WO2007001139A1 - A composition for treating or preventing a cancer comprising pyrrolopyridine derivatives - Google Patents

A composition for treating or preventing a cancer comprising pyrrolopyridine derivatives Download PDF

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Publication number
WO2007001139A1
WO2007001139A1 PCT/KR2006/002453 KR2006002453W WO2007001139A1 WO 2007001139 A1 WO2007001139 A1 WO 2007001139A1 KR 2006002453 W KR2006002453 W KR 2006002453W WO 2007001139 A1 WO2007001139 A1 WO 2007001139A1
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Prior art keywords
pyrrolo
dimethyl
hydrochloride
pyridine hydrochloride
pyridine
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PCT/KR2006/002453
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French (fr)
Inventor
Jae-Gyu Kim
Suk-Won Yoon
Young-Ae Yoon
Hyak-Woo Lee
Dong-Hoon Kim
Myung-Hun Cha
Yoo-Hoi Park
Byung-Nak Ahn
Heui-Il Kang
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Yuhan Corporation
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Publication of WO2007001139A1 publication Critical patent/WO2007001139A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a composition for treating or preventing a cancer comprising a pyrrolopyridine derivative or its salt and a pharmaceutically acceptable carrier.
  • the pyrrolopyridine ring includes pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine, or pyrrolo[3,2-b]pyridine.
  • composition for treating or preventing a cancer comprising a compound of formula (I) or its salt and a pharmaceutically acceptable carrier.
  • composition for treating or preventing a cancer comprising a compound of formula (I) or its salt and a pharmaceutically acceptable carrier: [8]
  • A, B, and D are, independently, N or CH; and one of A, B, and D is N and the others are CH, [11] R is hydrogen; a straight or branched C -C alkyl group; a straight or branched C -
  • R 2 is a C 1 -C 3 alkyl group
  • R is a C -C alkyl group or a benzyl group
  • R is hydrogen; an aminocarbonyl group optionally substituted with C -C cycloalkyl, and
  • R is a naphthyl group; a 1,2,3,4-tetrahydroisoquinolinyl group optionally substituted with C -C alkyl; a benzylamino group optionally one or two substituted with halogen; a benzyloxy group optionally substituted with one or two groups independently selected from the group consisting of halogen, trifluoromethyl, C -C alkyl, and C -C alkoxy; a phenyl-C -C alkyl group; a phenyl group; a methylsulfanylphenyl group; or a benzo[l,3]dioxolylmethoxy.
  • composition of the present invention preferably comprises those wherein
  • R is hydrogen; a straight or branched C -C alkyl group; a methyl group substituted
  • R is hydrogen
  • R is a naphthyl group; a 1,2,3,4-tetrahydroisoquinolinyl group optionally substituted with C -C alkyl; a benzylamino group; a benzyloxy group optionally substituted with one or two groups independently selected from the group consisting of halogen and C -C alkyl; or a phenyl-C -C alkyl group.
  • composition of the present invention also preferably comprises those wherein
  • A is N
  • both B and D are CH
  • R is a naphthyl group; a benzyloxy group optionally substituted with one or two groups independently selected from the group consisting of halogen, trifluoromethyl, C -C alkyl, and C -C alkoxy; a phenyl-C -C alkyl group; a methylsulfanylphenyl group; or a benzo[l,3]dioxolylmethoxy.
  • composition of the present invention also preferably comprises those wherein B is N, and both A and D are CH.
  • composition of the present invention also preferably comprises those wherein
  • both A and B are CH
  • R is a 1,2,3,4-tetrahydroisoquinolinyl group optionally substituted with C -C alkyl; a benzyloxy group optionally substituted with one or two groups independently selected from the group consisting of halogen, trifluoromethyl, C -C alkyl, and C -C alkoxy; a phenyl-C -C alkyl group; or a benzo[l,3]dioxolylmethoxy.
  • the compounds of formula (I) may be pharmaceutically acceptable non-toxic salt forms.
  • the non-toxic salts may include conventional acid addition salts used in the field of anti-cancer agents, e.g., salts originated from an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfonic acid, sulfamic acid, phosphoric acid, or nitric acid, and an organic acid such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, citric acid, maleic acid, malonic acid, methanesulfonic acid, tartaric acid, malic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, oxalic acid, or trifluoroacetic acid.
  • the non-toxic salts include conventional metal salt forms, e.g., salts originated from a metal
  • the compound of formula (I) or its salt may be prepared in accordance with the processes disclosed in WO 2006/025714, WO 2006/025715, WO 2006/025716, WO 2006/025717, and WO 2006/038773.
  • the compound of formula (I) or its salt may be prepared using a process which comprises: reacting a compound of formula (II) with a compound of formula (III) to obtain a compound of formula (Ia) and reacting the compound of formula (Ia) with R -X to obtain a compound of formula (I), in accordance with the following Reaction Scheme 1 described below:
  • the compound of formula (II) may be prepared using a known method (e.g., Tetrahedron 1987, 43, 2557, Tetrahedron 1990, 54, 6311, Eur. J. Med. Chem. 1996, 31,359 and /. Med. Chem. 1995, 38(20), 4131) and the compound of formula (III) is commercially available.
  • a known method e.g., Tetrahedron 1987, 43, 2557, Tetrahedron 1990, 54, 6311, Eur. J. Med. Chem. 1996, 31,359 and /. Med. Chem. 1995, 38(20), 4131
  • the compound of formula (III) is commercially available.
  • reaction of the compound of formula (II) and the compound of formula (III) may be performed in an anhydrous aprotic polar organic solvent, e.g., anhydrous tetrahydrofuran. Further, the reaction may be carried out at room temperature or at a temperature of -78 0 C ⁇ 0 0 C.
  • the compound of formula (Ia) is reacted with R -X to obtain a compound of formula (I).
  • the reaction of the compound of formula (Ia) and R -X may be performed in the presence of a base, such as sodium hydride or potassium te ⁇ t-butoxide. Further, the reaction may be carried out in an organic solvent, such as tetrahydrofuran or N,N - dimethylformamide, and at room temperature or at a temperature of 40 0 C ⁇ 100 0 C. In order to increase a reaction rate and/or a yield of the reaction, a catalytic amount of 18-crown-6 may be used.
  • the compound of formula (I) or its salt may be prepared using a process which comprises: (a) cyclizing the compound of formula (IV) to obtain a compound of formula (V); (b) halogenizing the compound of formula (V) to obtain a compound of (VI); (c) reacting the compound of formula (VI) with R -Y to obtain a compound of formula (Ia); and (d) reacting the compound of formula (Ia) with R -X to obtain a compound of formula (I), in accordance with the following Reaction Scheme 2 described below:
  • Y is hydrogen or boronic acid.
  • the compound of formula (IV) may be prepared using a known method (e.g., Tetrahedron, 1976, 32(12), 1383)
  • the cylization of the compound of formula (IV) may be carried out by refluxing the compound of formula (IV) in an organic solvent, e.g., diphenyl ether having a high boiling point.
  • organic solvent e.g., diphenyl ether having a high boiling point.
  • the compound of formula (V) may be converted to the compound of formula (VI), by refluxing the compound of formula (V) with a halogenizing agent, e.g., phosphorus oxychloride.
  • a halogenizing agent e.g., phosphorus oxychloride.
  • the compound of formula (Ia) is reacted with R -X to obtain a compound of formula (I).
  • the reaction of the compound of formula (Ia) and R -X may be performed in the presence of a base, such as sodium hydride or potassium te ⁇ t-butoxide. Further, the reaction may be carried out in an organic solvent, such as tetrahydrofuran or N, N - dimethylformamide, and at room temperature or at a temperature of 40 0 C ⁇ 100 0 C. In order to increase a reaction rate and/or a yield of the reaction, a catalytic amount of 18-crown-6 may be used.
  • composition of the present invention may include additives such as lactose or corn starch, lubricants such as magnesium stearate, emulsifiers, suspending agents, stabilizers, and isotonic agents. If necessary, sweetening agents and/or flavoring agents may be added.
  • additives such as lactose or corn starch
  • lubricants such as magnesium stearate, emulsifiers, suspending agents, stabilizers, and isotonic agents. If necessary, sweetening agents and/or flavoring agents may be added.
  • composition of the present invention may be administered orally or par- enterally, including intravenous, intraperitoneal, subcutaneous, rectal and topical routes of administration. Therefore, the composition of the present invention may be formulated into various forms such as tablets, capsules, aqueous solutions or suspensions.
  • carriers such as lactose, corn starch, and lubricating agents, e.g. magnesium stearate, are commonly added.
  • lactose and/or dried corn starch can be used as a diluent.
  • the active ingredient may be combined with emulsifying and/or suspending agents.
  • composition of the present invention may be in the form of an aqueous solution containing pharmaceutically acceptable carriers, e.g., saline, at a pH level of 7.4.
  • pharmaceutically acceptable carriers e.g., saline
  • the composition of the present invention may be administered for prevention and treatment of various cancers, such as gastric cancer, large intestininal carcinoma, colonic carcinoma, rectal cancer, pancreatic carcinoma, myelogenous leukemia, etc.
  • the compounds or its salt in the composition of the present invention may be administered in an effective amount ranging from about 0.1 mg/kg to about 20 mg/kg per day, preferably from about 0.5 mg/kg to about 10 mg/kg per day, to a subject patient.
  • the dosage may be changed according to the patient's age, weight, susceptibility, or symptom.
  • Step 2 (4-fluorobenzyl)-(3-nitropyridin-4-yl)-carbamic acid ?-butyl ester
  • Step 3 (2,3-dimethyl-lH-pyrrolo[3,2-b]pyridin-7-yl)-(4-fluorobenzyl)-carbamic acid ?-butyl ester
  • Step 4 of Preparation 4 using 3-(4-fluorobenzyloxy)-4-nitropyridine-N-oxide prepared in Step 1. The product was used in subsequent steps without further purification.
  • Step 2 4-( ⁇ / 7 -sec-butylidenhydrazino)-lH-pyridin-2-one
  • Step 2 was added to 200ml of diphenyl ether.
  • the reaction mixture was refluxed for 5 hours and then cooled to room temperature.
  • 200ml of n-hexane was added to the reaction mixture, which was then stirred and filtered.
  • the isolated solid was re- crystallized with methanol to give the titled compound (10.9 g, 73.2 %) as a pale yellow solid.
  • Step 3 1 -methyl- 1, 2,3, 4-tetrahydroisoquinoline
  • Step 2 l-(3-methylbut-2-enyl)-7-(l,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl- lH-pyrrolo[3,2-b]pyridine hydrochloride
  • the resulting residue was dissolved in ImI of ethyl acetate and then saturated with hydrochloric acid gas.
  • the resulting precipitate was filtered and then dried to give the titled compound (6.9 mg, 15.8 %) as a white solid.
  • Step 1 (l-allyl-2,3-dimethyl-lH-pyrrolo[3,2-b] pyridin-
  • Step 2 (l-allyl-2,3-dimethyl-lH-pyrrolo[3,2-b] pyridin-
  • Step 2 7-(4-fluorobenzyloxy)-l-isobutyl-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridine hydrochloride
  • the titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-fluorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 1 and l-iodo-2-methylpropane. (Yield: 86.0
  • Example 4 7-(4-fluorobenzyloxy)-2,3-dimethyl-l-(prop-2-ynyl) - 1 H- pyrrolo[3,2-b]pyridine hydrochloride [263] The titled compound was obtained as a pale yellow solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-fluorobenzyloxy)-2,3-dimethyl- lH-pyrrolo[3,2-b]pyridine prepared in Step 1 of Example 3 and propargyl bromide.
  • Example 5 l-benzyl-7-(4-fluorobenzyloxy)-2,3-dimethyl - 1 H- pyrrolo[3,2-b] pyridine hydrochloride [267] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-fluorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 1 of Example 3 and benzyl bromide. (Yield:
  • Example 6 l-cyclobutylmethyl-7-(4-fluorobenzyloxy)-2,3-dimethyl - 1 H- pyrrolo[3,2-b]pyridine hydrochloride [271] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-fluorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 1 of Example 3 and
  • Example 8 7-(4-fluorobenzyloxy)-l-propyl-2,3-dimethyl - 1 H- pyrrolo[3,2-b] pyridine hydrochloride
  • the titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-fluorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 1 of Example 3 and 1-iodopropane. (Yield:
  • Example 10 l-(2-fluorobenzyl)-7-(4-fluorobenzyloxy)-2,3-dimethyl - 1 H- pyrrolo[3,2-b]pyridine hydrochloride [287] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-fluorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 1 of Example 3 and 2-fluorobenzyl chloride.
  • Step 3 l-benzyl-7-(4-chlorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridine hydrochloride
  • the titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-chlorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 2 and benzyl bromide. (Yield: 69.5 %) [302] 1 H-NMR (400MHz, CDCl 3 ) ⁇ 8.36(d,lH), 7.30(m,5H), 6.98(d,2H), 6.84(d,lH),
  • Example 12 7-(4-chlorobenzyloxy)-2,3-dimethyl-l-(3-methylbut-2-enyl) - 1 H- pyrrolo[3,2-b]pyridine hydrochloride [305] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-chlorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 2 of Example 11 and
  • Example 13 l-(2-acetoxyethyl)-7-(4-chlorobenzyloxy)-2,3-dimethyl - 1 H- pyrrolo[3,2-b]pyridine hydrochloride [309] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-chlorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 2 of Example 11 and 2-bromoethyl acetate.
  • Example 16 7-(4-chlorobenzyloxy)-l-(4-chlorobenzyl)-2,3-dimethyl - 1 H- pyrrolo[3,2-b]pyridine hydrochloride [321] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-chlorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 2 of Example 11 and 4-chlorobenzyl bromide.
  • Example 17 7-(4-chlorobenzyloxy)-l-(2-fluorobenzyl)-2,3-dimethyl - 1 H- pyrrolo[3,2-b]pyridine hydrochloride [325] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-chlorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 2 of Example 11 and 2-fluorobenzyl bromide.
  • Step 2 7-(benzo[l,3]dioxol-5-ylmethoxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridine
  • Step 3 7-(benzo[l,3]dioxol-5-ylmethoxy)-l-(4-methylbenzyl)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine hydrochloride [347] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(benzo[l,3] dioxol-
  • Step 3 l-benzyl-7-(2,4-dichlorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b] pyridine hydrochloride [361] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(2,4-dichlorobenzyloxy)-2,3-dimethyl-l
  • Example 23 7-(2,4-dichlorobenzyloxy)-l-ethyl-2,3-dimethyl - 1 H- pyrrolo[3,2-b]pyridine hydrochloride [369] The titled compound was obtained as a pale yellow solid in accordance with the same procedures as in Step 2 of Example 1, using
  • Example 24 7-(2,4-dichlorobenzyloxy)-l-(4-fluorobenzyl)-2,3-dimethyl - 1 H- pyrrolo[3,2-b]pyridine hydrochloride [373] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(2,4-dichlorobenzyloxy)-2,3-dimethyl-l
  • Step 3 2,3-dimethyl-l-ethyl-7-(3-methylbenzyloxy)-lH-pyrrolo[3,2-b]pyridine hydrochloride
  • the titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(3-methylbenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 2 and iodoethane. (Yield: 69.0 %)
  • 1 H-NMR 400MHz, CDCl ) ⁇ 8.31(s,lH), 7.34(m,4H), 6.86(d,lH), 5.37(s,2H),
  • Example 27 l-allyl-2,3-dimethyl-7-(3-methylbenzyloxy) - 1 H- pyrrolo[3,2-b] pyridine hydrochloride [395] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(3-methylbenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 2 of Example 25 and allyl bromide. (Yield:
  • Step 3 l-cyclopropylmethyl-7-(2-ethoxybenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b
  • Example 29 l-(3-methoxybenzyl)-7-(2-ethoxybenzyloxy)-2,3-dimethyl - 1 H- pyrrolo[3,2-b]pyridine hydrochloride [413] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(2-ethoxybenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 2 of Example 28 and 3-methoxybenzyl bromide. (Yield: 79.5 %) [414] 1 H-NMR (400MHz, CDCl ) ⁇ 8.32(t,lH), 7.31(m,lH), 7.16(t,lH), 6.92(d,2H),
  • Example 30 l-(3-fluorobenzyl)-7-(2-ethoxybenzyloxy)-2,3-dimethyl - 1 H- pyrrolo[3,2-b]pyridine hydrochloride [417] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(2-ethoxybenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 2 of Example 28 and 3-fluorobenzyl bromide.
  • Step 3 l-cyclobutylmethyl-7-(3,5-difluorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine hydrochloride [431] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(3,5-difluorobenzyloxy)-2,3-dimethyl-l
  • Example 32 l-benzyl-7-(3,5-difluorobenzyloxy)-2,3-dimethyl - 1 H- pyrrolo[3,2-b]pyridine hydrochloride [435] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(3,5-difluorobenzyloxy)-2,3-dimethyl-l
  • Step 3 2,3-dimethyl-l-(4-methylbenzyl)-7-(4-trifluoromethylbenzyloxy)-lH- pyrrolo[3,2-b]pyridine hydrochloride [449]
  • the titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using
  • Step 2 7-(4-fluorobenzyloxy)-2,3-dimethyl- l-(prop-2-ynyl)- lH-pyrrolo[3,2-c] pyridine hydrochloride
  • Example 40 l-cyclopropylmethyl-7-(4-fluorobenzyloxy)-2,3-dimethyl - 1 H- pyrrolo[3,2-c]pyridine hydrochloride
  • Step 2 l-cyclopropylmethyl-2,3-dimethyl-4-(4-fluorobenzylamino)-lH- pyrrolo[3,2-c]pyridine hydrochloride
  • Step 2 of Example 41 using 2,3-dimethyl-4-(4-fluorobenzylamino)-lH-pyrrolo[3,2-c] pyridine obtained by treating the compound prepared in Step 1 of Example 41 with a saturated sodium hydrogencarbonate solution and benzyl bromide. (Yield: 58.4 %)
  • Step 2 of Example 41 using 2,3-dimethyl-4-(4-fluorobenzylamino)-lH-pyrrolo[3,2-c] pyridine obtained by treating the compound prepared in Step 1 of Example 41 with a saturated sodium hydrogencarbonate solution and 2-fluorobenzyl bromide. (Yield: 35.4 %)
  • Step 1 4-[ ⁇ / 7 -(l-methyl-3-phenylpropyliden)-hydrazino]-lH-pyridin-2-one
  • Step 4 3-benzyl-2-methyl-4-(l,2,3,4-tetrahydroisoquinolin-2-yl)-lH-pyrrolo[3,2-c] pyridine hydrochloride
  • the titled compound was obtained as a pale yellow solid in accordance with the same procedures as in Step 1 of Example 41, using 3-benzyl-4-chloro-2-methyl-lH- pyrrolo[3,2-c]pyridine prepared in Step 3 and 1,2,3,4-tetrahydroisoquinoline.
