2 H, CH2N), 3.25 (s, 3 H, OCH3), 2.82-2.87 (m, 2 H, CH2N), 2.72 (t, J = 6.9 Hz, 2 H, NCH2), 2.50 (t, J = 7.1 Hz, 2 H, NCH2), 1.40-1.60 (m, 4 H, NH2, CH2); MS (APCI) m/z 145 (MH+, 100%).
1-(3-Aminopropyl)-3-pyrrolidinecarbonitrile (304).
1 -[3-(1,3-Dioxo-1 ,3-dihydro-2H-isoindol-2-yl)propyl]-3-pyrrolidinecarbonitrile (303). A suspension of 3-pyrrolidinecarbonitrile (302) (Swidinsky, J., et al., J. Pharm. Sci. 1967, 56, 192-196) (4.5 g, 15.6 mmol), Λ/-(3-bromopropyl)phthalimide (3.48 g, 13.0 mmol), and K2CO3 (2.16 g, 15.6 mmol) in DMF (20 mL) was stirred at 100 0C for 1.5 h. The solution was cooled, the solvent evaporated and the residue partitioned between water (50 mL) and EtOAc (50 mL). The organic fraction was extracted with 1 M HCI (2 x 50 mL) and the acidic fraction washed with Et2O (2 x 20 mL). The acidic fraction was made basic with dilute aqueous NH3 solution and the alkaline solution was extracted with DCM (3 x 25 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with EtOAc, to give phthalimide 303 (1.70 g, 46%) as a colourless oil: 1H NMR δ 7.82-7.87 (m, 2 H, Harom), 7.69-7.74 (m, 2 H, Harom), 3.75-3.79 (m, 2 H, CH2), 2.87-2.93 (m, 2 H, CH2N), 2.52-2.60 (m, 5 H, CH2, CH2N1 CH), 2.06-2.15 (m, 1 H, CH2), 1.96-2.04 (m, 1 H, CH2), 1.87 (p, J = 7.0 Hz, 2 H, CH2); 13C NMR δ 168.4 (2), 133.9 (2), 132.2 (2), 123.1 (2), 122.1 , 57.2, 52.6 (2), 36.3, 29.1, 27.2, 26.1 ; HRMS (FAB+) calcd for C16H17N3O2 (M+) m/z 283.1321, found 283.1318.
1-(3-Aminopropyl)-3-pyrrolidinecarbonitrile (304). A solution of phthalimide 303 (5.96 g, 21.0 mmol) and N2H4 H2O (2.04 mL, 42.0 mmol in EtOH (60 mL) was stirred at reflux temperature for 2 h. The solution was cooled to 5 0C for 2 h, the precipitate filtered, washed with EtOH (5 mL) and the filtrate evaporated to half volume. The solution was cooled at 5 0C for a further 2 h, the precipitate filtered, washed with EtOH (5 mL) and the filtrate evaporated to give diamine 304 which was used without further purification: 1H NMR δ 2.94-3.02 (m, 1 H, CHCN), 2.90 (dd, J = 9.0, 7.9 Hz, 1 H, CH2), 2.82 (t, J = 6.8 Hz,
2 H, CH2N), 2.61-2.68 (m, 2 H, CH2N), 2.48-2.58 (m, 3 H, CH2N), 2.05-2.15 (m, 1 H, CH2), 2.03-2.11 (m, 1 H, CH2), 1.68 (p, J = 7.0 Hz, 2 H, CH2), NH2 not observed. 3-(4-Methoxy-1 -piperidinyl)propylamine (306).
2-[3-(4-Methoxy-1-piperidinyl)propyl]-1W-isoindole-1,3(2W)-dione (305). A suspension of 4-methoxypiperidine (286) (4.1 g, 35.3 mmol), Λ/-(3-bromoproρyl)phthalimide (9.0 g, 33.6 mmol) and K2CO3 (7.0 g, 50.4 mmol) in DMF (80 mL) was stirred at 50 0C for 16 h. The solution was cooled, the solvent evaporated and the residue partitioned between water (150 mL) and EtOAc (150 mL). The organic fraction was washed with water (2 x 50 mL) and brine (50 mL), dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give phthalimide 305 (6.0 g, 59 %) as a white solid: 1H NMR δ 7.81-7.86 (m, 2 H, Harom), 7.67-7.73 (m, 2 H, Harom), 3.75-3.79 (t, J = 7.0 Hz, 2 H, CH2N), 3.28 (s, 3 H, OCH3), 3.09-3.17 (m, 1 H, CHO), 2.63-2.70 (m, 2 H, CH2N), 2.39 (t, J = 7.0 Hz, 2 H, CH2N), 2.01-2.08 (m, 2 H, CH2N), 1.85 (p, J = 7.0 Hz, 2 H, CH2), 1.74-1.81 (m, 2 H, CH2), 1.37-1.46 (m, 2 H, CH2). Anal, calcd for C17H22N2O3: C, 67.5; H, 7.3; N, 9.3. Found: C, 67.3; H, 7.4; N, 9.3%.
3-(4-Methoxy-1-piperidinyl)propy!amine (306). A solution of phthalimide 305 (6.0 g, 19.8 mmol) and N2H4- H2O (1.9 mL, 40 mmo)l in EtOH (100 mL) was stirred at reflux temperature for 2 h. The solution was cooled to 5 0C for 2 h, the precipitate filtered, washed with EtOH (5 mL) and the filtrate evaporated to half volume. The solution was cooled at 5 0C for a further 2 h, the precipitate filtered, washed with EtOH (5 mL) and the filtrate evaporated. The residue was dissolved in 1 M HCI (50 mL), washed with Et2O (2 x 50 mL) and the pH of the aqueous fraction adjusted to 10 with dilute aqueous NH3 solution. The mixture was extracted with CHCI3 (4 x 50 mL), the combined organic fraction dried and the solvent evaporated to give diamine 306 (1.85 g, 54%) as a pale yellow oil: 1H NMR δ 3.33 (s, 3 H, OCH3), 3.17-3.24 (m, 1 H, CHO), 2.71-2.78 (m, 4 H, 2 x CH2N), 2.37 (dd, J = 7.5, 7.2 Hz, 2 H, CH2N), 2.08-2.13 (m, 2 H, CH2N), 1.85-1.93 (m, 2 H, CH2), 1.50-1.67 (m, 6 H, 2 x CH2, NH2); MS m/z 172 (M+, 5%), 128 (60), 57 (100); HRMS calcd for C9H20N2O (M+) m/z 172.1576, found 172.1571.
4-(4-Morpholinyl)butylamine (308). 2-[4-(4-Morpholinyl)butyl]-1H-isoindole-1,3(2W)-dione (307). A mixture of 4- bromobutylphthalimide (10.0 g, 35.4 mmol), K2CO3 (5.88 g, 42.5 mmol) and morpholine (4.6 mL, 53.1 mmol) in DMF (100 mL) was stirred at 100 0C for 8 h, cooled to 20 0C and the solvent evaporated. The residue was partitioned between EtOAc (300 mL) and water (300 mL), the organic fraction washed with water (2 x 50 mL) and brine (50 mL), dried and the solvent evaporated. The residue was purified by chromatography, eluting with EtOAc, to give phthalimide 307 (9.59 g, 94%) as a clear oil: 1H NMR δ 7.81-7.86 (m, 2 H, Harom), 7.68-7.73 (m, 2 H1 Haram), 3.66-3.72 (m, 6 H, 2 x CH2O, CH2N), 2.41 (br t, J = 4.5 Hz, 4 H, 2 x CH2N), 2.35 (br dd, J = 7.6, 7.4 Hz, 2 H, CH2N), 1.69-1.76 (m, 2 H, CH2), 1.50-1.58 (m, 2 H, CH2).
4-(4-Morpholinyl)butylamine (308). A solution of phthalimide 307 (9.42 g, 32.7 mmol) and N2H4 H2O (3.2 mL, 65.3 mmol) in EtOH (140 ml_) was stirred at reflux temperature for 2 h. The mixture was cooled to 0 0C, filtered, the filtrate cooled at 0 0C for 3 h, and filtered. The filtrate was evaporated and the residue dissolved in 1 M HCI. The solution was washed with ether (2 x 50 mL) and the pH adjusted to 10 with aqueous NH3 solution. The resulting mixture was extracted with CHCI3 (4 x 50 mL), the combined organic fraction dried and the solvent evaporated to give diamine 308 (Thompson, A. M.; et.al., J. Med. Chem., 1997, 40, 3915-3925) (2.0 g, 39%) as a colourless oil: 1H NMR δ 3.72 (br t, J = 4.7 Hz, 4 H, 2 x CH2O), 2.71 (br dd, J = 6.9, 6.7 Hz, 2 H, CH2N), 2.44 (br t, J = 4.6 Hz, 4 H, 2 x CH2N), 2.34 (br dd, J = 7.8, 7.0 Hz, 2 H, CH2N), 1.62 (br s, 2 H, NH2), 1.42-1.59 (m, 4 H, 2 x CH2).
