(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
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`Doc Ref. FPl
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`Appl. No. 11/797,082
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`(l 9) World Intellectual Property Organization
`Intemationa] Bureau
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`(43) International Publication Date
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`(10) International Publication Number
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`14 August 2003 (14.08.2003) ||||||l|l|||l|llllllllllllllllllll||l||ll|lllllIIIIIlllllllllllllllllllll||l||||||l||
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`W0 03/066579 A2
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`(51) International Patent Classification7:
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`C07C 259/00
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`(21) International Application Number:
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`PCT/USO3/03846
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`(22) International Filing Date: 7 February 2003 (07.02.2003)
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`(25) Filing Language:
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`(26) Publication Language:
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`English
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`English
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`(30) Priority Data:
`60/355,700
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`7 February 2002 (07.02.2002)
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`US
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`(71) Applicant (for all designated States except US): AXYS
`PHARMACEUTICALS [US/US]; 180 Kimball Way, So.
`San Francisco, CA 94080 (US).
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`(72) Inventors; and
`(75) Inventors/Applicants (for US only): LEAHY, Ellen M.
`[US/US]; 1185 Camellia Court, San Leandro, CA 94577
`(US). VERNER, ERIK J. [US/US]; 709 Catamaran Street,
`#1, Foster City, CA 94404 (US).
`
`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH,
`GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC,
`LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW,
`MX, M2, NO, NZ, OM, PH, PL, PT, RO, RU, SC, SD, SE,
`SG, SK, SL, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ,
`VC, VN, YU, ZA, ZM, ZW.
`
`(84) Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW),
`Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European patent (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
`ES, FI, FR, GB, GR, HU, IE, IT, LU, MC, NL, PT, SE, SI,
`SK, TR), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN,
`GQ, GW, ML, MR, NE, SN, TD, TG).
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`Declaration under Rule 4.17:
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`ofinventorship (Rule 4.1 7(iv)) for US only
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`Published:
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`without international search report and to be republished ‘
`upon receipt ofthat report
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`'
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`(74) Agents: BANSAL, Rekha et al.; CELERA, 180 Kimball
`Way, So. San Francisco, CA 94080 (US).
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`For two-letter codes and other abbreviations, refer to the ”Guid-
`ance Notes on Codes andA bbreviations ” appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
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`~-————_._.—___—_______—______
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`(54) Title: NOVEL BICYCLIC HYDROXAMATES AS INHIBITORS OF HISTONE DEACETYLASE
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`(57) Abstract: The present invention is directed to certain bicyclic hydroxamate derivatives that are inhibitors of histone deacetylase
`and are therefore useful1n the treatment of diseases associated with histone deacetylase activity. Pharmaceutical compositions and
`processes for preparing these compounds are also disclosed
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`5
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`NOVEL BICYCLIC HYDROXAMATES AS INHIBITORS OF HISTONE
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`DEACETYLASE
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`BACKGROUND OF THE INVENTION
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`10
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`Field of the Invention
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`The present invention is directed to certain bicyclic hydroxamate derivatives that are
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`inhibitors of histone deacetylase and are therefore useful in thetreatment of diseases associated
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`with histone deacetylase activity. Pharmaceutical compositions and processes for preparing
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`these compounds are also disclosed.
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`15
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`State of the Art
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`Interest in histone deacetylase enzymes (HDACs) as targets for pharmaceutical
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`development has centered on the role of HDACs in regulating genes associated with cell-cycle
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`progression and the development and progression of cancer (reviewed in Kramer et. a]. 2001.
`Trends Endocrinol. Metab. 12:294-300). Several studies have shown that treatment of various
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`cell lines with HDAC inhibitors leads to hyper acetylation of histone proteins and cell-cycle
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`arrest in late G1 phase or at the GM transition. Genes involved in the cell cycle that have
`been shown to be up regulated by HDAC inhibitors include p21,-p27, p53 and cyclin E. Cyclin
`A and cyclin D have been reported to be down regulated by HDAC inhibitors. In tumor cell
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`lines, several studies have shown that treatment with HDAC inhibitors can lead to growth
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`inhibition, growth arrest, terminal differentiation and/or apoptosis. In vivo studies have
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`demonstrated growth inhibition of tumors and a reduction in tumor metastasis as a result of
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`treatment with HDAC inhibitors.
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`The clearest link between abnormal HDAC activity and cancer occurs in acute
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`promyelocytic leukemia. In this condition, a chromosomal translocation leads to the fusion of
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`the retinoic acid receptor RARU. with the promyelocytic leukemia (PML) or promyelocytic
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`leukemia zinc-finger (PLZF) proteins. Both PML-RAROL and PIZF-RAROL promote the
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`progression of leukemia by repressing retinoic acid-regulated genes through the abnormal
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`recruitment of SMRT-mSin3—HDAC complex (Lin et. al., 1998, Nature 391:811-814; Grignani
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`et al., 1998, Nature 391 :815-818). Whereas the PML-RARa form of the disease is treatable
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`with retinoic acid, the PLZF—RARa form is resistant to this treatment. For a patient with the
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`retinoic acid-resistant form of the disease, the addition of the HDAC inhibitor sodium butyrate
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`to the dosing regimen led to complete clinical and cytogenic remission (Warrell et al., 1998,
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`J.Natl.Cancer.Inst. 90216214625)- PHDACs have also been associated with Huntington’s
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`disease (Steffan, et al., Nature 413:739—744, “Histone deacetylase inhibitors arrest
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`polyglutamine-dependent neurodegeneration in Drosophila”).
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`In summary, an increase in HDAC activity contributes to the pathology and/or
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`symptomatology of a number of diseases. Accordingly, molecules that inhibit the activity of
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`HDAC are useful as therapeutic agents in the treatment of such diseases.