  • Step 2 7-(l,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-lH-pyrrolo[2,3-c] pyridine hydrochloride
  • Step 3 l-allyl-7-(l,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-lH- pyrrolo[2,3-c]pyridine hydrochloride
  • Step 1 l-methyl-2-(3-nitropyridin-2-yl)-l,2,3,4-tetrahydroisoquinoline
  • Example 48 7-(4-chlorobenzylamino)-l-isobutyl-2,3-dimethyl - 1 H- pyrrolo[2,3-c]pyridine hydrochloride
  • Step 2 7-chloro-l-isobutyl-2,3-dimethyl-lH-pyrrolo[2,3-c]pyridine
  • Step 3 7-(4-chlorobenzylamino)-l-isobutyl-2,3-dimethyl-lH-pyrrolo[2,3-c] pyridine hydrochloride
  • Step 2 2-(/V-benzyl-./V-te7t-butoxycarbonyl)amino-3-nitropyridine
  • Step 3 7-( ⁇ f-benzyl- ⁇ tert-butyloxycarbonyl)amino-2,3-dimethyl-lH-pyrrolo[2,3-c] pyridine
  • 7.5 g of the titled compound was obtained as a yellow solid in accordance with the same procedures as in Step 1 of Example 1, using 2-(N-benzy ⁇ -N-tert - butyloxycarbonyl)amino-3-nitropyridine (17.5 g, 53.1 mmol) prepared in Step 2 and
  • Step 3 l-benzyl-2,3-dimethyl-7-phenethyl-lH-pyrrolo[2,3-c]pyridine hydrochloride
  • Step 1 2-(6-chloro-3-nitropyridin-2-yl)-l,2,3,4-tetrahydroisoquinoline
  • Step 2 2-(5-chloro-2,3-dimethyl-lH-pyrrolo[2,3-c] pyridin-
  • Step 3 7-(3,4-dihydro- lH-isoquinolin-2-yl)-2,3-dimethyl- lH-pyrrolo[2,3-c] pyridine-5-carbonitrile
  • Step 4 l-allyl-7-(3,4-dihydro-lH-isoquinolin-2-yl)-2,3-dimethyl-lH-pyrrolo[2,3-c] pyridine-5-carbonitrile
  • Step 5 l-allyl-7-(3,4-dihydro-lH-isoquinolin-2-yl)-2,3-dimethyl-lH-pyrrolo[2,3-c] pyridine-5-carboxylic acid
  • Step 6 l-allyl-7-(3,4-dihydro-lH-isoquinolin-2-yl)-2,3-dimethyl-lH-pyrrolo[2,3-c] pyridine-5-carboxylic acid cyclopropylamide
  • Inhibitory effects of a pyrrolopyridine derivative or its salt on human carcinoma cell proliferation were determined, using human lung tumor cells H460 (ATCC HTB- 177), colonic cancer cells HCT 116 (ATCC CCL-247), and human breast adenocarcinoma cells MCF-7(ATCC HTB-22).
  • Cells were seeded at a density of 1000 cells/well (H460, HCT 116) and 2000 cells/well (MCF-7) in 100 ul of growth medium (DMEM containing 5 % FBS), respectively.
  • the cells in 96 well plate were incubated at 37 0 C under 5 % CO to stabilize the cells. After 1 day, cells were treated with test compounds in each concentrations and then incubated further for 4 days.
  • 5-FU 5-fluorouracil
  • 5-FU 5-fluorouracil
  • MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide
  • the MTT-formazan generated by cellular reduction of MTT was solubilized in dimethylsulfoxide and the colorimetric absorbance at 540 nm was measured using microplate reader to determine viability of test compound treated carcinoma cells.
  • concentrations showing 50% inhibition of cell proliferation (IC s) of test compounds were calculated from each % inhibition value of compounds. The results are shown in Table 1.
  • the compounds of formula (I) or its salt have excellent inhibitory effects on carcinoma cell proliferation, thereby being useful for an anticancer agent.

Abstract

The present invention provides a composition for treating or preventing a cancer comprising a pyrrolopyridine derivative or its salt and a pharmaceutically acceptable carrier.

Description

Description
A COMPOSITION FOR TREATING OR PREVENTING A CANCER COMPRISING PYRROLOPYRIDINE DERIVATIVES
Technical Field
[1] The present invention relates to a composition for treating or preventing a cancer comprising a pyrrolopyridine derivative or its salt and a pharmaceutically acceptable carrier.
Background Art
[2] Conventional anticancer agents have various mechanisms, such as DNA alkylation, inhibition of DNA synthesis, apoptotic cell death, etc. However, since most of the mechanisms do not have sufficient specificity or selectivity to cancer cells, the majority of anticancer agents induce various toxicities and side effects, e.g., depilation, bone marrow depression, gastrointestinal mucosal damage, pain, emesis, etc.
Therefore, there has been a demand in the art to develop anticancer agents having low toxicity (i.e., high safety). [3] The present inventors have developed various pyrrolopyridine derivatives useful for an acid pump antagonist and filed patent applications thereof (WO 2006/025714, WO
2006/025715, WO 2006/025716, WO 2006/025717, and WO 2006/038773). The pyrrolopyridine ring includes pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine, or pyrrolo[3,2-b]pyridine.
Disclosure of Invention
Technical Problem [4] It has been found, surprisingly, that pyrrolopyridine derivatives or salts thereof have excellent anticancer effects. [5] It is therefore the object of the present invention to provide a composition for treating or preventing a cancer comprising a pyrrolopyridine derivative or its salt and a pharmaceutically acceptable carrier.
Technical Solution [6] According to an aspect of the present invention, there is provided a composition for treating or preventing a cancer comprising a compound of formula (I) or its salt and a pharmaceutically acceptable carrier.
Mode for the Invention [7] In accordance with an aspect of the present invention, there is provided a composition for treating or preventing a cancer comprising a compound of formula (I) or its salt and a pharmaceutically acceptable carrier: [8]
Figure imgf000003_0001
[9] wherein:
[10] A, B, and D are, independently, N or CH; and one of A, B, and D is N and the others are CH, [11] R is hydrogen; a straight or branched C -C alkyl group; a straight or branched C -
1 1 6 1
C alkyl group substituted with a group consisting of C -C alkoxy, C -C cycloalkyl, acetoxy, and 1,3-dioxolanyl; a C -C alkenyl group optionally substituted with C -C alkyl; a C -C alkynyl group; a benzyl group optionally substituted with halogen, straight or branched C -C alkyl, or straight or branched C -C alkoxy; or 2,3-dihydrobenzo[ 1 ,4]dioxinylmethyl,
[12] R2 is a C1-C3 alkyl group,
[13] R is a C -C alkyl group or a benzyl group,
[14] R is hydrogen; an aminocarbonyl group optionally substituted with C -C cycloalkyl, and
[15] R is a naphthyl group; a 1,2,3,4-tetrahydroisoquinolinyl group optionally substituted with C -C alkyl; a benzylamino group optionally one or two substituted with halogen; a benzyloxy group optionally substituted with one or two groups independently selected from the group consisting of halogen, trifluoromethyl, C -C alkyl, and C -C alkoxy; a phenyl-C -C alkyl group; a phenyl group; a methylsulfanylphenyl group; or a benzo[l,3]dioxolylmethoxy.
[16]
[17] Among the compounds of formula (I) or its salt, the composition of the present invention preferably comprises those wherein
[18] R is hydrogen; a straight or branched C -C alkyl group; a methyl group substituted
1 1 6 with C -C cycloalkyl or 1,3-dioxolanyl; a C -C alkenyl group substituted with C -C alkyl; a C -C alkynyl group; a benzyl group optionally substituted with halogen, straight or branched C 1 -C4 alkyl, or straight or branched C 1 -C4 alkoxy; or
2,3-dihydrobenzo[ 1 ,4] dioxinylmethyl, [19] R and R are a methyl group,
[20] R is hydrogen, and
[21] R is a naphthyl group; a 1,2,3,4-tetrahydroisoquinolinyl group optionally substituted with C -C alkyl; a benzylamino group; a benzyloxy group optionally substituted with one or two groups independently selected from the group consisting of halogen and C -C alkyl; or a phenyl-C -C alkyl group.
[22]
[23] Among the compounds of formula (I) or its salt, the composition of the present invention also preferably comprises those wherein
[24] A is N,
[25] both B and D are CH, and
[26] R is a naphthyl group; a benzyloxy group optionally substituted with one or two groups independently selected from the group consisting of halogen, trifluoromethyl, C -C alkyl, and C -C alkoxy; a phenyl-C -C alkyl group; a methylsulfanylphenyl group; or a benzo[l,3]dioxolylmethoxy.
[27]
[28] Among the compounds of formula (I) or its salt, the composition of the present invention also preferably comprises those wherein B is N, and both A and D are CH.
[29]
[30] Among the compounds of formula (I) or its salt, the composition of the present invention also preferably comprises those wherein
[31] D is N,
[32] both A and B are CH, and
[33] R is a 1,2,3,4-tetrahydroisoquinolinyl group optionally substituted with C -C alkyl; a benzyloxy group optionally substituted with one or two groups independently selected from the group consisting of halogen, trifluoromethyl, C -C alkyl, and C -C alkoxy; a phenyl-C -C alkyl group; or a benzo[l,3]dioxolylmethoxy.
[34]
[35] More preferred compounds of formula (I) or its salts, which are comprised in the composition of the present invention, are:
[36] l-(3-methylbut-2-enyl)-7-(l,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-lH-pyr rolo[3,2-b]pyridine hydrochloride;
[37] (l-allyl-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridin-7-yl)-(4-fluorobenzyl)-amine hydrochloride;
[38] 7-(4-fluorobenzyloxy)-l-isobutyl-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridine hydrochloride;
[39] 7-(4-fluorobenzyloxy)-2,3-dimethyl-l-(prop-2-ynyl)-lH-pyrrolo[3,2-b]pyridine hydrochloride;
[40] l-benzyl-7-(4-fluorobenzyloxy)-2,3-dimethyl- lH-pyrrolo[3,2-b]pyridine hydrochloride;
[41] l-cyclobutylmethyl-7-(4-fluorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridine hydrochloride; [42] 7-(4-fluorobenzyloxy)-2,3-dimethyl-l-(3-methylbut-2-enyl)-lH-pyrrolo[3,2-b]pyrid ine hydrochloride;
[43] 7-(4-fluorobenzyloxy)- l-propyl-2,3-dimethyl- lH-pyrrolo[3,2-b]pyridine hydrochloride;
[44] l-(4-ter?-butylbenzyl)-7-(4-fluorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridi ne hydrochloride;
[45] l-(2-fluorobenzyl)-7-(4-fluorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridine hydrochloride;
[46] l-benzyl-7-(4-chlorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridine hydrochloride;
[47] 7-(4-chlorobenzyloxy)-2,3-dimethyl- l-(3-methylbut-2-enyl)- lH-pyrrolo[3,2-b]pyri dine hydrochloride;
[48] l-(2-acetoxyethyl)-7-(4-chlorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridine hydrochloride;
[49] l-cyclopropylmethyl-7-(4-chlorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridin e hydrochloride;
[50] 7-(4-chlorobenzyloxy)-l-([l,3]dioxolan-2-ylmethyl)-2,3-dimethyl-lH-pyrrolo[3,2-b
]pyridine hydrochloride;
[51] 7-(4-chlorobenzyloxy)- l-(4-chlorobenzyl)-2,3-dimethyl- lH-pyrrolo[3,2-b]pyridine hydrochloride;
[52] 7-(4-chlorobenzyloxy)- l-(2-fluorobenzyl)-2,3-dimethyl- lH-pyrrolo[3,2-b]pyridine hydrochloride;
[53] 7-(4-chlorobenzyloxy)- l-ethyl-2,3-dimethyl- lH-pyrrolo[3,2-b]pyridine hydrochloride;
[54] 7-(4-chlorobenzyloxy)- l-(3-methoxybenzyl)-2,3-dimethyl- lH-pyrrolo[3,2-b]pyridi ne hydrochloride;
[55] 7-(benzo[l,3]dioxol-5-ylmethoxy)-l-(4-methylbenzyl)-2,3-dimethyl-lH-pyrrolo[3,
2-b]pyridine hydrochloride;
[56] l-benzyl-7-(2,4-dichlorobenzyloxy)-2,3-dimethyl- lH-pyrrolo[3,2-b]pyridine hydrochloride;
[57] 7-(2,4-dichlorobenzyloxy)- l-cyclopropylmethyl-2,3-dimethyl- lH-pyrrolo[3,2-b]pyr idine hydrochloride;
[58] 7-(2,4-dichlorobenzyloxy)-l-ethyl-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridine hydrochloride;
[59] 7-(2,4-dichlorobenzyloxy)-l-(4-fluorobenzyl)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyrid ine hydrochloride;
[60] 2,3-dimethyl-l-ethyl-7-(3-methylbenzyloxy)-lH-pyrrolo[3,2-b]pyridine hydrochloride; [61] 2,3-dimethyl-l-propyl-7-(3-methylbenzyloxy)-lH-pyrrolo[3,2-b]pyridine hydrochloride;
[62] l-allyl-2,3-dimethyl-7-(3-methylbenzyloxy)- lH-pyrrolo[3,2-b]pyridine hydrochloride;
[63] l-cyclopropylmethyl-7-(2-ethoxybenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridi ne hydrochloride;
[64] l-(3-methoxybenzyl)-7-(2-ethoxybenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridi ne hydrochloride;
[65] l-(3-fluorobenzyl)-7-(2-ethoxybenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridine hydrochloride;
[66] l-cyclobutylmethyl-7-(3,5-difluorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyri dine hydrochloride;
[67] l-benzyl-7-(3,5-difluorobenzyloxy)-2,3-dimethyl- lH-pyrrolo[3,2-b]pyridine hydrochloride;
[68] 2,3-dimethyl-l-(4-methylbenzyl)-7-(4-trifluoromethylbenzyloxy)-lH-pyrrolo[3,2-b
]pyridine hydrochloride;
[69] 2,3-dimethyl-l-(3-methoxybenzyl)-7-(4-trifluoromethylbenzyloxy)-lH-pyrrolo[3,2- b]pyridine hydrochloride;
[70] 1 -([ 1 ,3]dioxolan-2-ylmethyl)-7-( 1 ,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl- 1
H-pyrrolo[3,2-c]pyridine hydrochloride;
[71] 2-(l-ethyl-2,3-dimethyl-lH-pyrrolo[3,2-c]pyridin-7-yl)-l,2,3,4-tetrahydroisoquinoli ne hydrochloride;
[72] 2-[l-(2,3-dihydrobenzo[l,4]dioxin-6-ylmethyl)-2,3-dimethyl-lH-pyrrolo[3,2-c]pyri din-7-yl]-l,2,3,4-tetrahydroisoquinoline hydrochloride;
[73] 7-(4-fluorobenzyloxy)-2,3-dimethyl-l-(prop-2-ynyl)-lH-pyrrolo[3,2-c]pyridine hydrochloride;
[74] 7-(4-fluorobenzyloxy)- l-(2-methoxyethyl)-2,3-dimethyl- lH-pyrrolo[3,2-c]pyridine hydrochloride;
[75] l-cyclopropylmethyl-7-(4-fluorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-c]pyridin e hydrochloride;
[76] l-cyclopropylmethyl-2,3-dimethyl-4-(4-fluorobenzylamino)-lH-pyrrolo[3,2-c]pyri dine hydrochloride;
[77] l-benzyl-2,3-dimethyl-4-(4-fluorobenzylamino)-lH-pyrrolo[3,2-c]pyridine hydrochloride;
[78] 2,3-dimethyl-l-(2-fluorobenzyl)-4-(4-fluorobenzylamino)-lH-pyrrolo[3,2-c]pyridin e hydrochloride;
[79] 3-benzyl-2-methyl-4-(l,2,3,4-tetrahydroisoquinolin-2-yl)-lH-pyrrolo[3,2-c]pyridin e hydrochloride; [80] l-allyl-7-(l,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-lH-pyrrolo[2,3-c]pyridi ne hydrochloride;
[81] 2-(2,3-dimethyl-lH-pyrrolo[2,3-c]pyridin-7-yl)-l-methyl-l,2,3,4-tetrahydroisoquin oline hydrochloride;
[82] 2-(2,3-dimethyl-lH-pyrrolo[2,3-c]pyridin-7-yl)-l-methyl-l,2,3,4-tetrahydroisoquin oline sodium;
[83] 7-(4-chlorobenzylamino)-l-isobutyl-2,3-dimethyl-lH-pyrrolo[2,3-c]pyridine hydrochloride;
[84] 7-benzylamino-2,3-dimethyl- lH-pyrrolo[2,3-c]pyridine hydrochloride;
[85] l-benzyl-2,3-dimethyl-7-phenethyl- lH-pyrrolo[2,3-c]pyridine hydrochloride;
[86] l-(2-methoxyethyl)-2,3-dimethyl-7-phenethyl- lH-pyrrolo[2,3-c]pyridine hydrochloride;
[87] 2,3-dimethyl-l-(4-methylbenzyl)-7-phenethyl-lH-pyrrolo[2,3-c]pyridine hydrochloride;
[88] 2,3-dimethyl-7-(4-methylsulfanylphenyl)-lH-pyrrolo[2,3-c]pyridine;
[89] 2,3-dimethyl-7-(naphthalen-2-yl)- lH-pyrrolo[2,3-c]pyridine hydrochloride;
[90] l-(3-fluorobenzyl)-2,3-dimethyl-7-(naphthalen-2-yl)- lH-pyrrolo[2,3-c]pyridine hydrochloride; and
[91] l-allyl-7-(3,4-dihydro-lH-isoquinolin-2-yl)-2,3-dimethyl-lH-pyrrolo[2,3-c]pyridin e-5-carboxylic acid cyclopropylamide.
[92]
[93] Further, particularly preferred compounds of formula (I) or its salts, which are comprised in the composition of the present invention, are:
[94] l-cyclobutylmethyl-7-(4-fluorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridine hydrochloride;
[95] 7-(4-fluorobenzyloxy)- l-propyl-2,3-dimethyl- lH-pyrrolo[3,2-b]pyridine hydrochloride;
[96] 7-(4-chlorobenzyloxy)-2,3-dimethyl- l-(3-methylbut-2-enyl)- lH-pyrrolo[3,2-b]pyri dine hydrochloride;
[97] 7-(4-chlorobenzyloxy)-l-([l,3]dioxolan-2-ylmethyl)-2,3-dimethyl-lH-pyrrolo[3,2-b
]pyridine hydrochloride;
[98] 7-(4-chlorobenzyloxy)- l-(3-methoxybenzyl)-2,3-dimethyl- lH-pyrrolo[3,2-b]pyridi ne hydrochloride;
[99] 7-(2,4-dichlorobenzyloxy)- l-cyclopropylmethyl-2,3-dimethyl- lH-pyrrolo[3,2-b]pyr idine hydrochloride;
[100] 7-(2,4-dichlorobenzyloxy)-l-(4-fluorobenzyl)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyrid ine hydrochloride;
[101] 2,3-dimethyl-l-propyl-7-(3-methylbenzyloxy)-lH-pyrrolo[3,2-b]pyridine hy- drochloride;
[102] 2-[l-(2,3-dihydrobenzo[l,4]dioxin-6-ylmethyl)-2,3-dimethyl-lH-pyrrolo[3,2-c]pyri din-7-yl]-l,2,3,4-tetrahydroisoquinoline hydrochloride;
[103] 7-(4-fluorobenzyloxy)-2,3-dimethyl-l-prop-2-ynyl-lH-pyrrolo[3,2-c]pyridine hydrochloride;
[104] l-cyclopropylmethyl-7-(4-fluorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-c]pyridin e hydrochloride;
[105] 2-(2,3-dimethyl-lH-pyrrolo[2,3-c]pyridin-7-yl)-l-methyl-l,2,3,4-tetrahydroisoquin oline hydrochloride;
[106] 7-benzylamino-2,3-dimethyl- lH-pyrrolo[2,3-c]pyridine hydrochloride;
[107] 2,3-dimethyl-l-(4-methylbenzyl)-7-phenethyl-lH-pyrrolo[2,3-c]pyridine hydrochloride;
[108] 2,3-dimethyl-7-(naphthalen-2-yl)-lH-pyrrolo[2,3-c]pyridine hydrochloride; and
[109] l-(3-fluorobenzyl)-2,3-dimethyl-7-(naphthalen-2-yl)-lH-pyrrolo[2,3-c]pyridine hydrochloride.
