WO2013096150A1 - Substituted piperidines as hdm2 inhibitors - Google Patents

Substituted piperidines as hdm2 inhibitors Download PDF

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Publication number
WO2013096150A1
WO2013096150A1 PCT/US2012/069996 US2012069996W WO2013096150A1 WO 2013096150 A1 WO2013096150 A1 WO 2013096150A1 US 2012069996 W US2012069996 W US 2012069996W WO 2013096150 A1 WO2013096150 A1 WO 2013096150A1
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Prior art keywords
trifluoromethyl
carbonyl
oxy
piperidin
thiophen
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PCT/US2012/069996
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French (fr)
Inventor
Yao Ma
Manami Shizuka
Timothy J. Guzi
Yuan Liu
Yuan Tian
Brian R. Lahue
Craig R. Gibeau
Gerald W. Shipps, Jr.
Yaolin Wang
Stephane L. Bogen
Latha G. Nair
Weidong Pan
Matthew E. Voss
Margarita Kirova-Snover
W. Brent CLAYTON
Mark A. Mccoy
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Merck Sharp & Dohme Corp.
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Priority to US14/366,466 priority Critical patent/US9062071B2/en
Priority to EP12860596.1A priority patent/EP2793890B1/en
Publication of WO2013096150A1 publication Critical patent/WO2013096150A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to novel compounds useful as Human Double Minute 2 ("HDM2”) protein inhibitors, regulators or modulators,
  • compositions containing the compounds and potential methods of treatment using the compounds and compositions to potentially treat diseases such as, for example, cancer, diseases involving abnormal cell proliferation, and diseases caused by inadequate p53 levels.
  • the tumor suppressor protein p53 plays a central role in maintaining the integrity of the genome in a cell by regulating the expression of a diverse array of genes responsible for DNA repair, cell cycle and growth arrest, and apoptosis [May et a/., Oncogene 18 (53) (1999) p. 7621-7636; Oren, Cell Death Differ. 10 ⁇ 4 ⁇ (2003) p. 431-442 , Hall and Peters, Adv. Cancer Res., 68: (1996) p. 67-108; Hainaut et al., Nucleic Acid Res., 25: (1997) p.151-157; Sherr, Cancer Res., 60: (2000) p. 3689-95].
  • the cell In response to oncogenic stress signals, the cell triggers the p53 transcription factor to activate genes implicated in the regulation cell cycle, which thereby initiates either apoptosis or cell cycle arrest.
  • Apoptosis facilitates the elimination of damaged cells from the organism, while cell cycle arrest enables damaged cells to repair genetic damage [reviewed in Ko et al., Genes & Devel. 10: (1996) p.1054-1072; Levine, CeH 88: (1997) p. 323-331].
  • the loss of the safeguard functions of p53 predisposes damaged cells to progress to a cancerous state. Inactivating p53 in mice consistently leads to an unusually high rate of tumors [Donehower et al., Nature. 356: (1992) p. 215-221].
  • the p53 transcription factor promotes the expression of a number of cell cycle regulatory genes, including its own negative regulator, the gene encoding the Mouse Double Minute 2 (MDM2) protein [Chene, Nature Reviews Cancer 3: (2003) p. 102-109; Momand, Gene 242 (1-2): (2000) p. 15-29; Zheleva et al. Mini. Rev. Med. Chem. 3 (3): (2003) p. 257-270].
  • MDM2 protein Mouse Double Minute 2
  • HDM2 acts to down-regulate p53 activity in an auto- regulatory manner [Wu et al, Genes Dev., 7: (1993) p. 1 126-1 132; Bairak et al., EMBO J, 12: (1993) p. 461-468].
  • the MDM2 protein serves to maintain p53 activity at low levels [Wu et al, Genes Dev.. 7: (1993) p.1 126-1132; Barak et al., EMBO J, 12: (1993) p. 461-468].
  • p53 activity increases helping to prevent the propagation of permanently damaged clones of cells by induction of cell cycle and growth arrest or apoptosis.
  • MDM2 acts to down-regulate p53 activity.
  • MDM2 can bind to the N- terminal transcriptional activation domain of p53 to block expression of p53- responsive genes [Kussie et al., Science. 274: (1996) p. 948-953; Oliner et al., Nature, 362: (1993) p. 857-860; Momand et al, Cell, 69: (1992) p. 1237-1245].
  • MDM2 shuttles p53 from the nucleus to the cytoplasm to facilitate the proteolytic degradation of p53 [Roth et al, EMBO j, 17: (1998) p, 554-564;
  • MDM2 possesses an intrinsic E3 ligase activity for conjugating ubiquitin to p53 for degradation within the ubiquitin-dependent 26S proteosome pathway [Honda et al., FEBS Lett. 420: (1997) p. 25-27; Yasuda, Oncogene 19: (2000) p. 1473-1476].
  • MDM2 impedes the ability of the p53 transcription factor to promote the expression of its target genes by binding p53 in the nucleus.
  • Cis-lmidazolines Hoffmann La Roche Inc.
  • EP 0947494 A1 describes phenoxy acetic acid derivatives and phenoxy methyltetrazole that act as antagonists of MDM2 and interfere with the protein- protein interaction between MDM2 and p53, which results in anti-tumor properties (Hoffmann La Roche Inc.).
  • Duncan et al., J. Am. Chem. Soc. 123 (4): (2001) p. 554-560 describes a p-53-MDM2 antagonist, chlorofusin, from a Fusarium Sp.. Stoll et al., Biochemistry 40 (2) (2001) p. 336-344 describes chalcone derivatives that antagonize interactions between the human oncoprotein MDM2 and p53.
  • the present application discloses compounds that have potenCy in inhibiting or antagonizing the HDM2-p53 and MDM2-p53 interaction and/or activating p53 proteins in cells.
  • the present invention provides novel compounds having HDM2 or MDM2 antagonist activity, methods of preparing such compounds, pharmaceutical compositions comprising one or more of such compounds, methods of preparing pharmaceutical formulations comprising one or more of such compounds, methods of treatment or prevention of one or more diseases associated with HDM2, MDM2, p53, or p53 peptides by administering such compounds or pharmaceutical compositions.
  • the present invention provides a novel class of substituted piperidine compounds, pharmaceutical compositions comprising bne or more said compounds, and methods for using 5 said compounds for treating or preventing a disease associated with the HDM2 protein.
  • the present invention provides a compound of Formul
  • the present invention provides compounds illustrated as Formula I, as described above, or pharmaceutically acceptable salts or solvates thereof. Certain compounds of the invention unexpectedly demonstrate reduced CYP450 inhibitory liability (3A4) and/or good inhibition of HDM2 protein.
  • the present invention provides a compound of Formula I:
  • X is CR 3 or N
  • Y is CR 3 or N
  • Ring B is a 5 or 6-membered heteroaryl ring or phenyl
  • R 1 is independently selected from H, halo, CN, (CR a 2 ) n R 8 , -N(R 8 ) 2 , (C 3 -
  • R 2 is independently selected from H, halo, CN, amide, aryl, heterocyclic,
  • R 1 and R 2 are not both H;
  • R 3 is independently selected from the group consisting of: H, cyano, hydroxy, and alkoxy;
  • R 4 is heteroaryl which is optionally substituted with halo, halo-(Ci-C 6 )alkyl, (Ci- C 6 )alkyl, or -(Ci-C 6 )alkoxy;
  • R 5 is H, (Ci-C 6 )alkyl, (CrC 6 )alkenyl, (d-Ce ⁇ lkynyl, (CR b 2 ) t COOH, (CR b 2 ) t N(R 9 ) 2 ,
  • R 6 is independently (Ci-Ce)alkyl
  • R 7 is haloalkyl, -NR a C(0)R a , or C(0)N(R a ) 2 ;
  • R 8 is independently selected from H, halo, OH, CN, (Ci-C 6 )alkyl, (C3-
  • (Ci-C6)alkylheterocyclenyl and (Ci-C6)alkylheteroaryl wherein said alkyi, cycloalkyl, heterocyclic, heterocyclenyl and heteroaryl is optionally substituted with (C C 6 )alkyl, (CR a 2 ) n OR a , -N(R a ) 2 , (CR a 2 ) n COOR a , (CR a 2 ) n C(O)NR a R a , or
  • R 9 is independently H, (Ci-C 6 )alkyl, (C 3 -C 8 )cycloalkyl, heteroaryl, heterocyclenyl or heterocyclic, wherein the alkyi, cycloalkyl, heteroaryl, heterocyclenyl and heterocyclic is optionally substituted with (CrC 6 )alkyl, (C 3 -C 8 )cycloalkyl,
  • R 10 is independently (Ci-C 6 )alkyl
  • R a is independently H or (Ci-C6)alkyl, wherein the alkyi is optionally substituted with (C 0 -C 6 )alkyl-OH or -(C 0 -C 6 )alkylOMe;
  • R b is independently H or (Ci-Ce)alkyl
  • n 1 , 2, or 3;
  • n is independently 0, 1 , 2, 3, 4 or 5;
  • p 0, 1 , or 2;
  • q 0, 1 , 2, or 3;
  • r is 1 , 2 or 3;
  • t is O, 1 , 2 or 3 . or a pharmaceutically acceptable salt thereof.
  • X is CR 3 or N
  • Y is CR 3 or N
  • Ring B is a 5 or 6-membered heteroaryl ring or phenyl;
  • R 1 is independently selected from halo, CN, (CR a 2 ) n R 8 , -N(R 8 ) 2 , (C 3 - C 6 )cycloalkylCOOR 8 , (CR a 2 ) n COOR 8 , (CR a 2 ) n C(0)NR a R 8 ,
  • R 2 is independently selected from H, halo, CN, amide, aryl, heterocyclic,
  • R 3 is independently selected from the group consisting of: H, cyano, hydroxy, and alkoxy;
  • R 4 is heteroaryl which is optionally substituted with halo, halo-(Ci-C 6 )alkyl, (Gr Ce)alkyl, or -(Ci-C 6 )alkoxy;
  • R 5 is H, (Ci-C e )alkyl, (C C 6 )alkenyl, (C C 6 )alkynyl, (CR b 2 ) t COOH, (CR b 2 ) t N(R 9 ) 2 ,
  • R 6 is independently (d-C 6 )alkyl
  • R 7 is haloalkyl, -NR a C(0)R a , or C(0)N(R a ) 2 ;
  • R 8 is independently selected from H, halo, OH, CN, (Ci-C 6 )alkyl, (C 3 -
  • (Ci-C6)alkylheterocyclenyl and (Ci-C6)alkylheteroaryl wherein said alkyl, cycloalkyl, heterocyclic, heterocyclenyl and heteroaryl is optionally substituted with (d-CeJalkyl, (CR a 2 ) n OR a , -N(R a ) 2 , (CR a 2 ) n COOR a , (CR a 2 ) n C(O)NR a R a , or
  • R 9 is independently H, (Ci-C 6 )alkyl, (C 3 -C 8 )cycloalkyl, heteroaryl, heterocyclenyl or heterocyclic, wherein the alkyl, cycloalkyl, heteroaryl, heterocyclenyl and heterocyclic is optionally substituted with (Ci-C 6 )alkyl, (C 3 -C 8 )cycloalkyl,
  • R 10 is independently (Ci-C e )alkyl
  • R a is independently H or (CrC 6 )alkyl, wherein the alkyl is optionally substituted with (C 0 -C 6 )alkyl-OH or -(C 0 -C 6 )alkylOMe;
  • R is independently H or (C C 6 )alkyl
  • n 1 , 2, or 3;
  • n is independently 0, 1, 2, 3, 4 or 5;
  • r is 1 , 2 or 3;
  • t 0, 1 , 2 or 3 .