Example 185
3-(3-(4-(Dimethylamino)butanoyloxy)propyl)-7,8-dihydro-6H-indeno[5,6- e][1,2,4]triazine 1 -Oxide (309). A mixture of alcohol 70 (100 mg, 0.41 mmol), 4- (dimethylamino)butanoic acid hydrochloride (68 mg, 0.41 mmol), DCC (93 mg, 0.45 mmol), DMAP (5 mg, 0.04 mmol) and Et3N (0.06 mL, 0.41 mmol) in DCM (20 mL) was stirred at 20 0C for 16 h. The solvent was evaporated and the residue purified by chromatography, eluting with a gradient (0-10%) of MeOH/20% EtOAc/DCM, to give the ester 309 (137 mg, 94%) as a pale-brown oil: 1H NMR δ 8.25 (s, 1 H, H-9), 7.74 (s, 1 H, H- 5), 4.21 (t, J = 6.3 Hz, 2 H, CH2O), 3.06-3.15 (m, 6 H, H-6, H-8, CH2), 2.73 (br s, 2 H, H- 7), 2.56 [s, 6 H, N(CH3)2], 2.37 (t, J = 7.0 Hz, 2 H, CH2), 2.18-2.29 (m, 4 H, CH2), 1.92- 1.99 (m, 2 H, CH2); 13C NMR δ 172.6, 164.9, 154.9, 149.1 , 147.4, 132.3, 122.7, 114.2, 63.7, 57.7, 43.9 (2), 33.6, 33.2, 32.8, 31.3, 26.8, 25.7, 21.0; HRMS calcd for C19H26N4O3 (M+) m/z 358.2005, found 358.2006.
Example 186
3-(3-(2-(fert-Butoxycarbonylamino)-3-methylbutanoyloxy)propyl)-7,8-dihydro-6H- indeno[5,6-e][1,2,4]triazine 1 -Oxide (310). A mixture of alcohol 70 (50 mg, 0.20 mmol), Λ/-Boc Valine (44 mg, 0.20 mmol), DCC (46 mg, 0.22 mmol) and DMAP (2.5 mg, 0.02 mmol) in DCM (10 mL) was stirred at 20 0C for 1 h. The solvent was evaporated and the residue purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give the crude ester, which was suspended in DCM (2 ml_) and filtered to remove urea byproducts. The filtrate was concentrated to give crude ester 310 (84 mg, 93%) as a pale- brown gum: 1H NMR δ 8.27 (s, 1 H1 H-9), 7.76 (s, 1 H, H-5), 4.96-5.03 (m, 1 H, CH), 4.28 (t, J = 6.5 Hz, 2 H, CH2O), 3.08-3.16 (m, 6 H, H-6, H-8, CH2), 2.21-2.31 (m, 4 H, H-7, CH2), 2.08-2.17 (br m, 1 H, CH), 1.46 [s, 9 H, C(CH3U 0.97 (d, J = 6.9 Hz, 3 H, CH3), 0.91 (d, J = 6.9 Hz, 3 H, CH3), NH not observed; HRMS calcd for C23H32N4O5 (M+) m/z 444.2373, found 444.2382.
Example 189 Evaluation of the cytotoxicity of compounds by proliferation assay (IC50) under aerobic and hypoxic conditions.
Compounds representative of the invention were evaluated under both aerobic and hypoxic conditions in a proliferation assay (IC50), using two cell lines: human colon carcinoma HT29, and human cervical carcinoma SiHa (Table 1). Drug exposures were performed in 96-well plates (Nunc) either using a 37 0C humidified incubator (20% O2, 5% CO2) or in the incubator compartment (37 0C) of an anaerobic chamber (Shell Lab) where palladium catalyst scrubbed gas (90% N2, 5% H2, 5% CO2) ensures severe anoxia (<0.001% O2). For each experiment, compounds were simultaneously tested under both oxic and hypoxic conditions and included TPZ as an internal control. An 8-methyl-5-nitroquinoline derivative, SN 24349, known to require very low oxygen concentrations for bioactivation (Sum et al., Br. J. Cancer 1994, 70, 596-603) was used to confirm that strict hypoxia was present during the experiment. The assay acceptance criteria based on SN 24349 were: anoxic IC50 < 3 μM for HT29 and <1 μM for SiHa; HCR > 30 for HT29 and >100 for SiHa. Cell cultures were grown in αMEM (Gibco) containing 5% heat inactivated FCS and maintained in exponential growth phase. For each individual experiment an appropriate number of cells were seeded (HT29 = 1100; SiHa = 1500) into wells in αMEM + 10% FCS + 10 mM added glucose + 100 μM 2'- deoxycytidine (2'dCyd), and allowed to attach for 2-3 h. High glucose (final concentration 17 mM) and the presence of 2'-dCyd minimize hypoxia-induced cell cycle arrest. Cultures were then exposed to drugs, using 3-fold serial dilutions in duplicate, for a further 4 h. Subsequently cells were washed free of compound using complete media (without glucose/2'-dCyd) and allowed to grow for 5 (oxic) or 6 (anoxic) days. Plates were stained with sulforhodamine B as described previously (Wilson et al., J. Med. Chem. 1989, 32, 31-38) and IC50 values determined. IC5O = The concentration of drug to reduce viable cell numbers to 50% of control cell cultures grown under the same conditions but not exposed to drug.
HCR = Hypoxic cytotoxicity ratio is defined as the ratio of IC50 values under aerobic and hypoxic conditions (IC50 aerobic/IC5o hypoxic).
Table 1. Cytotoxicities of compounds of the invention under oxic and hypoxic conditions, and hypoxic selectivity (HCR) in proliferation assay.
Figure imgf000176_0001
Figure imgf000177_0001
Example 188
HT29 Excision assay. In vivo activity of single dose of compound 77 in combination with radiation. The activity of compound 77 against hypoxic cells in HT29 tumours is illustrated in Figure 1. Subcutaneous HT29 tumours (average of two largest diameters 8- 10 mm) were grown by inoculating 107 cells (obtained by enzymatic dissociation of multicellular spheroids) into CD-1 nude mice. Cmpd 77 was administered as a single i.p. dose (560 μmol/kg, which is 75% of the maximum tolerated dose) alone or 5 min after radiation (20 Gy). Tumours were excised 18 h after treatment and plated to determine the number of clonogens/g tumour tissue. Hypoxic cytotoxicity of compound 77 is demonstrated by the difference between the radiation-only and radiation + drug groups. This difference was statistically significant (p < 0.05) using ANOVA and Dunnett's test. Selectivity for hypoxic cells is demonstrated by the greater activity of 77 with radiation than as a single agent.
The activity of single doses of TPZ and compounds 61 and 77 against hypoxic cells in HT29 and an additional two human tumour models is illustrated in Figure 2. The drugs were administered i.p. at the stated doses 5 minutes after irradiation in experiments similar to that described above. All drugs were administered at 0.75 x MTD. The activity is measured as logs of cell kill in addition to the cell kill observed for radiation alone.
Example 189
Fractionated Tumour Excision assays. In vivo activity of multiple doses of drug in combination with fractionated radiation. The activity of multiple doses of compound 77 and TPZ against hypoxic cells in three human tumour xenografts is illustrated in Figure 3. Subcutaneous tumours (average of two largest diameters 8-10 mm) were grown by inoculating 107 cells into the midline of the back in CD-1 nude mice. Drugs were administered by i.p. injection at 100% of the MTD for twice daily (9am, 3pm) administration for 4 days, either alone or 30 min before each of 8 x 2.5 Gy local irradiation of the tumour. Tumours were excised 18 hr after treatment and plated to determine the number of clonogens/g tumour tissue. Antitumour activity is measured as logs of cell kill in addition to the cell kill observed for radiation alone. In each of the three tumour models investigated, administration of compound 77 or TPZ, 30 min before each radiation dose, gave significantly (P < 0.05) greater log cell kill compared to radiation alone (Figure 3). Compound 77 gave greater killing than TPZ in each tumour model. In SiHa tumours the log cell kill in addition to radiation alone was significantly greater (p<0.05, Student's t-test) for 77 plus radiation relative to TPZ plus radiation.
Wherein the foregoing description reference has been made to reagents, or integers having known equivalents thereof, then those equivalents are herein incorporated as if individually set forth.
While this invention has been described with reference to certain embodiments and examples, it is to be appreciated that further modifications and variations can be made to embodiments and examples without departing from the scope of the invention.