[HO]
[111] The compounds of formula (I) may be pharmaceutically acceptable non-toxic salt forms. The non-toxic salts may include conventional acid addition salts used in the field of anti-cancer agents, e.g., salts originated from an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfonic acid, sulfamic acid, phosphoric acid, or nitric acid, and an organic acid such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, citric acid, maleic acid, malonic acid, methanesulfonic acid, tartaric acid, malic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, oxalic acid, or trifluoroacetic acid. Further, the non-toxic salts include conventional metal salt forms, e.g., salts originated from a metal such as lithium, sodium, potassium, magnesium, or calcium. Such acid addition salts or metal salts may be prepared in accordance with any of the conventional methods.
[112]
[113] The compound of formula (I) or its salt may be prepared in accordance with the processes disclosed in WO 2006/025714, WO 2006/025715, WO 2006/025716, WO 2006/025717, and WO 2006/038773.
[114] For example, the compound of formula (I) or its salt may be prepared using a process which comprises: reacting a compound of formula (II) with a compound of formula (III) to obtain a compound of formula (Ia) and reacting the compound of formula (Ia) with R -X to obtain a compound of formula (I), in accordance with the following Reaction Scheme 1 described below:
[115] [116] Reaction Scheme 1 [117]
Figure imgf000009_0001
(H) (III)
Figure imgf000009_0002
(Ia) (I)
[118] [119] In the above Reaction Scheme 1, A, B, D, R , R , R , R , and R are the same as
1 2 3 4 5 defined in the above and X is halogen.
[120] The compound of formula (II) may be prepared using a known method (e.g., Tetrahedron 1987, 43, 2557, Tetrahedron 1990, 54, 6311, Eur. J. Med. Chem. 1996, 31,359 and /. Med. Chem. 1995, 38(20), 4131) and the compound of formula (III) is commercially available.
[121] The reaction of the compound of formula (II) and the compound of formula (III) may be performed in an anhydrous aprotic polar organic solvent, e.g., anhydrous tetrahydrofuran. Further, the reaction may be carried out at room temperature or at a temperature of -78 0C ~ 0 0C.
[122] The compound of formula (Ia) is reacted with R -X to obtain a compound of formula (I). The reaction of the compound of formula (Ia) and R -X may be performed in the presence of a base, such as sodium hydride or potassium teτt-butoxide. Further, the reaction may be carried out in an organic solvent, such as tetrahydrofuran or N,N - dimethylformamide, and at room temperature or at a temperature of 40 0C ~ 100 0C. In order to increase a reaction rate and/or a yield of the reaction, a catalytic amount of 18-crown-6 may be used.
[123] Further, the compound of formula (I) or its salt may be prepared using a process which comprises: (a) cyclizing the compound of formula (IV) to obtain a compound of formula (V); (b) halogenizing the compound of formula (V) to obtain a compound of (VI); (c) reacting the compound of formula (VI) with R -Y to obtain a compound of formula (Ia); and (d) reacting the compound of formula (Ia) with R -X to obtain a compound of formula (I), in accordance with the following Reaction Scheme 2 described below:
[124] [125] Reaction Scheme 2 [126]
Figure imgf000010_0001
(IV) (V)
Figure imgf000010_0002
(Vl)
(Ia)
Figure imgf000010_0003
(I)
[127] [128] In the above Reaction Scheme 2, A, B, D, R , R , R , R , R and X are the same as
1 2 3 4 5 defined in the above and Y is hydrogen or boronic acid.
[129] [130] The compound of formula (IV) may be prepared using a known method (e.g., Tetrahedron, 1976, 32(12), 1383)
[131] The cylization of the compound of formula (IV) may be carried out by refluxing the compound of formula (IV) in an organic solvent, e.g., diphenyl ether having a high boiling point.
[132] The compound of formula (V) may be converted to the compound of formula (VI), by refluxing the compound of formula (V) with a halogenizing agent, e.g., phosphorus oxychloride.
[133] The compound of formula (VI) is reacted with R -Y to obtain a compound of formula (Ia), using a known method (e.g., Tetrahedron 1987, 43, 2557, Tetrahedron 1990, 54, 6311, Eur. J. Med. Chem. 1996, 31,359 and /. Med. Chem. 1995, 38(20), 4131).
[134] The compound of formula (Ia) is reacted with R -X to obtain a compound of formula (I). The reaction of the compound of formula (Ia) and R -X may be performed in the presence of a base, such as sodium hydride or potassium teτt-butoxide. Further, the reaction may be carried out in an organic solvent, such as tetrahydrofuran or N, N - dimethylformamide, and at room temperature or at a temperature of 40 0C ~ 100 0C. In order to increase a reaction rate and/or a yield of the reaction, a catalytic amount of 18-crown-6 may be used.
[135]
[136] The composition of the present invention may include additives such as lactose or corn starch, lubricants such as magnesium stearate, emulsifiers, suspending agents, stabilizers, and isotonic agents. If necessary, sweetening agents and/or flavoring agents may be added.
[137] The composition of the present invention may be administered orally or par- enterally, including intravenous, intraperitoneal, subcutaneous, rectal and topical routes of administration. Therefore, the composition of the present invention may be formulated into various forms such as tablets, capsules, aqueous solutions or suspensions. In the case of tablets for oral use, carriers such as lactose, corn starch, and lubricating agents, e.g. magnesium stearate, are commonly added. In the case of capsules for oral administration, lactose and/or dried corn starch can be used as a diluent. When an aqueous suspension is required for oral use, the active ingredient may be combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled in order to render the preparation isotonic. The composition of the present invention may be in the form of an aqueous solution containing pharmaceutically acceptable carriers, e.g., saline, at a pH level of 7.4. The solutions may be introduced into a patient's intramuscular blood-stream by local bolus injection.
[138] The composition of the present invention may be administered for prevention and treatment of various cancers, such as gastric cancer, large intestininal carcinoma, colonic carcinoma, rectal cancer, pancreatic carcinoma, myelogenous leukemia, etc. The compounds or its salt in the composition of the present invention may be administered in an effective amount ranging from about 0.1 mg/kg to about 20 mg/kg per day, preferably from about 0.5 mg/kg to about 10 mg/kg per day, to a subject patient. Of course, the dosage may be changed according to the patient's age, weight, susceptibility, or symptom.
[139] Hereinafter, the present invention will be described more specifically by examples.
However, the following examples are provided only for illustrations and thus the present invention is not limited to or by them.
[140]
[141] Preparation 1. 2-(3-nitropyridin-4-yl)-l,2,3,4-tetrahydroisoquinoline
[142]
[143] Step 1: 4-chloro-3-nitropyridine
[144] 4-Hydroxy-3-nitropyridine (10 g, 71.38 mmol) was added to 100 ml of phosphorus oxychloride. The reaction mixture was refluxed for 1 hour and then concentrated under reduced pressure. The resulting residue was added to 500 ml of ice water and then neutralized with 2N sodium hydroxide solution. The reaction mixture was extracted with 300 ml of methylene chloride. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure to give the titled compound (9.2 g, 92.0 %) as a pale yellow solid.
[145] Rf (n-hexane/ethyl acetate = 2/1 , v/v) = 0.5
[146] 1H-NMR (400MHz, CDCl ) δ 9.12(s,lH), 8.69(d,lH), 7.55(d,lH)
[147]
[148] Step 2: 2-(3-nitropyridin-4-yl)-l,2,3,4-tetrahydroisoquinoline
[149] Sodium hydride (386.4 mg, 9.66 mmol) was added at 0 0C to a solution of
1,2,3,4-tetrahydroisoquinoline (1.06 ml, 8.05 mmol) in Λ/,Λf-dimethylformamide (30 ml). The reaction mixture was stirred for 10 minutes at the same temperature. 4-Chloro-3-nitropyridine (1.124 g, 7.09 mmol) prepared in Step 1 was slowly added to the reaction mixture, which was then stirred for 2 hours at room temperature. The reaction mixture was diluted with 10 ml of water and 100 ml of ethyl acetate and then washed with water (100 ml X 2). The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure to give the titled compound (1.13 g, 89.3 %) as a yellow solid.
[150] Rf (n-hexane/ethyl acetate = 2/ 1 , v/v) = 0.3
[151] 1H-NMR (400MHz, CDCl ) δ 8.86(s,lH), 8.36(d,2H), 7.22(m,3H), 7.12(m,lH),
6.96(d,lH), 4.35 (s,2H), 3.53(t,2H), 3.03(t,2H)
[152] [153] Preparation 2. 4-(4-fluorobenzyloxy)-3-nitropyridine
[154] 4-Chloro-3-nitropyridine (2.0 g, 12.62 mmol) prepared in Step 1 of Preparation 1 was slowly added to a suspension of 4-fluorobenzyl alcohol (2.04 ml, 18.92 mmol), potassium carbonate (1.74 g, 12.62 mmol), and potassium hydroxide (2.38 g, 50.48 mmol) in 100 ml of anhydrous toluene. A catalytic amount of tris[2-(2-methoxyethoxy)ethyl] amine was added to the reaction mixture, which was then stirred for 1 hour at room temperature and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane = 1/1, v/v) to give the titled compound (2.5 g, 86.3 %) as a white solid.
[155] Rf (n-hexane/ethyl acetate = 2/1, v/v) = 0.4
[156] 1H-NMR (400MHz, CDCl ) δ 8.57(s,lH), 7.28(m,3H), 7.16(m,2H), 6.70(d,lH),
5.05(s,2H)
[157]
[158] Preparation 3. (2,3-dimethyl - 1 H- pyrrolo[3,2-b] pyridin-
7-yl)-(4-fluorobenzyl)-carbamic acid t -butyl ester
[159]
[160] Step 1: (4-fluorobenzyl)-(3-nitropyridin-4-yl)-amine
[161] Sodium carbonate (3.20 g, 30.27 mmol) and 4-fluorobenzylamine (2.14 ml, 18.92 mmol) were added to a solution of 4-chloro-3-nitropyridine (3.0 g, 18.92 mmol) prepared in Step 1 of Preparation 1 in 30 ml of anhydrous ΛζN-dimethylformamide. The reaction mixture was stirred for 1 hour at 80 0C. The reaction mixture was diluted with 10 ml of water and 100 ml of ethyl acetate and then washed with water (100 ml X 2). The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure to give the titled compound (3.01 g, 83.5 %) as a yellow solid.
[162] 1H-NMR (400MHz, CDCl ) δ 8.60(s,lH), 7.29(m,3H), 7.18(m,2H), 6.70(d,lH),
5.20(s,2H)
[163]
[164] Step 2: (4-fluorobenzyl)-(3-nitropyridin-4-yl)-carbamic acid ?-butyl ester
[165] Di-teλt-butyl dicarbonate (8.13 g, 37.25 mmol) and 4-(dimethylamino)pyridine
(2.27 g, 18.63 mmol) were added to a solution of
(4-fluorobenzyl)-(3-nitropyridin-4-yl)-amine (3.07 g, 12.42 mmol) prepared in Step 1 in 100ml of tetrahydrofuran. The reaction mixture was stirred for 24 hours and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane = 1/1, v/v) to give the titled compound (2.9 g, 75.6 %) as yellow oil.
[166] 1H-NMR (400MHz, CDCl ) δ 8.60(s,lH), 7.29(m,3H), 7.18(m,2H), 6.70(d,lH), 5.10(s,2H), 1.3(s,9H)
[167]
[168] Step 3: (2,3-dimethyl-lH-pyrrolo[3,2-b]pyridin-7-yl)-(4-fluorobenzyl)-carbamic acid ?-butyl ester
[169] (4-Fluorobenzyl)-(3-nitropyridin-4-yl)-carbamic acid ?-butyl ester (10.2 g) prepared in Step 2 was dissolved in anhydrous tetrahydrofuran (200 ml) under a nitrogen atmosphere. 1 -Methyl- 1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution, 110 ml, 130.5 mmol) was added at -78 0C to the solution. The reaction mixture was stirred at -20 0C for 5 hours. An ammonium chloride solution (20 %(w/v), 20 ml) was added to the reaction mixture, which was then extracted with ethyl acetate (200 ml X 2). The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/methanol = 10/1, v/v) to give the titled compound (3.8 g, 28.9 %) as a pale yellow solid.
[170] 1H-NMR (400MHz, CDCl ) δ 8.31(d,lH), 8.12(s,lH), 7.40(m,lH), 7.18(d,2H),
7.09(d,2H), 3.16(s,3H), 2.53(s,3H), 2.48(s,3H), 1.41(s,9H)
[171]
[172] Preparation 4. 2-(4-nitropyridin-3-yl)-l,2,3,4-tetrahydroisoquinoline
[173]
[174] Step 1: 3-bromopyridine-/V-oxide
[175] Hydrogen peroxide (30 %, 41 ml) was added to a solution of 3-bromopyridine (32 g, 0.202 mol) in 120 ml of acetic acid. The reaction mixture was stirred for 9 hours at 70 - 80 0C and then concentrated under reduced pressure. The reaction mixture was alkalized with excess of sodium carbonate, diluted with 100 ml of methylene chloride, and then filtered to discard insoluble materials. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was used in the subsequent step without further purification.
[176]
[177] Step 2: 3-bromo-4-nitropyridine-/V-oxide
[178] 128 ml of cone, nitric acid and 77 ml of cone, sulfuric acid were slowly added at 0 -
5 0C to a solution of 3-bromopyridine-/V-oxide (31.9 g, 0.181 mol) prepared in Step 1 in 77 ml of cone, sulfuric acid. The reaction mixture was stirred at 90 0C for 2 hours, and then cooled to room temperature. The reaction mixture was added to 1 L of ice water, brought to pH 8 with a sodium hydroxide solution (50 %) and then filtered. The isolated precipitate was dried to give the titled compound (29.3 g, 72.0 %) as a yellow solid.
[179] Rf (n-hexane/ethyl acetate = 1/1, v/v) = 0.3
[180] 1H-NMR (400MHz, CDCl ) δ 8.6(s,lH), 8.4-7.9(m,2H) [181]
[182] Step 3: 2-(4-nitro-l-oxypyridin-3-yl)-l,2,3,4-tetrahydroisoquinoline
[183] 3-Bromo-4-nitropyridine-/V-oxide (1.0 g, 4.53 mmol) prepared in Step 2 was added to a mixture of tert-butanol (30 ml), potassium teτt-butoxide (507 mg, 4.53 mmol), and 1,2,3,4-tetrahydroisoquinoline (0.79 ml, 6.34 mmol). The reaction mixture was stirred for 12 hours at room temperature. Water (10 ml) was added to the reaction mixture, which was then extracted with ethyl acetate (100 ml). The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/ n-hexane = 1/1, v/v) to give the titled compound (600 mg) as a yellow solid.
[ 184] Rf (n-hexane/ethyl acetate = 1/1 , v/v) = 0.2
[185] 1H-NMR (400MHz, CDCl ) δ 8.13(s,lH), 7.83(d,lH), 7.71(d,lH), 7.24(m,3H),
7.09(m,lH), 4.32(s,2H), 3.46(t,2H), 3.06(t,2H)
[186]
[187] Step 4: 2-(4-nitropyridin-3-yl)- 1,2,3,4-tetrahydroisoquinoline
[188] Phosphorus trichloride (3.81 ml, 28.9 mmol) was slowly added at 0 0C to a solution of 2-(4-nitro-l-oxypyridin-3-yl)-l,2,3,4-tetrahydroisoquinoline (8.5 g, 25.3 mmol) in 100ml of ethyl acetate. The reaction mixture was stirred for 1 hour at room temperature and alkalized with 2N sodium hydroxide solution. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure to give the titled compound (65.3 %) as a yellow solid. The product was used in subsequent steps without further purification.
[189]
[190] Preparation 5. 3-(4-fluorobenzyloxy)-4-nitropyridine
[191]
[192] Step 1: 3-(4-fluorobenzyloxy)-4-nitropyridine-/V-oxide
[193] The titled compound was obtained in accordance with the same procedures as in
Preparation 2, using 3-bromo-4-nitropyridine-/V-oxide prepared in Step 2 of Preparation 4 and 4-fluorobenzyl alcohol (Yield: 14.6 %).
[194] Rf (n-hexane/ethyl acetate = 1/1, v/v) = 0.2
[195] 1H-NMR (400MHz, CDCl3) δ 8.5(s,lH), 8.33(d,lH), 8.20(m,2H), 8.17(d,lH), 8.15
(m,2H), 5.21(s,2H)
[196]
[197] Step 2: 3-(4-fluorobenzyloxy)-4-nitropyridine
[198] The titled compound was obtained in accordance with the same procedures as in
Step 4 of Preparation 4, using 3-(4-fluorobenzyloxy)-4-nitropyridine-N-oxide prepared in Step 1. The product was used in subsequent steps without further purification.
[199] [200] Preparation 6. 4-chloro-2,3-dimethyl - I H- pyrrolo[3,2-c]pyridine
[201]
[202] Step 1: 4-hydrazino-lH-pyridin-2-one
[203] 2,4-Dihydroxypyridine (20.3 g, 183.0 mmol) was slowly added at room temperature to a mixture of 2-methoxyethanol (400 ml) and a hydrazine solution (35 wt.%, 80ml). The reaction mixture was refluxed for 24 hours and then concentrated under reduced pressure. The resulting residue was re-crystallized with ethanol to give the titled compound (20.1 g, 88.3 %) as a white solid.
[204] Rf (methylene chloride/methanol = 10/1, v/v) = 0.1
[205] 1H-NMR (400MHz, CDCl ) δ 10.30 (brs, IH), 7.67 (s, IH), 7.10 (d, IH), 5.79 (d,
IH), 5.54 (s, IH), 3.91 (brs, 2H)
[206]
[207] Step 2: 4-(Λ/7-sec-butylidenhydrazino)-lH-pyridin-2-one
[208] 4-Ηydrazino-lH-pyridin-2-one (20.1 g, 161.0 mmol) prepared in Step 1 and
2-butanone (21.6 ml, 241.0 mmol) was added to 400ml of ethanol. The reaction mixture was refluxed for 4 hours, cooled to 0 0C, and then filtered. The isolated solid was washed with cooled ethanol and then dried to give the titled compound as a white solid (Yield: 75.0 %).