  • X is CR 3 or N
  • Y is CR 3 or N
  • Ring B is a 5 or 6-membered heteroaryl ring or phenyl
  • R 1 is independently selected from H, halo, CN, (CR a 2 ) n R 8 , -N(R 8 ) 2l (C 3 - C 6 )cycloalkylCOOR 8 , (CR a 2 ) n COOR 8 , (CR a 2 ) n C(0)NR a R 8 ,
  • R 2 is independently selected from H, halo, CN, amide, aryl, heterocyclic,
  • R 3 is independently selected from the group consisting: of: H, cyano, hydroxy, and alkoxy;
  • R 4 is thienyl, optionally substituted with CFs, CBr 3 , CCI 3 , CH 3 , Br, CI, F, or -OCH 3 .
  • R 5 is H, ( i-C e )alkyl, (Ci-C 6 )alkenyl, (Ci-C 6 )alkynyl, (CR b 2 ) t COOH, (CR b 2 ) t N(R 9 ) 2 ,
  • R 6 is independently (Ci-Ce)alkyl
  • R 7 is haloalkyl, -NR a C(0)R a , or C(0)N(R a ) 2 ;
  • R 8 is independently selected from H, halo, OH, CN, (Ci-C 6 )alkyl, (C 3 - C 8 )cycloalkyl, heterocylic, heterocyclenyl, heteroaryl, (Ci-Ce)alkylheterocyclic,
  • R 9 is independently H, (C C 6 )alkyl, (C 3 -C8)cycloalkyl, heteroaryl, heterocyclenyl or heterocyclic, wherein the alkyl, cycloalkyl, heteroaryl, heterocyclenyl and heterocyclic is optionally substituted with (CrC 6 )alkyl, (C 3 -C 8 )cycloalkyl,
  • R 10 is independently (C C 6 )alkyl
  • R a is independently H or (Ci-C6)alkyl, wherein the aikyl is optionally substituted with (C 0 -C 6 )alkyl-OH or -(C 0 -C 6 )alkylOMe;
  • R b is independently H or (CrC ⁇ alkyl
  • n 1 , 2, or 3;
  • n is independently 0, 1, 2, 3, 4 or 5;
  • p 0, 1 , or 2;
  • q 0, 1 , 2, or 3;
  • r is 1 , 2 or 3;
  • t 0, 1 , 2 or 3 .
  • R 4 is
  • thienyl optionally substituted with CF 3 , CBr 3 , CCI 3 , CH 3 , Br, CI, F, or -OCH 3 .
  • the present invention also provides compounds under Formula II,
  • X is CH and Y is N, or X is N and Y is CH;
  • Ring B is a 5 or 6-membered heteroaryl ring or phenyl
  • R 1 is independently selected from H, halo, CN, (CR a 2 ) n R 8 , -N(R 8 ) 2 , C 3 -
  • CecycloalkylCOOR 8 (CR a 2 ) n COOR 8 , (CR a 2 ) n C(0)NR a R 8 ,
  • R 2 is independently selected from H, halo, CN, amide, aryl, heterocyclic,
  • R 5 is H, (Ci-Ce)alkyl, (d-C 6 )alkenyl, (CrC 6 )alkynyl, (CR b 2 ) t COOH, (CR b 2 ) t N(R 9 ) 2 , (CR b 2 ) t OR 9 or (CR b 2 ) t R 9 ;
  • R 8 is independently selected from H, halo, OH, CN, (Ci-C 6 )aikyl, (C 3 - C 8 )cycloalkyl, heterocylic, heterocyclenyi, heteroaryl, (Ci-C6)alkylheterocyclic, (Ci-Ce)alkylheterocyclenyl and (Ci-Cejalkylheteroaryl, wherein said alkyl, cycloalkyl, heterocyclic, heterocyclenyi and heteroaryl is optionally substituted with (Ci-C 6 )alkyl, (CR a 2 ) n OR a , -N(R a ) 2 , (CR a 2 ) n COOR a , (CR a 2 ) n C(O)NR a R a , or (CR a 2 ) n NR a C(O)R a .
  • R 9 is independently H, (Ci-C6)alkyl, (C 3 -C 8 )cycloalkyl, heteroaryl, heterocyclenyi or heterocyclic, wherein the alkyl, cycloalkyl, heteroaryl, heterocyclenyi and heterocyclic is optionally substituted with (Ci-C6)alkyl, (C3-C8)cycloalkyl,
  • R a is independently H or (Ci-C 6 )alkyl, wherein the alkyl is optionally substituted with (C 0 -C 6 )alkyl-OH or (C 0 -C 6 )alkylOMe;
  • R b is independently H or (Ci-C 6 )alkyl
  • n 1 or 2;
  • n is independently 0, 1 , 2, 3 or 4;
  • r is 1 or 2 ;
  • t is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 are not both H.
  • the present invention also provides compounds under Formula III:
  • the present invention also provides compounds under Formula IV:
  • the present invention also provides compounds under Formula V:
  • R 2 and R 2 ' are independently H, Br or CI,
  • the present invention also provides compounds under Formula VA:
  • R 2 and R 2 ' are independently H, Br or CI,
  • the present invention also provides compounds under Formula VI:
  • R 1 is selected from (C 3 - C 6 )cycloalkylCOOR a (CR a 2 ) n COOR a , (CR a 2 )nO(CR a 2 )nCOOR a , and
  • R 1 is (CR a 2 ) n C(0)NR a S0 2 R 8 .
  • R 1 is (CR a 2 ) n COOR a .
  • R 1 is (CH 2 ) n COOH, and n is 2 or 3.
  • R 1 is (CH 2 ) n COOH, and n is 2 .
  • R is-CH 2 C(CH 3 )2COOH, -CH(CH 3 )CH 2 COOH, -cyclopentyl-COOH ⁇ or CH 2 OCH 2 COOH.
  • R 1 is H, -CH 2 C(CH 3 ) 2 COOH
  • R 1 is -cyclopentyl-COOH, (dR a 2 ) n CO(lH,
  • morpholinylmethyl or C(O)NH 2l wherein n is 0, 1 , 2, 3 or 4.
  • R 2 is CI or Br.
  • R 5 is methyl
  • heterocyclic is CH(CH 3 )COOH, CH 2 CH 2 COOH or 5-6 membered heterocyclic, said heterocyclic optionally substituted with (Ci-C 3 )alkyl, (C 3 -C 5 )cycloalkyl, (CR a 2 ) n COOH, or (CR a 2 ) n OR b .
  • the heterocyclic is morpholinyl, p l,
  • heterocylic is
  • R 8 is selected from H, halo, OH, CN, (CrC 6 )alkyl, (C 3 -C 8 )cycloalkyl, heterocylic, heteroaryl, (Ci- C 6 )alkylheterocyclic, and (Ci-C 6 )alkylheteroaryl, wherein said alkyl, cycloalkyl, heterocyclic and heteroaryl is optionally substituted with (Ci-C 6 )alkyl, (CR a 2 ) n OR a , -N(R a ) 2 , (CR a 2 ) n COOR a , (CR a 2 ) n C(O)NR a R a , or (CR a 2 ) n NR a C(O)R a .
  • R 9 is independently H, (Ci- Ce)alkyl or heterocyclic, wherein the alkyl and heterocyclic is optionally substituted with (Ci-C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (CR a 2 ) n COOH, or (CR a 2 ) n OR b ;
  • X is CH and Y is N.
  • r is 1.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C1-C10 as in “C1-C10 alkyl” is defined to include groups having 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbons in a linear or branched arrangement.
  • C1-C10 alkyl specifically includes methyl, ethyl, n-propyl, /-propyl, n-butyl, i-butyl, /-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and so on.
  • alkylheterocyclyl refers to the alkyl portion of the moiety and does not describe the number of atoms in the heterocyclyl portion of the moiety. In an embodiment, if the number of carbon atoms is not specified, the "alkyl” of “alkylaryl”, “alkylcycloalkyl” and “alkylheterocyclyl” refers to C1-C12 alkyl and in a further embodiment, refers to C1-C6 alkyl.
  • cycloalkyl means a monocyclic saturated or unsaturated aliphatic hydrocarbon group having the specified number of carbon atoms.
  • the cycloalkyi is optionally bridged (i.e., forming a bicyclic moiety), for example with a methylene, ethylene or propylene bridge.
  • the cycloalkyi may be fused with an aryl group such as phenyl, and it is understood that the cycloalkyi substituent is attached via the cycloalkyi group.
  • cycloalkyi includes cyclopropyl, methyl-cyclop ropy I, 2,2-dimethyl-cyclobutyl, 2-ethyi-cyclopentyl, cyclohexyl, cyclopentenyl, cyclobutenyl and so on.
  • alkyl refers to C1-C12 alkyl and in a further embodiment, “alkyl” refers to C1-C6 alkyl. In an embodiment, if the number of carbon atoms is not specified,
  • cycloalkyi refers to C3-C10 cycloalkyi and in a further embodiment, “cycldalkyl” refers to C3-C7 cycloalkyi.
  • examples of “alkyi” include methyl, ethyl, /7-propyl, / " -propyl, n-butyl, i-butyl and / ' -butyl.
  • alkylene means a hydrocarbon diradical group having the specified number of carbon atoms.
  • alkylene includes -CH2-, - CH2CH2- and the like.
  • alkylene refers to C1-C12 alkylene and in a further embodiment, “alkylene” refers to C1-C6 alkylene.
  • alkenyl refers to a non-aromatic hydrocarbon radical, straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond.
  • C2-C6 alkenyl means an alkenyl radical having from 2 to 6 carbon atoms.