Claims

Claims:
A compound of Formula I or a pharmacologically acceptable salt thereof,
Figure imgf000180_0001
Formula I
wherein
n = 0 or 1; and
each X at one or more of the available carbons 5-8 on the benzo ring is independently selected from the following groups, H, halo, R, OH, OR, OC(O)H, OC(O)R, OC(O)NH2, OC(O)NHR, OC(O)NRR, OP(O)(OH)2, OP(O)(OR)2, NO2, NH2, NHR, NRR, NHC(O)H, NHC(O)R, NRC(O)R, NHC(O)NH2, NHC(O)NRR, NRC(O)NHR, SH, SR, S(O)H, S(O)R, SO2R, SO2NH2, SO2NHR, SO2NRR, CF3, CN, CO2H, CO2R, CHO, C(O)R, C(O)NH2, C(O)NHR, C(O)NRR, CONHSO2H, CONHSO2R, CONRSO2R, cyclic C3-C7 alkylamino, imidazolyl, C1-C6 -alkylpiperazinyl and morpholinyl;
wherein each R is independently selected from an optionally substituted C1-S alkyl, an optionally substituted C2^ alkenyl group or an optionally substituted C3-7 cyclic alkyl group, and wherein the one or more optional substituents are each independently selected from; halo, OH, OR1, OC(O)R1, OC(O)NH21 OC(O)NHR1, OC(O)NR1R1, OP(O)(OH)2, OP(O)(OR1)2, NO2, NH2, NHR1, NR1R1, N+(-O")R1R1, NHC(O)H, NHC(O)R1, NR1C(O)R1, NHC(O)NH2, NHC(O)NR1R1, NR1C(O)NHR1, SH, SR1, S(O)H, S(O)R1, SO2R1, SO2NH2, SO2NHR1, SO2NR1R1, CF3, CN, CO2H, CO2R1, CHO, C(O)R1, C(O)NH2, C(O)NHR1, C(O)NR1R1, C(O)NHSO2R1, C(O)NR1SO2R1, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more R1 groups, halo, OH, OR1, OC(O)R1, OC(O)NH2, OC(O)NHR1, OC(O)NR1R1, OP(O)(OH)2, OP(O)(OR1)2, NO2, NH2, NHR1, NR1R1, N+(-O' )R1R\ NHC(O)H, NHC(O)R1, NR1C(O)R1, NHC(O)NH2, NHC(O)NR1R1, NR1C(O)NHR1, SH, SR1, S(O)H, S(O)R1, SO2R1, SO2NH2, SO2NHR1, SO2NR1R1, CF3, CN, CO2H, CO2R1, CHO, C(O)R1, C(O)NH2, C(O)NHR1, C(O)NR1R1, CONHSO2H, C(O)NHSO2R1 and C(O)NR1SO2R1;
R can also represent an optionally substituted C4.8 aryl or an optionally substituted heteroaryl group having up to 12 carbon atoms, and wherein the one or more optional substituents are each independently selected from; halo, OH, OR1, OC(O)R1, OC(O)NH2, OC(O)NHR1, OC(O)NR1R1, OP(O)(OH)2, OP(O)(OR1)2, NO2, NH2, NHR1, NR1R1, N+(-0' )R1R1, NHC(O)H, NHC(O)R1, NR1C(O)R1, NHC(O)NH2, NHC(O)NR1R1, NR1C(O)NHR1, SH, SR1, S(O)H, S(O)R1, SO2R1, SO2NH2, SO2NHR1, SO2NR1R1, CF3, CN, CO2H, CO2R1, CHO, C(O)R1, C(O)NH2, C(O)NHR1, C(O)NR1R1, C(O)NHSO2R1, C(O)NR1SO2R1, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more R1 groups, halo, OH, OR1, OC(O)R1, OC(O)NH21 OC(O)NHR1, OC(O)NR1R1, OP(O)(OH)2, OP(O)(OR1)2, NO21 NH2, NHR1, NR1R1, N+KOR1R1, NHC(O)H, NHC(O)R1, NR1C(O)R1, NHC(O)NH2, NHC(O)NR1R1, NR1C(O)NHR1, SH, SR1, S(O)H, S(O)R1, SO2R1, SO2NH2, SO2NHR1, SO2NR1R1, CF3, CN, CO2H, CO2R1, CHO, C(O)R1, C(O)NH2, C(O)NHR1, C(O)NR1R1, CONHSO2H, C(O)NHSO2R1 and C(O)NR1SO2R1; and wherein each heteroaryl group contains one or more heteroatoms in its ring system which are each independently selected from O, N or S; wherein each R1 is independently selected from an optionally substituted C1-6 alkyl or an optionally substituted C2.6 alkenyl group and wherein the one or more optional substituents are each independently selected from; halo, OH, OR2, OC(O)R2, OC(O)NH2, OC(O)NHR2, OC(O)NR2R2, OP(O)(OH)2, OP(O)(OR2)2, NO2, NH2, NHR2, NR2R2, N+(-O" )R2R2, NHC(O)H, NHC(O)R2, NR2C(O)R2, NHC(O)NH2, NHC(O)NR2R2, NR2C(O)NHR2, SH, SR2, S(O)H, S(O)R2, SO2R2, SO2NH2, SO2NHR2, SO2NR2R2, CF3, CN, CO2H, CO2R2, CHO, C(O)R2, C(O)NH2, C(O)NHR2, C(O)NR2R2, C(O)NHSO2R2, C(O)NR2SO2R2, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more R2 groups, halo, OH, OR2, OC(O)R2, OC(O)NH2, OC(O)NHR2, OC(O)NR2R2, OP(O)(OH)2,
OP(O)(OR2)2, NO2, NH2, NHR2, NR2R2, N+(-O)R2R2, NHC(O)H, NHC(O)R2, NR2C(O)R2, NHC(O)NH2, NHC(O)NR2R2, NR2C(O)NHR2, SH, SR2, S(O)H, S(O)R2, SO2R2, SO2NH2, SO2NHR2, SO2NR2R2, CF3, CN, CO2H, CO2R2, CHO, C(O)R2, C(O)NH2, C(O)NHR2, C(O)NR2R2, CONHSO2H, C(O)NHSO2R2 and C(O)NR2SO2R2; wherein each R2 is independently selected from C1-6 alkyl, C2-6 alkenyl, OH, OMe, NO2, NH2, CF3, CN, CO2H or SH; and
wherein W represents NH, NMe, CH2, SO, SO2, or O; and
A represents H or an optionally substituted Ci-6 alkyl group or an optionally substituted C2-6 alkenyl group or an optionally substituted C3-7 cyclic alkyl group wherein the one or more optional substituents are each independently selected from halo, OH, OR3, OC(O)R3, OC(O)NH2, OC(O)NHR3, OC(O)NR3R3, OP(O)(OH)2, OP(O)(OR3),, NO2, NH2, NHR3, NR3R3, N+(-O")R3R3, NHC(O)H, NHC(O)R3, NR2C(O)R3, NHC(O)NH2, NHC(O)NR3R3,
NR2C(O)NHR3, SH, SR3, S(O)H, S(O)R3, SO2R3, SO2NH2, SO2NHR3, SO2NR3R3, CF3, CN, CO2H, CO2R, CHO, C(O)R3, C(O)NH2, C(O)NHR3, C(O)NR3R3, CONHSO2H, C(O)NHSO2R3, C(O)NR3SO2R3, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more R3 groups, halo, OH, OR3, OC(O)R3, OC(O)NH2, OC(O)NHR3, OC(O)NR3R3, OP(O)(OH)2, OP(O)(OR3)2, NO2, NH2, NHR3, NR3R3, N+(-O")R3R3, NHC(O)H, NHC(O)R3, NR3C(O)R3, NHC(O)NH2, NHC(O)NR3R3, NR3C(O)NHR3, SH, SR3, S(O)H, S(O)R3, SO2R3, SO2NH2, SO2NHR3, SO2NR3R3, CF3, CN, CO2H, CO2R3, CHO, C(O)R3, C(O)NH2, C(O)NHR3, C(O)NR3R3, CONHSO2H, C(O)NHSO2R3, and C(O)NR3SO2R3; or
A represents an optionally substituted C4-C8 aryl or an optionally substituted heteroaryl group having up to 12 carbon atoms, and wherein the one or more optional substituents are each independently selected from; halo, OH, OR3, OC(O)R3, OC(O)NH2, OC(O)NHR3, OC(O)NR3R3, OP(O)(OH)2, OP(O)(OR3)2, NO2, NH2, NHR3, NR3R3, N+(O )R3R3, NHC(O)H, NHC(O)R3, NR2C(O)R3, NHC(O)NH2, NHC(O)NR3R3, NR2C(O)NHR3, SH, SR3, S(O)H, S(O)R3, SO2R3, SO2NH2, SO2NHR3, SO2NR3R3, CF3, CN, CO2H, CO2R, CHO, C(O)R3, C(O)NH2, C(O)NHR3, C(O)NR3R3, CONHSO2H, C(O)NHSO2R3, C(O)NR3SO2R3, cyclic C3- C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more R3 groups, halo, OH, OR3, OC(O)R3, OC(O)NH2, OC(O)NHR3, OC(O)NR3R3, OP(O)(OH)2, OP(O)(OR3)2, NO2, NH2, NHR3, NR3R3, N+(-O )R3R3, NHC(O)H, NHC(O)R3, NR3C(O)R3, NHC(O)NH2, NHC(O)NR3R3, NR3C(O)NHR3, SH, SR3, S(O)H, S(O)R3, SO2R3, SO2NH2, SO2NHR3, SO2NR3R3, CF3, CN, CO2H, CO2R3, CHO, C(O)R3, C(O)NH2, C(O)NHR3, C(O)NR3R3, CONHSO2H, C(O)NHSO2R3 