[209] Rf (methylene chloride/methanol = 10/1, v/v) = 0.3
[210] 1H-NMR (400MHz, CDCl ) δ 10.48 (brs, IH), 9.05 (s, IH), 7.03 (d, IH), 6.00 (d,
IH), 5.65 (s, IH), 2.18 (q, 2H), 1.97 (s, 3H), 0.99 (t, 3H)
[211]
[212] Step 3: 2,3-dimethyl-l,5-dihydropyrrolo[3,2-c]pyridin-4-one
[213] 4-(Λ^-sec-butylidenhydrazino)-lH-pyridin-2-one (16.6 g, 92.6 mmol) prepared in
Step 2 was added to 200ml of diphenyl ether. The reaction mixture was refluxed for 5 hours and then cooled to room temperature. 200ml of n-hexane was added to the reaction mixture, which was then stirred and filtered. The isolated solid was re- crystallized with methanol to give the titled compound (10.9 g, 73.2 %) as a pale yellow solid.
[214] Rf (ethyl acetate, 100%) = 0.2
[215] 1H-NMR (400MHz, CDCl ) δ 10.99 (brs, IH), 10.55 (brs, IH), 6.84 (d, IH), 6.24
(d, IH), 2.24 (s, 3H), 2.17 (s, 3H)
[216]
[217] Step 4: 4-chloro-2,3-dimethyl-lH-pyrrolo[3,2-c]pyridine
[218] 2,3-Dimethyl-l,5-dihydropyrrolo[3,2-c]pyridin-4-one (6.0 g, 37.0 mmol) prepared in Step 3 was added to phosphorus oxychloride (230 ml). The reaction mixture was refluxed for 6 hours, cooled to room temperature, and then filtered. The isolated solid was dissolved in methanol, alkalized with a saturated ammonia-methanol solution, and then concentrated under reduced pressure. The resulting residue was filtered using silica gel layer and then re-crystallized to give the titled compound (2.87 g, 43.0 %) as a pale yellow solid.
[219] Rf (ethyl acetate/n-hexane = 1/1, v/v) = 0.4
[220] 1H-NMR (400MHz, CDCl ) δ 11.55 (brs, IH), 7.82 (d, IH), 7.25 (d, IH), 2.36 (s,
3H), 2.33 (s, 3H)
[221]
[222] Preparation 7. l-methyl-l,2,3,4-tetrahydroisoquinoline
[223]
[224] Step l: iV-(2-phenylethyl)-acetamide
[225] 2N Sodium hydroxide solution (30 ml) was added to a solution of phenethylamine
(50 g, 413 mmol) in dichloromethane (50 ml). Acetyl chloride (33 ml, 457 mmol) was slowly added to the reaction mixture, which was then stirred overnight. The reaction mixture was diluted with dichloromethane and then washed with water and a saturated sodium chloride solution. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure to give the titled compound (59 g) as a white solid. The product was used in the subsequent step without further purification.
[226]
[227] Step 2: l-methyl-3,4-dihydroisoquinoline
[228] A mixture of JV-(2-phenylethyl)-acetamide (12 g, 73.5 mmol) prepared in Step 1 and polyphosphoric acid (200ml) was refluxed for 3 hours. The reaction mixture was cooled to room temperature, poured into ice water, alkalized with 2N potassium hydroxide solution, and then extracted with ethyl acetate. The separated organic layer was washed with a saturated sodium chloride solution, dried on anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (dichloromethane/methanol=10/l, v/v) to give the titled compound (4.1 g, 38 %) as brown oil. The product was used in the subsequent step without further purification.
[229]
[230] Step 3: 1 -methyl- 1, 2,3, 4-tetrahydroisoquinoline
[231] Sodium borohydride (2.12 g, 56 mmol) was slowly added at 0 0C to a solution of l-methyl-3,4-dihydroisoquinoline (4.1 g, 28 mmol) prepared in Step 2 in methanol (100ml). The reaction mixture was stirred overnight at room temperature. IN hydrochloric acid was added to the reaction mixture, which was then concentrated under reduced pressure. The resulting residue was alkalized with potassium hydroxide and then extracted with dichloromethane. The separated organic layer was washed with a saturated sodium chloride solution, dried on anhydrous magnesium sulfate and then concentrated under reduced pressure to give the titled compound (3.8 g, 92 %) as brown oil. The product was used in subsequent steps without further purification.
[232]
[233] Example 1. l-(3-methylbut-2-enyl)-7-(l,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl - 1 H- pyrrolo[3,2-b]pyridine hydrochloride
[234]
[235] Step 1: 2-(2,3-dimethyl-lH-pyrrolo[3,2-b] pyridin-
7-yl)- 1 ,2,3,4-tetrahydroisoquinoline
[236] 2-(3-Nitropyridin-4-yl)-l,2,3,4-tetrahydroisoquinoline (5 g, 19.58 mmol) prepared in Preparation 1 was dissolved in anhydrous tetrahydrofuran (200 ml) under a nitrogen atmosphere. 1 -Methyl- 1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution, 80 ml, 117.5 mmol) was slowly added at -78 0C to the reaction mixture, which was then stirred at -20 0C for 5 hours. 20% (w/v) ammonium chloride solution (20 ml) was added to the reaction mixture, which was then extracted with ethyl acetate (200 ml X 2). The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/methylene chloride/methanol = 10/10/1, v/v/v) and then concentrated to give the titled compound (2.1 g, 25.3 %) as a pale yellow solid
[237] 1H-NMR (400MHz, CDCl ) δ 8.26(d,lH), 7.77(s,lH), 7.19(m,4H), 6.59(d,lH),
4.46(s,2H), 3.64(t,2H), 3.04(t,2H), 2.41(s,3H), 2.30(s,3H)
[238]
[239] Step 2: l-(3-methylbut-2-enyl)-7-(l,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl- lH-pyrrolo[3,2-b]pyridine hydrochloride
[240] 4-Bromo-2-methyl-2-butene (0.07 ml, 0.162 mmol) was slowly added to a solution of 2-(2,3-dimethyl-lH-pyrrolo[3,2-b]pyridin-7-yl)-l,2,3,4-tetrahydroisoquinoline (30 mg, 0.108 mmol) prepared in Step 1, potassium teτt-butoxide (13.6 mg, 0.162 mmol), and a catalytic amount of 18 -crown- 6 in anhydrous tetrahydrofuran (2ml). The reaction mixture was stirred at room temperature for 12 hours and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/methylene chloride/methanol = 10/10/1, v/v/v) and then concentrated. The resulting residue was dissolved in ImI of ethyl acetate and then saturated with hydrochloric acid gas. The resulting precipitate was filtered and then dried to give the titled compound (6.9 mg, 15.8 %) as a white solid.
[241] 1H-NMR (400MHz, CDCl ) δ 8.35(s,lH), 7.51(m,4H), 7.10(s,lH), 4.86(d,2H),
4.39(s,2H), 4.10(m,lH), 3.57(m,2H), 2.95(m,2H), 2.56(s,3H), 2.35(s,3H), 1.89(s,6H)
[242] [243] Example 2. (l-allyl-2,3-dimethyl - 1 H- pyrrolo[3,2-b] pyridin-
7-yl)-(4-fluorobenzyl)-amine hydrochloride
[244]
[245] Step 1: (l-allyl-2,3-dimethyl-lH-pyrrolo[3,2-b] pyridin-
7-yl)-(4-fluorobenzyl)-carbamic acid ?-butyl ester hydrochloride
[246] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using (2,3-dimethyl-lH-pyrrolo[3,2-b] pyridin- 7-yl)-(4-fluorobenzyl)-carbamic acid ?-butyl ester prepared in Preparation 3 and allyl bromide. (Yield: 88.6 %) The product was used in the subsequent step without further purification.
[247]
[248] Step 2: (l-allyl-2,3-dimethyl-lH-pyrrolo[3,2-b] pyridin-
7 - y I)- (4-fluorobenzy 1) - amine hydrochloride
[249] (l-Allyl-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridin-7-yl)-(4-fluorobenzyl)-carbamic acid ?-butyl ester hydrochloride (101.3 mg) prepared in Step 1 was dissolved in 5 ml of ethyl acetate. The reaction mixture was saturated with hydrochloric acid gas for 5 minutes and then stirred at room temperature for 1 hour. The resulting precipitate was filtered and then dried to give the titled compound (35.3 mg) as a white solid.
[250] 1H-NMR (400MHz, CDCl ) δ 7.91(t,lH), 7.11(m,2H), 6.48(s,lH), 6.48(m,lH),
6.35(m,lH), 6.11(m,lH), 5.26(d,lH), 5.05(s,2H), 4.71(d,lH), 4.56(d,2H), 2.42(s,3H), 2.28(s,3H)
[251]
[252] Example 3. 7-(4-fluorobenzyloxy)-l-isobutyl-2,3-dimethyl - 1 H- pyrrolo[3,2-b] pyridine hydrochloride
[253]
[254] Step 1: 7-(4-fluorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridine
[255] 4-(4-Fluorobenzyloxy)-3-nitropyridine (4.8 g, 19.34 mmol) prepared in Preparation
2 was dissolved in anhydrous tetrahydrofuran (200 ml) under a nitrogen atmosphere. 1 -Methyl- 1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution, 116 ml, 58.02 mmol) was slowly added at -78 0C to the reaction mixture, which was then stirred at -20 0C for 5 hours. 20% (w/v) ammonium chloride solution (20 ml) was added to the reaction mixture, which was then extracted with ethyl acetate (200 ml X 2). The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/methylene chloride/methanol = 10/10/1, v/v/v) to give the titled compound (2.45 g, 28.3 %) as a pale yellow solid
[256] 1H-NMR (400MHz, CDCl ) δ 8.29(d, IH), 7.97(s, IH), 7.43(m,2H), 7.10(m,2H),
6.60(d,lH), 5.18(s,2H), 2.39(s,3H), 2.30(s,3H) [257]
[258] Step 2: 7-(4-fluorobenzyloxy)-l-isobutyl-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridine hydrochloride [259] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-fluorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 1 and l-iodo-2-methylpropane. (Yield: 86.0
%) [260] 1H-NMR (400MHz, CDCl ) δ 8.34(d,lH), 7.25(m,5H), 5.68(s,2H), 4.85(d,2H),
2.56(s,3H), 2.33(s,3H), 1.78(m,lH), 1.58(d,6H) [261] [262] Example 4. 7-(4-fluorobenzyloxy)-2,3-dimethyl-l-(prop-2-ynyl) - 1 H- pyrrolo[3,2-b]pyridine hydrochloride [263] The titled compound was obtained as a pale yellow solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-fluorobenzyloxy)-2,3-dimethyl- lH-pyrrolo[3,2-b]pyridine prepared in Step 1 of Example 3 and propargyl bromide.
(Yield: 58.6 %) [264] 1H-NMR (400MHz, CDCl ) δ 8.37(s,3H), 7.53(m,2H), 7.16(m,2H), 6.94(s,lH),
5.41(s,2H), 5.12(s,2H), 2.56(s,3H), 2.50(s,3H), 2.38(s,lH) [265] [266] Example 5. l-benzyl-7-(4-fluorobenzyloxy)-2,3-dimethyl - 1 H- pyrrolo[3,2-b] pyridine hydrochloride [267] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-fluorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 1 of Example 3 and benzyl bromide. (Yield:
89.3 %) [268] 1H-NMR (400MHz, CDCl ) δ 8.37(s,lH), 7.29(m,3H), 7.01(m,4H), 6.84(s,lH),
6.66(m,2H), 5.56(s,2H), 5.22(s,2H), 2.61(s,3H), 2.38(s,3H) [269] [270] Example 6. l-cyclobutylmethyl-7-(4-fluorobenzyloxy)-2,3-dimethyl - 1 H- pyrrolo[3,2-b]pyridine hydrochloride [271] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-fluorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 1 of Example 3 and
(bromomethyl)cyclobutane. (Yield: 78.6 %) [272] 1H-NMR (400MHz, CDCl ) δ 8.37(s,lH), 7.50(m,2H), 7.18(m,3H), 5.37(s,2H),
4.28(s,2H), 2.54(m,lH), 2.55(s,3H), 2.45(s,3H), 1.79(m,3H), 1.57(m,3H) [273] [274] Example 7. 7-(4-fluorobenzyloxy)-2,3-dimethyl-l-(3-methylbut-2-enyl) - 1 H- pyrrolo[3,2-b]pyridine hydrochloride
[275] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-fluorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 1 of Example 3 and
4-bromo-2-methyl-2-butene. (Yield: 59.8 %) [276] 1H-NMR (400MHz, CDCl ) δ 8.35(s,lH), 7.43(m,2H), 7.14(m,2H), 6.85(s,lH),
5.36(s,2H), 5.04(m,lH), 4.94(s,2H), 2.54(s,3H), 2.39(s,3H), 1.58(s,6H) [277] [278] Example 8. 7-(4-fluorobenzyloxy)-l-propyl-2,3-dimethyl - 1 H- pyrrolo[3,2-b] pyridine hydrochloride [279] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-fluorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 1 of Example 3 and 1-iodopropane. (Yield:
78.5 %) [280] 1H-NMR (400MHz, CDCl ) δ 8.36(s,lH), 7.48(m,2H), 7.17(m,2H), 6.89(s,lH),
5.34(s,2H), 4.17(t,2H), 2.54(s,3H), 2.40(s,3H), 1.66(m,2H), 0.72(t,3H) [281] [282] Example 9. l-(4- tert -butylbenzyl)-7-(4-fluorobenzyloxy)-2,3-dimethyl - 1 H- pyrrolo[3,2-b]pyridine hydrochloride [283] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-fluorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 1 of Example 3 and 4-teτt-butylbenzyl chloride. (Yield: 68.2 %) [284] 1H-NMR (400MHz, CDCl ) δ 8.35(s,lH), 7.29(d,2H), 6.99(m,4H), 6.90(s,lH),
6.61(s,2H), 5.60(s,2H), 5.22(s,2H), 2.60(s,3H), 2.38(s,3H), 1.32(s,9H) [285] [286] Example 10. l-(2-fluorobenzyl)-7-(4-fluorobenzyloxy)-2,3-dimethyl - 1 H- pyrrolo[3,2-b]pyridine hydrochloride [287] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-fluorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 1 of Example 3 and 2-fluorobenzyl chloride.
(Yield: 86.3 %) [288] 1H-NMR (400MHz, CDCl ) δ 8.43(s,lH), 7.53(m,2H), 7.27(m,lH), 7.05(m,4H),
6.23(m,2H), 5.61(s,2H), 5.30(s,2H), 2.63(s,3H), 2.49(s,3H) [289] [290] Example 11. l-benzyl-7-(4-chlorobenzyloxy)-2,3-dimethyl - 1 H- pyrrolo[3,2-b] pyridine hydrochloride [291] [292] Step 1: 4-(4-chlorobenzyloxy)-3-nitropyridine
[293] The titled compound was obtained as a white solid in accordance with the same procedures as in Preparation 2, using 4-chloro-3-nitropyridine prepared in Step 1 of
Preparation 1 and 4-chlorobenzyl alcohol. (Yield: 78.0 %) [294] 1H-NMR (400MHz, CDCl ) δ 9.04(s,lH), 8.62(d,lH), 7.40(m,4H), 7.04(d,lH),
5.28(d,lH) [295]
[296] Step 2: 7-(4-chlorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridine
[297] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 1 of Example 1, using 4-(4-chlorobenzyloxy)-3-nitropyridine prepared in Step 1 and 1 -methyl- 1-propenyl magnesium bromide. (Yield: 23.8 %) [298] 1H-NMR (400MHz, CDCl ) δ 8.28(d, IH), 8.02(s, IH), 7.38(m,4H), 6.58(d, IH),
5.19(s,2H), 2.40 (s,3H), 2.30(s,3H) [299] [300] Step 3: l-benzyl-7-(4-chlorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridine hydrochloride [301] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-chlorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 2 and benzyl bromide. (Yield: 69.5 %) [302] 1H-NMR (400MHz, CDCl3) δ 8.36(d,lH), 7.30(m,5H), 6.98(d,2H), 6.84(d,lH),
6.68(d,2H), 5.57(s,2H), 5.23(s,2H), 2.60(s,3H), 2.38(s,3H) [303] [304] Example 12. 7-(4-chlorobenzyloxy)-2,3-dimethyl-l-(3-methylbut-2-enyl) - 1 H- pyrrolo[3,2-b]pyridine hydrochloride [305] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-chlorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 2 of Example 11 and
4-bromo-2-methyl-2-butene. (Yield: 58.6 %) [306] 1H-NMR (400MHz, CDCl3) δ 8.33(d, IH), 7.41(m, 4H), 6.85(d,lH), 5.39(s,2H),
5.05(m,lH), 4.95(d,2H), 2.54(s,3H), 2.32(s,3H), 1.41(s,6H) [307] [308] Example 13. l-(2-acetoxyethyl)-7-(4-chlorobenzyloxy)-2,3-dimethyl - 1 H- pyrrolo[3,2-b]pyridine hydrochloride [309] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-chlorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 2 of Example 11 and 2-bromoethyl acetate.
(Yield: 77.6 %) [310] 1H-NMR (400MHz, CDCl ) δ 8.33(d,lH), 7.45(m,4H), 6.92(d,lH), 5.38(s,2H), 4.59(d,2H), 4.25(d,23H), 2.62(s,3H), 2.45(s,3H), 2.06(s,3H) [311] [312] Example 14. l-cyclopropylmethyl-7-(4-chlorobenzyloxy)-2,3-dimethyl - I H- pyrrolo[3,2-b]pyridine hydrochloride
[313] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-chlorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 2 of Example 11 and
(bromomethyl)cyclopropane. (Yield: 88.1 %) [314] 1H-NMR (400MHz, CDCl ) δ 8.34(d,lH), 7.44(m,4H), 6.89(d,lH), 5.36(s,2H),
4.22(d,2H), 2.55(s,3H), 2.44(s,3H), 1.10(m,lH), 0.48(d,2H), 0.20(d,2H) [315] [316] Example 15. 7-(4-chlorobenzyloxy)-l-([l,3]dioxolan-2-ylmethyl)-2,3-dimethyl ■
1 H- pyrrolo[3,2-b]pyridine hydrochloride [317] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-chlorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 2 of Example 11 and
2-bromomethyl-l,3-dioxolane. (Yield: 58.4 %) [318] 1H-NMR (400MHz, CDCl ) δ 8.28(d,lH), 7.44(m,4H), 6.86(d,lH), 5.38(s,2H),
5.09(m,lH), 4.53(s,2H), 3.76(s,2H), 3.60(s,2H), 2.58(s,3H), 2.46(s,3H) [319] [320] Example 16. 7-(4-chlorobenzyloxy)-l-(4-chlorobenzyl)-2,3-dimethyl - 1 H- pyrrolo[3,2-b]pyridine hydrochloride [321] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-chlorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 2 of Example 11 and 4-chlorobenzyl bromide.