  • Alkenyl groups include ethenyl, propenyl, butenyl, 2-methylbutenyl and cyclohexenyl. The straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated.
  • Alkenylene means a diradical group of an alkenyl group that is defined above.
  • alkynyl refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present.
  • C2-C6 alkynyl means an alkynyl radical having from 2 to 6 carbon atoms.
  • Alkynyl groups include ethynyl, propynyl, butynyl, 3-methylbutynyl and so on.
  • the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated.
  • substittients ma'y be defined with a range of carbons that includes zero, such as (Co-C6)alkylene-aryl. If aryl is taken to be phenyl, this definition would include phenyl itself as well as -CH2Ph, - CH2CH2Ph, CH(CH3)CH2CH(CH3)Ph, and so on.
  • Aryl is intended to mean any stable monocyclic, bicyclic or tricyclic carbon ring of up to 7 atoms in each ring, wherein at least one ring is aromatic.
  • aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl and biphenyl.
  • the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring.
  • aryl is an aromatic ring of 6 to 14 carbon atoms, and includes a carbocyclic aromatic group fused with a 5-or 6-membered cycloalkyl group such as indan.
  • carbocyclic arornatic groups include, but are not limited to, phenyl, naphthyl, e.g. 1 -naphthyl and 2-naphthyl; anthracenyl, e.g. 1-anthracenyl, 2-anthracenyl; phenanthrenyl; fluorenonyl, e.g. 9- fluorenonyl, indanyl and the like.
  • heteroaryl represents a stable monocyclic, bicyclic or tricyclic ring of up to 7 atoms ih each ring, wherein at least one ring is aromatic and contains carbon and from 1 to 4 heteroatoms selected from the group consisting of O, N and S.
  • heteroaryl refers to a monocyclic, bicyclic or tricyclic aromatic ring of 5- to 14-ring atoms of carbon and from one to four heteroatoms selected from O, N, or S.
  • heteroaryl is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl. In cases where the heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively.
  • Heteroaryl groups within the scope of this definition include but are not limited to acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinoline.
  • heteroaryl examples include, but are not limited to pyridyl, e.g., 2-pyridyl (also referred to as a-pyridyl), 3-pyridyl (also referred to as ⁇ -pyridyl) and 4-pyridyl (also referred to as ( ⁇ - pyridyl); thienyl, e.g., 2-thienyl and 3-thienyl; furanyl, e.g., 2-furanyl and 3-furanyl; pyrimidyl, e.g., 2-pyrimidyl and 4-pyrimidyl; imidazolyl, e.g., 2-imidazolyl; pyranyl, e.g., 2-pyranyl and 3-pyranyl; pyrazolyl, e.g., 4-pyrazoiyl and 5-pyrazblyl;
  • thiazolyl e.g., 2-thiazolyl, 4-thiazolyl and 5-thiazolyl; ihiadiazblyl; isothiazolyl; oxazolyl, e.g., 2-oxazoyl, 4-oxazoyl and 5-oxazoyl; isbxazoyl; pyrrolyl; pyridazinyl; pyrazinyl and the like.
  • heteroaryl may also include a “fused polycyclic aromatic", which is a heteroaryl fused with one or more other heteroaryl or nonaromatic heterocyclic ring.
  • fused polycyclic aromatic examples include, quinolinyl and isoquinolinyl, e.g.
  • 2-benzothienyl and 3-benzothiehyl ; indolyl, e.g. 2-indolyl and 3-ihdolyl; benzothiazolyl, e.g., 2-benzothiazolyl; benzooxazolyl, e.g., 2-benzooxazolyl; benzimidazolyl, e.g. 2-benzoimidazolyi; isoindolyl, e.g. 1- isoindolyl and 3-isoindolyl; benzotriazolyl; purinyl; thianaphthenyi, pyrazinyland the like.
  • Heterocyclyl means a non-aromatic saturated monocyclic, bicyclic, tricyclic or spirocyclic ring system comprising up to 7 atoms in each ring.
  • the heterocyclyl contains 3 to 14, or 5 to 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example, nitrogen, oxygen, phosphor or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclyls contain about 5 to about 6 ring atoms.
  • the heterocycle may be fused with an aromatic aryl group such as phenyl or heterocyclenyl.
  • the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom.
  • the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N- oxide, S-oxide or S,S-dioxide.
  • suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl,
  • An example of such a moiety is pyrrolidone:
  • heteroatoms contained in a specified heterocyclyl group the expression, "having one to x heteroatoms selected from the groups of N, O, P and S" (wherein x is a specified integer), for example, means that each heteroatom in the specified heterocyclyl is independently selected fror l the specified selection of heteroatoms. Attachment of a heterocyclyl substituent can occur via a carbon atom or via a heteroatom.
  • Heterocyclenyl means a norvaromatic monocyclic, bicyclic, tricyclic or spirocyclic ring system comprising up to 7 atoms in each ring.
  • the heterocyclenyl contains 3 to 14, or 5 to 10 ring atonhs, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen, phosphor or sulfur atom respectively is present as a ring atom.
  • the nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • suitable heterocyclenyl groups include 1 ,2,3,4- tetrahydropyridinyl, 1 ,2-dihydropyridinyl, 1 ,4-dihydropyridinyl, 1 ,2,3,6-tetrahydropyridinyl, 1 ,4,5,6- tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4- dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7- oxabicyclo[2.2.1]heptenyl
  • the expression, "having one to x heterbatOrns selectel from the group of N, O, P and S" (wherein x is an a specified integer)) fbr example, means that each heteroatom in the specified heterocyclenyl is indepehdently selected from the specified selection of heteroatoms.
  • alkylaryl group is an alkyl group substituted wit an aryl group, for example, a phenyl group. Suitable aryl groups are described herein and suitable alkyl groups are described herein. The bond to the parent moiety is through the aryl group.
  • alkylheteroaryl group is an alkyl group substituted with a heteroaryl group. Suitable heteroaryl groups are described herein and suitable alkyl groups are described herein. The bond to the parent moiety is through the heteroaryl group.
  • alkylheterocyclyl group is an alkyl group substituted with a heterocyclyl group. Suitable heterocyclyl groups are described herein and suitable alkyi groups are described herein. The bond to the parent moiety is through the heterocyclyl group.
  • alkylheterocyclenyl group is an alkyi group substituted with a heterocyclenyl group. Suitable heterocyclenyl groups are described herein and suitable alkyi groups are described herein. The bond to the parent moiety is through the heterocyclenyl group.
  • alkylcycloalkyl group is an alkyi group substituted with a cycloalkyl group. Suitable cycloalkyl groups are described herein and suitable alkyi groups are described herein. The bond to the parent moiety is through the cycloalkyl group.
  • arylalkyl group is an aryl group substituted with an alkyi group. Suitable aryl groups are described herein and suitable alkyi groups are described herein. The bond to the parent moiety is through the alkyi group.
  • heteroarylalkyl group is a heteroaryl group substituted with an alkyi group. Suitable heteroaryl groups are described herein and suitable alkyi groups are described herein. The bond to the parent moiety is through the alkyi group.
  • heterocyclylalkyl group is a heterocyclyl group substituted with an alkyi group. Suitable heterocyclyl groups are described hereih arid suitable alkyi groups are described herein. The bond to the parent moiety is through the alkyi group.
  • heterocyclenylalkyl group is a heterocyclenyl group substituted with an alkyi group. Suitable heterocyclenyl groups are described herein and suitable alkyi groups are described herein. The bond to the parent moiety is through the alkyi group.
  • cycloalkylalkyl group is a cycloalkyl group substituted with an alkyi group. Suitable cycloalkyl groups are described herein and suitable alkyi groups are described herein. The bond to the parent moiety is through the alkyi group.
  • aryloxy group is an aryl group that is attached to a compound via an oxygen (e.g., phenoxy).
  • alkoxy group is a straight chain or branched C1-C12 or cyclic C3-C1 2 alkyi group that is connected to a compound via an oxygen atom.
  • alkoxy groups include but are not limited to methoxy, ethoxy and propoxy.
  • arylalkoxy group is an arylalkyl group that is attached to a compound via an oxygen on the alkyl portion of the arylalkyl (e.g., phenylmethoxy).
  • arylamino group is an aryl group that is attached to a compound via a nitrogen.
  • alkylamino group is an alkyl group that is attached to a compound via a nitrogen.
  • an "arylalkylamino group” is an arylalkyl group that is attached to a compound via a nitrogen on the alkyl portion of the arylalkyl.
  • alkylsulfonyl group is an alkyl group that is attached to a compound via the sulfur of a sulfonyl group.
  • substituents When a moiety is referred to as “unsubstituted” or not referred to as “substituted” or “optionally substituted”, it means that the moiety does not have any substituents. When a moiety is referred to as substituted, it denotes that any portion of the moiety that is known to one skilled in the art as being available for substitution can be substituted.
  • the phrase "optionally substituted with one or more substituents” means, in one embodiment, one substituent, two substituents, three substituents, four substituents or five substituents.
  • the substitutable group can be a hydrogen atom that is replaced with a group other than hydrogen (i.e., a substituent group). Multiple substituent groups can be present.
  • substituents When multiple substituents are present, the substituents can be the same or different and substitution can be at any of the substitutable sites. Such means for substitution are well known in the art.
  • groups that are substituents are: alkyl, alkenyl or alkynyl groups (which can also be substituted, with one or more substituents), alkoxy groups (which can be substituted), a halogen or halo group (F, CI, Br, I), hydroxy, nitro, oxo, -CN, -COH, -COOH, amino, azido, N-alkylamino or N,N-dialkylamino (in which the alkyl groups can also be substituted), N-arylamino or N,N-diarylamino (in which the aryl groups can also be substituted), esters (-C(O)-OR, where R can be a group such as alkyl,
  • protecting groups When a functional group in a compound is termed "protected”, this means that the group is in modified form to preclude' undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinar skill ih the art as well as by reference to standard textbooks such as, for exahnple, T. W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York.
  • variable e.g., aryl, heterocycle, R 2 , etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • an active agent or a pharmacologically active agent
  • reference to “a carrier” includes mixtures of two or more carriers as well as a single carrier, and the like.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • the atoms may exhibit their natural isotopic abundances, or one or more of thi atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I.
  • different isotopic forms of hydrogen (H) include protium (1 H) and deuterium (2H).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds within generic Formula I can be prepared without undue
  • Certain isotopically-labelled compounds of Formula (I) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Certain isotopically-labelled compounds of Formula (I) can be useful for medical imaging purposes.