and C(O)NR3SO2R3; and each heteroaryl group includes one or more heteroatoms in its ring system which are each independently selected from O, N or S; wherein each R3 is independently selected from an optionally substituted C1-6 alkyl or an optionally substituted C2-6 alkenyl group and wherein the one or more optional substituents are each independently selected from; halo, OH1 OR4, OC(O)R4, OC(O)NH2, OC(O)NHR4, OC(O)NR4R4, OP(O)(OH)2, OP(O)(OR4)2, NO2, NH2, NHR4, NR4R4, N+KOR4R4, NHC(O)H, NHC(O)R4, NR4C(O)R4, NHC(O)NH2, NHC(O)NR4R4, NR4C(O)NHR4, SH, SR4, S(O)H, S(O)R4, SO2R4, SO2NH2, SO2NHR4, SO2NR4R4, CF3, CN, CO2H, CO2R, CHO, C(O)R4, C(O)NH2, C(O)NHR4, C(O)NR4R4, CONHSO2H, C(O)NHSO2R4, C(O)NR4SO2R4, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more R4 groups, halo, OH, OR4, OC(O)R4, OC(O)NH2, OC(O)NHR4, OC(O)NR4R4, OP(O)(OH)2, OP(O)(OR4)2, NO2, NH2, NHR4, NR4R4, N+(-O" )R4R4, NHC(O)H, NHC(O)R4, NR4C(O)R4, NHC(O)NH2, NHC(O)NR4R4, NR4C(O)NHR4, SH, SR4, S(O)H, S(O)R4, SO2R4, SO2NH2, SO2NHR4, SO2NR4R4, CF3, CN, CO2H, CO2R, CHO, C(O)R4, C(O)NH2, C(O)NHR4, C(O)NR4R4, CONHSO2H, C(O)NHSO2R4 and C(O)NR4SO2R4; wherein each R4 is independently selected from C1-4 alkyl, C2^ alkenyl, halo, OH, OC1-C4, NO2, NH2, CF3, CN, CO2H, COCN or SH;
or wherein W and A together represent H or halo;
Z represents an optionally substituted 4-8 membered saturated ring system fused to the benzo ring in the 6,7-positions or the 7,8-positions;
wherein the one or more optional substituents of the ring system are each independently selected from halo, R5, OH, OR5, OC(O)R5, OC(O)NH2 OC(O)NHR5, OC(O)NR5R5, OP(O)(OH)2, OP(O)(OR5)2, NO2, NH2, NHR5, NR5R5, N+(O )R5R5, NHC(O)H, NHC(O)R5, NR5C(O)R5, NHC(O)NH2, NHC(O)NR5R5, NR5C(O)NHR5, SH, SR5, S(O)H, S(O)R5, SO2R5, SO2NH2, SO2NHR5, SO2NR5R5, CF3, CN, CO2H, CO2R, CHO, C(O)R5, C(O)NH2, C(O)NHR5, C(O)NR5R5, C(O)NHSO2H, C(O)NHSO2R5, C(O)NR5SO2R5, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more R5 groups halo, R5, OH, OR5, OC(O)R5, OC(O)NH2 OC(O)NHR5, OC(O)NR5R5, OP(O)(OH)2,
OP(O)(OR5)2, NO21 NH2, NHR5, NR5R5, N+(-O )R5R5, NHC(O)H, NHC(O)R5, NR5C(O)R5, NHC(O)NH2, NHC(O)NR5R5, NR5C(O)NHR5, SH, SR5, S(O)H, S(O)R5, SO2R5, SO2NH2, SO2NHR5, SO2NR5R5, CF3, CN, CO2H, CO2R, CHO, C(O)R5, C(O)NH2, C(O)NHR5, C(O)NR5R5, C(O)NHSO2H, C(O)NHSO2R5 and C(O)NR5SO2R5 wherein each R5 is independently selected from an optionally substituted C1-6 alkyl or an optionally substituted C2-6 alkenyl group or an optionally substituted C3-7 cyclic alkyl group and wherein the one or more optional substituents are each independently selected from; halo, R6, OH, OR6, OC(O)R6, OC(O)NHR6, OC(O)NR6R6, OP(O)(OH)2, OP(O)(OR6)2, NO2, NH2, NHR6, NR6R6, N+(-O")R6R6, NHC(O)R6, NR6C(O)R6, NHC(O)NR6R6, NR6C(O)NHR6, SH, SR6, S(O)R6, SO2R6, SO2NHR6, SO2NR6R6, CF3, CN, CO2H, CO2R, CHO, C(O)R6, C(O)NH2, C(O)NHR6, C(O)NR6R6, C(O)NHSO2R6, C(O)NR6SO2R6, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrotidinyl and azetidinyl; wherein each of the groups imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more R6 groups, halo, OH, OR6, OC(O)R6, OC(O)NH2 , OC(O)NHR6, OC(O)NR6R6, OP(O)(OH)2, OP(O)(OR6)2, NO2, NH2, NHR6, NR6R6, N+(-O-)R6R6, NHC(O)H, NHC(O)R6, NR6C(O)R6, NHC(O)NH2, NHC(O)NR6R6, NR6C(O)NHR6, SH, SR6, S(O)H, S(O)R6, SO2R6, SO2NH2, SO2NHR6, SO2NR6R6, CF3, CN, CO2H, CO2R6, CHO, C(O)R6, C(O)NH2, C(O)NHR6, C(O)NR6R6, C(O)NHSO2H, C(O)NHSO2R6 and C(O)NR6SO2R6 wherein each R6 is independently selected from C1-6 alkyl, C2-6 alkenyl, halo, OH, OMe, NO2, NH2, CF3, CN, CO2H or SH; and
wherein the optionally substituted 4-8 membered ring system includes one or more carbon atoms and/or one or more ring system moieties selected from O, NH, NR7, CONH, CONR7, NHCO, NR7CO, wherein each R7 is independently selected from an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl group or an optionally substituted C3-7 cyclic alkyl group and wherein the one or more optional substituents are each independently selected from halo, R8, OH, OR8, OC(O)R8, OC(O)NH2, OC(O)NHR8, OC(O)NR8R8, OP(O)(OH)2, OP(O)(OR5)2, NO2, NH2, NHR8, NR8R8, N+(-O")R8R8, NHC(O)H, NHC(O)R8, NR8C(O)R8, NHC(O)NH2, NHC(O)NR8R8, NR8C(O)NHR8, SH, SR8, S(O)H, S(O)R8, SO2R8, SO2NH2, SO2NHR8, SO2NR8R8, CF3, CN, CO2H, CO2R, CHO, C(O)R8, C(O)NH2, C(O)NHR8, C(O)NR8R8, C(O)NHSO2H, C(O)NHSO2R8, C(O)NR8SO2R8, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more R8 groups, halo, R8, OH, OR8, OC(O)R8, OC(O)NH2, OC(O)NHR8, OC(O)NR8R8, OP(O)(OH)2, OP(O)(OR5)2, NO2, NH2, NHR8, NR8R8, N+(-O )R8R8, NHC(O)H, NHC(O)R8, NR8C(O)R8, NHC(O)NH2, NHC(O)NR8R8, NR8C(O)NHR8, SH, SR8, S(O)H, S(O)R8, SO2R8, SO2NH2, SO2NHR8, SO2NR8R8, CF3, CN, CO2H, CO2R, CHO, C(O)R8, C(O)NH2, C(O)NHR8, C(O)NR6R8, C(O)NHSO2H, C(O)NHSO2R8 and C(O)NR8SO2R8; wherein each R8 is independently selected from an optionally substituted C1-6 alkyl, an optionally substituted C2.6 alkenyl group or an optionally substituted C3.7 cyclic alkyl group and wherein the one or more optional substituents is each independently selected from; halo, OH, OR9, OC(O)R9, OC(O)NH2, OC(O)NHR9, OC(O)NR9R9, OP(O)(OH)2, OP(O)(OR9)2, NO2, NH2, NHR9, NR9R9, N+KOR9R9, NHC(O)H, NHC(O)R9, NR9C(O)R9, NHC(O)NH2, NHC(O)NR9R9, NR9C(O)NHR9, SH, SR9, S(O)H, S(O)R9, SO2R9, SO2NH2, SO2NHR9, SO2NR9R9, CF3, CN, CO2H, CO2R, CHO, C(O)R9, C(O)NH2, C(O)NHR9, C(O)NR9R9, C(O)NHSO2H, C(O)NHSO2R9, C(O)NR9SO2R9, cyclic C3-C7 alkylaminσ, imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more R9 groups, halo, OH, OR9, OC(O)R9, OC(O)NH2, OC(O)NHR9, OC(O)NR9R9, OP(O)(OH)2, OP(O)(OR9)2, NO2, NH2, NHR9, NR9R9, N+KOR9R9, NHC(O)H, NHC(O)R9, NR9C(O)R9, NHC(O)NH2, NHC(O)NR9R9, NR9C(O)NHR9, SH, SR9, S(O)H, S(O)R9, SO2R9, SO2NH2, SO2NHR9, SO2NR9R9, CF3, CN, CO2H, CO2R, CHO, C(O)R9, C(O)NH2, C(O)NHR9, C(O)NR9R9, C(O)NHSO2H, C(O)NHSO2R9, and C(O)NR9SO2R9; wherein each R9 is independently selected from C1-6 alkyl, C2-6 alkenyl, halo, OH, OMe, NO2, NH2, CF3, CN, CO2H or SH.