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`Summary of the Invention
`
`In a first aspect, this invention provides a compound of Formula I:
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`1
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`R, n3
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`15
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`wherein:
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`R1 is hydrogen or alkyl;
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`R2 is hydrogen;
`
`@3th
`R5
`R2
`
`o
`
`I
`
`Arl is phenylene or a six membered heteroarylene ring containing one or two nitrogen
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`20
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`ring atoms, the rest of the ring atoms being carbon; wherein said Arl group is optionally
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`substituted with one or two groups independently selected from alkyl, halo, hydroxy, alkoxy,
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`haloalkoxy, or haloalkyl;
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`_
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`35
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`Ar2 is aryl, benzimidazol-Z-yl, cycloalkyl or heterocycloalkyl;
`R3 is hydrogen, alkyl, halo, hydroxy, or alkoxy; and
`R4 and Rs are independently selected from the group consisting of hydrogen, alkyl,
`halo, haloalkyl, nitro, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, optionally substituted
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`phenyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, cycloalkyl,
`heterocycloaminoalkyl, -X-R°, or -(C1__6alkylene)-Y-R7 where X and Y are independently -O-,
`-s-, -so-, -SOz-, -NR8-, -co—, -NR9co—, -C0NR‘°-, -NR”SOz~, -SOzNR'2—, -NHC(O)O-, -
`OC(O)NH;, -NR‘3CONR”-, or -NR'SSOZNR'°— where R6 and R7 are independently hydrogen,
`alkyl, h-ydroxyalkyl, optionally substituted phenyl, Optionally substituted heteroaryl, optionally
`substituted heterocycloalkyl, cycloalkyl, optionally substituted phenylalkyl, optionally
`substituted phenoxyalkyl, optionally substituted phenylalkenyl, optionally substituted
`phenylaminoalkyl, optionally substituted heteroaralltyl, optionally substituted
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`heteroaryloxyalkyl, optionally substituted heterocycloalkylalkyl, or cycloalkylalkyl, R8, R9,
`R”, R”, and R‘5 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or optionally
`substituted phenylalkyl; R10, R12, R”, and R16 are independently hydrogen, alkyl, optionally
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`2
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`10
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`15
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`substituted phenylalkyl, alkoxy, hydroxyalkyl, haloalkyl, alkoxyalkyl, carboxyalkyl,
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`cyanoalkyl, aminoalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl,
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`dialkylaminocarbonylalkyl, or acyl or R4 and R5 together form methylenedioxy; and individual
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`isomers, mixtures of isomers; or a pharmaceutically acceptable salt thereof provided that: (i) at
`least one of R3, R4 and R5 is not hydrogen; (ii) when Ar2 is cycloalkyl, then at least two of R3,
`R4 and R5 are hydrogen; (iii) when R1 and R3 are hydrogen, Arl is phenylene and AI2 is phenyl,
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`and one of R4 and R5 is methoxy, then the other of R4 and R5 is not —0R6 where R6 is
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`cyclopentyl or phenylpentyl; (iv) when ArI is phenylene and Ar2 is phenyl then at least one of
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`R3, R4 and R5 is not alkyl; (v) when Arl is phenylene, Ar2 is aryl and is located at the 3-
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`position of the phenylene ring, then Ar2 is not substituted with an optionally substituted
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`phenyl; (vi) when Ar1 is phenylene and 'AI2 is phenyl, and R4 or R5 is —CONRl°R6 or —(C1-
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`Galkylene)-CONR'°R7 then said R4 or R5 is not located at the 4-position of the phenyl ring; and
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`(vii) when Arl is phenylene and Ar2 is phenyl and two of R3, R4 and R5 are hydrogen, then the
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`remaining of R3, R4 and R5 is not niIIo.
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`A.
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`Preferably, the compound of Formula I is represented by Formula Ia:
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`20
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`wherein:
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`R4
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`o
`NQLNQHH
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`R5
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`Ia
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`Air] is phenylene or' a six membered heteroarylene ring containing one or two nitrogen
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`ring atoms, the rest of the ring atoms being carbon; wherein said Arl group is optionally
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`substituted with one or two groups independently selected from alkyl, halo,.hydroxy, alkoxy,
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`tn'fluoromethoxy, or trifluoromethyl;
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`Ar2 is aryl, benzimidazol-Z—yl, cycloalkyl or heterocycloalkyl and is located at the 4-
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`position of Ar];
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`R4 and R5 are independently selected from the group consisting of hydrogen, alkyl,
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`halo, haloalky], cyano, carboxy, carboxyalky], alkoxycarbonyl, Optionally substituted phenyl,
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`optionally substituted heteroaryl, optionally substituted heterocycloalkyl, cycloalkyl, -X-R6, or
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`-(C1_.5alkylene)-Y-R7 where x and Y are independently —0-, -s-, -so-, -so;-, -NR"-, -CO—, -
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`NR9CO-, -c0NR’°-, -NR“SOz-, -SOzNR12-, -NHC(O)O-, -OC(O)NH-, -NR”CONR”-, or -
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`NR15802NR16- where R6 and R7 are independently hydrogen, alkyl, hydroxyalkyl, optionally
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`substituted phenyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl,
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`cycloalkyl, optionally substituted phenylalkyl, optionally substituted phenoxyalkyl, optionally
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`substituted heteroaralkyl, optionally substituted heteroaryloxyalkyl, optionally substituted
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`heterocycloalkylalkyl, or cycloalkylalkyl, R8, R9, R”, R”, and R15 are independently
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`hydrogen, alkyl, or optionally substituted phenylalkyl; R”, R”, R”, and R16 are independently
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`hydrogen, alkyl, optionally substituted phenylalkyl, alkoxy, hydroxyalkyl, haloalkyl,
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`alkoxyalkyl, carboxyalkyl, cyanoalkyl, aminoalkyl, aminocarbonylalkyl,
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`alkylaminocarbonylalkyl, diallcylaminocarbonylalkyl, or acyl or R4 and R5 together form
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`methylenedioxy; and individual isomers, mixtures of isomers; or a pharmaceutically acceptable
`salt thereof.