  • those compounds labeled with positron-emitting isotopes like 11 C or 18 F can be useful for application in Positron Emission Tomography (PET) and those labeled with gamma ray emitting isotopes like 123 l can be Useful for application in Single Photon Emission Computed Tomography (SPECT).
  • PET Positron Emission Tomography
  • SPECT Single Photon Emission Computed Tomography
  • isotopic substitution of a compound at a site where epimerization occurs may slow or reduce the epimerization process and thereby retain the more active or efficacious form of the compound for a longer period of time.
  • stereoisomers When structures of the same constitution differ in respect to the spatial arrangement of certain atoms or groups, they are stereoisomers, and the considerations that are significant in analyzing their interrelationships are topological. If the relationship between two stereoisomers is that of an object and its nonsuperimposable mirror image, the two structures are enantiomeric, and each structure is said to be chiral. Stereoisomers also include diastereomers, cis-trans isomers and conformational isomers. Diastereoisomers can be chiral or achiral, and are not mirror images of one another.
  • Cis-trans isomers differ only in the positions of atoms relative to a specified planes in cases where these atoms are, or are considered as if they were, parts of a rigid structure.
  • Conformational isomers are isomers that can be interconverted by rotations about formally single bonds. Examples of such conformational isomers include cyclohexane
  • a mixture of enantiomers is often balled an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racehnic mixture.
  • Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the Formulas of the invention, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the Formula.
  • one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines (bonds to atoms below the plane).
  • the Cahn-lnglod-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.
  • the compounds of the present invention contain one chiral center, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as a racemic mixtures.
  • the enantiomers can be resolved by methods known to those skilled in the art, such as formation of diastereoisomeric salts which may be separated, for example, by crystallization (see, CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC Press, 2001)); formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with ari
  • enantiomer-specific reagent for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent.
  • a further step is required to liberate the desired enantiomeric form.
  • specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
  • Designation of a specific absolute configuration at a chiral carbon of the compounds of the invention is understood to mean that the designated enantiomeric form of the compounds is in enantiomeric excess (ee) or in other words is substantially free from the other enantiomer.
  • the "R” forms of the compounds are substantially free from the “S” forms of the compounds and are, thus, in enantiomeric excess of the "S” forms.
  • “S” forms of the compounds are substantially free of “R” forms of the compounds and are, thus, in enantiomeric excess of the "R” forms.
  • Enantiomeric excess is the presence of a particular enantiomer at greater than 50%.
  • the specific absolute configuration is designated, the
  • enantiomeric excess of depicted compounds is at least about 90%.
  • a compound of the present invention When a compound of the present invention has two or more chiral carbons it can have more than two optical isomers and can exist in
  • the compound when there are two chiral carbons, the compound can have up to 4 optical isomers and 2 pairs of enantiomers
  • the pairs of enantiomers are mirror image stereoisomers of one another.
  • the stereoisomers that are not mirror-images e.g., (S,S) and (R,S)
  • the diastereoisomeric pairs may be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above.
  • the present invention includes each diastereoisomer of such compounds and mixtures thereof.
  • One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogeri- bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • Solvate encompasses both solution-phase and isolatable solvates.
  • suitable solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
  • One or more compounds of the invention may optionally be converted to a solvate.
  • Preparation of solvates is generally known.
  • M. Caira et al, J. Pharmaceutical Sci., 93(3). 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water.
  • Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001).
  • a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient
  • the active compounds disclosed can also be prepared in any solid or liquid physical form.
  • the compound can be in a crystalline form, in amorphous form, and have any particle size.
  • the compound particles may be micronized, or may be agglomerated, particulate granules, powders, oils, oily suspensions or any other form of solid or liquid physical form.
  • the compounds of the present invention may also exhibit polymorphism.
  • This invention further includes different polymorphs df the compounds of the present invention.
  • polymorph refers to a particular crystalline state of a substance, having particular physical properties such as X-ray diffraction, IR spectra, melting point, and the like.
  • the compounds of Formula I can form salts which are also within the scope of this invention.
  • Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated.
  • the term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • zwitterions inner salts may be formed and are included within the term "salt(s)" as used herein.
  • Salts of the compounds of the Formula I may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, brganic amines) such as dicyclohexylamines, t-butyl amines, and salts with amiho acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be
  • agents such as lower alkyl halides (e.g. methyl, ethyl, arid butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyi halides (e.g. benzyl and phenethyl bromides), and others.
  • lower alkyl halides e.g. methyl, ethyl, arid butyl chlorides, bromides and iodides
  • dialkyl sulfates e.g. dimethyl, diethyl, and dibutyl sulfates
  • long chain halides e.g. decyl, lauryl, and stearyl chlorides, bromides and iod
  • pharmaceutical composition is also intended to encompass both the bulk composition and individual dosage units comprised of more than one (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients.
  • the bulk composition and each individual dosage unit can contain fixed amounts of the afore-said "more than one pharmaceutically active agents”.
  • the bulk composition is material that has hot yet been formed into individual dosage units.
  • An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like.
  • the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.
  • Isolation of the compound at various stages of the reaction may be achieved by standard techniques such as ⁇ f6r example, filtration, evapbration of solvent and the like. Purification of the product and the like, may also be performed by standard techniques such ds recryltaiiization, distillation, sublimation, chromatography, conversion to a suitable derivative. Such techniques are well known to those skilled in the art.
  • the compounds of this invention may be analyzed for their composition and purity as well as
  • this invention provides pharmaceutical
  • compositions comprising the compounds of the invention as an active ingredient.
  • the pharmaceutical compositions generally additionally comprise a
  • carrier materials pharmaceutically acceptable carrier diluent, excipient or carrier
  • the present invention discloses methods for preparing pharmaceutical compositions comprising the compounds as an active ingredient.
  • the active ingredients will typically be administered in admixture with suitable carrier materials suitably selected with respect to the intended form of administration, i.e. oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional
  • the active drug component may be combined with any oral non-toxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like.
  • suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated in the mixture.
  • Powders and tablets may be comprised of from about 5 to about 95 percent inventive composition.
  • Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes.
  • Lubricants in these dosage forms include boric acid, sodium benzoate, sodium acetate, sodium chloride, and tt e like.
  • Disintegrahts include starch, methylcellulose, guar gum and the like. Sweetening and flavoring agents and preservatives may also be included Where appropriate.
  • compositions of the present invention may be formulated in sustained release form to provide the rite controlled release of any one or more of the components or active ingredients to optimize the therapeutic effects.
  • Suitable dosage forms for sustained release include layered tablets containing layers of Varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated poroUs polymeric matrices.
  • Liquid form preparations include solutions, suspensions arid emulsions.
  • water or water-propylene glycol solutions may be included for parenteral injections or sweeteners and pacifiers may be added for oral solutions, suspensions and emulsions.
  • Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier such as inert compressed gas, e.g. nitrogen.
  • a pharmaceutically acceptable carrier such as inert compressed gas, e.g. nitrogen.
  • a low melting wax such as a mixture of fatty acid glycerides such as cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein by stirring or similar mixing. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool to solidify. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
  • the compounds of the invention may also be deliverable transdermally.
  • transdermal compositions may take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • the compound is administered orally.
  • the pharmaceutical preparation is in a unit dosage form.
  • the preparation is subdivided into suitably sized unit dbses containing appropriate quantities of the active components, e.g., an effective amount td achieve the desired purpose.
  • the quantity of the inventive active composition in a unit dose of preparation may be generally varied or adjusted from about 1.0 milligram to about 1 ,000 milligrams, preferably from about 1.0 to about 500 milligrams, and typically from about 1 to about 250 milligrams, according to the particular application.
  • the actual dosage employed may be varied depending upon the patient's age, sex, weight and severity of the condition being treated. Such techniques are well known to those skilled in the art.
  • the total daily dosage may be divided and administered in portions during the day as required.
  • the human oral dosage form containing the active ingredients can be administered 1 or 2 times per day.
  • the amount and frequency of the administration will be regulated according to the judgment of the attending clinician.
  • a generally recommended daily dosage regimen for oral administration may range from about 1.0 milligram to about 1 ,000 milligrams per day, in single or divided doses.
  • kits comprising a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.
  • kits comprising an amount of at least one compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound and an amount df at least One anticancer therapy and /or anti-cancer agent described below, wherein the amounts of the two or more ingredients result in desired therapeutic effect.
  • Capsule - refers to a special container or enclosure made of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active ingredients.
  • Hard shell capsules are typically made of blends of relatively high gel strength bone arid pork skin gelatins. The capsule itself may contain small amounts of dyes, opaquing agents, plasticizers and preservatives.
  • Tablet- refers to a compressed or molded solid dosage form containing the active ingredients with suitable diluents
  • the tablet can be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation or by compaction.
  • Oral gels- refer to the active ingredients dispersed or solubilized in a hydrophillic semi-solid matrix.
  • Powders for constitution refer to powder blends containing the active ingredients and suitable diluents which can be suspended in water or juices.
  • Diluent - refers to substances that usually rhake up the major portion of the composition or dosage form. Suitable diluents include but are not limited to sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corn, rice and potato; and celluloses such as microcrystalline cellulose.
  • the amount of diluent in the composition can range from about 10 to about 90% by weight of the total composition.
  • Disintegrants - refers to materials added to the composition to help it break apart (disintegrate) and release the medicaments. Suitable disintegrants include but are not limited to modified starches such as sodium carboxymethyl starch; methylcellulose, microcrystalline celluloses and sodium croscarmellose; and sodium alginate. The amount of disintegrant in the composition can range from about 2 to about 10% by weight of the composition.
  • Lubricant - refers to a substance added to the dosage form to enable the tablet, granules, etc. after it has been compressed, to release from the mold or die by reducing friction or wear.
  • Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting point waxes; and water soluble lubricants such as high molecular weight polyethylene glycols and d,l-leucine. Lubricants are usually added at the very last step before compression, since they must be present on the surfaces of the granules and in between them and the parts of the tablet press. The amount of lubricant in the composition can range from about 0.2 to about 5% by weight of the composition.
  • Suitable glidents include silicon dioxide and talc.
  • the amount of glident in the composition can range from about 0.1 % to about 5% by weight of the total composition.
  • Coloring agents - excipients that provide coloration to the composition or the dosage form.
  • excipients can include food grade dyes and food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide.
  • the amount of the coloring agent can vary from about 0.1 to about 5% by weight of the composition.
  • HDM2, Hdm2, hDM2, and hdm2 are all equivalent representations of the Human Double Minute 2 protein.
  • MDM2, Mdm2, mDM2, and mdm2 are all equivalent representations mouse Double Minute 2 protein.