(Yield: 85.3 %) [322] 1H-NMR (400MHz, CDCl ) δ 8.36(s,lH), 7.30(m,4H), 7.04(d,2H), 6.88(s,lH),
6.60(d,2H), 5.51(s,2H), 5.23(s,2H), 2.59(s,3H), 2.37(s,3H) [323] [324] Example 17. 7-(4-chlorobenzyloxy)-l-(2-fluorobenzyl)-2,3-dimethyl - 1 H- pyrrolo[3,2-b]pyridine hydrochloride [325] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-chlorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 2 of Example 11 and 2-fluorobenzyl bromide.
(Yield: 86.0 %) [326] 1H-NMR (400MHz, CDCl ) δ 8.38(s,lH), 7.28(m,3H), 6.99(m,4H), 6.73(s,lH),
6.13(s,lH), 5.62(s,2H), 5.30(s,2H), 2.61(s,3H), 2.38(s,3H) [327] [328] Example 18. 7-(4-chlorobenzyloxy)-l-ethyl-2,3-dimethyl - 1 H- pyrrolo[3,2-b] pyridine hydrochloride
[329] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-chlorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 2 of Example 11 and iodoethane. (Yield: 88.3 %)
[330] 1H-NMR (400MHz, CDCl ) δ 8.33(s,lH), 7.44(m,4H), 6.89(s,lH), 5.38(s,2H),
4.35(d,2H), 2.53(s,3H), 2.42(s,3H), 1.29(t,3H)
[331]
[332] Example 19. 7-(4-chlorobenzyloxy)-l-(3-methoxybenzyl)-2,3-dimethyl - 1 H- pyrrolo[3,2-b]pyridine hydrochloride
[333] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-chlorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 2 of Example 11 and 3-methoxybenzyl chloride. (Yield: 79.8 %)
[334] 1H-NMR (400MHz, CDCl3) δ 8.35(s,lH), 7.39(m,lH), 7.27(s,lH), 7.18(t,lH),
7.00(d,2H), 6.82(d,2H), 6.22(d,2H), 5.52(s,2H), 5.22(s,2H), 3.77(s,3H), 2.59(s,3H), 2.37(s,3H)
[335]
[336] Example 20. 7-(benzo[l,3] dioxol-
5-ylmethoxy)-l-(4-methylbenzyl)-2,3-dimethyl - 1 H- pyrrolo[3,2-b]pyridine hydrochloride
[337]
[338] Step 1: 4-(benzo[l,3]dioxol-5-ylmethoxy)-3-nitropyridine
[339] The titled compound (3.08 g) was obtained as a yellow solid in accordance with the same procedures as in Preparation 2, using 4-chloro-3-nitropyridine (3.0 g, 18.92 mmol) prepared in Step 1 of Preparation 1 and piperonyl alcohol (3.45 ml, 18.92 mmol). (Yield: 88.6 %)
[340] 1H-NMR (400MHz, CDCl3) δ 9.02(s,lH), 8.60(d,lH), 7.06(d,lH), 6.91(t,2H),
6.84(d,lH), 5.99(s,2H), 5.21(s,2H)
[341]
[342] Step 2: 7-(benzo[l,3]dioxol-5-ylmethoxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridine
[343] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 1 of Example 1, using 4-(benzo[l,3] dioxol- 5-ylmethoxy)-3-nitropyridine prepared in Step 1 and 1 -methyl- 1-propenyl magnesium bromide. (Yield: 28.9 %)
[344] 1H-NMR (400MHz, CDCl ) δ 8.28(d,lH), 7.94(s,lH), 6.94(m,2H), 6.82(d,lH),
6.60(d,lH), 5.99(s,2H), 5.11(s,2H), 2.39(s,3H), 2.21(s,3H) [345]
[346] Step 3: 7-(benzo[l,3]dioxol-5-ylmethoxy)-l-(4-methylbenzyl)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine hydrochloride [347] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(benzo[l,3] dioxol-
5-ylmethoxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridine prepared in Step 2 and
4-methylbenzyl chloride. (Yield: 66.0 %) [348] 1H-NMR (400MHz, CDCl3) δ 8.33(d, IH), 7.08(d,2H), 6.88(m,2H), 6.63(m,3H),
6.42(s,lH), 5.99(s,2H), 5.52(s,2H), 5.16(s,2H), 2.58(s,3H), 2.47(s,3H), 2.32(s,3H) [349] [350] Example 21. l-benzyl-7-(2,4-dichlorobenzyloxy)-2,3-dimethyl - 1 H- pyrrolo[3,2-b]pyridine hydrochloride [351]
[352] Step 1: 4-(2,4-dichlorobenzyloxy)-3-nitropyridine
[353] The titled compound was obtained as a white solid in accordance with the same procedures as in Preparation 2, using 4-chloro-3-nitropyridine (3.0 g, 18.92 mmol) prepared in Step 1 of Preparation 1 and 2,4-dichlorobenzyl alcohol. (Yield: 89.3 %) [354] 1H-NMR (400MHz, CDCl3) δ 9.05(s,lH), 8.60(d,lH), 7.13(d,lH), 5.29(d,lH)
[355]
[356] Step 2: 7-(2,4-dichlorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridine
[357] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 1 of Example 1, using 4-(2,4-dichlorobenzyloxy)-3-nitropyridine prepared in Step 1 and 1 -methyl- 1-propenyl magnesium bromide. (Yield: 28.6 %) [358] 1H-NMR (400MHz, CDCl ) δ 8.29(d,lH), 8.01(s,lH), 7.52(m,3H), 6.53(d,lH),
5.18(s,2H), 2.41(s,3H), 2.31(s,3H) [359] [360] Step 3: l-benzyl-7-(2,4-dichlorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b] pyridine hydrochloride [361] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(2,4-dichlorobenzyloxy)-2,3-dimethyl-l
H-pyrrolo[3,2-b]pyridine prepared in Step 2 and benzyl bromide. (Yield: 86.4 %) [362] 1H-NMR (400MHz, CDCl ) δ 8.33(d,lH), 7.43(s,3H), 7.11(m,2H), 6.89(m,lH),
6.67(m,2H), 5.58(s,2H), 5.32(s,2H), 2.64(s,3H), 2.41(s,3H) [363] [364] Example 22. 7-(2,4-dichlorobenzyloxy)-l-cyclopropylmethyl-2,3-dimethyl - 1
H- pyrrolo[3,2-b]pyridine hydrochloride [365] The titled compound was obtained as a white solid In accordance with the same procedures as in Step 2 of Example 1, using 7-(2,4-dichlorobenzyloxy)-2,3-dimethyl-l H-pyrrolo[3,2-b]pyridine prepared in Step 2 of Example 21 and
(bromomethyl)cyclopropane. (Yield: 78.3 %) [366] 1H-NMR (400MHz, CDCl ) δ 8.41(d,lH), 7.60(m,2H), 7.52(m,lH), 7.38(m,lH),
5.45(s,2H), 4.33(d,2H), 2.56(s,3H), 2.47(s,3H), l.l l(m,lH), 0.48(m,2H), 0.19(m,2H) [367] [368] Example 23. 7-(2,4-dichlorobenzyloxy)-l-ethyl-2,3-dimethyl - 1 H- pyrrolo[3,2-b]pyridine hydrochloride [369] The titled compound was obtained as a pale yellow solid in accordance with the same procedures as in Step 2 of Example 1, using
7-(2,4-dichlorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridine prepared in Step 2 of Example 21 and iodoethane,. (Yield: 75.9 %) [370] 1H-NMR (400MHz, CDCl ) δ 8.37(d,lH), 7.55(s,lH), 7.52(d,lH), 7.43(d,lH),
6.93(d,lH), 5.45(s,2H), 4.34(m,2H), 2.58(s,3H), 2.42(s,3H), l.l l(t,3H) [371] [372] Example 24. 7-(2,4-dichlorobenzyloxy)-l-(4-fluorobenzyl)-2,3-dimethyl - 1 H- pyrrolo[3,2-b]pyridine hydrochloride [373] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(2,4-dichlorobenzyloxy)-2,3-dimethyl-l
H-pyrrolo[3,2-b]pyridine prepared in Step 2 of Example 21 and 4-fluorobenzyl bromide. (Yield: 75.5 %) [374] 1H-NMR (400MHz, CDCl ) δ 8.40(d,lH), 7.44(s,lH), 7.19(m,2H), 6.90(m,3H),
6.38(m,2H), 5.52(s,2H), 5.32(s,2H), 2.61(s,3H), 2.39(s,3H) [375] [376] Example 25. 2,3-dimethyl-l-ethyl-7-(3-methylbenzyloxy) - 1 H- pyrrolo[3,2-b] pyridine hydrochloride [377]
[378] Step 1: 4-(3-methylbenzyloxy)-3-nitropyridine
[379] The titled compound was obtained as a yellow solid in accordance with the same procedures as in Preparation 2, using 4-chloro-3-nitropyridine prepared in Step 1 of
Preparation 1 and 3-methylbenzyl alcohol. (Yield: 89.8 %) [380] 1H-NMR (400MHz, CDCl3) δ 9.03(s,lH), 8.62(d,lH), 7.45(m,4H), 7.09(d,lH),
5.35(d,lH), 1.53(s,3H) [381]
[382] Step 2: 7-(3-methylbenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridine
[383] The titled compound was obtained as a pale yellow solid in accordance with the same procedures as in Step 1 of Example 1, using
4-(3-methylbenzyloxy)-3-nitropyridine prepared in Step 1 and 1 -methyl- 1-propenyl magnesium bromide. (Yield: 28.3 %) [384] 1H-NMR (400MHz, CDCl ) δ 8.29(d,lH), 8.01(s,lH), 7.40(m,4H), 6.58(d,lH),
5.23(s,2H), 2.40(s,3H), 2.30(s,3H), 1.55(s,lH) [385]
[386] Step 3: 2,3-dimethyl-l-ethyl-7-(3-methylbenzyloxy)-lH-pyrrolo[3,2-b]pyridine hydrochloride [387] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(3-methylbenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 2 and iodoethane. (Yield: 69.0 %) [388] 1H-NMR (400MHz, CDCl ) δ 8.31(s,lH), 7.34(m,4H), 6.86(d,lH), 5.37(s,2H),
4.38(m,2H), 2.53(s,3H), 2.42(s,3H), 2.40(s,3H), 1.29(t,3H) [389] [390] Example 26. 2,3-dimethyl-l-propyl-7-(3-methylbenzyloxy) - 1 H- pyrrolo[3,2-b
] pyridine hydrochloride [391] The titled compound was obtained as a pale yellow solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(3-methylbenzyloxy)-2,3-dimethyl
-lH-pyrrolo[3,2-b]pyridine prepared in Step 2 of Example 25 and 1-iodopropane.
(Yield: 78.2 %) [392] 1H-NMR (400MHz, CDCl3) δ 8.34(s,lH), 7.34(m,4H), 6.88(s,lH), 5.33(s,2H),
4.20(t,2H), 2.40(s,3H), 2.17(s,3H), 1.69(m,2H), 0.75(t,3H) [393] [394] Example 27. l-allyl-2,3-dimethyl-7-(3-methylbenzyloxy) - 1 H- pyrrolo[3,2-b] pyridine hydrochloride [395] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(3-methylbenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 2 of Example 25 and allyl bromide. (Yield:
72.3 %) [396] 1H-NMR (400MHz, CDCl3) δ 8.33(d,lH), 7.31(m,3H), 6.85(d,lH), 5.90(m,lH),
5.35(s,2H), 5.15(d,lH), 4.97(s,2H), 4.57(d,lH), 2.57(s,3H), 2.39(s,6H) [397] [398] Example 28. l-cyclopropylmethyl-7-(2-ethoxybenzyloxy)-2,3-dimethyl - 1 H- pyrrolo[3,2-b]pyridine hydrochloride [399]
[400] Step 1: 4-(2-ethoxybenzyloxy)-3-nitropyridine
[401] The titled compound was obtained as a yellow solid in accordance with the same procedures as in Preparation 2, using 4-chloro-3-nitropyridine prepared in Step 1 of
Preparation 1 and 2-ethoxybenzyl alcohol. (Yield: 65.9 %) [402] 1H-NMR (400MHz, CDCl ) δ 9.04(s,lH), 8.62(d,lH), 7.32(m,4H), 7.04(d,lH),
5.33(d,lH), 2,87(m,2H), 1.2(t,3H) [403]
[404] Step 2: 7-(2-ethoxybenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridine
[405] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 1 of Example 1, using 4-(2-ethoxybenzyloxy)-3-nitropyridine prepared in Step 1 and 1 -methyl- 1-propenyl magnesium bromide. (Yield: 25.5 %) [406] 1H-NMR (400MHz, CDCl ) δ 8.30(d,lH), 8.01(s,lH), 7.25(m,4H), 6.58(d,lH),
5.30(s,2H), 3.12(m,2H), 2.41(s,3H), 2.26(s,3H), 1.21(t,3H) [407] [408] Step 3: l-cyclopropylmethyl-7-(2-ethoxybenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b
]pyridine hydrochloride [409] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(2-ethoxybenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 2 and (bromomethyl)cyclopropane. (Yield:
82.5 %) [410] 1H-NMR (400MHz, CDCl ) δ 8.33(t,lH), 7.39(m,2H), 6.96(m,3H), 5.44(s,2H),
4.23(d,2H), 4.12(m,2H), 2.55(s,3H), 2.43(s,3H), 1.41(t,3H), 1.12(m,lH), 0.43(m,2H),
0.20(m,2H) [411] [412] Example 29. l-(3-methoxybenzyl)-7-(2-ethoxybenzyloxy)-2,3-dimethyl - 1 H- pyrrolo[3,2-b]pyridine hydrochloride [413] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(2-ethoxybenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 2 of Example 28 and 3-methoxybenzyl bromide. (Yield: 79.5 %) [414] 1H-NMR (400MHz, CDCl ) δ 8.32(t,lH), 7.31(m,lH), 7.16(t,lH), 6.92(d,2H),
6.84(m,3H), 6.26(s,2H), 5.57(s,2H), 5.35(s,2H), 4.01(m,2H), 3.68(s,3H), 2.57(s,3H),
2.35(s,3H), 1.34(t,3H) [415] [416] Example 30. l-(3-fluorobenzyl)-7-(2-ethoxybenzyloxy)-2,3-dimethyl - 1 H- pyrrolo[3,2-b]pyridine hydrochloride [417] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(2-ethoxybenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine prepared in Step 2 of Example 28 and 3-fluorobenzyl bromide.
(Yield: 86.7 %) [418] 1H-NMR (400MHz, CDCl3) δ 8.33(d,lH), 7.33(t,lH), 7.19(m,lH), 6.94(t,3H),
6.85(m,2H), 6.43(m,2H), 5.55(s,2H), 5.34(s,2H), 3.99(m,2H), 2.59(s,3H), 2.36(s,3H),
1.34(t,3H) [419] [420] Example 31. l-cyclobutylmethyl-7-(3,5-difluorobenzyloxy)-2,3-dimethyl - 1 H- pyrrolo[3,2-b]pyridine hydrochloride
[421]
[422] Step 1: 4-(3,5-difluorobenzyloxy)-3-nitropyridine
[423] The titled compound was obtained as a yellow solid in accordance with the same procedures as in Preparation 2, using 4-chloro-3-nitropyridine prepared in Step 1 of
Preparation 1 and 3,5-difluorobenzyl alcohol. (Yield: 78.0 %) [424] 1H-NMR (400MHz, CDCl3) δ 9.06(s,lH), 8.73(s,lH), 8.65(d,lH), 7.40(s,lH),
7.35(s,lH), 7.04(d,lH), 5.28(d,lH) [425]
[426] Step 2: 7-(3,5-difluorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridine
[427] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 1 of Example 1, using 4-(3,5-difluorobenzyloxy)-3-nitropyridine prepared in Step 1 and 1 -methyl- 1-propenyl magnesium bromide. (Yield: 20.4 %) [428] 1H-NMR (400MHz, CDCl ) δ 8.75(s,lH), 8.66(d,lH), 8.01(s,lH), 7.40(s,lH),
7.35(s,lH), 7.04(d,lH), 5.28(d,lH), 2.11(s,3H), 2.35(s,3H) [429] [430] Step 3: l-cyclobutylmethyl-7-(3,5-difluorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-b]pyridine hydrochloride [431] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(3,5-difluorobenzyloxy)-2,3-dimethyl-l
H-pyrrolo[3,2-b]pyridine prepared in Step 2 and (bromomethyl)cyclobutane. (Yield:
70.5 %) [432] 1H-NMR (400MHz, CDCl ) δ 8.36(s,lH), 7.02(m,2H), 6.91(m,lH), 6.82(m,lH),
5.36(s,2H), 4.35(d,2H), 2.67(m,lH), 2.55(s,3H), 2.44(s,3H), 1.73(m,2H), 1.67(m,2H) [433] [434] Example 32. l-benzyl-7-(3,5-difluorobenzyloxy)-2,3-dimethyl - 1 H- pyrrolo[3,2-b]pyridine hydrochloride [435] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(3,5-difluorobenzyloxy)-2,3-dimethyl-l
H-pyrrolo[3,2-b]pyridine prepared in Step 2 of Example 31 and benzyl bromide.
(Yield: 80.9 %) [436] 1H-NMR (400MHz, CDCl ) δ 8.35(d,lH), 7.42(m,4H), 6.80(m,4H), 6.55(d,lH),
5.60(s,2H), 5.25(s,2H), 2.62(s,3H), 2.45(s,3H) [437] [438] Example 33. 2,3-dimethyl-l-(4-methylbenzyl)-7-(4-trifluoromethylbenzyloxy) -
1 H- pyrrolo[3,2-b]pyridine hydrochloride [439] [440] Step 1: 4-(4-trifluoromethylbenzyloxy)-3-nitropyridine
[441] The titled compound was obtained as a yellow solid in accordance with the same procedures as in Preparation 2, using 4-chloro-3-nitropyridine prepared in Step 1 of
Preparation 1 and 4-trifluoromethylbenzyl alcohol. (Yield: 89.5 %) [442] 1H-NMR (400MHz, CDCl ) δ 9.03(s,lH), 8.66(d,lH), 7.38(m,4H), 7.02(d,lH),
5.29(d,lH) [443]
[444] Step 2: 7-(4-trifluoromethylbenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridine
[445] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 1 of Example 1, using
4-(4-trifluoromethylbenzyloxy)-3-nitropyridine prepared in Step 1 and
1 -methyl- 1-propenyl magnesium bromide. (Yield: 29.5 %) [446] 1H-NMR (400MHz, CDCl ) δ 8.28(d,lH), 8.01(s,lH), 7.36(m,4H), 6.57(d,lH),
5.20(s,2H), 2.41(s,3H), 2.31(s,3H) [447] [448] Step 3: 2,3-dimethyl-l-(4-methylbenzyl)-7-(4-trifluoromethylbenzyloxy)-lH- pyrrolo[3,2-b]pyridine hydrochloride [449] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using
7-(4-trifluoromethylbenzyloxy)-2,3-dimethyl- lH-pyrrolo[3,2-b]pyridine prepared in
Step 2 and 4-methylbenzyl bromide. (Yield: 88.6 %) [450] 1H-NMR (400MHz, CDCl ) δ 8.37(d,lH), 7.55(d,2H), 7.16(m,2H), 7.13(d,2H),
6.81(m,lH), 6.58(d,2H), 5.55(s,2H), 5.32(s,2H), 2.61(s,3H), 2.38(s,3H), 2.35(s,3H) [451] [452] Example 34.