2 A compound as claimed in claim 1 wherein Z represents an optionally substituted 5-7 membered saturated ring system fused to the benzo ring in the 6,7-positions or the 7,8-positions; wherein the one or more optional substituents of the ring system are each independently selected from halo, Ci-C6 alkyl, OH, OCi-C6alkyl, OC(O)CrC6alkyl, OC(O)NH2, OC(O)NHC1-Cβalkyl, OC(O)N(d-C6alkyl)2, OP(O)(OH)2, OP(O)(O C1- C6alkyl)2, NO2, NH2, NHCrCβalkyl, N(CrC6alkyl)2, N+KO(C1-C6 alkyl)2, NHC(O)H, NHC(O)Ci-Cβalkyl, N(C1-Cβalkyl)C(O)Ci-Cβ alkyl, NHC(O)NH2, NHC(O)N (d-Cβalkylfc, NC1-C6 alkylC(O)NHCrCβ alkyl, SH, SC1-C6 alkyl, S(O)H, S(O)CrC6alkyl, SO2d-Cβalkyl, SO2NH2, SO2NHC1-C6 alkyl, SO2N(C1-C6 alkyl)2, CF3, CN, CO2H, CO2C1-C6 alkyl, CHO, C(O)C1-C6 alkyl, C(O)NH2, C(O)NHCrC6alkyl, C(O)N(C1-C6 a!kyl)2, C(O)NHSO2H, C(O)NHSO2C1-C6 alkyl, C(O)N(C1-C6 alkyl)SO2(CrC6 alkyl), cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the substituents are optionally substituted by one or more halo, C1-C6 alkyl, OH, O C1-C6 alkyl, and wherein the optionally substituted ring system includes one or more carbon atoms and/or one or more ring system moieties selected from O, NH, N(C1-C6 alkyl), CONH, CON(C1-C6 alkyl), NHCO, N(CrC6 alkyl)CO, wherein each C1-C6 alkyl is optionally substitued with one or more halo, C1-C6 alkyl, OH, OC1-C6 alkyl, OP(O)(OH)2, OP(O)(O C1-C6 alkyl)2, NO2, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, SH, S(C1-C6 alkyl), S(O)H, S(O)C1-C6 alkyl, SO2 C1- C6 alkyl, SO2NH2, CF3, CN, CO2H, CO2R, CHO, C(O) C1-C6 alkyl, C(O)NH2, C(O)NH C1- C6 alkyl, C(O)N(C1-C6 alkyl)2, C(O)NHSO2H1 C(O)NHSO2R8, C(O)NR8SO2R8, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl.
3 A compound as claimed in claim 1 or claim 2 wherein Z represents a 5, 6 or 7 membered ring, optionally substituted with one or more substituents selected from C1-6 alkyl wherein the alkyl is optionally substituted with one or more OH, NH and N(C1-C6 alkyl)2, and wherein the ring optionally includes one or more O, NH or N(C1-C6 alkyl) moieties.
4 A compound as claimed in any one of claims 1 to 3 wherein Z represents a 5, 6 or 7 membered ring, optionally substituted with CH3, CH2OH, N(CH3)2, CH2CH3, (CH2)2OH, and wherein the ring optionally includes one or more O, NH or N(C1-C6 alkyl) moieties.
5 A compound as claimed in any one of claims 1 to 4 wherein Z represents a 5 or 6 membered ring optionally substituted with CH3, CH2OH, N(CH3)2, CH2CH3, (CH2)2OH, and wherein the 5 or 6 membered ring is selected from the following:
Figure imgf000186_0001
6 A compound of any one of claims 1 to 5 wherein Z represents an unsubstituted 5 membered carbon ring. 7 A compound of any one of claims 1 to 6 wherein W represents -NH, or -CH2.
8 A compound of any one of claims 1 to 7 wherein A represents H or an optionally substituted Ci-6 alky! group or an optionally substituted C2-6 alkenyl group wherein the one or more optional substituents are each independently selected from halo, OH, OC1-6 alkyl, OC(O) C1-6 alkyl, OC(O)NH21 OC(O)NH CL6 alkyl, OC(O)N(CL6 alkyl)2, OP(O)(OH)2, OP(O)(O C1-6 alkyl)2, NO2, NH2, NHC1-6 alkyl, N(CL6 alkyl)2, NHC(O)H, NHC(O)C1-6 alkyl, NR2C(O)CL6 alkyl, NHC(O)NH2, NHC(O)N(CL6 alkyl)2, N(C1-6 alkyl)C(O)NHCL6 alkyl, CF3, CN, CO2H, CO2 C1-6 alkyl, CHO, C(O)C1-6 alkyl, C(O)NH2, C(O)NHC1-6 alkyl, C(O)N(C1-6 alkyl)2, CONHSO2H, C(O)NHSO2CL6 alkyl, C(O)NCL6 alkylSO2C1-6 alkyl, cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl; wherein each of the groups imidazolyl, piperazinyl, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl and azetidinyl are optionally substituted by one or more groups selected from halo, OH, OC1-6 alkyl, OC(O) CL6 alkyl, OC(O)NH21 OC(O)NH C1-6 alkyl, OC(O)N(CL6 alkyl)2, OP(O)(OH)2, OP(O)(OCL6 alkyl)2, NO2, NH2, NHC1-6 alkyl, N(C1-6 alkyl)2, NHC(O)H, NHC(O)C1-6 alkyl, NC1-6 alkylC(O)C1-6 alkyl, NHC(O)NH2, NHC(O)N(C1-6 alkyl)2, NC1-6 alkylC(O)NHC1-6 alkyl, CF3, CN, CO2H, CO2 C1-6 alkyl, CHO, C(O) C1-6 alkyl, C(O)NH2, C(O)NH C1-6 alkyl, C(O)N(C1-6 alkyl), CONHSO2H, C(O)NHSO2(C1-6 alkyl), and C(O)NC1-6 alkylSO2CL6 alkyl.
9 A compound of any one of claims 1 to 8 wherein A represents an optionally substituted -CrCealkyl, CrC6alkyl OH, -N(C1-C6alkyl)2, -N(C1-C6alkyl)OC1-C6alkyl, -C1- C6alkylN(CrC6alkyl)2, -CrCealkylNζCrCealkyl), CrCealkylOC^Cealkyl, -CrCealkylOCr C6alkyl, -CrC6alkylNazetidine, -C1-C6alkylOP(O)(OH)2, -CrCealkylNpyrrolidine, -CrCealkylNpiperidine, -CrC6alkyl N(2,6-(di CrC6alkyl)piperidine), -C1-
C6alkylNmorpholine, -CrCβalkylazepane, -CrCβalkylNoxazepine,
Figure imgf000187_0001
C1- C6alkylN(CrC6alkyl)2, CrCealkylOC^CrCsalkyKNCOaCrCealkyl) Chalky!, wherein the one or more substituents are each independently selected from OH, CrCεalkyl, OC1- Cβalkyl or CN.
10 A compound of any one of claims 1 to 6 wherein W and A together represent H, halo, NH2, NHCH2CH3, -CH2CH2CH2NMe2, -CH2CH2CH2OH, -NH(CH2)2N(Me)2, - NHCH2CH2OH,
-NHCH2CH2NEt2, -NHCH2CH2NPr2, -CH2CH2CH2N(Me)CH2CH2OMe, -N(CH2CH2OMe)2, -NHCH2CH2N(Me)CH2CH2CH2OMe, -NHCHaCHzNazetidine-S-OMe,
-CH2CH2CH2OP(O)(OH)2, -CH2CH2CH2Npyrrolidine, -NHCH2CH2Npiperidine, -NHCH2CH2N-(2,6-diMepiperidine), -CHaCHaCHaNazetidine-S-OMe, -NHCHaCHzCHzNpiperidine-S-OMe, -NHCHaCHzNpiperidine^-OMe, -CHzCHaCHzNpiperidine, -NHCH2CH2Nmorpholine, -NHCH2CH2Nazepane, -NHCH2CH2Noxazepine, -NHCHZCH2CH2OH, -NHCH2CH2CH2N(Me)CH2CH2OMe, -NHCHaCHzCHsNazetidineOMe, -NHCH2CH2CH2N(pyrrolidine-3-CN), -NHCHzCHaCHzNpiperidine-ΦOMe, -NHCHzCHzCHzNmorpholine, -NHCHzCHzCHzCHaNmorpholine, -CH2CH2CH2OC(O)CH2CH2CHN(Me)2, and -CH2CH2CH2OC(O)CH(NHCO2tBu)CH2Me2.
11 A compound as claimed in any one of claims 1 to 6 or 10 wherein W and A together represent halo, -NHCHzCHzCHzNmorpholine, -NHCH2CH2N(Me)2 or - CH2CH2CH2NMe2.