  • the compounds of Formula I can be inhibitors or antagonists of the
  • the pharmacological properties of the compounds of Formula I can be used to treat or prevent cancer, treat or prevent other disease states associated with abnormal cell proliferation, and treat or prevent diseases resulting from inadequate levels of p53 protein in cells.
  • cancer to be the name for diseases in which the body's cells become abnormal and divide without control.
  • Cancers that may be treated by the compounds, compositions and methods of the invention include, but are not limited to: Cardiac: sarcorha
  • angiosarcoma fibrosarcoma, rhabdomyosarcoma, liposarcoma
  • myxoma rhabdomyoma
  • fibroma lipoma and teratoma
  • Lung brohchogehib carcinoma (squamous cell, undifferentiated small cell, undifferentiated large dell,
  • adenocarcinoma adenocarcinoma
  • alveolar (bronchiolar) carcinoma brohchial adenoma
  • sarcoma adenocarcinoma
  • lymphoma adenocarcinoma
  • mesothelioma mesothelioma
  • Gastrointestinal esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma) colorectal; Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, le
  • hepatoma hepatocellular carcinoma
  • cholangiocarcinoma hepatoblastoma
  • angiosarcoma hepatocellular adenoma
  • hemangioma Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma,
  • osteochronfroma osteocartilaginous exostoses
  • benign chondroma osteochronfroma
  • Nervous system skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [
  • cystadenocarcinoma mucinous cystadenocarcinoma, unclassified carcinoma] granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial catcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinorna, squamous cell carcinoma, botryoid sarcoma (embrydnal rhabdomyosarcoma), fallopian tubes (carcinoma), breast; Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lympho
  • cancerous cell includes a cell afflicted by any one of the above-identified conditions.
  • cancers that may be treated by the compounds, compositions and methods of the invention include, but are not limited to: lung cancer, pancreatic cancer, colon cancer, colorectal cancer, myeloid leukemias, acute myelogenous leukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, thyroid cancer, myelodysplastic syndrome, bladder carcinoma, epidermal carcinoma, melanoma, breast cancer, prostate cancer, head and neck cancers, ovarian cancer, brain cancers, cancers of mesenchymal origin, sarcomas, tetracarcinomas, neuroblastomas, kidney carcinomas, hepatomas, non-Hodgkin's lymphoma, multiple myeloma, and anaplastic thyroid carcinoma.
  • cancers that may be treated by the compounds, compositions and methods of the invention include, but are not limited to: breast, prostate, colon, colorectal, lung, brain, testicular, stomach, pancrease, skin, small intestine, large intestine, throat, head and neck, oral, bone, liver, bladder, kidney, thyroid and blood.
  • liposarcoma liposarcoma, colorectal cancer, gastric cancer and melanoma.
  • ALL acute lymphoblastic leukemia
  • lymphoma lymphoma, lung, breast and glioblastoma.
  • the compounds of the invention are also useful in preparing a
  • the compounds of the invention are for the potential treatment of cancer.
  • the compounds of Formula I can be useful to the treatment of a variety of cancers, including, but not limited to: carcinoma, including, but not limited to, of the bladder, breast, colon, rectum, endometrium, kidney, liver, lung, head and neck, esophagus, gall bladder, cervix, pancreas, prostrate, larynx, ovaries, stomach, uterus, sarcoma and thyroid cancer;
  • carcinoma including, but not limited to, of the bladder, breast, colon, rectum, endometrium, kidney, liver, lung, head and neck, esophagus, gall bladder, cervix, pancreas, prostrate, larynx, ovaries, stomach, uterus, sarcoma and thyroid cancer;
  • hematopoietic tumors of the lymphoid lineage including leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non- Hodgkins lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma, and Burkett's lymphoma;
  • hematopoetic tumors of myeloid lineage including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and
  • tumors of the central and peripheral nervous system including
  • melanoma skin (non-melanomal) cancer, mesothelioma (cells), seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
  • the compounds of Formula I could abt as agent to induce cell death which may be useful in the treatment of any disease process which features abnormal celllular proliferation eg, cancers of various origin and tissue types, inflammation, immunological disorders.
  • the compounds of Formula I could act as reversible cytostatic agents which may be useful in the treatment of any disease process which features abnormal celllular proliferation
  • inhibitors could act as reversible cytostatic agents which may be useful in the treatment of any disease process which features abnormal cell proliferation, e.g., benign prostrate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty, or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections.
  • Chemoprevention is defined as inhibiting the development of invasive cancer by either blocking the initiating mutagenic event by blocking the progression of pre-malignant cells that have already suffered an insult or inhibiting tumor relapse.
  • Compounds of Formula I may also be useful in inhibiting tumor
  • Another aspect of this invention is a potential method of treating a mammal (e.g., human) having a disease or condition associated with HDM2 by administering a therapeutically effective amount of at least one compound of
  • the invention also provides a method of inhibiting one or more HDM2 proteins in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.
  • Another aspect of the present invention is a potential method of treating, or slowing the progression of a disease associated with one or more HDM2 proteins in a patient, comprising administering to a patient in need thereof, a
  • Another aspect of the present invention is a potential method of treating, or slowing the progression of a disease associated with inadequate p53 levels in a patient, comprising administering to a patient in need thereof, a therapeutically effective amount of at least one compound of the present invention or a
  • Yet another aspect of the present invention is a potential method of treating one or more diseases associated with HDM2, comprising administering to a mammal in need of such treatment an amount of a first compound, which is a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof; and an amount of at least one second compound, the second compound being an anti-cancer agent, wherein the amounts of the first
  • Another aspect of the present invention is a potential method of treating one or more diseases associated with inadequate p53 levels, comprising administering to a mammal in need of such treatment an amount of a first compound, which is a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof; and an amount of at least one second compound, the second compound being an anti-cancer agent, wherein the amounts of the first compound and the second compound result in a therapeutic effect.
  • a first compound which is a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof
  • Another aspect of the present invention is a potential method of treating, or slowing the progression of, a disease associated with a HDM2 protein comprising administering to a patient in need thereof, a therapeutically effective amount of a pharmaceutical composition comprising in combination at least one pharmaceutically acceptable carrier and at least one compound according to the present invention, or a pharmaceutically acceptable salt or solvate thereof.
  • Another aspect of the present invention is a potential method of treating, or slowing the progression of, a disease associated with inadequate p53 levels in a patient, comprising administering to a patieht in need thereof, a therapeutically effective amount of a pharmaceutical composition comprising in combination at least one pharmaceutically acceptable carrier and at least one compound according to the present invention, or a pharmaceutically acceptable salt or solvate thereof.
  • the dosage is about 0.001 to 500 mg/kg of body weight/day of the compound of Formula I. In another embodiment, the dosage is about 0.01 to 25 mg/kg of body weight/day of a compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound.
  • Effective amount or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
  • Patient includes both human and animals.
  • “Mammal” means humans and other mammalian animals.
  • the instant compounds are also useful in combination with therapeutic, chemotherapeutic and anti-cancer agents.
  • Combinations of the presently disclosed compounds with therapeutic, chemotherapeutic and anti-cancer agents are within the scope of the invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V .T ' . Devita and S. Hellman (editors), 6 th edition (February 15, 2001 ), Lippincott Williams & Wilkins
  • agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor
  • cytotoxic/cytostatic agents cytotoxic/cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, inhibitors of cell proliferation and survival signaling, bisphosphohates, aromatase inhibitors, siRNA therapeutics, ⁇ -secretase inhibitors, agents that interfere with receptor tyrosine kinases (RTKs) and agents that interfere with cell cycle checkpoints.
  • the instant compounds are also useful when co-administered with radiation therapy.
  • the compounds of the present invention can be present in the same dosage unit as the anticancer agent or in separate dosage units.
  • Another aspect of the present invention is a potential method of treating one or more diseases associated with HDM2, comprising administering to a mammal in need of such treatment an amount of a first compound, which is a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof; and an amount of at least oiie second compound, the second compound being an anti-cancer agent different from the compounds of the present invention, wherein the amounts of the first compound and the second compound result in a therapeutic effect.
  • a first compound which is a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof
  • Non-limiting examples of suitable anti-cancer agents include cytostatic [ agents, cytotoxic agents, targeted therapeutic agents (small molecules, biologies, siRNA and microRNA) against cancer and neoplastic diseases,
  • anti-metabolites such as methoxtrexate, 5-fluorouracil, gemcitabine,
  • alkylating agents such as temozolomide, cyclophosphamide
  • DNA interactive and DNA damaging agents such as cisplatin, oxaliplatin, doxorubicin,
  • topoisomerase II inhibitors such as etoposide, doxorubicin,
  • topoisomerase I inhibitors such as irinotecan, topotecan
  • tubulin interacting agents such as paclitaxel, docetaxel, Abraxane,
  • PARP Poly(ADP-ribose) polymerase
  • MMP Matrix metalloprotease
  • Protease inhibitors such as cathepsin D and cathepsin K inhibitors
  • Proteosome or ubiquitination inhibitors such as bortezomib
  • Bcl-2 inhibitors such as ABT-263
  • HSP Heat shock protein
  • HDAC Histone deacetylase
  • SAHA vorinostat
  • anti-estrogens such as tamoxifen, fulvestrant
  • SERM selective estrogen receptor modulators
  • LHRH agonists such as leuprolide
  • Cytochrome P450 C17 lyase (CYP450c17, also called 17a- hydroxylase/17,20 lysase) inhibitors, such as Abiraterone acetate, VN/124-1.
  • TAK-700 Cytochrome P450 C17 lyase (CYP450c17, also called 17a- hydroxylase/17,20 lysase) inhibitors, such as Abiraterone acetate, VN/124-1.
  • aromatase inhibitors such as letrozble, anastrozole, exemestane,
  • EGFR kinase inhibitors such as geftinib, erlotinib, laptinib
  • multi-targeted kinases serine/threonine and/or tyrosine kinase inhibitors
  • ABL kinase inhibitors imatudib and nilotinib, dasatinib
  • VEGFR-1 , VEGFR-2, PDGFR, KDR, FLT, c-Kit, Tie2, Raf, MEK and ERK inhibitors such as sunitinib, sorafenib, Vandetanib, pazopanib, PLX-4032, Axitinib, PTK787, GSK-1120212
  • Cyclin-dependent kinase inhibitors such as CDK1 and CDK2
  • PI3K and mTOR inhibitors such as GDC-0941 , BEZ-235, BKM-120 and AZD-8055
  • Rapamycin and its analogs such as Temsirolimus, everolimus, and
  • anti-erbB1 antibodies such as cetuximab, panitumumab,
  • anti-erbB2 antibodies such as trastuzumab
  • anti-CD52 antibodies such as Alemtuzumab
  • anti-CD20 antibodies such as Rituximab
  • anti-CD33 antibodies such as Gemtuzumab ozogamicin
  • anti-VEGF antibodies such as Avastin
  • TRIAL ligands such as Lexatumumab, mapatumumab, and AMG-655
  • Anti-CTLA-4 antibodies such as ipilimumab
  • anti-IGF-1 R antibodies such as dalotuzumab (MK-0646) and
  • Compounds of Formula I may also be administered sequentially with known anticancer or cytotoxic agents when a combination formulation is inappropriate.