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`Within this preferred group (A), a more preferred group of compounds is that wherein:
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`(i)
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`Ar1 is phenylene, Ar2 is phenyl wherein R4 is hydrogen and R5 is cyano, optionally
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`substituted phenyl, optionally substituted heteroaryl, -X-R6 (where X is —0-, ~NH-, -SOz-, -
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`co-, -NHCO-, -c0NR‘°-, -NHSOz- or -NHCONH— [where R10 is hydrogen, alkyl or
`haloalkyl; and R6 is alkyl (except when X is -O— or —NH—), hydroxyalkyl, optionally
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`substituted phenyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl,
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`optionally substituted phenylalkyl, optionally substituted phenoxyalkyl, or optionally
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`substituted heteroaralkyl], or -(C1_6alkylene)-Y-R7 [where Y is -CO- or -CONR'°-; and R7
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`is alkyl, hydroxyalkyl, optionally substituted phenyl, optionally substituted heteroaryl,
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`optionally substituted heterocycloalkyl, optionally substituted phenylalkyl, optionally
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`substituted phenoxyalkyl, or optionally substituted heteroaralkyl and R10 is hydrogen or
`alkyl] and is located at the the 3-postion of the phenyl ring. Even more preferably R5 is -
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`~, NH802CH3, -802CH3, thiophen—B-yl, cyano, iNHSOzphenyl, hydroxymethyl,.-NHSOZ(3-
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`:chlorophenyl), ~NHSO;(4-fluorophenyl), -NHSOz(3,4-dichlorophenyl), -NHCOphenyl, -
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`NHSOz(benzyl), —NHSOz(4-chlorophenyl), -NHSO¢(3-tn'fluoromethylphenyl), -NHSOZ(4~
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`methoxyphenyl), -NHCO(3,4-dichlorophenyl), -NHCONH(3-methoxyphenyl), -NHCO(3,4-
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`dimethoxyphenyl), -NHSOz(2,5-dimethoxyphenyl), -NHSOz(4-tn'fluoromethoxyphenyl), -
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`NHCO(3-fluorophenyl), —NHCO(2,4-dichlorophenyl), -CONthenyl, -NHCO(4-
`methylphenyl), -NHCO(3-tlifluoromethylphenyl), -0benzyl, -O-(3-methoxybenzyl), -
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`NHCO(3,4—methylenedioxyphenyl), -NHCO(4-methoxyphenyl), -CONH(benzyl), -
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`CONH(3,3,3—lrifluoroethyl), -NHCO(3-methylbutyl), -CONH(CH3), -NHCOCH(CH3)2, -
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`NHCO(benzyl), -NHCO(CH2)2phenyl, -NHC0(CH2)2(4-tn'fluorophenyl), -NHCO(CH2)2(4-
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`methoxyphenyl), -NHCO(3,5-dichlorophenyl), -NHCO(CH20)phenyI, -NHCO(3-
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`35
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`methylbutyl), -NHCOCH2thiophen-2-yl, -NHC0(CH2)2(2,4-dichlorophenyl), -
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`NHCO(CH2)2(3,4-methylenedioxyphenyl), -NHCO(4-trifluoromethylphenyl), -NHCO(4-
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`ethoxyphenyl), -NHCO(4-dimethylaminophenyl), -NHCO(4-fluorophenyl), -NHCO(2,4-
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`difluorophenyl), -NHCO(4-chlorophenyl), -CON(CH3)2, -NHCO(4-isopropylphenyl), -
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`NHCO(4—trifluoromethoxyphenyl), -NHCO(3-fluoro—4-methoxyphenyl), -NHCO(4-
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`methoxy-Z-methylphenyl), —NHCO(2,4—dimethoxyphenyl), -NHCO(4-chloro-2-
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`methoxyphenyl), -NHCO(pyn'din-4—yl), -NHCO(pyridin-3-yl), -COmorpholin-4-yl,
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`-CON(CH3)(phenyl), -CONH(4—chlorophenyl), -CONH(CH2)2(4-methoxyphenyl), -
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`CONH(4-ch]orobenzyl), -CONH(CH2)2phenyl, -CONH(CH2)20H, -COpiperidin-1-yl, —
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`NHCO(2-methylphenyl), -NHCO(2,4-dimethylphenyl), -NHCO(2,5-dimethylphenyl), -
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`NHCO(2—methylthiophen-5-yl), -CH2CONH(CH2)2(4-methoxyphenyl), -CH2CONHCH2(4—
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`chlorophenyl), -CH2CON(CH3)2, -CH2CO(morpholinr4-yl, -CH2CON(CH3)(phenyl), -
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`CH2CONH(CH2)2phenyl, or -CH2CONH(4-chlorophenyl). Most preferably, R5 is -
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`NHCOR6, -C0NHR6, or -NHSO;R6 where R6 is alkyl, hydroxyalkyl, optionally substituted
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`phenyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, Optionally
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`substituted phenylalkyl, optionally substituted phenoxyalkyl. or optionally substituted
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`heteroaralkyl. Most preferably, R5 is -NHSOzphenyl,
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`-NHSOz(4—methoxyphenyl), -NHSOz(4-chlorophenyl), -NHCO(phenyl), -NHCO(2,4-
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`dichlorophenyl), -NHCO(4-methylphenyl), -NHCO(3,4—methlenedioxyphenyl), -NHCO(4-
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`methoxyphenyl), -NHCO(4-chlorophenyl), -NHCO(4-methoxy-Z-methylphenyl), -
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`NHCO(2,4-dirnethylphenyl), -NHCO(3,4-dichlorophenyl), -NHCO(3,4»dimethoxyphenyl), -
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`NHCO(4-ethoxyphenyl), -NHCO(4-fluorophenyl), -NHCO(2,4-difluorophenyl), -NHCO(4-
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`dimethylaminophenyl), or —NHSOz(benzyl).