12 A compound as claimed in any one of claims 1 to 11 wherein each X on the benzo ring is H.
13 A compound or a pharmacologically acceptable salt thereof selected from the following: 8,9-Dihydro-7H-indeno[5,4-e][1 ,2,4]triazin-3-amine 1-oxide;
3-Chloro-8,9-dihydro-7H-indeno[5,4-e][1 ,2,4]triazine 1-oxide;
Λ/1,Λ/1-Dimethyl-Λ/2-(1-oxido-8,9-dihydro-7H-indeno[5,4-e][1 ,2,4]triazin-3-yl)-1 ,2- ethanediamine;
/V1,Λ/1-Dimethyl-Λ/2-(1 ,4-dioxido-8,9-dihydro-7H-indeno[5,4-e][1 ,2,4]triazin-3-yl)-1 ,2- ethanediamine;
A/1,/\/1-Diethyl-/V2-(1-ox!do-8,9-dihydro-7H-indeno[5,4-e][1,2,4]triazin-3-yl)-1 ,2- ethanediamine;
Λ/\Λ/1-Diethyl-Λ/2-(1 ,4-dioxido-8,9-dihydro-7H-indeno[5,4-e][1 ,2,4]triazin-3-yl)-1 ,2- ethanediamine; Λ/1-(1-Oxido-8,9-dihydro-7H-indeno[5,4-e][1 ,2,4]triazin-3-yl)-Λ/2,Λ/2-dipropyl-1 ,2- ethanediamine;
Λ/1-(1-Oxido-8,9-dihydro-7H-indeno[5,4-e][1 ,2,4]triazin-3-yl)-Λ/2,Λ/2-dipropyl-1 ,2- ethanediamine;
Λ/-[2-(1-Piperidinyl)ethyl]-8,9-dihydro-7H-indeno[5,4-e][1,2,4]triazin-3-amine 1-oxide; A/-[2-(1-Piperidinyl)ethyl]-8,9-dihydro-7A7-indeno[5,4-e][1 ,2,4]triazin-3-amine 1 ,4-dioxide;
Λ/-[3-(1-Morpholinyl)propyl]-8,9-dihydro-7/-/-indeno[5,4-e][1 ,2,4]triazin-3-amine 1-oxide; A/-[3-(1-Morpholinyl)propyl]-8,9-dihydro-7H-indeno[5,4-e][1,2,4]tria2in-3-amine 1 ,4-dioxide;
7,8-Dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 -oxide;
7,8-Dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 ,4-dioxide;
3-Chloro-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 -oxide; Λ/\N1-Dimethyl-Λ/2-(1-oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)-1 ,2- ethanediamine;
Λ/1-(1 ,4-Dioxido-7,8-dihydro-6/7-indeno[5,6-e][1 ,2,4]triazin-3-yl)-Λ/2,Λ/2-dimethyl-1 ,2- ethanediamine;
2-[(1-Oxido-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazin-3-yl)amino]ethanol; 2-[(1 ,4-Dioxido-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazin-3-yl)amino]ethanol;
Λ/1-(1-Oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)-Λ/2,Λ/2-diethyl-1 ,2- ethanediamine;
Λ/1-(1 ,4-Dioxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)-Λ/2,Λ/2-diethyl-1 ,2- ethanediamine; Λ/1-(1-Oxido-7,8-dihydro-6f/-indeno[5,6-e][1 ,2,4]triazin-3-yl)-Λ/2,Λ/2-dipropyl-1 ,2- ethanediamine;
Λ/1-(1 ,4-Dioxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)-Λ/2,Λ/2-dipropyl-1 ,2- ethanediamine;
Λ/1-(1-Oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)-Λ/2-(2-methoxyethyl)-Λ/2- methyl-1 ,2-ethanediamine;
Λ/1-(1 ,4-dioxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)-Λ/2-(2-methoxyethyl)-Λ/2- methyl-1 ,2-ethanediamine;
Λ/1 -(3-Methoxypropyl)-Λ/1 -methyl-Λ/2-( 1 -oxido-7 , 8-dihydro-6A7-indeno[5, 6-e][ 1 , 2,4]triazi n-3- yl)-1 ,2-ethanediamine; Λ/1-(1 ,4-Dioxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)-N2-(3-methoxypropyl)-Λ/2- methyl-1 ,2-ethanediamine;
Λ/-[2-(3-Methoxy-1 -azetidinyl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 - oxide;
Λ/-[2-(3-Methoxy-1-azetidinyl)ethyl]-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 ,4- dioxide;
Λ/-[2-(1 -Piperidinyl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 -oxide;
Λ/-[2-(1-Piperidinyl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 ,4-dioxide;
Λ/-[2-(2,6-Dimethyl-1-piperidinyl)ethyl]-7,8-dihydro-6/-/-indeno[5,6-e][1,2,4]triazin-3-amine
1 -oxide; Λ/-[2-(2,6-Dimethyl-1-piperidinyl)ethyl]-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazin-3-amine
1 ,4-dioxide; Λ/-[2-(3-Methoxy-1-piperidinyl)ethyl]-7,8-dihydro-6W-indeno[5,6-e][1 ,2,4]triazin-3-amine 1- oxide;
Λ/-[2-(3-Methoxy-1-piperidinyl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine
1 ,4-dioxide; Λ/-[2-(4-Methoxy-1 ~piperidinyl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 - oxide;
Λ/-[2-(4-Methoxy-1-piperidinyl)ethyl]-7,8-dihydro-6H-indeπo[5,6-e][1,2,4]triazin-3-amine
1 ,4-dioxide;
Λ/-[2-(4-Morpholinyl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 -oxide; /V-[2-(4-Morpholinyl)ethyl]-7,8-dihydro-6W-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 ,4-dioxide;
Λ/-[2-(1-Azepanyl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 -oxide;
Λ/-[2-(1-Azepanyl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 ,4-dioxide;
/V-[2-(1 ,4-Oxazepan-4-yl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 -oxide;
N-[Z-(1 ,4-Oxazepan-4-yl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 ,4- dioxide;
3-[(1-Oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)amino]-1-propanol;
3-[(1 ,4-Dioxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)amino]-1 -propanol;
/V1-(1-Oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)-Λ/3-(2-methoxyethyl)-/V3- methyl-1 ,3-propanediamine; Λ/1-(1 ,4-Dioxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)-Λ/3-(2-methoxyethyl)-Λ/3- methyl-1 ,3-propanediamine;
Λ/-[3-(3-Methoxy-1 -azetidinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 - oxide;
Λ/-[3-(3-Methoxy-1-azetidinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 ,4-dioxide;
1-{3-[(1-Oxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-yl)amino]propyl}-3- pyrrolidinecarbonitrile;
1-{3-[(1,4-Dioxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)amino]propyl}-3- pyrrolidinecarbonitrile; Λ/-[3-(4-Methoxy-1-piperidinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine
1 -oxide;
Λ/-[3-(4-Methoxy-1-piperidinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine
1 ,4-dioxide;
Λ/-[3-(4-Morpholinyl)propyl]-7,8-dihydro-6f/-indeno[5,6-e][1 ,2,4]triazin-3-amine 1-oxide; Λ/-[3-(4-Morpholinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 ,4-dioxide;
Λ/-[4-(4-Morpholinyl)butyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1-oxide; /V-[4-(4-Morpholinyl)butyl]-7,8-dihydro-6f/-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 ,4-dioxide;
7,8-Dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 -oxide;
7,8-Dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 ,4-dioxide;
3-lodo-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 -oxide; Ethyl-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triaziπe 1 -oxide;
3-Ethyl-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 ,4-dioxide;
3-Allyl-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazine 1 -oxide;
3-(1 -Oxido-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazin-3-yl)-1 -propanol;
3-(1,4-Dioxido-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazin-3-yl)-1-propanol; 3-(3-(Di-fert-butoxyphosphoryloxy)propyl)-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazine 1- oxide;
3-(3-(Di-fert-butoxyphosphoryloxy)propyl)-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 ,4- dioxide;
3-(1 ,4-Dioxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)propyl dihydrogen phosphate;
3-[3-(4-Morpholinyl)propyl]-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazine 1 -oxide;
3-[3-(4-Morpholinyl)propyl]-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazine 1 ,4-dioxide;
Λ/,Λ/-Dimethyl-3-(1-oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)-1-propanamine;
Λ/-[3-(1 ,4-Dioxido-7,8-dihydro-6H-indeno[5t6-e][1 ,2,4]triazin-3-yl)propyl]-Λ/,Λ/- dimethylamine;
/V,Λ/-Bis(2-methoxyethyl)-3-(1-oxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-yl)-1- propanamine;
Λ/-[3-(1,4-Dioxido-7,8-dihydro-6/-/-indeno[5,6-e][1,2,4]triazin-3-yl)propyl]-Λ/,Λ/-bis(2- methoxyethyl)amine; 3-[3-(3-Methoxy-1-azetidinyl)propyl]-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazine 1-oxide;
3-[3-(3-Methoxy-1-azetidinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 ,4- dioxide;
3-[3-(1-Pyrrolidinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1-oxide;
3-[3-(1-Pyrrolidinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 ,4-dioxide; 3-[3-(1-Piperidinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1-oxide;
3-[3-(1-Piperidinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 ,4-dioxide;
7-Methyl-7,8-dihydro-6/-/-indeno[5,6-e][1,2,4]triazin-3-amine 1-oxide;