  • the invention is not limited in the sequence of administration; compoUrids Of Formula I may be administered either concurrent with, prior to or after
  • this invention includes combinations comprisihg an amount of at least one compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and an amount of one or more anti-cancer treatments and anti-cancer agents listed above wherein the amounts of the compounds/treatments result in desired therapeutic effect.
  • Estrogen receptor modulators refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of mechanism.
  • estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381 , LY1 17081 , toremifene, fulvestrant, 4- [7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H- 1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate, 4,4'- dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.
  • Androgen receptor modulators refers to compounds which interfere or inhibit the binding of androgens to the receptor, regardless of mechanism.
  • Examples of androgen receptor modulators include finasteride and other 5a- reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and
  • Retinoid receptor modulators refers to compounds which interfere or inhibit the binding of retinoids to the receptor, regardless of mechanism.
  • retinoid receptor modulators examples include bexarotene, tretinoin, 13- cis-retinoic acid, 9-cis-retinoic acid, a-difluoromethylomithine, ILX23-7553, trans- N-(4'-hydroxyphenyl) retinamide, and N-4-carboxyphenyl retinamide.
  • Cytotoxic/cytostatic agents refer to compounds which cause cell death or inhibit cell proliferation primarily by interferihg directly with the cell's functioning or inhibit or interfere with cell myosis, including alkylating agents, tumor necrosis factors, intercalators, hypoxia activatable compounds, microtubule
  • inhibitors/microtubule-stabilizing agents inhibitors of mitotic kinesins 1 , histone deacetylase inhibitors, inhibitors of kinases involved in mitotic progression, inhibitors of kinases involved in growth factor and cytokine signal transduction pathways, antimetabolites, biological response modifiers, hormonal/anti-hormonal therapeutic agents, haematopoietic growth factors, monoclonal antibody targeted therapeutic agents, topoisomerase inhibitors, proteosome inhibitors, ubiquitin ligase inhibitors, and aurora kinase inhibitors.
  • cytotoxic/cytostatic agents include, but are not limited to, platinum coordinator compounds, sertenef, cachectin, ifosfamide, tasonerrriih, lonidamine, carboplatin, altretamine, prednimustihe, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide, cis- aminedichloro(2-methyl-pyridine)platinum, benzylguanine, glufosfamide,
  • hypoxia activatable compound is tirapazamine.
  • proteosome inhibitors include but are not limited to lactacystin and MLN-341 (Velcade).
  • microtubule inhibitors/microtubule-stabilising agents include taxanes in general. Specific compounds include paclitaxel (Taxol ® ), vindesine sulfate, 3 ⁇ 4'-didehydro-4'-deoxy-8'-norvincaleukoblastine, docetaxol (Taxotere ® ),
  • inhibitors of mitotic kinesins include, but are not limited to inhibitors of KSP, inhibitors of MKLP1 , inhibitors of CENP-E, inhibitors of MCAK and inhibitors of Rab6-KIFL.
  • histone deacetylase inhibitors include, but are hot limited to, SAHA, TSA, oxamflatin, PXD101 , MG98 and scriptaid. Further reference to other histone deacetylase inhibitors may be found in the following manuscript; Miller, T.A. et al. J. Med. Chem. 46(24):5097-5116 (2003).
  • “Inhibitors of kinases involved in mitotic progression” include, but are not limited to, inhibitors of aurora kinase, inhibitors of Polo-like kinases (PLK; in particular inhibitors of PL.K-1), inhibitors of bub-1 and inhibitors of bub-R1.
  • PLK Polo-like kinases
  • An example of an "aurora kinase inhibitor” is VX-680.
  • Antiproliferative agents includes antisense RNA and DNA
  • oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 , and INX3001 , and antimetabolites such as enocitabine, carmofUr, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'- methylidenecytidine, 2'-fluoromethylene-2'-deoxycytidine, N-[5-(2,3-dihydro- benzofuryl)sulfonyl]-N'-(3,4-dichlorophenyl)urea, N6-[4-
  • Examples of monoclonal antibody targeted therapeutic agents include those therapeutic agents which have cytotoxic agents or radioisotopes attached to a cancer cell specific or target cell specific monoclonal antibody. Examples include Bexxar.
  • HMG-CoA reductase inhibitors refers to inhibitors of 3-hydroxy-3- methylglutaryl-CoA reductase. Examples of HMG-CoA reductase inhibitors that may be used include but are not limited to lovastatin (MEVACOR®; see U.S.
  • HMG-CoA reductase inhibitor as Used herein includes all pharmaceutically acceptable lactdne and open-acid forms (i.e., where the lactone ring is opened to form the free acid) as well as salt and ester forms of compounds which have HMG-CoA reductase inhibitory activity, and therefor the use of such salts, esters, open-acid and lactone forms is included within the scope of this invention.
  • Prenyl-protein transferase inhibitor refers to a compound w iidh inhibits any one or any combination of the prenyl-protein transferase enzymes, including farnesyl-protein transferase (FPTase), geranylgeranyl-protein transferase type I (GGPTase-l), and geranylgeranyl-protein transferase type-ll (GGPTase-ll, also called Rab GGPTase).
  • FPTase farnesyl-protein transferase
  • GGPTase-l geranylgeranyl-protein transferase type I
  • GGPTase-ll also called Rab GGPTase
  • prenyl-protein transferase inhibitors can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701 , WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S. Patent No. 5,420,245, U.S. Patent No. 5,523,430, U.S. Patent No. 5,532,359, U.S. Patent No. 5,510,510, U.S. Patent No. 5,589,485, U.S. Patent No.
  • Angiogenesis inhibitors refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism.
  • angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFR1) and Flk-1/KDR
  • VEGFR2 inhibitors of epidermal-derived, fibroblast-derived, or platelet derived growth factors, MMP (matrix metalloprotease) inhibitors, integrin blockers, interferon-oc, interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidal anti-inflammatories (NSAIDs) like aspirin a d ibUprofen as well as selective cyclooxy-genase-2 inhibitors like celecoxib and rofecoxib ⁇ PNAS, Vol. 89, p. 7384 (1992); JNCI, Vol. 69, p. 475 (1982); Arch. Opthalmol., Vol.
  • NSAIDs nonsteroidal anti-inflammatories
  • steroidal anti-inflammatories such as corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone, methylpred, betamethasone
  • carboxyamidotriazole such as corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone, methylpred, betamethasone
  • combretastatin A-4 squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1 , angiotensin II antagonists (see Fernandez et al., J. Lab. Clin. Med. 105:141-145 (1985)), and antibodies to VEGF (see, Nature Biotechnology, Vol. 17, pp.963-968 (October 1999); Kim et al., Nature, 362, 841- 844 (1993); WO 00/44777; and WO 00/61186).
  • angiogenesis inhibitors include, but are not limited to, endostatin, ukrain, ranpirnase, IM862, 5-methoxy-4-[2-methyl-3-(3-methyl-2- butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate,
  • agents that modulate or inhibit angiogenesis and may also be used in combination with the compounds of the 5 instant invention include agents that modulate or inhibit the coagulation and fibrinolysis 5 systems (see review in Clin. Chem. La. Med. 38:679-692 (2000)).
  • agents that modulate or inhibit the coagulation and fibrinblysis pathways include, but are not limited to, heparin (see Thromb. Haemost. 80:10-23 (1998)), low molecular weight heparins and carboxypeptidase U inhibitors (also known as inhibitors of active thrombin activatable fibrinolysis inhibitor [TAFIa]) (see Thrombosis Res. 101 :329-354 (2001)).
  • TAFIa inhibitors have been described in U.S. Ser. Nos. 60/310,927 (filed August 8, 2001) and 60/349,925 (filed January 18, 2002).
  • Agents that interfere with cell cycle checkpoints refer to compounds that inhibit protein kinases that transduce cell cycle checkpoint signals, thereby sensitizing the cancer cell to DNA damaging agents.
  • agents include inhibitors of ATR, ATM, the CHK1 1 and CHK12 kinases and cdk and cdc kinase inhibitors and are specifically exemplified by 7-hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.
  • agents that interfere with receptor tyrosine kinases refer to compounds that inhibit RTKs and therefore mechanisms involved in oncogenesis and tumor progression. Such agents include inhibitors of c-Kit, Eph, PDGF, Flt3 and c-Met. Further agents include inhibitors of RTKs as described by Bume- Jensen and Hunter, Nature, 411 :355-365, 2001.
  • Inhibitors of cell proliferation and survival signalling pathway refer to compounds that inhibit signal transduction cascades downstream of cell surface receptors.
  • Such agents include inhibitors of serine/threonine kinases (including but not limited to inhibitors of Akt such as described in WO 02/083064, WO 02/083139, WO 02/083140, US 2004-0116432, WO 02/083138, US 2004-
  • inhibitors of Raf kinase for example PLX-4032
  • inhibitors 1 of ⁇ for example Arry-162, RO-4987655 and GSK-1 120212
  • inhibitors of mTOR for example AZD-8055, BEZ-235 and everolimus
  • inhibitors of PI3K for example GDC-0941 , BKM-120.
  • NSAID's which are potent COX-2 inhibiting agents.
  • an NSAID is potent if it possesses an IC50 for the inhibitioh of COX-2 of 1 ⁇ or less as measured by cell or microsomal assays.
  • NSAID's which are selective COX-2 inhibitors are defined as those which possess a specificity for inhibiting COX-2 over COX-1 of at least 100 fold as measured by the ratio of IC50 for COX-2 over IC50 for COX-1 evaluated by cell or microsomal assays.
  • Such compounds include, but are not limited to those disclosed in U.S. Patent
  • Inhibitors of COX-2 can be useful in the instant method of treatment are: 3- phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone; and 5-chloro-3-(4- methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine; or a pharmaceutically acceptable salt thereof.
  • Compounds that have been described as specific inhibitors of COX-2 and are therefore useful in the present invention include, but are not limited to, the following: parecoxib, BEXTRA® and CELEBREX® or a pharmaceutically acceptable salt thereof.