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`»
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`(ii) Within this preferred group (A), another even'more preferred group ofcompounds is'
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`that wherein Arl is phenylene, Ar2 is phenyl; R4 is alkyl, halo, alkOxy', --NHCOR'6 (where R6
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`is optionally substituted phenyl) or -CONR6R10 (where R6 is hydrogen, alkyl, optionally
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`substituted phenyl, optionally substituted phenylalkyl or hydroxyalkyl and R10 is hydrogen,
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`alkyl, alkoxy, carboxyalkyl, hydroxyalkyl, aminocarbonylalkyl, or aminoalkyl), and is at the
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`3—position of the phenyl ring; and R5 is alkyl, halo, alkoxy, carboxy, -C0NR'5R10 (where R6 is
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`hydrogen, alkyl, optionally substituted phenyl, optionally substituted phenylalkyl or
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`hydroxyalkyl and R10 is hydrogen, alkyl, alkoxy, carboxyalkyl, hydroxyalkyl,
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`aminocarbonylalkyl, or aminoalkyl), -C0R6 (where R6 is optionally substituted
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`heterocycloalkyl), or -NHSOZR‘S (where R6 is optionally substituted phenyl) and is at the 5-
`position of the phenyl(Ar2) ring provided that at least one of R4 and R5 is -NHCOR6, -
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`CONRGR“), -CONR°R'°, -C0R‘5 or -NHSOzR6. Preferably the Arzring is 5—
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`(benzylaminocarbonyl)—3-(phenylcarbonylarnino)phenyl, 5-(carboxy)—3—
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`(phenylcarbonylamino)phenyl, 5-(morpholin—4—ylcarbonyl)-3-(phenylcarbonylarnino)phenyl,
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`5-(N,N-dimethylaminocarbonyl)—3-(4-methylphenylcarbonylamino)phenyl, 5-(morpholin-4-
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`ylcarbbnyl)-3-(4—methylphenylcarbonylamino)phenyl, 5-(pheny1aminocarbonyl)-3—(4—
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`methyl-phenylcarbonylamino)phenyl, 5-(N,N-dimethylaminocarbonyl)-3—(4-
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`methoxyphenylcarbonyl-amino)phenyl, 5-(morpholin—4-ylcarbonyl)-3-(4—methoxyphenyl-
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`carbonylamino)phenyl,
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`10
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`5-(phenylaminocarbonyl)-3-(4—methoxyphenylcarbonylamino)phenyl, 5-(N,N—dimethyl- .
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`aminocarbonyl)-3~(3,4-dimethoxyphenylcarbonylamino)phenyl, 5-(N,N—dimethyl-
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`aminocarbonyl)-3-(phenylcarbonylamino)phenyl, 5-(morpholin-4—ylcarbony])—3-(3,4-
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`dimcthoxyphenylcarbony]amino)phenyl, 5—(phenylaminocarbonyl)-3-(3,4-
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`dimethoxyphenylcarbonylamino)phenyl, 5-(piperidin-1-ylcarbonyl)-3-(4-methylphenyl-
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`carbonylamino)phenyl, 5-(piperazin-l-ylcarbonyl)-3-(4—methylphenylcarbonylamino)phenyl,
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`5-(N—methylaminocarbonyl)-3-(4—methylphenylcarbonylamino)phenyl, 5-(N-carboxymethyl-
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`N-methylaminocarbony])-3—(4-methylpheny]carbonylamino)phenyl, 5-(N—aminocarbonyl-
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`methylaminocarbonyD-3-(4-mcthylphenylcarbony]amino)-phenyl, 5—[N—(2-N-methylamino-
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`ethyl)-N~mcthylaminocarbony]]—3—(4-methylphenylcarbonylamino)]-phenyl, 5-(N-carboxy—
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`methylaminocarbonyl)-3-(4-methylphenylcarbonylamino)-phenyl, 5-(N,N-dimethyl-
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`aminocarbonyl)—3-(3,4-methylcnephenylcarbonylamino)-phenyl, 5-(morpholin-4—yl-
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`'carbonyl)-3-(3,4-methylenephenylcarbony]amino)-phenyl, 5-(phenylaminocarbonyl)—3—(3,4-
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`methylene-phenylcarbonylamino)—phenyl, 5—(N,N-dimethylaminocarbonyl)-3-(2,4-dichloro-
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`phenylcarbonylamino)-phenyl, 5-(phenylaminocarbonyl)-3—(2,4—dichlorophenyl-
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`CarbOnylamino)-phenyl, 5-(N,N-dimethylaminocarbonyl)-3-_(4-chlorophenylcarbonylamino)-
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`25 -
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`phen'yl, 5—(morpholin—4-ylcarbonyl)-3-(4—chloropheny10a:bonylamino)-phenyl, 5-(N—ethyl-N-
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`methyl—aminocarbonyl)-3—(4-methylphenylcarbonylamino)-pheny1, 5-(4-methylpiperazin-1 -