2,3-dimethyl-l-(3-methoxybenzyl)-7-(4-trifluoromethylbenzyloxy) - 1 H- pyrrolo[3,2-b]pyridine hydrochloride [453] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using
7-(4-trifluoromethylbenzyloxy)-2,3-dimethyl- lH-pyrrolo[3,2-b]pyridine prepared in
Step 2 of Example 33 and 3-methoxybenzyl bromide. (Yield: 89.0 %) [454] 1H-NMR (400MHz, CDCl ) δ 8.34(t,lH), 7.55(d,2H), 7.18(m,3H), 6.83(d,2H),
6.22(s,2H), 5.54(s,2H), 5.30(s,2H), 3.70(s,3H), 2.60(s,3H), 2.38(s,3H) [455] [456] Example 35. 1-([1,3] dioxolan-
2-ylmethyl)-7-(l,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl - 1 H- pyrrolo[3,2-c]pyridine hydrochloride [457] [458] Step 1: 2-(2,3-dimethyl-lH-pyrrolo[3,2-c] pyridin-
7-yl)- 1 ,2,3,4-tetrahydroisoquinoline [459] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 1 of Example 1, using
2-(4-nitropyridin-3-yl)-l,2,3,4-tetrahydroisoquinoline prepared in Preparation 4.
(Yield: 19.5 %) [460] 1H-NMR (400MHz, CDCl ) δ 10.21(s,lH), 8.50(s,lH), 7.88(s,lH), 7.21(m,3H),
7.07(d,lH), 4.35(s,2H), 3.49(t,2H), 3.15(t,2H), 2.54(s,3H), 2.27(s,3H) [461] [462] Step 2: 1-([1,3] dioxolan-
2-ylmethyl)-7-(l,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-lH-pyrrolo[3,2-c]pyri dine hydrochloride [463] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 2-(2,3-dimethyl-lH-pyrrolo[3,2-c] pyridin-
7-yl)-l,2,3,4-tetrahydroisoquinoline prepared in Step 1 and
2-bromomethyl-l,3-dioxolane. (Yield: 55.8 %) [464] 1H-NMR (400MHz, CDCl ) δ 8.35(s,lH), 8.10(s,lH), 7.85(m,2H), 7.23(m,3H),
5.91(d,2H), 4.35(s,2H), 4.04(m,4H), 3.96(s,2H), 2.79(m,2H), 2.38(s,3H), 2.29(s,H) [465] [466] Example 36. 2-(l-ethyl-2,3-dimethyl - 1 H- pyrrolo[3,2-c] pyridin-
7-yl)-l,2,3,4-tetrahydroisoquinoline hydrochloride [467] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 2-(2,3-dimethyl-lH-pyrrolo[3,2-c] pyridin-
7-yl)-l,2,3,4-tetrahydroisoquinoline prepared in Step 1 of Example 35 and iodoethane.
(Yield: 65.8 %) [468] 1H-NMR (400MHz, CDCl ) δ 8.65(s,lH), 8.13(s,lH), 7.23(m,3H), 7.08(m,lH),
4.59(m,2H), 4.23(m,2H), 3.51(m,2H), 3.23(m,2H), 2.45(s,3H), 2.34(s,3H), 1.25(d,3H) [469] [470] Example 37. 2-[l-(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-2,3-dimethyl - 1
H- pyrrolo[3,2-c]pyridin-7-yl]-l,2,3,4-tetrahydroisoquinoline hydrochloride [471] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 2-(2,3-dimethyl-lH-pyrrolo[3,2-c] pyridin-
7-yl)-l,2,3,4-tetrahydroisoquinoline prepared in Step 1 of Example 35 and
6-bromomethyl-2,3-dihydrobenzo[l,4]dioxine. (Yield: 35.3 %) [472] 1H-NMR (400MHz, CDCl ) δ 8.36(s,lH), 7.58(m,4H), 7.15(s,lH), 7.10(m,3H),
5.16(s,2H), 4.69(s,2H), 4.33(m,2H), 3.57(m,2H), 3.01(m,2H), 2.57(s,3H), 2.47(s,3H) [473] [474] Example 38. 7-(4-fluorobenzyloxy)-2,3-dimethyl-l-(prop-2-ynyl) - 1 H- pyrrolo[3,2-c]pyridine hydrochloride
[475]
[476] Step 1: 7-(4-fluorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-c]pyridine hydrochloride
[477] 3-(4-Fluorobenzyloxy)-4-nitropyridine (6.6 g, 26.59 mmol) prepared in Preparation
5 was dissolved in anhydrous tetrahydrofuran (300 ml) under a nitrogen atmosphere. 1 -Methyl- 1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution, 80 ml) was added at -78 0C to the solution, which was then stirred at -20 0C for 5 hours. 20% (w/v) ammonium chloride solution (20 ml) was added to the reaction mixture, which was then extracted with ethyl acetate (200 ml X 2). The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/methanol = 10/1, v/v) and then concentrated. The resulting residue was dissolved in 10 ml of ethyl acetate and then saturated with hydrochloric acid gas. The resulting precipitate was filtered and then dried to give the titled compound (910 mg, 13.5 %) as a white solid.
[478] Rf (ethyl acetate/methanol = 10/1, v/v) = 0.2
[479] 1H-NMR (400MHz, CDCl ) δ 8.46(s,lH), 8.20(s,lH), 7.94(s,lH), 7.43(m,2H),
7.09(m,2H), 5.18(s,2H), 2.36(s,3H), 2.25(s,3H)
[480]
[481] Step 2: 7-(4-fluorobenzyloxy)-2,3-dimethyl- l-(prop-2-ynyl)- lH-pyrrolo[3,2-c] pyridine hydrochloride
[482] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-fluorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-c]pyridine (20.0 mg, 0.073 mmol) obtained by treating the compound prepared in Step 1 with a saturated sodium hydrogencarbonate solution and propargyl bromide (0.08 ml, 0.109 mmol). (Yield: 40.1 %)
[483] Rf (ethyl acetate/methylene chloride/methanol = 10/1/1, v/v/v) = 0.4
[484] 1H-NMR (400MHz, CDCl ) δ 8.55(s,lH), 7.94(s,lH), 7.49(d,2H), 7.14(d,2H),
5.30(s,2H), 5.21(s,2H), 2.50(s,3H), 2.42(s,lH), 2.32(s,3H)
[485]
[486] Example 39. 7-(4-fluorobenzyloxy)-l-(2-methoxyethyl)-2,3-dimethyl - 1 H- pyrrolo[3,2-c]pyridine hydrochloride
[487] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-fluorobenzyloxy)-2,3-dimethyl-lH- pyrrolo[3,2-c]pyridine obtained by treating the compound prepared in Step 1 of Example 38 with a saturated sodium hydrogencarbonate solution and 2-bromoethyl methyl ether. (Yield: 54.3 %) [488] 1H-NMR (400MHz, CDCl ) δ 8.54(s,lH), 7.91(s,lH), 7.44(d,2H), 7.15(d,2H),
5.30(s,2H), 5.21(t,2H), 3.57(d,2H), 3.21(s,3H), 2.46(s,3H), 2.05(s,3H)
[489]
[490] Example 40. l-cyclopropylmethyl-7-(4-fluorobenzyloxy)-2,3-dimethyl - 1 H- pyrrolo[3,2-c]pyridine hydrochloride
[491] The titled compound was obtained as a pale yellow solid in accordance with the same procedures as in Step 2 of Example 1, using 7-(4-fluorobenzyloxy)-2,3-dimethyl- lH-pyrrolo[3,2-c]pyridine obtained by treating the compound prepared in Step 1 of Example 38 with a saturated sodium hydrogencarbonate solution and (bromomethyl)cyclopropane. (Yield: 58.4 %)
[492] 1H-NMR (400MHz, CDCl ) δ 8.55(s,lH), 7.95(s,lH), 7.46(d,2H), 7.17(d,2H),
5.28(s,2H), 4.29(d,2H), 2.44(s,3H), 2.32(s,3H), 1.21(m,lH), 0.48(d,2H), 0.22(d,2H)
[493]
[494] Example 41. l-cyclopropylmethyl-2,3-dimethyl-4-(4-fluorobenzylamino) - 1 H- pyrrolo[3,2-c]pyridine hydrochloride
[495]
[496] Step 1: 2,3-dimethyl-4-(4-fluorobenzylamino)-lH-pyrrolo[3,2-c]pyridine hydrochloride
[497] A mixture of 4-chloro-2,3-dimethyl-lH-pyrrolo[3,2-c]pyridine (1.16 g, 6.43 mmol) prepared in Preparation 6 and 4-fluorobenzylamine (3 ml) was stirred at 160 0C for 12 hours. The reaction mixture was cooled to room temperature and then purified with silica gel column chromatography (ethyl acetate: 100%) and then concentrated. The resulting residue was dissolved in 10 ml of ethyl acetate and then saturated with hydrochloric acid gas. The resulting precipitate was filtered and then dried to give the titled compound (1.47 g, 85.0 %) as a white solid.
[498] 1H-NMR (400MHz, CDCl /CD OD) δ 7.44 (brs, 3H), 7.06 (brs, 2H), 6.90 (brs,
IH), 4.87 (brs, 2H), 2.33 (brs, 6H)
[499]
[500] Step 2: l-cyclopropylmethyl-2,3-dimethyl-4-(4-fluorobenzylamino)-lH- pyrrolo[3,2-c]pyridine hydrochloride
[501] The compound prepared in Step 1 was treated with a saturated sodium hydrogen- carbonate solution to obtain 2,3-dimethyl-4-(4-fluorobenzylamino)-lH-pyrrolo[3,2-c] pyridine. Sodium hydride (60 %, 4.9 mg, 0.118 mmol) was added at room temperature to a solution of 2,3-dimethyl-4-(4-fluorobenzylamino)-lH-pyrrolo[3,2-c]pyridine (20 mg, 0.065 mmol) in 1 ml of Λ/,./V-dimethylformamide. The reaction mixture was stirred for 30 minutes. (Bromomethyl)cyclopropane (0.046 ml, 0.0515 mmol) was slowly added to the reaction mixture, which was then stirred at room temperature for 1 hour. The reaction mixture was diluted with 10 ml of ethyl acetate and then washed with 10 ml of water three times. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated. The resulting residue was dissolved in 1 ml of ethyl acetate and then saturated with hydrochloric acid gas. The resulting precipitate was filtered and then dried to give the titled compound as a white solid. (Yield: 65.5 %)
[502] 1H-NMR (400MHz, CDCl ) δ 7.79 (brs, IH), 7.50 (brs, 2H), 7.07 (brs, 2H), 6.81
(brs, IH), 5.87(brs, IH), 5.12 (brs, 2H), 3.97 (brs, 2H), 2.39 (brs, 3H), 2.35 (brs, 3H), 1.12 (brs, IH), 0.62 (m, 2H), 0.34 (m, 2H)
[503]
[504] Example 42. l-benzyl-2,3-dimethyl-4-(4-fluorobenzylamino) - 1 H- pyrrolo[3,2-c]pyridine hydrochloride
[505] The titled compound was obtained in accordance with the same procedures as in
Step 2 of Example 41, using 2,3-dimethyl-4-(4-fluorobenzylamino)-lH-pyrrolo[3,2-c] pyridine obtained by treating the compound prepared in Step 1 of Example 41 with a saturated sodium hydrogencarbonate solution and benzyl bromide. (Yield: 58.4 %)
[506] 1H-NMR (400MHz, CDCl ) δ 7.73-6.78(m, 1 IH), 6.07 (brs, IH), 5.28 (brs, 2H),
5.12(brs, 2H), 2.42 (brs, 3H), 2.25 (brs, 3H)
[507]
[508] Example 43. 2,3-dimethyl-l-(2-fluorobenzyl)-4-(4-fluorobenzylamino) - 1 H- pyrrolo[3,2-c]pyridine hydrochloride
[509] The titled compound was obtained in accordance with the same procedures as in
Step 2 of Example 41, using 2,3-dimethyl-4-(4-fluorobenzylamino)-lH-pyrrolo[3,2-c] pyridine obtained by treating the compound prepared in Step 1 of Example 41 with a saturated sodium hydrogencarbonate solution and 2-fluorobenzyl bromide. (Yield: 35.4 %)
[510] 1H-NMR (400MHz, CDCl ) δ 7.78 (brs, IH), 7.52 (brs, 2H), 7.31 (brs, 2H), 7.08
(m, 3H), 6.79 (brs, IH), 6.53 (brs, IH), 6.07 (brs, IH), 5.32 (brs, 2H), 5.15(brs, 2H), 2.43 (brs, 3H), 2.27 (brs, 3H)
[511]
[512] Example 44. 3-benzyl-2-methyl-4-(l,2,3,4-tetrahydroisoquinolin-2-yl) - 1 H- pyrrolo[3,2-c]pyridine hydrochloride
[513]
[514] Step 1: 4-[Λ/7-(l-methyl-3-phenylpropyliden)-hydrazino]-lH-pyridin-2-one
[515] The titled compound (7.30 g) was obtained as a white solid in accordance with the same procedures as in Step 2 of Preparation 6, using 4-hydrazino-lH-pyridin-2-one (5.39 g, 43.1 mmol) prepared in Step 1 of Preparation 6 and 4-phenyl-2-butanone (9.70 ml, 64.6 mmol). (Yield: 66.5 %) The product was used in the subsequent step without further purification. [516]
[517] Step 2: 3-benzyl-2-methyl-l,5-dihydropyrrolo[3,2-c]pyridin-4-one
[518] The titled compound (6.41 g) was obtained as a white solid in accordance with the same procedures as in Step 3 of Preparation 6, using 4-[N' -
(l-methyl-3-phenylpropyliden)-hydrazino]-lH-pyridin-2-one (7.30 g, 28.6 mmol) prepared in Step 1. (Yield: 94 %) [519] 1H-NMR (400MHz, CDCl ) δ 10.99 (brs, IH), 10.55 (brs, IH), 7.33(m,5H), 6.86
(d, IH), 6.25 (d, IH), 5.10(s,2H), 2.25 (s, 3H) [520]
[521] Step 3: 3-benzyl-4-chloro-2-methyl-lH-pyrrolo[3,2-c]pyridine
[522] The titled compound (1.74 g) was obtained as a pale yellow solid in accordance with the same procedures as in Step 4 of Preparation 6, using
3-benzyl-2-methyl-l,5-dihydropyrrolo[3,2-c]pyridin-4-one (4.82 g, 20.2 mmol) prepared in Step 2. (Yield: 33 %) [523] 1H-NMR (400MHz, CDCl ) δ 10.54 (brs, IH), 7.32(m,5H), 7.12 (d, IH), 6.28 (d,
IH), 5.11(s,2H), 2.28 (s, 3H) [524] [525] Step 4: 3-benzyl-2-methyl-4-(l,2,3,4-tetrahydroisoquinolin-2-yl)-lH-pyrrolo[3,2-c] pyridine hydrochloride [526] The titled compound was obtained as a pale yellow solid in accordance with the same procedures as in Step 1 of Example 41, using 3-benzyl-4-chloro-2-methyl-lH- pyrrolo[3,2-c]pyridine prepared in Step 3 and 1,2,3,4-tetrahydroisoquinoline. (Yield:
89.7 %) [527] 1H-NMR (400MHz, CDCl ) δ 7.82 (brs, IH), 7.55 (brs, IH), 7.26-7.02 (m, 6H),
6.90 (brs, 2H), 6.44 (m, IH), 4.55 (brs, 2H), 4.13 (brs, 2H), 3.84 (brs, 2H), 2.94 (brs,
2H), 2.42 (s, 3H) [528] [529] Example 45. l-allyl-7-(l,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl - 1 H- pyrrolo[2,3-c]pyridine hydrochloride [530]
[531] Step 1: 2-(l,2,3,4-tetrahydroisoquinolin-2-yl)-3-nitropyridine
[532] The titled compound (4.8 g) was obtained as a yellow solid in accordance with the same procedures as in Step 1 of Preparation 3, using 2-chloro-3-nitropyridine (3.0 g,
18.92 mmol) and 1,2,3,4-tetrahydroisoquinoline (2.37 ml, 18.92 mmol). (Yield: 98 %) [533] 1H-NMR (400MHz5CDCl ) δ 8.35(d,lH), 8.17(d,lH), 7.19(m,3H), 7.11(m,lH),
6.73(m,lH), 4.48(s,2H), 3.76(t,2H), 3.01(t,2H) [534] [535] Step 2: 7-(l,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-lH-pyrrolo[2,3-c] pyridine hydrochloride
[536] 7-(l,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-lH-pyrrolo[2,3-c]pyridine was obtained in accordance with the same procedures as in Step 1 of Example 1, using 2-(l,2,3,4-tetrahydroisoquinolin-2-yl)-3-nitropyridine (4.8 g, 18.8 mmol) prepared in Step 1 and 1 -methyl- 1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution, 112 ml). The resulting residue was dissolved in ethyl acetate and then saturated with hydrochloric acid gas. The resulting precipitate was filtered and then dried to give 1.3 g of the titled compound as a yellow solid.
[537] 1H-NMR (400MHz5CDCl ) δ 13.05(brs,lH), 11.59(brs,lH), 7.54(brs,lH),
7.08(brs,lH), 6.98(m,lH), 6.91(brs,lH), 6.78(s,2H), 5.04(s,2H), 3.97(s,2H), 2.89(s,2H), 2.63(s,3H), 2.14(s,3H)
[538]
[539] Step 3: l-allyl-7-(l,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-lH- pyrrolo[2,3-c]pyridine hydrochloride
[540] Sodium hydride (60%, 40 mg, 0.999 mmol) and allyl bromide (0.385 ml, 0.399 mmol) were added at 0 0C to a solution of
7-(l,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-lH-pyrrolo[2,3-c]pyridine hydrochloride (92.3 mg, 0.333 mmol) prepared in Step 2 in anhydrous tetrahydrofuran (10 ml). The reaction mixture was stirred at room temperature for 12 hours and then poured into ice. The reaction mixture was dried on anhydrous magnesium sulfate and then concentrated. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=l/5, v/v). The resulting solid was dissolved in 1 ml of ethyl acetate and then saturated with hydrochloric acid gas. The resulting precipitate was filtered and then dried to give 23.7 mg of the titled compound as a white solid.
[541] 1H-NMR (400MHz5CDCl ) δ 8.14(d,lH), 7.46(d,lH), 7.21(m,3H), 7.03(d,lH),
5.18(m,lH), 5.14(d,lH), 5.05(s,2H), 4.55(br,2H), 4.50(d,lH), 3.91(t,2H), 3.12(t,2H), 2.42(s,3H), 2.30(s,3H)
[542]
[543] Example 46. 2-(2,3-dimethyl - 1 H- pyrrolo[2,3-c] pyridin-
7-yl)-l-methyl-l,2,3,4-tetrahydroisoquinoline hydrochloride
[544]
[545] Step 1: l-methyl-2-(3-nitropyridin-2-yl)-l,2,3,4-tetrahydroisoquinoline
[546] The titled compound was obtained as pale yellow oil in accordance with the same procedures as in Step 1 of Preparation 3, using 1 -methyl- 1, 2,3, 4-tetrahydroisoquinoline prepared in Preparation 7 and 2-chloro-3-nitropyridine. The product was used in the subsequent step without further purification.