  • integrin blockers refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ⁇ 3 integrin, to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ⁇ 5 integrin, to compounds which antagonize, inhibit or counteract binding of a physiological ligand to both the ⁇ 3 integrin and the ⁇ 5 integrin, and to compounds which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed oh capillary endothelial cells.
  • the term also refers to antagonists of the ⁇ 6. « ⁇ . «1 ⁇ 1 > «2 ⁇ 1 , ⁇ 5 ⁇ 1.
  • «6 ⁇ 1 and ⁇ 6 ⁇ 4 integrins The term also refers to antagonists of any combination of ⁇ ⁇ ⁇ 3, ⁇ ⁇ ⁇ 5> ⁇ 6. ⁇ ⁇ 8> ⁇ *1 ⁇ 1 , ⁇ 2 ⁇ 1 , ⁇ , 6 ⁇ 1 and 6 ⁇ 4 integrins.
  • PPAR- ⁇ and PPAR- ⁇ are the nuclear peroxisome proliferator-activated receptors ⁇ and ⁇ .
  • the expression of PPAR- ⁇ on endothelial cells and its involvement in angiogenesis has been reported in the literature (see J. Cardiovasc. Pharmacol. 1998; 31 :909-913; J. Biol. Chem. 1999;274:9i 16-9121 ; Invest. Ophthalmol Vis. Sci. 2000; 41 :2309-2317). More recently, PPAR- ⁇ agonists have been shown to inhibit the angiogenic response to VEGF in vitro; both troglitazone and rosiglitazone maleate inhibit the
  • MDR inhibitors include inhibitors of p-glycoprotein (P-gp), such as LY335973 ⁇ 4, XR9576, OC144-093, R101922, VX853 and PSC833 (valspodar).
  • a compound of the present invention may be employed in conjunction with anti-emetic agents to treat nausea or emesis, including acute, delayed, late- phase, and anticipatory emesis, which may result from the use of a compound of the present invention, alone or with radiation therapy.
  • a compound of the present invention may be used in conjunction with other anti-emetic agents, especially neurokinin-1 receptor antagonists, 5HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron, and zatisetron, GABAB receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S. Patent Nos. 2,789,118, 2,990,401 , 3,048,581 , 3,126,375, 3,929,768, 3,996,359, 3,928,326 and
  • an antidopaminergic such as the phehothiazines (for example prochlorperazine, fluphenazine, thioridazine and mesoridazine), metoclopramide or dronabinol.
  • phehothiazines for example prochlorperazine, fluphenazine, thioridazine and mesoridazine
  • metoclopramide metoclopramide
  • conjunctive therapy with an anti-emesis agent selected from a neurokinin-1 receptor antagonist, a 5HT3 receptor antagonist and a corticosteroid is disclosed for the treatment or prevention of emesis that may result upon administration of the instant compounds.
  • the neurokinin-1 receptdr antagonist for use in conjunction with the compounds of the present invention is selected from: 2-(R)- (1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo- 1 H,4H-1 ,2,4-triazolo)methyl)morpholine, or a pharmaceutically acceptable salt thereof, which is described in U.S. Patent No. 5,719,147,
  • a compound of the instant invention may also be administered with ah agent useful in the treatment of anemia.
  • ah agent useful in the treatment of anemia is, for example, a continuous eythropoiesis receptor activator (such as epoetin alfa).
  • a compound of the instant invention may also be administered with an agent useful in the treatment of neutropenia.
  • a neutropenia treatment agent is, for example, a hematopoietic growth factor which regulates the production and function of neutrophils such as a human granulocyte colony stimulating factor, (G-CSF).
  • G-CSF human granulocyte colony stimulating factor
  • Examples of a G-CSF include filgrastim.
  • a compound of the instant invention may also be administered with art immunologic-enhancing drug, such as levamisole, isoprinosine and Zadaxin.
  • art immunologic-enhancing drug such as levamisole, isoprinosine and Zadaxin.
  • a compound of the instant invention may also be useful for treating or preventing cancer in combination with P450 inhibitors including: xenobiotics, quinidine, tyramine, ketoconazole, testosterone, quinine, methyrapone, caffeine, phenelzine, doxorubicin, troleandomycin, cyclobenzaprine, erythromycin, cocaine, furafyline, cimetidine, dextromethorphan, ritonavir, indinavir, amprenavir, diltiazem, terfenadine, verapamil, Cortisol, itraconazole, mibefradil, nefazodone and nelfinavir.
  • P450 inhibitors including: xenobiotics, quinidine, tyramine, ketoconazole, testosterone, quinine, methyrapone, caffeine, phenelzine, doxorubicin, troleandomycin, cyclo
  • a compound of the instant invention may also be useful for treating or preventing cancer in combination with Pgp and/or BCRP inhibitors including: cyclosporin A, PSC833, GF120918, cremophorEL, fumitremorgin C, Ko132, Ko134, Iressa, Imatnib mesylate, EKI-785, CM 033, novobiocin, diethylstilbestrol, tamoxifen, resperpine, VX-710, tryprostatin A, flavonoids, ritonavir,, saquinavir, nelfinavir, omeprazole, quinidine, verapamil, terferiadine, ketoconazole, nifidepine, FK506, amiodarone, XR9576, indinavir, amprenavir, Cortisol, testosterone, LY335979, OC144-093, erythromycin, vincristine, digoxin and talinolol
  • a cbmpound of the instant invention may also be useful for treating or preventing cancer, including bone cancer, in combination with bisphosphonates (understood to include bisphosphonates, diphosphonates, bisphosphonic acids and diphosphonic acids).
  • bisphosphonates include but are not limited to: etidronate (Didronel), pamidronate (Aredia), alendronate (Fbsamax), risedronate (Actonel), zoledronate (Zometa), ibahdronate (Boniva), incadronate or cimadronate, clodronate, EB-1053, minodronate, neridronate, piridronate and tiludronate including any and all pharmaceutically acceptable salts, derivatives, hydrates and mixtures thereof.
  • a compound of the instant invention may also be useful for treating or preventing breast cancer in combination with aromatase inhibitors.
  • aromatase inhibitors include but are not limited to: anastrozole, letrozole and exemestane.
  • a compound of the instant invention may also be useful for treating or preventing cancer in combination with siRNA therapeutics.
  • the compounds of the instant invention may also be administered in combination with ⁇ -secretase inhibitors and/or inhibitors of NOTCH signaling.
  • Such inhibitors include compounds described in WO 01/90084, WO 02/30912, WO 01/70677, WO 03/013506, WO 02/36555, WO 03/093252, WO 03/093264, WO 03/093251 , WO 03/093253, WO 2004/039800, WO 2004/039370, WO 2005/030731 , WO 2005/014553, USSN 10/957,251 , WO 2004/08991 1 , WO 02/081435, WO 02/081433, WO 03/018543, WO 2004/031137, WO
  • 60/670469 and including compounds of the instant invention, are also useful in combination with potassium salts, magnesium salts, beta-blockers (such as atenolol) and endothelin-a (ETa)antagonists with the goal of maintaihing cardiovascular homeostasis.
  • potassium salts magnesium salts
  • beta-blockers such as atenolol
  • ETa endothelin-a
  • Inhibitors of Akt as disclosed in the following publications; WO 02/083064, WO 02/083139, WO 02/083140, US 2004-01 16432, WO 02/083 38, US 2004- 0102360, WO 03/086404, WO 03/086279, WO 03/086394, WO 03/084473, WO 03/086403, WO 2004/041 162, WO 2004/096131 , WO 2004/096129, WO
  • 60/670469 and including compounds of the instant invention, are also useful in combination with insulin, insulin secretagogues, PPAR-gamma agonists, metformin, somatostatin receptor agonists such as octreotide, bPP4 inhibitors, sulfonylureas and alpha-glucosidase inhibitors with the goal of maintaihing glucose homeostasis.
  • PPAR-gamma agonists metformin
  • somatostatin receptor agonists such as octreotide, bPP4 inhibitors, sulfonylureas and alpha-glucosidase inhibitors
  • a compound of the instant invention may also be useful for treating or preventing cancer in combination with PARP inhibitors: olaparib, MK 827 and veliparib.
  • a compound of the instant invention may also be useful for treating cancer in combination with the following chemotherapeutic agents: abarelix (Plenaxis depot®); aldesleukin (Prokine®); Aldesleukin (Proleukin®); Alemtuzumabb (Campath®); alitretinoin (Panretin®); allopurinol (Zyloprim®); altretamine
  • Myleran® calusterone (Methosarb®); capecitabine (Xeloda®); carboplatin (Paraplatin®); carmustine (BCNU®, BiCNU®); carmustine (Gliadel®); carmustine with Polifeprosan 20 Implant (Gliadel Wafer®); celecoxib (Celebrex®); cetuximab (Erbitux®); chlorambucil (Leukeran®); cispiatin (PlatiHbl®); cladribine
  • dacarbazine (DTIC-Dome®); dactinomyciri, actinorriycin D (Coimegeh®);
  • doxorubicin (Adriamycin PFS®); doxorubicin (Adriamycln®, .