3-Chloro-7-methyl-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazine 1 -oxide;
Λ/1,Λ/1-Dimethyl-Λ/2-(7-methyl-1-oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)-1 ,2- ethanediamine; Λ^.Λ^-Dimethyl-Λ^-Cy-methyl-i^^ioxido-Z.β-dihydro-βH-indenotS.β-elli .Z^ltriazin-S-yl)-
1 ,2-ethanediamine;
7-Methyl-Λ/-[3-(4-morpholinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e3[1 ,2,4]triazin-3-amine 1- oxide; 7-Methyl-Λ/-[3-(4-morpholinyl)propyl]-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazin-3-amine
1 ,4-dioxide;
3-lodo-7-methyl-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 -oxide;
3-(7-Methyl-1-oxido-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazin-3-yl)propanal;
7-Methyl-3-[3-(4-morpholinyl)propyl]-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazine 1 -oxide; 7-Methyl-3-[3-(4-morpholinyl)propyl]-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazine 1 ,4- dioxide;
3-(7-Methyl-1 ,4-dioxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-yl)-1-propanol;
Λ/7,Λ/7-Dimethyl-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine-3,7-diamine 1 -oxide;
3-Chloro-Λ/,Λ/-dimethyl-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-7-amine 1-oxide; Λ/3-Ethyl-Λ/7,Λ/7-dimethyl-7,8-dihydro-6/-/-indeno[5,6-e][1,2,4]triazine-3,7-diamine 1-oxide;
Λ/3-Ethyl-Λ/7,Λ/7-dimethyl-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine-3,7-diamine 1 ,4- dioxide;
7-(Dimethylamino)-3-ethyl-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1-oxide;
7-(Dimethylamino)-3-ethyl-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 ,4-dioxide; (3-Amino-1-oxido-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazin-7-yl)methanol;
(3-Bromo-1-oxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-7-yl)methanol;
[3-(Ethylamino)-1-oxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-7-yl]methanol;
[3-(Ethylamino)-1 ,4-dioxido-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-7-yl]methanol;
7-({[tenf-Butyl(dimethyl)silyl]oxy}methyl)-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1-oxide;
7-({[ferf-Butyl(dimethyl)silyl]oxy}methyl)-3-iodo-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine
1-oxide;
7-({[fert-Butyl(dimethyl)silyl]oxy}methyl)-3-ethyl-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine
1 -oxide; (3-Ethyl-1 ,4-dioxido-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazin-7-yl)methanol;
3-Allyl-7-({[te/f-butyl(dimethyl)silyl]oxy}methyl)-7,8-dihydro-6/-/-indeno[5,6-e][1,2,4]triazine
1-oxide;
3-[7-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-1-oxido-7,8-dihydro-6H-indeno[5,6- e][1 ,2,4]triazin-3-yl]-1 -propanol; 7-({[te/if-Butyl(dimethyl)silyl]oxy}methyl)-3-[3-(4-morpholinyl)propyl]-718-dihydro-6H- indeno[5,6-e][1 ,2,4]triazine 1-oxide; {3-[3-(4-Morpholinyl)propyl]-1-oxido-7,8-dihydro-6/-/-indeπo[5,6-e][1 ,2,4]triazin-7- yljmethanol;
{3-[3-(4-Morpholinyl)propyl]-1 ,4-dioxido-7,8-dihydro-6/-/-indeno[5,6-e][1,2,4]triazin-7- yl}methanol; (3-Ethyl-1-oxido-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazin-7-yl)methanol;
3-Ethyl-7-(4-morpholinylmethyl)-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 -oxide;
3-Ethyl-7-(4-morpholinylmethyl)-7,8-dihydro-6/-/-indeno[5I6-e][1 ,2,4]triazine 1 ,4-dioxide;
2-(3-Amino-1-oxido-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazin-7-yl)ethanol;
2-(3-lodo-1-oxido-7,8-dihydro-6W-indeno[5,6-e][1 ,2,4]triazin-7-yl)ethanol; 3-lodo-7-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-7,8-dihydro-6/-/-indeno[5,6- e][1 ,2,4]triazine 1 -oxide;
3-Ethyl-7-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-7,8-dihydro-6H-indeno[5,6- e][1 ,2,4]triazine 1 -oxide;
2-(3-Ethyl-1-oxido-7,8-dihydro-6/-/-indeno[5,6-e][1,2,4]triazin-7-yl)ethanol; 2-(3-Ethyl-1 ,4-dioxido-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-7-yl)ethaπol;
3-Ethyl-7-[2-(4-morpholinyl)ethyl]-7,8-dihydro-6W-indeno[5,6-e][1 ,2,4]triazine 1 -oxide;
3-Ethyl-7-[2-(4-morpholinyl)ethyl]-7,8-dihydro-6/-/-indeno[5,6-e][1 ,2,4]triazine 1 ,4-dioxide;
7,8,9, 10-Tetrahydronaphtho[2, 1 -e][1 ,2,4]triazin-3-amine 1 -oxide;
3-Chloro-7,8,9, 10-tetrahydronaphtho[2, 1 -e][1 ,2,4]triazine 1 -oxide; ^.Λ/^Dimethyl-Λ/^i-oxido^.δ.g.iO-tetrahydronaphthop.i-elti^^triazin-S-yO-i ^- ethanediamine;
A/1-(1 ,4-Dioxido-7,8,9, 10-tetrahydronaphtho[2, 1 -e][1 ,2,4]triazin-3-yl)-Λ/2,Λ/2-dimethyl-1 ,2- ethanediamine;
6,7,8,9-Tetrahydronaphtho[2,3-e][1 ,2,4]triazin-3-amine 1-oxide; 3-Chloro-6,7,8,9-tetrahydronaphtho[2,3-e][1,2,4]triazine 1-oxide;
Λ/1-(1-Oxido-6,7,8,9-tetrahydronaphtho[2,3-e][1 ,2,4]triazin-3-yl)-Λ/2,Λ/2-dimethyl-1 ,2- ethanediamine;
Λ/1-(1 ,4-Dioxido-6,7,8,9-tetrahydronaphtho[2,3-e][1 ,2,4]triazin-3-yl)-Λ/2,Λ/2-dimethyl-1 ,2- ethanediamine; Λ/-[3-(4-Morpholinyl)propyl]-6,7,8,9-tetrahydronaphtho[2,3-e][1 ,2,4]triazin-3-amine 1-oxide;
Λ/-[3-(4-Morpholinyl)propyl]-6,7,8,9-tetrahydronaphtho[2,3-e][1 ,2,4]triazin-3-amine 1 ,4- dioxide;
7,8,9, 10-Tetrahydro-6Ay-cyclohepta[g][1,2,4]benzotriazin-3-amine 1-oxide;
3-Chloro-7,8,9,10-tetrahydro-6/-/-cyclohepta[g][1 ,2,4]benzotriazine 1-oxide; ^.A/^Dimethyl-Λ/^CI-oxido^.δ^.iO-tetrahydro-ΘH-cycloheptatglli ^.^benzotriazin-S-yl)-
1 ,2-ethanediamine; Λ/1-(1 ,4-Dioxido-7,8,9, 10-tetrahydro-6H-cyclohepta[g][1 ,2,4]benzotriazin-3-yl)-Λ/2,Λ/2- dimethyl-1 ,2-ethanediamine;
6,7-Dihydrofuro[3,2-g][1 ,2,4]benzotriazin-3-amine 1 -oxide; 3-Chloro-6,7-dihydrofuro[3,2-g][1 ,2,4]benzotriazine 1 -oxide; N\N1-Dimethyl-Λ/z-(1-oxido-6,7-dihydrofuro[3,2-g][1 ,2,4]benzotriazin-3-yl)-1 ,2- ethanediamine;
Λ/1-(1 ,4-Dioxido-6,7-dihydrofuro[3,2-g][1 ,2,4]benzotriazin-3-yl)-Λ/2,Λ/2-dimethyl-1 ,2- ethanediamine; Λ/-[3-(4-Morpholinyl)propyl]-6,7-dihydrofuro[3,2-g][1 ,2,4]benzotriazin-3-amine 1-oxide; /V-[3-(4-Morpholinyl)propyl]-6,7-dihydrofuro[3,2-g][1 ,2,4]benzotriazin-3-amine 1 ,4-dioxide; 3-Amino-7,8-dihydrobenzofuro[6,5-e][1 ,2,4]triazine 1-oxide; 1 ,4-Dioxido-7,8-dihydrofuro[2,3-g][1 ,2,4]benzotriazin-3-ylamine; 3-Chloro-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1-oxide; Λ/1-(1-Oxido-7,8-dihydrofuro[2,3-g][1 ,2,4]benzotriazin-3-yl)-Λ/2,Λ/2-dimethyl-1 ,2- ethanediamine;
Λ/1-(1 ,4-Dioxido-7,8-dihydrofuro[2,3-g][1 ,2,4]benzotriazin-3-yl)-Λ/2,Λ/2-dimethyl-1 ,2- ethanediamine;
Λ/1-(1-Oxido-7,8-dihydrofuro[2,3-g][1 ,2,4]benzotriazin-3-yl)-Λ/2,Λ/2-diethyl-1 ,2- ethanediamine; Λ/1-(1 ,4-Dioxido-7,8-dihydrofuro[2,3-g][1 ,2,4]benzotriazin-3-yl)-Λ/2,Λ/2-diethyl-1 ,2- ethanediamine;
Λ/-[3-(4-Morpholinyl)propyl]-7,8-dihydrofuro[2,3-g][1 ,2,4]benzotriazin-3-amine 1 -oxide; Λ/-[3-(4-Morpholinyl)propyl]-7,8-dihydrofuro[2,3-g][1 ,2,4]benzotriazin-3-amine 1 ,4-dioxide; 3-lodo-7,8-dihydrobenzofuro[6,5-e][1 ,2,4]triazine 1-oxide; 3-(1-Oxido-7,8-dihydrofuro[2,3-g][1 ,2,4]benzotriazin-3-yl)propanal;
3-[3-(4-Morpholinyl)propyl]-7,8-dihydrofuro[2,3-g][1 ,2,4]benzotriazine 1-oxide; 3-[3-(4-Morpholinyl)propyl]-7,8-dihydrofuro[2,3-g][1 ,2,4]benzotriazine 1 ,4-dioxide; [1 ,3]Dioxolo[4,5-g][1 ,2,4]benzotriazin-3-amine 1-oxide; 3-Chloro[1 ,3]dioxolo[4,5-g][1 ,2,4]benzotriazine 1-oxide; Λ/1,Λ/1-Dimethyl-Λ/2-(1-oxido[1 ,3]dioxolo[4,5-g][1 ,2,4]benzotriazin-3-yl)-1 ,2-ethanediamine; Λ/1-(1 ,4-Dioxido[1 ,3]dioxolo[4,5-g][1 ,2,4]benzotriazin-3-yl)-Λ/2,Λ/2-dimethyl-1 ,2- ethanediamine;
9,10-Dihydro-8/-/-chromeno[6,5-e][1 ,2,4]triazin-3-amine 1-oxide; 3-Chloro-9,10-dihydro-8/-/-chromeno[6,5-e][1,2,4]triazine 1-oxide; Λ/1,Λ/1-Dimethy!-Λ/2-(1-oxido-9,10-dihydro-8H-chromeno[6,5-e][1,2,4]triazin-3-yl)-1 ,2- ethanediamine; Λ/1-(1 ,4-Dioxido-9,10-dihydro-8H-chromeno[6,5-e][1,2,4]triazin-3-yl)-Λ/2,Λ/2-dimethyl-1,2- ethanediamine;
7,8-Dihydro-6/-/~chromeno[6,7-e][1 ,2,4]triazin-3-amine 1 -oxide;
3-Chloro-7,8-dihydro-6H-chromeno[6,7-e][1 ,2,4]tria2ine 1 -oxide; Λ/1,W1-Dimethyl-Λ/z-(1-oxido-7)8-clihydro-6H-chromeno[6t7-θ][1 ,2,4]triazin-3-yl)-1 ,2- ethanediamine;
Λ/1-(1 ,4-Dioxido-7,8-dihydro-6H-chromeno[6,7-e][1 ,2,4]triazin-3-yl)-Λ/2,Λ/2-dimethyl-1 ,2- ethanediamine;