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`ylcarbonyl)-3—(4-methylphenylcarbonylamino)-pheny], 5-(3-(RS)-aminocarbonylpiperidin-1-
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`ylcarbonyl)-3-(4-methylphenylcarbonylamino)-pheny1, 5-(MN-diethylaminocarbonyl)-3-(4-
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`methylphenyl-carbonylamino)-phenyl, 5-(2-N-methy]aminoethylaminocarbonyl)—3—(4—
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`methylphenyl-carbonylamino)-phenyl, 5-(4-hydroxypiperidin—1-ylcarbonyl)-3-(4-
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`methylphenyl-carbonylgminoyphenyl, 5-(pyrrolidin-1-ylcaxbonyl)-3-(4-methylphenyl-
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`carbonylaminoyphenyl, 5-(3-(RS)-hydxoxymethylpiperidin-I-ylcarbonyl)—3-(4-methyl-
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`phenylcarbonylamino)-phenyl, 5-(2-(RS)-hydroxymethylpipefidin-1-ylcarbonyl)-3—(4-
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`methylphenylcarbonylamino)—phenyl, 5-(N-2-hydroxycthyl-N-methylaminocarbonyl)-3-(4-
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`methylphenylcarbonylamino)—phenyl, 5-(N—4—chlorobenzyllaminocarbonyl)-3-(4-methyl-
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`phenylcarbonylamino)—pheny], 5-(N-3-mcthylbutylaminocarbonyl)-3-(4-methylpheny1—
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`carbonylamino)—phenyl, 5-(N-2-phenylethylaminocarbonyl)-3-(4-methylphenylcarbonyl-
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`amino)phenyl, 5-[N-2—(4-mcthoxyphenyl)ethylaminocarbonyl)]-3-(4-methylphenylcarbonyl-
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`amino)—phenyl, 5-(N-methyl-N-methoxyaminocarbonyD-3-(4-meflly1ph6nylcarb0nyl-
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`amino)phenyl, 5-(N-methyl-N-phenylarrfinocarbonyl)~3-(4-methylphenylcarbonylamino)-
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`phenyl, 5-(N—benzylaminocarbonyl)-3-(4-methylphenylcaxbonylamino)-phenyl, 5-(N—2-
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`hydroxyethylaminocarbonyl)—3-(4-methylphenylcarbonylamino)-phenyl,
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`5-[N,N-bis(2-hydroxyethyl)aminocarbony]]-3-(4—methy]phenylcarbonylamino)-phenyl,
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`5-(4—(RS)-hydroxymcthylpiperidin-1-y]carbonyl)-3-(4-methylphenylcarbonylamino)—pheny],
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`5-(3-(RS)-methoxycarbonylpiperidin—1-ylcarbonyl)-3-(4-methylphenylcarbonylaminoy
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`pheny], 5-(4-(RS)-aminocarbonylpiperidin-1-ylcarbonyl)-3-(4—methylphenyl-
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`carbonylamino)-phenyl, 5-(2-(S)-aminocarbonylpyrrolidin-1-ylcarbonyl)-3-(4-methylphenyl-
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`carbonylamino)—phenyl, 5-(4-(RS-methoxycarbonylpiperidin-1—y1carbonyl)-3—(4-methylf
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`phenylcarbonylamino)-phcny], 5-[N—(dimethylaminocarbonylmethyI)—N-(methyl)amino-
`
`carbonyl]-3—(4-methyl-phenylcarbonylamino)—phenyl, 5-[N—(aminocarbonylmethyl)—N—
`
`(methyl)aminocarbonyl]-3~(4-methylphenylcarbonylamino)—phenyl, 5-[N-(methylamino-
`
`carbonylmethyl)amino-carbonyl]-3—(4-methylphenylcarbonylamino)-phenyl, 5-[N-[(2—
`
`hydroxy)—1-hydroxymethyl)ethyl]-aminocarbonyl-S-(4-methylphenylcarbonylamino)-phenyl,
`
`3-(2,4-dichlorophenylcarbonyl-amino)-5-(piperidin-l-ylcarbonyl)-phenyl, 3-(2,4-dichloro-
`
`phenylcarbonyl-amino}5-(pyrrolidin-l-ylcarbonyl)—phenyl, 3-(2,4—dichlorophenylcarbonyl-
`
`amino)-5-(ZS-hydroxymethylpyrrolidin-1-ylcarbonyI)-phenyl, or 3-(2,4-dichlorophenyl-
`
`' carbonyl-amino)—5-(2R-hydroxymet.hylpyrrolidin-1-ylcarbonyl)-phenyl. Most preferably A12
`_- :is 5—(N,N—dimethylaminocarbonyl)-3-(4-methoxyphenylcarbonylamino)phenyl, 5-
`
`. (phenylaminocarbonyl)-3-(4.-methoxyphenylcarbonyl-amino)pheny], 5-(piperidin—l-
`
`ylcarbonyI)-3-(4—methylphenylcarbonylamino)phenyl, 5-(morpholin-4-ylcarbonyl)—3o(2,4-
`
`dichlorophenylcarbonylamino)phenyl, 5-(2-hydroxymefllylpiperidin-1-ylcarbonyl)-3-(4-
`methylphenylcarbouylainino)phenyl, 5-(N,N—dimethylaminocarbonyl)—3-(4-methylphenyl-
`carbonylamino)pheny_l, 5-(N-methoxy-N-methylaminocarbonyl)-3-(4-methylphenyl-
`
`carbonylamino)phenyl, 5-(pyrrolidin-1-ylcarbonyl)—3-(2,4-dichlorophenylcarbonylamino)-
`phenyl, 5-(piperidin-1-yIcarbonyI)—3-(2,4—dichlorophcnylcarbonylamino)phenyl, 5—(N,N-
`dimethylaminocarbonyl)-3-(4-methylphenyl-carbonylamino)phenyl, 5-(N,N-dimethy]-
`aminocarbonyl)—3-(3,4-dimethoxyphenylcarbonyl-amino)phenyl, 5-(N,N-dimethyl-
`
`aminocarbonyI)-3-(2,4—dichlorophenylcarbonylamino)phenyl,
`
`5-(N,N-dimethylaminocarbonyl)-3-(4-chlorophenylcarbonylamino)phenyl, 5-(N-ethyl-N—
`methylaminocarbonyl)—3-(4-methylphenylcarbonylamino)phcnyl, 5-(N,N-diethyl-
`
`aminocarbonyl)-3-(4-melhylphenylcarbonylamino)phenyl, or 5-(piperidin-l-ylcarbonyl)-3-
`(4-methylphenylcarbony]amino)phenyl.
`
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`(B).
`
`Another preferred group of compounds of Formula I is those wherein:
`
`ArI is phenylene and Ar2 is benzimidazol-Z-yl or heterocycloalkyl and R1 is hydrogen.
`
`(C).