[547] [548] Step 2: 2-(2,3-dimethyl-lH-pyrrolo[2,3-c] pyridin-
7-yl)-l-methyl-l,2,3,4-tetrahydroisoquinoline hydrochloride
[549] 2-(2,3-dimethyl-lH-pyrrolo[2,3-c]pyridin-7-yl)-l-methyl-l,2,3,4-tetrahydroisoquin oline was obtained in accordance with the same procedures as in Step 1 of Example 1, using l-methyl-2-(3-nitropyridin-2-yl)-l,2,3,4-tetrahydroisoquinoline prepared in Step 1 as a starting material. 1.2 g of 2-(2,3-dimethyl-lH-pyrrolo[2,3-c] pyridin- 7-yl)-l-methyl-l,2,3,4-tetrahydroisoquinoline was dissolved in 30 ml of ethyl acetate and then saturated with hydrochloric acid gas. The resulting precipitate was filtered and then dried to give the titled compound as a white solid. (Yield: 40 %)
[550] 1H-NMR (400MΗz,CDCl ) δ 8.58 (bs,lH), 7.93 (m,lH), 6.97 (m,5H), 5.20 (q,lH),
3.91 (m,lH), 3.59 (t,lH), 3.02 (m,lH), 2.83 (d,lH), 2.35 (s,3H), 2.19 (s,3H), 1.27 (d,3H)
[551]
[552] Example 47. 2-(2,3-dimethyl - 1 H- pyrrolo[2,3-c] pyridin-
7-yl)-l-methyl-l,2,3,4-tetrahydroisoquinoline sodium
[553] The compound prepared in Example 46 was treated with a saturated sodium hydro- gencarbonate solution to obtain 2-(2,3-dimethyl-lH-pyrrolo[2,3-c] pyridin- 7-yl)-l-methyl-l,2,3,4-tetrahydroisoquinoline. A solution of 2-(2,3-dimethyl-lH- pyrrolo[2,3-c]pyridin-7-yl)-l-methyl-l,2,3,4-tetrahydroisoquinoline (78.5 mg, 0.27 mmol) and sodium hydride (6.5 mg, 0.27 mmol) in anhydrous tetrahydrofuran (2ml) was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The resulting residue was re-crystallized to give 75 mg of the titled compound as a pale yellow solid.
[554] 1H-NMR (400MHz, CDCl ) δ 7.94(d, IH), 7.90(brs, IH), 7.20(s, 4H), 7.05(d, IH),
5.19(m, IH), 3.90(m, IH), 3.65(m, IH), 3.10(m, IH), 2.94(dd, IH), 2.38(s, 3H), 2.19(s, 3H), 1.37(d, 3H)
[555]
[556] Example 48. 7-(4-chlorobenzylamino)-l-isobutyl-2,3-dimethyl - 1 H- pyrrolo[2,3-c]pyridine hydrochloride
[557]
[558] Step 1: 7-chloro-2,3-dimethyl-lH-pyrrolo[2,3-c]pyridine
[559] 2-Chloro-3-nitropyridine (8 g, 50.46 mmol) was dissolved in anhydrous tetrahydrofuran (200ml) under a nitrogen atmosphere. 1 -Methyl- 1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution, 252 ml, 126.15 mmol) was slowly added at -78 0C to the solution. The reaction mixture was stirred at -20 0C for 2 hours. An ammonium chloride solution (20 %) was added to the reaction mixture, which was then extracted with ethyl acetate. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/ n-hexane = 1/3, v/v) to give the titled compound (2.73 g, 30 %) as a pale yellow solid.
[560] 1H-NMR (400 MHz, CDCl3) δ 8.45(brs, IH), 7.97(d, IH), 7.30(d, IH), 2.43(s, 3H),
2.21(s, 3H)
[561]
[562] Step 2: 7-chloro-l-isobutyl-2,3-dimethyl-lH-pyrrolo[2,3-c]pyridine
[563] Sodium hydride (60%, 33 mg, 0.83 mmol) was added to a solution of
7-chloro-2,3-dimethyl-lH-pyrrolo[2,3-c]pyridine (100 mg, 0.53 mmol) prepared in Step 1 in anhydrous tetrahydrofuran (2.8 ml). The reaction mixture was stirred at room temperature for 30 minutes. l-Iodo-2-methylpropane (64 ml, 0.67 mmol) was added to the reaction mixture, which was then stirred overnight at room temperature. Water was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane = 1/9, v/v) to give the titled compound (108 mg, 86 %) as a white solid.
[564] 1H-NMR (400 MHz, CDCl ) δ 7.94 (d, IH), 7.29 (d, IH), 4.25 (s, br, 2H), 2.38 (s,
3H), 2.22 (m, 4H), 0.89 (d, 6H)
[565]
[566] Step 3: 7-(4-chlorobenzylamino)-l-isobutyl-2,3-dimethyl-lH-pyrrolo[2,3-c] pyridine hydrochloride
[567] Cesium carbonate (97 mg, 0.317 mmol), (S) -
(-)-2,2'-bis(diphenylphosphino)-l,l'-binaphthalene (20 mg, 0.0317 mmol), and 7-chloro-l-isobutyl-2,3-dimethyl-lH-pyrrolo[2,3-c]pyridine (50 mg, 0.211 mmol) prepared in Step 2 were added to a solution of tris(dibenzylideneacetone)dipalladium(0) (11 mg, 0.0106 mmol) and 4-chlorobenzylamine (40 ml, 0.317 mmol) in toluene (1.1 mL). The reaction mixture was refluxed for 40 hours and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane = 15/85, v/v). The resulting residue was dissolved in 2 ml of ethyl acetate and then saturated with hydrochloric acid gas. The resulting precipitate was filtered and then dried to give the titled compound (15 mg, 21 %) as a white solid.
[568] 1H-NMR (400 MHz, CDCl ) δ 7.64 (t, IH), 7.46 (d, 2H), 7.29 (d, 2H), 6.87 (d,
IH), 6.43 (br, IH), 5.09 (d, 2H), 4.11 (d, 2H), 2.35 (s, 3H), 2.16 (s, 3H), 1.89 (m, IH), 0.77 (d, 6H)
[569]
[570] Example 49. 7-benzylamino-2,3-dimethyl - 1 H- pyrrolo[2,3-c]pyridine hydrochloride [571]
[572] Step 1: 2-benzylamino-3-nitropyridine
[573] The titled compound was obtained as a yellow solid in accordance with the same procedures as in Step 1 of Preparation 3, using 2-chloro-3-nitropyridine and benzylamine. (Yield: 91 %)
[574] Rf (ethyl acetate/n-hexane = 1/5, v/v) = 0.5
[575] 1H-NMR (400 MHz, CDCl ) δ 8.52 (brs, IH), 8.44 (m, 2H), 7.31 (m, 5H), 6.68 (m,
IH), 4.87 (d, 2H) [576]
[577] Step 2: 2-(/V-benzyl-./V-te7t-butoxycarbonyl)amino-3-nitropyridine
[578] 17.5 g of the titled compound was obtained as yellow oil in accordance with the same procedures as in Step 2 of Preparation 3, using 2-benzylamino-3-nitropyridine
(12.2 g, 53.2 mmol) prepared in Step 1 and di-teτt-butyl dicarbonate (36.68 ml, 160 mmol).
[579] Rf (ethyl acetate/n-hexane = 1/5, v/v) = 0.4
[580] 1H-NMR (400 MHz, CDCl ) δ 8.58 (m, IH), 8.21 (m, IH), 7.44 (m, 2H), 7.28 (m,
2H), 7.22 (m, 2H), 5.24 (s, 2H), 1.36 (s, 9H) [581] [582] Step 3: 7-(Λf-benzyl-Λ^tert-butyloxycarbonyl)amino-2,3-dimethyl-lH-pyrrolo[2,3-c] pyridine [583] 7.5 g of the titled compound was obtained as a yellow solid in accordance with the same procedures as in Step 1 of Example 1, using 2-(N-benzy\-N-tert - butyloxycarbonyl)amino-3-nitropyridine (17.5 g, 53.1 mmol) prepared in Step 2 and
1 -methyl- 1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution, 318 ml,
159mmol).
[584] Rf (ethyl acetate/n-hexane = 1/1 , v/v) = 0.1
[585] 1H-NMR (400 MHz, CDCl ) δ 7.30 (m, 2H), 7.13 (m, 2H), 7.11 (m, IH), 7.04 (d,
IH), 6.78 (d, IH), 4.74 (s, 2H), 2.44 (s, 3H), 2.15 (s, 3H) [586]
[587] Step 4: 7-benzylamino-2,3-dimethyl-lH-pyrrolo[2,3-c]pyridine hydrochloride
[588] 7-(N-benzyl-N-ter?-butyloxycarbonyl)amino-2,3-dimethyl-lH-pyrrolo[2,3-c]pyridin e (37.0 mg) prepared in Step 3 was dissolved in ethyl acetate and then saturated with hydrochloric acid gas. The resulting precipitate was filtered and then dried to give the titled compound (29.0 mg, 96 %) as a white solid. [589] 1H-NMR (400 MHz, CDCl /MeOD) δ 7.42 (m, 2H), 7.32 (m, 2H), 7.24 (m, IH),
7.14 (d, IH), 6.84 (d, IH), 4.74 (s, 2H), 2.44 (s, 3H), 2.15 (s, 3H) [590] [591] Example 50. l-benzyl-2,3-dimethyl-7-phenethyl - 1 H- pyrrolo[2,3-c]pyridine hydrochloride
[592]
[593] Step 1: 3-phenethyl-2-nitropyridine
[594] 2-Chloro-3-nitropyridine (4.37 g, 27.6 mmol), phenethylboronic acid (4.6 g, 30.4 mmol), tetrakis(triphenylphosphine)palladium (0) (3.19 g, 2.76 mmol), and potassium carbonate (11.4 g, 82.8 mmol) were added to 1,4-dioxane (60 ml). The reaction mixture was refluxed for 24 hours and then cooled to room temperature. The reaction mixture was filtered with a Celite pad and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=l/10, v/v) and then crystallized with ethyl ether to give the titled compound (4.1 g, 55 %) as a white solid. The product was used in the subsequent step without further purification.
[595] 1H-NMR (400MHz, CDCl ) δ 8.78 (d,lH), 8.21 (d,lH), 7.35(m,lH), 7.29 (m,4H),
7.22 (m,lH), 3.42 (m,2H), 3.11 (m,2H)
[596]
[597] Step 2: 2,3-dimethyl-7-phenethyl-lH-pyrrolo[2,3-c]pyridine
[598] The titled compound was obtained as a yellow solid in accordance with the same procedures as in Step 1 of Example 1, using 3-phenethyl-2-nitropyridine prepared in Step 1 as a strarting material. (Yield: 43 %)
[599] 1H-NMR (400MHz5CDCl ) δ 7.92(d, IH), 7.73(d, IH), 7.22(m, 3H), 7.11(d,2H),
3.54(t, 2H), 3.16(t, 2H), 2.54(s, 3H), 2.30(s,3H)
[600]
[601] Step 3: l-benzyl-2,3-dimethyl-7-phenethyl-lH-pyrrolo[2,3-c]pyridine hydrochloride
[602] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 2,3-dimethyl-7-phenethyl-lH- pyrrolo[2,3-c]pyridine prepared in Step 2 and benzyl bromide. (Yield: 52 %)
[603] 1H-NMR (400MHz5CDCl ) δ 8.16(bs, IH), 7.64(bs, IH), 7.3 l(m, 3H), 7.23(m,3H),
7.12(bs, 2H), 6.71(bs, 2H), 5.40(bs, 2H), 3.57(bs,2H), 3.14(bs,2H), 2.42(s,3H), 2.37(s,3H)
[604]
[605] Example 51. l-(2-methoxyethyl)-2,3-dimethyl-7-phenethyl - 1 H- pyrrolo[2,3-c
] pyridine hydrochloride
[606] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 2,3-dimethyl-7-phenethyl-lH- pyrrolo[2,3-c]pyridine prepared in Step 2 of Example 50 and 2-bromoethyl methyl ether. (Yield: 49 %)
[607] 1H-NMR (400MHz, CDCl ) δ 8.13(s, IH), 7.56(s, IH), 7.29(m, 4H), 7.23(m,lH), 4.36(bs, 2H), 3.85(bs, 2H), 3.58(s, 3H), 3.24(bs,2H),3.20(s,3H), 2.48(s,3H), 2.29(s,3H) [608] [609] Example 52. 2,3-dimethyl-l-(4-methylbenzyl)-7-phenethyl - 1 H- pyrrolo[2,3-c
] pyridine hydrochloride
[610] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 2,3-dimethyl-7-phenethyl-lH- pyrrolo[2,3-c]pyridine prepared in Step 2 of Example 50 and 4-methylbenzyl chloride. (Yield: 56 %)
[611] 1H-NMR (400MHz, CDCl ) δ 8.16(s, IH), 7.63(s, IH), 7.25(m, 3H), 7.03(m,4H),
6.59(bs, 2H), 3.58(bs, 2H), 3.14(bs, 2H), 2.41(s,3H),2.35(s,3H), 2.31(s,3H)
[612]
[613] Example 53. 2,3-dimethyl-7-(4-methylsulfanylphenyl) - 1 H- pyrrolo[2,3-c] pyridine
[614]
[615] Step 1: 3-nitro-2-(4-methylthiophenyl)pyridine
[616] The titled compound (6.3 g) was obtained as a white solid in accordance with the same procedures as in Step 1 of Example 50, using 2-chloro-3-nitropyridine (4.37 g, 27.6 mmol) and (4-methylthiophenyl)boronic acid (5.8 g, 30.4 mmol). (Yield: 77 %) The product was used in the subsequent step without further purification.
[617]
[618] Step 2: 2,3-dimethyl-7-(4-methylsulfanylphenyl)-lH-pyrrolo[2,3-c]pyridine
[619] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 1 of Example 1, using 3-nitro-2-(4-methylthiophenyl)pyridine prepared in Step 1 as a strarting material. (Yield: 35 %)
[620] 1H-NMR (400MHz5CDCl ) δ 8.31(d,lH), 8.17(bs,lH), 7.82(d,2H), 7.41(d,2H),
7.35 (d,lH), 2.54(s,3H), 2.41(s,3H), 2.24(s,3H)
[621]
[622] Example 54. 2,3-dimethyl-7-(naphthalen-2-yl) - 1 H- pyrrolo[2,3-c]pyridine hydrochloride
[623]
[624] Step 1: 2-(naphthalen-2-yl)-3-nitropyridine
[625] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 1 of Example 50, using 2-naphthylboronic acid. (Yield: 72 %) The product was used in the subsequent step without further purification.
[626]
[627] Step 2: 2,3-dimethyl-7-(naphthalen-2-yl)-lH-pyrrolo[2,3-c]pyridine hydrochloride
[628] 2,3-dimethyl-7-(naphthalen-2-yl)-lH-pyrrolo[2,3-c]pyridine was obtained in accordance with the same procedures as in Step 1 of Example 1, using 2-(naphthalen-2-yl)-3-nitropyridine prepared in Step 1 as a starting material. 0.9 g of 2,3-dimethyl-7-(naphthalen-2-yl)-lH-pyrrolo[2,3-c]pyridine was dissolved in 20 ml of ethyl acetate and then saturated with hydrochloric acid gas. The resulting precipitate was filtered and then dried to give the titled compound as a white solid. (Yield: 46 %)
[629] 1H-NMR (400MΗz,CDCy δ 8.37(d,lH), 8.33(s,lH), 8.20(d,lH), 8.01(s,lH), 7.95
(m,lH), 7.85(m,lH), 7.55(m,2H), 7.35(d,lH),7.10(d,lH), 2.44(s,3H), 2.17(s,3H)
[630]
[631] Example 55. l-(3-fluorobenzyl)-2,3-dimethyl-7-(naphthalen-2-yl) - 1 H- pyrrolo[2,3-c]pyridine hydrochloride
[632] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 1, using 2,3-dimethyl-7-(naphthalen-2-yl)-lH- pyrrolo[2,3-c]pyridine obtained by treating the compound of Example 54 with a saturated sodium hydrogencarbonate solution and 3-fluorobenzyl chloride. (Yield: 43 %)
[633] 1H-NMR (400MHz5CDCl ) δ 8.23(s,lH), 8.15(s,lH), 7.82(m,2H), 7.76(d,2H), 7.56
(m,3H), 7.08(m,lH), 6.91(t,lH), 5.98(d,lH),5.90(d,lH), 5.01(s,2H), 2.43(s,3+3H)
[634]
[635] Example 56. l-allyl-7-(3,4-dihydro - 1 H- isoquinolin-2-yl)-2,3-dimethyl - 1 H- pyrrolo[2,3-c]pyridine-5-carboxylic acid cyclopropylamide
[636]
[637] Step 1: 2-(6-chloro-3-nitropyridin-2-yl)-l,2,3,4-tetrahydroisoquinoline
[638] 2,6-Dichloro-3-nitropyridine (10 g, 51.8 mmol) and sodium carbonate (8.8 g, 82.9 mmol) were added to anhydrous Λ/,Λf-dimethyrformamide(250 ml). 1,2,3,4-Tetrahydroisoquinoline (7.14 ml, 82.9 mmol) was added at 0 0C to the reaction mixture, which was then stirred at 0 0C for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/ n-hexane = 1/5, v/v) to give the titled compound (10 g, 81 %) as a yellow solid.
[639] 1H-NMR^OOMHz, CDCl ) δ 8.12(d, IH), 7.20(m, 3H), 7.12(m, IH), 6.68(d, IH),
4.47(s, 2H), 3.75(t, 2H), 3.02(t, 2H)
[640]
[641] Step 2: 2-(5-chloro-2,3-dimethyl-lH-pyrrolo[2,3-c] pyridin-
7-yl)- 1 ,2,3,4-tetrahydroisoquinoline
[642] The titled compound was obtained as yellow oil in accordance with the same procedures as in Step 1 of Example 1, using
2-(6-chloro-3-nitropyridin-2-yl)-l,2,3,4-tetrahydroisoquinoline prepared in Step 1. (Yield: 37 %) [643] 1H-NMR^OOMHz, CDCl ) δ 8.12(s, IH), 7.15(m, 4H), 6.98(s, IH), 4.60(s, 2H),
3.7 l(t, 2H), 3.04(t, 2H), 2.36(s, 3H), 2.13(s, 3H)
[644]
[645] Step 3: 7-(3,4-dihydro- lH-isoquinolin-2-yl)-2,3-dimethyl- lH-pyrrolo[2,3-c] pyridine-5-carbonitrile
[646] A solution of 2-(5-chloro-2,3-dimethyl-lH-pyrrolo[2,3-c] pyridin-
7-yl)-l,2,3,4-tetrahydroisoquinoline (1.8 g, 3.94 mmol) prepared in Step 2 and copper(I) cyanide (705 mg, 7.88 mmol) in anhydrous Λ/,./V-dimethylformamide (30 ml) was refluxed for 48 hours and then cooled to room temperature. 50 ml of ethyl acetate was added to the reaction mixture and then filtered to discard insoluble materials. Water was added to the filtrate, which was then extracted with ethyl acetate. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane = 1/3, v/v) to give the titled compound (120 mg, 15 %) as a white solid.