/V-[3-(4-Morpholinyl)propyl]-7,8-dihydro-6H-chromeno[6,7-e][1 ,2,4]triazin-3-amine 1-oxide; Λ/-[3-(4-Morpholinyl)propyl]-7,8-dihydro-6H-chromeno[6,7-e][1 ,2,4]triazin-3-amine 1 ,4- dioxide;
7-Ethyl-1-oxido-7,8-dihydro-6H-[1 ,2,4]triazino[5,6-flisoindol-3-ylamine;
7-Ethyl-1 ,4-dioxido-7,8-dihydro-6H-[1 ,2,4]triazino[5,6-flisoindol-3-ylamine;
7-Methyl-6,7,8,9-tetrahydro[1 ,2,4]triazino[6,5-gr]isoquinolin-3-amine 1 -oxide; 3-Chloro-7-methyl-6,7,8,9-tetrahydro[1,2,4]triazino[6,5-g]isoquinoline 1 -oxide;
Λ/-Ethyl-7-methyl-6,7,8,9-tetrahydro[1,2,4]triazino[6,5-g]isoquinolin-3-amine 1-oxide;
Λ/-Ethyl-7-methyl-6,7,8,9-tetrahydro[1 ,2,4]triazino[6,5-g]isoquinolin-3-amine 1 ,4-dioxide;
3-Ethyl-7-methyl-6,7,8,9-tetrahydro[1 ,2,4]triazino[6,5-g]isoquinoline 1-oxide;
3-Ethyl-7-methyl-6,7,8,9-tetrahydro[1 ,2,4]triazino[6,5-g]isoquinoline 1 ,4-dioxide; θ-Methyl^.δ^.iO-tetrahydroIi ^^ltriazinotδ.δ-ftlisoquinolin-S-amine 1-oxide;
3-Chloro-9-methyl-7,8,9,10-tetrahydro[1 ,2,4]triazino[5,6-h]isoquinoline 1-oxide;
3-Ethyl-9-methy!-7,8,9,10-tetrahydro[1 ,2,4]triazino[5,6-/7]isoquinoline 1-oxide;
3-Ethyl-9-methyl-7,8,9,10-tetrahydro[1 ,2,4]triazino[5,6-/7]isoquinoline 1 ,4-dioxide;
3-(3-(4-(Dimethylamino)butanoyloxy)propyl)-7,8-dihydro-6Ay-indeno[5,6-e][1 ,2,4]triazine 1- oxide; and
3-(3-(2-(teAf-Butoxycarbonylamino)-3-methylbutanoyloxy)propyl)-7,8-dihydro-6/-/- indeno[5,6-e][1,2,4]triazine 1-oxide.
14 A compound of Formula I as claimed in any one of claims 1 to 13 selected from 3- [3-(4-Morpholinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazine 1 ,4-Dioxide or N-[Z-
(4-Morpholinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1 ,2,4]triazin-3-amine 1 ,4-dioxide,
15 A method of therapy for treating cancers including the step of administering a compound of Formula I as defined in any one of claims 1 to 14 in a therapeutically effective amount to a subject having tumour cells. 16 The method as claimed in claim 15 wherein the subject's tumour cells are in a hypoxic environment.
17 The method as claimed in claim 15 or claim 17 including the further step of administering radiotherapy to the subject before, during or after the administration of the compound of Formula I.
18 The method as claimed in any one of claims 15 to 17 further including the step of administering one or more chemotherapeutic agents to the subject before, during or after the administration of the compound of Formula I.
19 The method as claimed in claim 18 wherein the one or more chemotherapeutic agents are selected from Cisplatin or other platinum-based derivatives, Temozolomide or other DNA methylating agents, Cyclophosphamide or other DNA alkylating agents, Doxorubicin, mitoxantrone, camptothecin or other topoisomerase inhibitors, Methotrexate, gemcitabine or other antimetabolites and Docetaxel or other taxanes.
20 The method as claimed in any one of claims 15 to 19 wherein the subject is human.
21 A pharmaceutical composition including a therapeutically effective amount of a compound of formula I as defined in any one of claims 1 to 14 and a pharmaceutically acceptable excipient, adjuvant, carrier, buffer or stabiliser.
22 The use in the manufacture of a medicament of a therapeutically effective amount of a compound of Formula I as defined in any one of claims 1 to 14 or a therapeutically effective composition as defined in claim 21 for treating a subject having tumour cells.
23 The use as claimed in claim 22 wherein the subject's tumour cells are in a hypoxic environment.
24 The use as claimed in claim 22 or claim 23, wherein the medicament is further adapted so as to allow radiotherapy to be additionally administered to the subject before, during or after the administration of the medicament. 25 The use as claimed in any one of claims 22 to 24, wherein the medicament is further adapted so as to allow one or more chemotherapeutic agents to be additionally administered to the subject before, during or after the administration of the medicament.
26 The use as claimed in claim 25 wherein the one or more chemotherapeutic agents are selected from Cisplatin or other platinum-based derivatives, Temozolomide or other DNA methylating agents, Cyclophosphamide or other DNA alkylating agents, Doxorubicin, mitoxantrone, camptothecin or other topoisomerase inhibitors, Methotrexate, gemcitabine or other antimetabolites and Docetaxel or other taxanes.
27 The use as claimed in any one of claims 22 to 26 wherein the subject is human.
28 A method of improving the response of a tumour in a subject to radiotherapy, comprising the steps of: (a) administering to the subject a pharmaceutical composition comprising a compound of Formula I as defined in any one of claims 1 to 14 in an amount sufficient to kill or radiosensitise hypoxic cells in tumours, and (b) subjecting the tumour to radiation either before or after administration of the said pharmaceutical composition.
29 The method as claimed in claim 28 wherein the subject is human.
30 A method of making a compound of Formula I or a pharmacologically acceptable salt thereof,
Figure imgf000197_0001
Formula I
wherein, n, X, Z, W and A are as defined in any one of claims 1 to 14, the method including the steps of reacting a nitroaniline compound of Formula
Figure imgf000197_0002
Formula Il wherein X and Z are as defined above for a compound of Formula I, with cyanamide followed by a cyclisation step under basic conditions to give a mono-oxide compound of Formula I where n represents 0 and of optionally oxidising the mono-oxide compound of Formula I to form a dioxide compound of Formula I where n represents 1.
31 The method as claimed in claim 30 further including the steps of converting a monoxide of Formula III
Figure imgf000198_0001
Formula III wherein X and Z are as defined above for a compound of Formula I; to a mono-oxide compound of Formula IV
Figure imgf000198_0002
Formula IV wherein X and Z are as defined above for a compound of Formula III and W and A are as defined in claim 30 and together represent other than halo; and of optionally oxidising the resulting mono-oxide compound to form a dioxide compound of Formula I
Figure imgf000198_0003
Formula I where n represents 1 and X, Z, W and A are as defined in claim 30.
32 The method as claimed in claim 31 , wherein halo of Formula III represents chloro, bromo or iodo.
33 A method of making a compound of Formula I as defined in any one of claims 1 to 14 including the step of reacting a nitroaniline compound of Formula Il
Figure imgf000199_0001
Formula Il Formula V wherein X and Z are as defined in claim 1 for a compound of Formula I, with sodium hypochlorite in the presence of a base to form a furoxan of Formula V wherein X and Z are as defined in claim 1 for a compound of Formula I, and reacting the compound of Formula V with a substituted cyanamide to give a dioxide compound of Formula I where n represents 1.
34 A method of making a compound of Formula I as defined in claim 30 with reference to Schemes 1 to 37 and 52.
35 A compound of Formula I obtained by the method as claimed in any one of claims 30 to 34.
PCT/NZ2006/000064 2005-03-31 2006-03-31 Tricyclic 1,2,4-triazine oxides and compositions therefrom for therapeutic use in cancer treatments WO2006104406A1 (en)

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AT06733153T ATE491695T1 (en) 2005-03-31 2006-03-31 TRICYLIC 1,2,4-TRIAZINE OXIDES AND COMPOSITIONS THEREOF FOR THERAPEUTIC USE IN CANCER TREATMENT
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WO2014187744A1 (en) 2013-05-23 2014-11-27 Bayer Pharma Aktiengesellschaft Pharmaceutical composition and the use thereof, and application regime of said pharmaceutical composition for on-demand contraception
WO2015091645A1 (en) 2013-12-18 2015-06-25 Basf Se Azole compounds carrying an imine-derived substituent

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