`
`Yet another preferred group of compounds of Formula I is that wherein:
`
`RI and R2 are hydrogen, AI2 is located at the 4-position of the Ar] ring; R3 and R4 are
`
`hydrogen; and R5 is located at the 3-position of the Ar2 ring, the ring atom attaching the Ar2
`
`ring to the Ar1 ring being the l-position and is cyano, optionally substituted phenyl,
`
`optionally substituted heteroaryl, -X-R6 [where X is —O-, -NH-, -SOz-, -CO—, —NR9CO-,
`
`-c0NR‘°-, -NR”SO;- or -NR”CONR'4- where R”, R‘ ‘, R” and R” are hydrogen and R10 is
`
`hydrogen, alkyl or haloalkyl; and R‘5 is hydrogen (when X is not —0- or —NH-), alkyl (when
`
`X is not —0- or —NH-), hydroxyalkyl, optionally substituted phenyl, optionally substituted
`
`heteroaryl, optionally substituted heterocycloalkyl, optionally substituted phenylalky],
`
`optionally substituted phenoxyalkyl, or optionally substituted heteroaralkyl], or -(C1_6_
`alkylene)-Y-R7 [where Y is -0-, -CO- or -C0NR‘0 and R7 is hydrogen, alkyl, hydroxyalkyl,
`
`optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted
`
`heterocycloalkyl, optionally substituted phenylalkyl, optionally substituted phenoxyalkyl, or
`
`optionally substituted heteroaralkyl and R10 is hydrogenor alkyl]. More preferably R5 is -X-
`R6 (where x is -NHCO-, -CONR‘°—, or -NHSOz- where R” is hydrogen, alkyl or haloalkyl;
`and R6 is hydrogen, alkyl, hydroxyalkyl, optionally substituted phenyl, optionally substituted
`
`,heteroaryl, optionally substituted heterocycloalkyl, optionally substituted phenylalkyl,
`
`optionally substituted phenoxyalkyl, or optionally substituted, heteroaralkyl).
`Preferably ArI is phenylene and Ar2 is phenyl and R5 is -NHCOR§, -CONHRG, or -
`NHSOZR6 where R6 is alkyl, hydroxyalkyl, optionally substituted phenyl, optionally
`
`- substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted
`
`phenylalkyl, optionally substituted phenoxyalkyl, or optionally substituted heteroaralkyl.
`Most preferably R5 is -NH802CH3, -SOZCH3, thiophen-B-yl, cyano, -NHSOzphenyl,
`hydroxymethyl, —NHSOz(3-chlorophenyl), -NHSO;(4-fluorophenyl), -NHSOZ(3,4-
`
`dichlorophenyl), -NHCOphenyl, -NHSOz(benzyl), -NHSOz(4-chlorophenyl), -NHSOz(3-
`
`trifluoromethylphenyl), -NHSOZ(4-methoxyphenyl), -NHCO(3,4-dichlorophenyl), -
`
`NHCONH(3-methoxyphenyl), -NHCO(3,4-dimethoxyphenyl), -NHSOz(2,5—
`
`dimethoxyphenyl), -NHS02(4-trifluoromethoxyphenyl), -NHCO(3-fluorophenyl), ~NHCO(2,4-
`
`dichlorophenyl), -CONthenyl, -NHCO(4—methylphenyl), -NHCO(3-trifluoromethylphenyl),
`
`-Obenzyl, -O-(3-methoxybenzyl), -NHCO(3,4-methylenedioxyphenyl), -NHCO(4-
`
`methox‘yphenyl), -CONH(benzyl), -CONH(3,3,3-trifluoroethyl), -NHCO(3-methylbutyl), -
`
`10
`
`15
`
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`CONI-I(CH3), -NHCOCH(CH3)2, -NHCO(benzyl), -NHCO(CH2)2Phenyl, -NHCO(CH2)2(4—
`trifluorophenyl), ~NHCO(CH252(4-memoxyphenyl), -NHCO(3,S-dichlorophenyl), -
`
`NHCO(CH20)phenyl, -NHCO(3—methylbutyl), -NHCOCH2thiophen-2-yl, -NHCO(CH2)2(2,4-
`
`dichlorophenyl), -NHCO(CH2)2(3,4-methylenedioxyphenyl), -NHCO(4—trifluoromethyl-
`
`phenyl), -NHCO(4-ethoxyphenyl), -NHCO(4—dimethylamjnophenyl), -NHCO(4-flu0ro-
`
`phenyl), -NHCO(2,4-difluorophenyl), -NHCO(4-chlorophenyl), -CON(CH3)2. -NHCO(4-
`
`isopropylphenyl), -NHCO(4-u-ifluoromethoxyphenyl), -NHCO(3-fluoro-4—methoxyphenyl), —
`
`NHCO(4-methoxy-Z-methylphenyl), —NHCO(2,4—dimethoxyphenyl), -NHCO(4-chloro-2-
`
`methoxyphenyl), —NHCO(pyn'din—4-yl), —NHCO(pyridin-3—yl), -COmorpholin-4-yl,
`
`-CON(CH3)(phenyl), -CONH(4-chlorophenyl), -CONH(CH2)2(4-methoxyphenyl), —CONH(4-
`
`chlorobenzyl), -CONH(CH2)2phenyl, -C0NH(CH2)20H, ~COpipen'din-l-yl, -NHCO(2-methyl-
`
`phenyl), -NHCO(2,4—dimethylphenyl), -NHCO(2,5-dimethylphenyl), -NHCO(2—methyl-
`
`thiophen-S—yl), -CH2CONH(CH2)2(4-methoxyphenyl), -CH2CONHCH2(4-chlorophenyl), —
`
`CH2CON(CH3)2, -CH2CO(morpholin-4-yl, -CH2CON(CH3)(phenyl), -CH2CONH(CH2)2-
`
`phenyl, or -CH2CONH(4-chlorophenyl). Particularly preferably R5 is—NHSOzphenyl,
`
`-NHSO;(4—methoxyphenyl), -NHSOz(4—chlorophenyl), -N'HCO(phenyl), -NHCO(2,4-
`
`_. dichlorophenyl), -NHCO(4—methylphenyl), -NHCO(3,4—methlenedioxyphenyl), -NHCO(4-
`
`- methoxyphenyl), -NHCO(4-chlorophenyl), -NHCO(4-methoxy—2-rnethylpheny]), -NHCO(2,4-
`
`: dimethylphenyl),-'-NHCO(3,4-dichlorophenyl), -NHCO(3,4-dimethoxyphenyl), -NI-ICO(4-
`
`ethoxyphenyl), -NHCO(4-fluorop_henyl), -NHCO(2,4-difluorophenyl), —NHCO(4-dimethyl‘-
`
`aminophenyl), or —NHSOz(benzyl).