[647] 1H-NMR^OOMHz, CDCl ) δ 8.12(s, IH), 7.50(s, IH), 7.20(m, 4H), 4.67(s, 2H),
3.78(t, 2H), 3.1 l(t, 2H), 2.42(s, 3H), 2.20(s, 3H)
[648]
[649] Step 4: l-allyl-7-(3,4-dihydro-lH-isoquinolin-2-yl)-2,3-dimethyl-lH-pyrrolo[2,3-c] pyridine-5-carbonitrile
[650] The titled compound was obtained as a white solid in accordance with the same procedures as in Step 2 of Example 41, using 7-(3,4-dihydro-lH- isoquinolin- 2-yl)-2,3-dimethyl-lH-pyrrolo[2,3-c]pyridine-5-carbonitrile prepared in Step 3 and allyl iodide. (Yield: 56 %)
[651] 1H-NMR^OOMHz, CDCl ) δ 7.66(s, IH), 7.17(m, 3H), 7.09(m, IH), 5.84(m, IH),
5.10(d, 3H), 4.63(d, IH), 4.341(br, 2H), 3.44(br, 2H), 3.07(br, 2H), 2.33(s, 3H), 2.17(s, 3H)
[652]
[653] Step 5: l-allyl-7-(3,4-dihydro-lH-isoquinolin-2-yl)-2,3-dimethyl-lH-pyrrolo[2,3-c] pyridine-5-carboxylic acid
[654] Potassium hydroxide (502 mg, 8.9 mmol) was added to a solution of l-allyl-7-(3,4-dihydro-lH-isoquinolin-2-yl)-2,3-dimethyl-lH-pyrrolo[2,3-c]pyridine-5- carbonitrile (300 mg, 0.89 mmol) prepared in Step 4 in a mixed solvent of ethanol (7 ml) and water (1 ml). The reaction mixture was refluxed for 72 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane = 1/1, v/v) to give the titled compound (210 mg, 73 %) as a white solid.
[655] 1H-NMR^OOMHz, CDCl ) δ 8.21(s, IH), 7.21(m, 3H), 7.09(m, IH), 5.86(m, IH),
5.12(br, 2H), 5.09(d, IH), 4.65(d, IH), 4.36(brs, 2H), 3.50(br, 2H), 3.0(br, 2H), 2.33(s, 3H), 2.10(s, 3H)
[656]
[657] Step 6: l-allyl-7-(3,4-dihydro-lH-isoquinolin-2-yl)-2,3-dimethyl-lH-pyrrolo[2,3-c] pyridine-5-carboxylic acid cyclopropylamide
[658] l-Allyl-7-(3,4-dihydro- lH-isoquinolin-2-yl)-2,3-dimethyl- lH-pyrrolo[2,3-c]pyridin e-5-carboxylic acid (20 mg, 0.056 mmol) prepared in Step 5, 1-hydroxybenzotriazole hydrate (11.4 mg, 0.085 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16.3 mg, 0.085 mmol), and cyclopropylamine (5.8 D, 0.085 mmol) were dissolved in dichloromethane (1 ml). The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane = 1/3, v/v) to give the titled compound (9.1 mg, 65 %) as a white solid.
[659] 1H-NMR^OOMHz, CDCl ) δ 8.16(s, IH), 7.85(s, IH), 7.18(m, 3H), 7.11(m, IH),
5.85(m, IH), 5.10(brs, 2H), 5.05(d, IH), 4.62(d, IH), 4.30(br, 2H), 3.40(br, 2H), 3.00(br, 2H), 2.90(m, IH), 2.32(s, 3H), 2.27(s, 3H), 0.84(t, 2H), 0.58(t, 2H)
[660]
[661] Test Example. Inhibitory Effects on Carcinoma Cell Proliferation
[662]
[663] Inhibitory effects of a pyrrolopyridine derivative or its salt on human carcinoma cell proliferation were determined, using human lung tumor cells H460 (ATCC HTB- 177), colonic cancer cells HCT 116 (ATCC CCL-247), and human breast adenocarcinoma cells MCF-7(ATCC HTB-22). Cells were seeded at a density of 1000 cells/well (H460, HCT 116) and 2000 cells/well (MCF-7) in 100 ul of growth medium (DMEM containing 5 % FBS), respectively. The cells in 96 well plate were incubated at 37 0C under 5 % CO to stabilize the cells. After 1 day, cells were treated with test compounds in each concentrations and then incubated further for 4 days. 5-FU (5-fluorouracil) was used as a comparative compound. After incubation, living cells were stained with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT, Sigma) for 4 hours. The MTT-formazan generated by cellular reduction of MTT was solubilized in dimethylsulfoxide and the colorimetric absorbance at 540 nm was measured using microplate reader to determine viability of test compound treated carcinoma cells. The concentrations showing 50% inhibition of cell proliferation (IC s) of test compounds were calculated from each % inhibition value of compounds. The results are shown in Table 1.
[664] Table 1
Figure imgf000045_0001
[665] [666] As shown in Table 1, the compounds of formula (I) or its salt have excellent inhibitory effects on carcinoma cell proliferation. Industrial Applicability
[667] The compounds of formula (I) or its salt have excellent inhibitory effects on carcinoma cell proliferation, thereby being useful for an anticancer agent.

Claims

Claims
[1] A composition for treating or preventing a cancer comprising a compound of formula (I) or its salt and a pharmaceutically acceptable carrier:
Figure imgf000046_0001
wherein, A, B, and D are, independently, N or CH; and one of A, B, and D is N and the others are CH,
R is hydrogen; a straight or branched C -C alkyl group; a straight or branched C
1 1 6
-C alkyl group substituted with a group consisting of C -C alkoxy, C -C cycloalkyl, acetoxy, and 1,3-dioxolanyl; a C -C alkenyl group optionally
2 6 substituted with C -C alkyl; a C -C alkynyl group; a benzyl group optionally substituted with halogen, straight or branched C -C alkyl, or straight or branched
1 4
C -C alkoxy; or 2,3-dihydrobenzo[l,4]dioxinylmethyl, R is a C -C alkyl group, R is a C -C alkyl group or a benzyl group,
R is hydrogen; an aminocarbonyl group optionally substituted with C -C cycloalkyl, and
R is a naphthyl group; a 1,2,3,4-tetrahydroisoquinolinyl group optionally substituted with C -C alkyl; a benzylamino group optionally one or two substituted with halogen; a benzyloxy group optionally substituted with one or two groups independently selected from the group consisting of halogen, triflu- oromethyl, C -C alkyl, and C -C alkoxy; a phenyl-C -C alkyl group; a phenyl group; a methylsulfanylphenyl group; or a benzo[l,3]dioxolylmethoxy. [2] The composition according to claim 1, wherein R is hydrogen; a straight or branched C -C alkyl group; a methyl group substituted with C -C cycloalkyl or 1,3-dioxolanyl; a C -C alkenyl group substituted with C -C alkyl; a C -C alkynyl group; a benzyl group optionally substituted with halogen, straight or branched C -C alkyl, or straight or branched C -C alkoxy; or 2,3-dihydrobenzo[ 1 ,4] dioxinylmethyl, R and R are a methyl group, R is hydrogen, and
4
R is a naphthyl group; a 1,2,3,4-tetrahydroisoquinolinyl group optionally substituted with C -C alkyl; a benzylamino group; a benzyloxy group optionally substituted with one or two groups independently selected from the group consisting of halogen and C -C alkyl; or a phenyl-C -C alkyl group.
[3] The composition according to claim 1, wherein
A is N, both B and D are CH, and
R is a naphthyl group; a benzyloxy group optionally substituted with one or two groups independently selected from the group consisting of halogen, triflu- oromethyl, C -C alkyl, and C -C alkoxy; a phenyl-C -C alkyl group; a methyl- surf any lphenyl group; or a benzo[l,3]dioxolylmethoxy.
[4] The composition according to claim 1, wherein B is N, and both A and D are
CH.
[5] The composition according to claim 1, wherein
D is N, both A and B are CH, and
R is a 1,2,3,4-tetrahydroisoquinolinyl group optionally substituted with C -C alkyl; a benzyloxy group optionally substituted with one or two groups independently selected from the group consisting of halogen, trifluoromethyl, C -C
1 3 alkyl, and C -C alkoxy; a phenyl-C -C alkyl group; or a benzo[l,3] diox- olylmethoxy.
[6] The composition according to claim 1, wherein the compound of formula (I) or its salt is selected from the group consisting of: l-(3-methylbut-2-enyl)-7-(l,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-lH-p yrrolo[3,2-b]pyridine hydrochloride;
(l-allyl-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridin-7-yl)-(4-fluorobenzyl)-amine hydrochloride;
7-(4-fluorobenzyloxy)- l-isobutyl-2,3-dimethyl- lH-pyrrolo[3,2-b]pyridine hydrochloride;
7-(4-fluorobenzyloxy)-2,3-dimethyl-l-(prop-2-ynyl)-lH-pyrrolo[3,2-b]pyridine hydrochloride; l-benzyl-7-(4-fluorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridine hydrochloride; l-cyclobutylmethyl-7-(4-fluorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridi ne hydrochloride;
7-(4-fluorobenzyloxy)-2,3-dimethyl-l-(3-methylbut-2-enyl)-lH-pyrrolo[3,2-b]py ridine hydrochloride;
7-(4-fluorobenzyloxy)- l-propyl-2,3-dimethyl- lH-pyrrolo[3,2-b]pyridine hydrochloride; l-(4-tert-butylbenzyl)-7-(4-fluorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyr idine hydrochloride; l-(2-fluorobenzyl)-7-(4-fluorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridi ne hydrochloride; l-benzyl-7-(4-chlorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridine hydrochloride;
7-(4-chlorobenzyloxy)-2,3-dimethyl-l-(3-methylbut-2-enyl)-lH-pyrrolo[3,2-b]p yridine hydrochloride; l-(2-acetoxyethyl)-7-(4-chlorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridi ne hydrochloride; l-cyclopropylmethyl-7-(4-chlorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyri dine hydrochloride;
7-(4-chlorobenzyloxy)-l-([l,3]dioxolan-2-ylmethyl)-2,3-dimethyl-lH-pyrrolo[3, 2-b]pyridine hydrochloride;
7-(4-chlorobenzyloxy)-l-(4-chlorobenzyl)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridi ne hydrochloride;
7-(4-chlorobenzyloxy)-l-(2-fluorobenzyl)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridi ne hydrochloride;
7-(4-chlorobenzyloxy)-l-ethyl-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridine hydrochloride;
7-(4-chlorobenzyloxy)-l-(3-methoxybenzyl)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyri dine hydrochloride;
7-(benzo[ 1 ,3]dioxol-5-ylmethoxy)- 1 -(4-methylbenzyl)-2,3-dimethyl- lH-pyrrolo[ 3,2-b]pyridine hydrochloride; l-benzyl-7-(2,4-dichlorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridine hydrochloride;
7-(2,4-dichlorobenzyloxy)-l-cyclopropylmethyl-2,3-dimethyl-lH-pyrrolo[3,2-b] pyridine hydrochloride;
7-(2,4-dichlorobenzyloxy)- l-ethyl-2,3-dimethyl- lH-pyrrolo[3,2-b]pyridine hydrochloride;
7-(2,4-dichlorobenzyloxy)-l-(4-fluorobenzyl)-2,3-dimethyl-lH-pyrrolo[3,2-b]py ridine hydrochloride;
2,3-dimethyl- l-ethyl-7-(3-methylbenzyloxy)- lH-pyrrolo[3,2-b]pyridine hydrochloride;
2,3-dimethyl-l-propyl-7-(3-methylbenzyloxy)-lH-pyrrolo[3,2-b]pyridine hydrochloride; l-allyl-2,3-dimethyl-7-(3-methylbenzyloxy)-lH-pyrrolo[3,2-b]pyridine hydrochloride; l-cyclopropylmethyl-7-(2-ethoxybenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyri dine hydrochloride; l-(3-methoxybenzyl)-7-(2-ethoxybenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyr idine hydrochloride; l-(3-fluorobenzyl)-7-(2-ethoxybenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridi ne hydrochloride; l-cyclobutylmethyl-7-(3,5-difluorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]p yridine hydrochloride; l-benzyl-7-(3,5-difluorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridine hydrochloride;
2,3-dimethyl-l-(4-methylbenzyl)-7-(4-trifluoromethylbenzyloxy)-lH-pyrrolo[3,2 -b]pyridine hydrochloride;
2,3-dimethyl-l-(3-methoxybenzyl)-7-(4-trifluoromethylbenzyloxy)-lH-pyrrolo[3 ,2-b]pyridine hydrochloride; l-([l,3]dioxolan-2-ylmethyl)-7-(l,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl - lH-pyrrolo[3,2-c]pyridine hydrochloride;
2-(l-ethyl-2,3-dimethyl-lH-pyrrolo[3,2-c]pyridin-7-yl)-l,2,3,4-tetrahydroisoquin oline hydrochloride;
2-[l-(2,3-dihydrobenzo[l,4]dioxin-6-ylmethyl)-2,3-dimethyl-lH-pyrrolo[3,2-c]p yridin-7-yl]- 1 ,2,3,4-tetrahydroisoquinoline hydrochloride; 7-(4-fluorobenzyloxy)-2,3-dimethyl-l-(prop-2-ynyl)-lH-pyrrolo[3,2-c]pyridine hydrochloride;
7-(4-fluorobenzyloxy)-l-(2-methoxyethyl)-2,3-dimethyl-lH-pyrrolo[3,2-c]pyridi ne hydrochloride; l-cyclopropylmethyl-7-(4-fluorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-c]pyri dine hydrochloride; l-cyclopropylmethyl-2,3-dimethyl-4-(4-fluorobenzylamino)-lH-pyrrolo[3,2-c]p yridine hydrochloride; l-benzyl-2,3-dimethyl-4-(4-fluorobenzylamino)-lH-pyrrolo[3,2-c]pyridine hydrochloride;
2,3-dimethyl-l-(2-fluorobenzyl)-4-(4-fluorobenzylamino)-lH-pyrrolo[3,2-c]pyri dine hydrochloride;
3-benzyl-2-methyl-4-(l,2,3,4-tetrahydroisoquinolin-2-yl)-lH-pyrrolo[3,2-c]pyrid ine hydrochloride; l-allyl-7-(l,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-lH-pyrrolo[2,3-c]pyr idine hydrochloride;
2-(2,3-dimethyl-lH-pyrrolo[2,3-c]pyridin-7-yl)-l-methyl-l,2,3,4-tetrahydroisoqu inoline hydrochloride; 2-(2,3-dimethyl-lH-pyrrolo[2,3-c]pyridin-7-yl)-l-methyl-l,2,3,4-tetrahydroisoqu inoline sodium;
7-(4-chlorobenzylamino)-l-isobutyl-2,3-dimethyl-lH-pyrrolo[2,3-c]pyridine hydrochloride;
7-benzylamino-2,3-dimethyl-lH-pyrrolo[2,3-c]pyridine hydrochloride; l-benzyl-2,3-dimethyl-7-phenethyl-lH-pyrrolo[2,3-c]pyridine hydrochloride; l-(2-methoxyethyl)-2,3-dimethyl-7-phenethyl-lH-pyrrolo[2,3-c]pyridine hydrochloride;
2,3-dimethyl- l-(4-methylbenzyl)-7-phenethyl- lH-pyrrolo[2,3-c]pyridine hydrochloride;
2,3-dimethyl-7-(4-methylsulfanylphenyl)-lH-pyrrolo[2,3-c]pyridine; 2,3-dimethyl-7-(naphthalen-2-yl)-lH-pyrrolo[2,3-c]pyridine hydrochloride; l-(3-fluorobenzyl)-2,3-dimethyl-7-(naphthalen-2-yl)-lH-pyrrolo[2,3-c]pyridine hydrochloride; and l-allyl-7-(3,4-dihydro-lH-isoquinolin-2-yl)-2,3-dimethyl-lH-pyrrolo[2,3-c]pyrid ine-5-carboxylic acid cyclopropylamide.
[7] The composition according to claim 1, wherein the compound of formula (I) or its salt is selected from the group consisting of: l-cyclobutylmethyl-7-(4-fluorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyridi ne hydrochloride;
7-(4-fluorobenzyloxy)- l-propyl-2,3-dimethyl- lH-pyrrolo[3,2-b]pyridine hydrochloride;
7-(4-chlorobenzyloxy)-2,3-dimethyl-l-(3-methylbut-2-enyl)-lH-pyrrolo[3,2-b]p yridine hydrochloride;
7-(4-chlorobenzyloxy)-l-([l,3]dioxolan-2-ylmethyl)-2,3-dimethyl-lH-pyrrolo[3, 2-b]pyridine hydrochloride;
7-(4-chlorobenzyloxy)-l-(3-methoxybenzyl)-2,3-dimethyl-lH-pyrrolo[3,2-b]pyri dine hydrochloride;
7-(2,4-dichlorobenzyloxy)-l-cyclopropylmethyl-2,3-dimethyl-lH-pyrrolo[3,2-b] pyridine hydrochloride;
7-(2,4-dichlorobenzyloxy)-l-(4-fluorobenzyl)-2,3-dimethyl-lH-pyrrolo[3,2-b]py ridine hydrochloride;
2,3-dimethyl- l-propyl-7-(3-methylbenzyloxy)-lH-pyrrolo[3,2-b]pyridine hydrochloride;
2-[l-(2,3-dihydrobenzo[l,4]dioxin-6-ylmethyl)-2,3-dimethyl-lH-pyrrolo[3,2-c]p yridin-7-yl]- 1 ,2,3,4-tetrahydroisoquinoline hydrochloride; 7-(4-fluorobenzyloxy)-2,3-dimethyl-l-prop-2-ynyl-lH-pyrrolo[3,2-c]pyridine hydrochloride; l-cyclopropylmethyl-7-(4-fluorobenzyloxy)-2,3-dimethyl-lH-pyrrolo[3,2-c]pyri dine hydrochloride;
2-(2,3-dimethyl-lH-pyrrolo[2,3-c]pyridin-7-yl)-l-methyl-l,2,3,4-tetrahydroisoqu inoline hydrochloride;
7-benzylamino-2,3-dimethyl-lH-pyrrolo[2,3-c]pyridine hydrochloride; 2,3-dimethyl- l-(4-methylbenzyl)-7-phenethyl- lH-pyrrolo[2,3-c]pyridine hydrochloride;
2,3-dimethyl-7-(naphthalen-2-yl)- lH-pyrrolo[2,3-c]pyridine hydrochloride; and l-(3-fluorobenzyl)-2,3-dimethyl-7-(naphthalen-2-yl)-lH-pyrrolo[2,3-c]pyridine hydrochloride.
PCT/KR2006/002453 2005-06-27 2006-06-26 A composition for treating or preventing a cancer comprising pyrrolopyridine derivatives WO2007001139A1 (en)

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