`
`-.
`
`'
`
`‘
`
`'3-
`
`,
`
`‘
`
`(D).
`
`Yet another preferred group of compounds of Formula I is that wherein:
`RI and R2 are hydrogen, Ar2 is located at the 4-position of the Ar1 ring; R3 is hydrogen,
`R“ is located at the 3-position and R5 at the 5-position of the Ar2 ring, the ring atom attaching
`the Ar2 ring to the Ar1 ring being the 1-posiu'on. Preferably, R4 is alkyl, halo, alkoxy,
`—NHCOR6 (where R6 is 'optionally substituted phenyl) or -CONR6Rl0 (where R6 is hydrogen,
`
`alkyl, optionally substituted phenyl, optionally substituted phenylalkyl or hydroxyalkyl and R10
`
`is hydrogen, alkyl, alkoxy, carboxyalky], hydroxyalkyl, aminocarbonylalkyl, or aminoalkyl);
`and R5 is alkyl, halo, alkoxy, carboxy, -CONR6Rlo (where R6 is hydrogen, alkyl, optionally
`substituted phenyl, optionally substituted phenylalkyl or hydroxyalkyl and R'0 is hydrogen,
`
`alkyl, alkoxy, carboxyalkyl, hydroxyalkyl, aminocarbonylalkyl, or aminoalkyl), -COR6 (where
`R6 is optionally substituted heterocycloalkyl), or -NHSO;R6 (where R6 is optionally substituted
`phenyl) provided that at least one of R4 and R5 is other than alkyl, halo, alkoxy, or carboxy
`when Arl is phenylene and Ar2 is phenyl. Preferably, ArI is phenylene and Arzis phenyl.
`
`10
`
`15
`
`20
`
`25.
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`Most preferably the Ar2 n'ng is 5-(bcnzylamin0carbonyl)—3—(phenylcarbony]amino)-
`
`phenyl, 5-(carboxy)—3-(phenylcarbonylamino)phenyl, 5-(morpholin-4—ylcarbonyI)-3-
`
`(phenylcarbonylanfino)phenyl, 5-(N,N-dimethylaminocarbonyl)-3-(4-methylphenylcarbonyl-
`
`amino)phenyl, 5-(morpholin-4-ylcarbonyl)-3—(4—methylphenylcarbonylamjno)phenyl, 5—
`
`(phenylaminocarbonyl)-3—(4-methyl-phenylcarbonylamino)phenyl, 5-(MN-dimethylamino—
`
`carbonyl)-3-(4-methoxyphenylcaIbonyl-amino)phenyl, 5-(morpholin-4-ylcarbonyl)-3-(4-
`
`methoxyphenyl-carbony]amino)phenyl, 5-(phcnylaminocarbonyl)-3—(4—methoxyphenyl-
`
`carbonylamino)phenyl, 5-(N,N—dimethyl-aminocarbonyl)—3-(3,4-dimethoxyphenyl-
`
`carbonylamino)phenyl, 5-(N,N-dimethyl-aminocarbony])-3-(phenylcarbonylamino)phenyl,
`
`5-(morpholin—4-ylcaIbonyl)-3-(3,4-dimethoxyphenylcarbonylamino)pheny],
`
`5-(phenylaminocarbonyl)-3-(3,4-dimethoxyphenylcarbonylamino)phenyl, 5-(piperidin-1-yl-
`
`carbonyl)-3-(4-methylphenyl—carbonylamino)phenyl, 5-(piperazin-1-ylcarbonyl)-3-(4—
`
`methylphenylcarbonylamino)phenyl, 5-(N-methylaminocarbonyl)-3-(4-methylphenyl-
`
`carbonylamino)phenyl, 5-(N-carboxymethyl-N-methylaminocarbonyl)-3-(4-methylphenyl-
`
`carbonylamino)phenyl, 5-(N-aminocaIbonyl-methylaminocarbonyl)-3—(4-methylpheny1-
`
`carbonylamino)-phenyl, 5-[N-(Z-N-methylamino-ethyl)—N-methylaminocarbonyl]-3-(4-
`
`methylphenylcarbonylamino)]-phenyl, 5-(N-carboxy—methylaminocarbonyl)-3-(4—methy]-
`
`phenylcarbonylamino)-phenyl, 5—(N,N—dimethyl-aminociarbonyl)-3-(3,4—methylcne-
`
`phenylcarbonylamino)—phenyl, 5-(morpholin-4—yl—carbbnyl)—3-(3,4-methylene—
`
`phenylcarbonylamino)-phenyl, 5-(phcnylaminocarbonyl)—3—(3,4-methylene-
`
`phenylcarbonylamino)-'phenyl, 5-(N,N-dimethylaniinocarbonyl)-3-(2,4-dichloro-
`
`phenylcarbonylamino)—phenyl, 5—(phenylaminocarbonyl)-3-(2,4-dichlorophenyl-
`
`carbonylamino)—phenyl, 5-(MN—dimethylaminocarbonyl)-3-(4-chlorophenylcarbonylamino}
`
`phenyl, 5-(morpholin-4-ylcarbonyl)-3-(4-chlorophenylcarbonylamino)-phenyl, 5-(N-ethyl-N-
`
`methyl—amjnocarbonyl)-3—(4-methylphenylcarbonylamino)-pheny], 5-(4-methylpiperazin—1-
`
`ylcarbonyl)—3-(4~mcfl1ylphenylcarbonylamino)-phcnyl, 5-(3-(RS)-aminocarbonylpipexidin-1-
`
`ylcarbonyl)-3-(4—methylphenylcarbonylamino)-pheny], 5-(N,N—diethylaminocarbonyl)—3-(4—
`
`methylphenyl-carbonylamino)—phenyl, 5-(2—N-methylaminoethy]aminocarbonyl)-3—(4~
`
`methylphenyl-carbonylamino)—phenyl, 5-(4-hydroxypiperidin-1-yIcarbonyl)-3-(4-methyl-
`
`phenyl—carbonylamino)—phenyl, 5-(pynolidin-l—ylcarbonyl)-3-(4-methylphcnylcarbonyl-
`
`amino)-phenyl, 5-(3-(RS)-hydroxymethylpipefidin-1-ylcarbonyl)-3-(4-methylphenyl-
`
`carbonylamino)-phenyl, 5-(2-(RS)-hydroxymethylpipen'din-1-y]carbonyl)-3-(4—
`
`methylphenylcarbonylamino)-phenyl, 5-(N-2-hydroxyethyl-N-methylaminocarbonyl)-3-(4-
`
`10
`
`15
`
`20
`
`‘25
`
`30
`
`35
`
`10
`
`

`

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`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`methylphenylcarbonylamino)-phenyl, 5-(N-4-chlorobenzyllaminocarbonyl)—3-(4-
`
`methylphenylcarbonylamino)-phenyl, 5—(N-3-methylbutylaminocarbonyl)-
`
`3-(4-methylphenylcarbonylamino)-phenyl, 5-(N-2-phenylethylaminocarbonyl)-
`
`3-(4-methylphenylcarbonylamino)~phenyl, 5-[N-2-(4-methoxyphenyl)ethylaminocarbonyl)]-
`
`3-(4-methylphenylcarbonylamino)—phenyl, 5-(N-methyl-N—methoxyaminocarbonyl)-
`
`3-(4—methylphenylcarbonyl-amino)phenyl, 5-(N-methyl-N—phenylaminocarbonyl)-
`
`3-(4-methylphenylcarbonylamino)-phenyl, 5-(N-benzylaminocarbonyl)-
`
`3-(4—methylphenylcarbonylamino)-pheny], 5-(N-2-hydroxyethylaminocarbonyl)-
`
`3—(4—methylphenylcarbonylamino)—phenyl, 5-[N,N-bis(2-hydroxyethyl)amjnocarbonyl}
`
`3-(4-methylphenylcarbonylamino)—phenyl, 5-(4-(RS)-hydroxymethylpiperidin-l-ylcarbonyl)-
`
`3-(4-methylphenylcarbony]amino)-phenyl, 5-(3-(RS)-methoxycarbonylpiperidin-1-yl-
`
`carbonyl)-3-(4—methylphenylcarbonylamino)-phenyl, 5-(4-(RS)-aminocarblonylpiperidin-1~
`
`ylcarbonyl)-3-(4-methylphenyl-carbonylamino)—phenyl, 5-(2-(S)-aminocarbonylpyrrolidin-1-
`
`ylcarbonyl)-3-(4-methylphenylcarbonylamino)-phenyl, 5-(4-(RS)-methoxycarbonylpiperidin-
`
`1-ylcarbonyl)-3-(4-methylphenylcarbonylamino)—phenyl, 5-[N-(dimcthylamino—
`
`carbonylmethyl)-N-(methyl)aminocarbonyl]-3-(4-methyl-phcnylcarbonylamino)-phenyl,
`
`5-[N-(aminocarbonylmethyl)-N-(methyl)aminocarbonyl]~3-(4—methylphenylcarbonylamino)-
`
`phenyl, 5-[N—(methylaminocarbonylmethyl)amino-carbonylj-3-(4—methylphenylcarbonyl-
`
`arnino)-phenyl, 5—[N-[(2—hydroxy)—1-hydroxymethyl)ethylr]-aminocarbony]-3-(4-methyl-
`
`phenylcarbonylaminoyphenyl, 3-(2,4-dichlorophenylcarbonyl-amino)-5-(piperidin-l-yl-
`
`carbony1)-phenyl, 3-(2,4-dichlorophenylcarbonyl-amino)-5-(pyrrolidin-l-ylcarbonyl)—phenyl,
`
`3-(2,4—dichlorophenylcarbonyl-amino)-5-(2S-hydroxymethylpynolidin-‘1-ylcarbonyl)-
`
`phenyl, or 3-(2,4-dichlorophenylcarbonyl—amino)-5-(2R-hydroxymethylpyrrolidin-1—yl~
`
`carbonyl)-phenyl. Particularly preferably Ar2 is 5-(N,N-dimethylaminocarbonyl)—3-(4-
`
`methoxyphcnylcarbonylamino)phenyl, 5-(phenylaminocarbonyl)-3-(4-methoxyphenyl-
`
`carbonyl-amino)phenyl, 5-(pipcridin-l-ylcarbonyl)—3-(4—mcthylphenylcarbonyl-
`
`amino)phenyl, 5-(morpholin-4—ylcarbonyl)-3-(2,4-dichlorophenylcarbonylamino)phenyl, 5-
`
`(2—hydroxymethylpiperidin-1-ylcarbonyl)-3-(4-methylphenylcarbonylamino)phenyl, 5-(N,N-
`
`dimethylaminocarbonyl)—3-(4-methylphenylcarbonylamjno)phenyl, 5-(N-methoxy-N-
`
`methylaminocarbonyl)-3-(4»methylphenylcarbonylamino)phenyl, 5-(pyn'olidin-1-yl-
`
`carbonyl)—3-(2,4-dichlorophenylcarbonylamino)phenyl, 5-(piperidin-l-ylcarbonyl)-3-(2,4-
`
`dichlorophenylcarbonylami