  • Rubex® doxorubicin (Adriamycin PFS Injection®); doxorubicin liposomal (Doxil®); dromostanolone propionate (Dromostanolohe ®); dromostanolone propionate (Masterone Injection®); eculizumab injection (Soiiris®); Elliott's B ; Solution (Elliott's B Solution®); eltrombopag (Promacta®); epirubiciri (Ellence®); Epoetin alfa (epogen®); erlotinib (Tarceva®); estramustine (Emcyt®); ethinyl estradiol; etoposide phosphate (Etopophos®); etoposide, VP-16 (Vepesid®); everolimus tablets (Afinitor®); exemestane (Aromasin®); ferumoxytol (Fera
  • fludarabine Fludarabine
  • fluorouracil 5-FU
  • fulvestrant Fluorouracil
  • gefitinib Iressa®
  • gemcitabine Gamzar®
  • gemtuzumab ozogamicin Mylotarg®
  • goserelin acetate Zoladex Implant®
  • goserelin acetate Zoladex®
  • histrelin acetate Histrelin implant®
  • hydroxyurea Hydrea®
  • Ibritumomab Tiuxetan Zevalin®; idarubicin (Idamycin®); ifosfamide (IFEX®); imatinib mesylate (Gleevec®); interferon alfa 2a (Roferon A®); Interferon alfa-2b (Intron A®); iobenguane I 123 injection (AdreView®); irinotecan (Camptosar®); ixabepilone (Ixempra®); lapatinib tablets (Tykerb®); lenalidomide (Revlimid®); letrozole (Femara®); leucovorin (Wellcovorin®, Leucovorin®); Leuprolide Acetate (Eligard®); levamisole (Ergamisol®); lomustine, CCNU (CeeBU®);
  • meclorethamine nitrogen mustard (Mustargen®); megestrol acetate (Megace®); melphalan, L-PAM (Alkeran®); mercaptopurine, 6-MP (Purinethol®); mesna
  • Mesnex® mesna (Mesnex tabs®); methotrexate (Methotrexate®); rriethoxsalen (Uvadex®); 8-methoxypsoralen; mitomycin C (Mutamycin®); mitotane
  • phenpropionate Durabolin-50®; nelarabine (Arranon®); nilotinib (Tasigna®); Nofetumomab (Verluma®); ofatumumab (Arzerra®); Oprelvekin (Neumega®); oxaliplatin (Eloxatin®); paclitaxel (Paxene®); paclitaxei (Taxol®); paclitaxel protein-bound particles (Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®); panitumumab (Vectibix®); pazopanib tablets (Votrienttm®);
  • pegademase (Adagen (Pegademase Bovine)®); pegasparga e (Oncaspar®); Pegfilgrastim (Neulasta®); pemetrexed disodium (Alimta®); pentostatiri
  • Mithramycin Mithracin®
  • porfimer sodium Porfimer sodium
  • pralatrexate injection Fluoride injection
  • procarbazine Musmice®
  • quinacrine Atabrine®
  • rapamycin Mithramycin
  • Rasburicase Elitek®
  • raloxifene hydrochloride Evista®
  • Rituximab Rituxan®
  • romidepsin Istodax®
  • romiplostim Nplate®
  • sargramostim Leukine®
  • temozolomide Temodar®
  • temsirolimus Torisel®
  • teniposide VM-26
  • Tositumomab (Bexxar®); Tositumomab/l-131 tositumomab (Bexxar®); trans- retinoic acid; Trastuzumab (Herceptin®); tretinoin, ATRA (Vesanoid®);
  • the acid chloride 6 (40 mg, 75.6 pmolj was dissolved in CH 2 CI2 (0.8 mL).
  • the reaction was stirred at room temperature for 3 h.
  • the reaction was concentrated and was purified by silica gel chromatography (EtOAc/hexanes * , gradient, 30% to 50%).
  • Oxalyl chloride (388 ⁇ , 4.08 mmol) was added to a stirred solution of DMSO (580 ⁇ , 8.16 mmol) in CH 2 CI 2 (18 mL) ai -78 °C under N 2 and was stirred for 5 min.
  • a solution of the alcohol (608 mg, 2.54 mmol) in CH2CI2 (2.0 mL) was added to the reaction mixture and was stirred at -78 °C for 1 h.
  • 3N (1,42 mL, 10.2 mmol) was added and the solution was warmed to room temperature and was stirred for 1 h.
  • the reaction mixture was quenched with sat'd aqueous NaHC03. The layers were separated and the aqueous layers was extracted with CH2CI2 (2 x 20 mL). The organic layers were washed with brine, dried over gS0 4 , filtered and concentrated to obtain the corresponding aldehyde.
  • the crude product 12 was purified by silica gel chromatography (EtOAc/hexanes, gradient, 10% to 30%).

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Abstract

The present invention provides a compound of Formula I(The formula should be inserted here) as described herein or a pharmaceutically acceptable salt or solvate thereof. The representative compounds are useful as inhibitors of the HDM2 protein. Also disclosed are pharmaceutical compositions comprising the above compounds and potential methods of treating cancer using the same.

Description

Substituted Piperidines as HDM2 Inhibitors
Field of the Invention
The present invention relates to novel compounds useful as Human Double Minute 2 ("HDM2") protein inhibitors, regulators or modulators,
pharmaceutical compositions containing the compounds and potential methods of treatment using the compounds and compositions to potentially treat diseases such as, for example, cancer, diseases involving abnormal cell proliferation, and diseases caused by inadequate p53 levels. Background of the Invention
The tumor suppressor protein p53 plays a central role in maintaining the integrity of the genome in a cell by regulating the expression of a diverse array of genes responsible for DNA repair, cell cycle and growth arrest, and apoptosis [May et a/., Oncogene 18 (53) (1999) p. 7621-7636; Oren, Cell Death Differ. 10 {4} (2003) p. 431-442 , Hall and Peters, Adv. Cancer Res., 68: (1996) p. 67-108; Hainaut et al., Nucleic Acid Res., 25: (1997) p.151-157; Sherr, Cancer Res., 60: (2000) p. 3689-95]. In response to oncogenic stress signals, the cell triggers the p53 transcription factor to activate genes implicated in the regulation cell cycle, which thereby initiates either apoptosis or cell cycle arrest. Apoptosis facilitates the elimination of damaged cells from the organism, while cell cycle arrest enables damaged cells to repair genetic damage [reviewed in Ko et al., Genes & Devel. 10: (1996) p.1054-1072; Levine, CeH 88: (1997) p. 323-331]. The loss of the safeguard functions of p53 predisposes damaged cells to progress to a cancerous state. Inactivating p53 in mice consistently leads to an unusually high rate of tumors [Donehower et al., Nature. 356: (1992) p. 215-221].
The p53 transcription factor promotes the expression of a number of cell cycle regulatory genes, including its own negative regulator, the gene encoding the Mouse Double Minute 2 (MDM2) protein [Chene, Nature Reviews Cancer 3: (2003) p. 102-109; Momand, Gene 242 (1-2): (2000) p. 15-29; Zheleva et al. Mini. Rev. Med. Chem. 3 (3): (2003) p. 257-270]. The MDM2 protein
(designated HDM2 in humans) acts to down-regulate p53 activity in an auto- regulatory manner [Wu et al, Genes Dev., 7: (1993) p. 1 126-1 132; Bairak et al., EMBO J, 12: (1993) p. 461-468]. In the absence of oncogenic stress signals, i.e., under normal cellular conditions, the MDM2 protein serves to maintain p53 activity at low levels [Wu et al, Genes Dev.. 7: (1993) p.1 126-1132; Barak et al., EMBO J, 12: (1993) p. 461-468]. However, in response to cellular DNA damage or under cellular stress, p53 activity increases helping to prevent the propagation of permanently damaged clones of cells by induction of cell cycle and growth arrest or apoptosis.
The regulation of p53 function relies on an appropriate balance between the two components of this p53-MDM2 auto-regulatory system. Indeed, this balance appears to be essential for cell survival. There are at least three ways that MDM2 acts to down-regulate p53 activity. First, MDM2 can bind to the N- terminal transcriptional activation domain of p53 to block expression of p53- responsive genes [Kussie et al., Science. 274: (1996) p. 948-953; Oliner et al., Nature, 362: (1993) p. 857-860; Momand et al, Cell, 69: (1992) p. 1237-1245]. Second, MDM2 shuttles p53 from the nucleus to the cytoplasm to facilitate the proteolytic degradation of p53 [Roth et al, EMBO j, 17: (1998) p, 554-564;
Freedman et al., Mol Cell Biol. 18: (1998) p. 7288-7293; Tao and Levine, Proc. Natl. Acad. Sci. 96: (1999) p. 3077-30801. Finally, MDM2 possesses an intrinsic E3 ligase activity for conjugating ubiquitin to p53 for degradation within the ubiquitin-dependent 26S proteosome pathway [Honda et al., FEBS Lett. 420: (1997) p. 25-27; Yasuda, Oncogene 19: (2000) p. 1473-1476]. Thus, MDM2 impedes the ability of the p53 transcription factor to promote the expression of its target genes by binding p53 in the nucleus. Attenuating the p53-MDM2 auto- regulatory system can have a critical effect on cell homeostasis. Consistently, a correlation between the overexpression of MDM2 and tumor formation has been reported fChene, Nature 3: (2003) p. 102-109]. Functional inactivation of wild type p53 is found in many types of human tumors. Restoring the function of p53 in tumor cells by anti-MDM2 therapy would result in slowing the tumor proliferation and instead stimulate apoptosis. Not surprisingly then, there is currently a substantial effort being made to identify new anticancer agents that hinder the ability of HDM2 to interact with p53 [Chene, Nature 3: (2003) p. 102- 109]. Antibodies, peptides, and antisense oligonucleotides have been
demonstrated to destroy the p53 -MDM2 interaction, which would release p53 from the negative control of MDM2, leading to activation of the p53 pathway allowing the normal signals of growth arrest and/or apoptosis to function, which offers a potential therapeutic approach to treating cancer and other diseases characterized by abnormal cell proliferation. [See, e.g., Blaydes et al., Oncogene 14: (1997) p. 1859-1868; Bottger et al., Oncogene 13 (10): (1996) p. 2141-2147].
Small molecules, said to antagonize the p53-MDM2 interaction, have been described. WO 00/15657 (Zeneca Limited) describes piperizine-4-phenyl derivatives as inhibitors of the interaction between MDM2 and p53. Grasberger et al. (J. Med. Chem., 48 (2005) p. 909-912) (Johnson & Johnson Pharmaceutical Research & Development L.L. C.) describes discovery and co-crystal structure of benzodiazepinedione as HDM2 antagonists that activate p53 in cells: Galatin et al. (J. Med. Chem. 47 (2004) p. 4163-4165) describes a nonpeptidic sulfonamide inhibitor of the p53-MDM2 interaction and activator of p53 dependent
transcription in MDM2-overexpressing cells.
U.S. Pub. No. 2004/0259867 A1 and 2004/0259884 A1 describes Cis- imidazoles (Hoffmann La Roche Inc.) and WO2005/110996A1 and WO
03/051359 describes Cis-lmidazolines (Hoffmann La Roche Inc.) as compounds that inhibit the interaction of MDM2 with p53-like peptides resulting in
antiproliferation. WO 2004/080460 A1 describes substituted piperidine
compounds as MDM2-p53 inhibitors for treating cancer* (Hoffmann La Roche Inc.). EP 0947494 A1 describes phenoxy acetic acid derivatives and phenoxy methyltetrazole that act as antagonists of MDM2 and interfere with the protein- protein interaction between MDM2 and p53, which results in anti-tumor properties (Hoffmann La Roche Inc.). Duncan et al., J. Am. Chem. Soc. 123 (4): (2001) p. 554-560 describes a p-53-MDM2 antagonist, chlorofusin, from a Fusarium Sp.. Stoll et al., Biochemistry 40 (2) (2001) p. 336-344 describes chalcone derivatives that antagonize interactions between the human oncoprotein MDM2 and p53.
There is a need for effective inhibitors of the HDM2 or MDM2 protein in order to treat or prevent cancer, other disease states associated with cell proliferation, diseases associated with HDM2, or diseases caused by inadequate p53 activity. The present application discloses compounds that have potenCy in inhibiting or antagonizing the HDM2-p53 and MDM2-p53 interaction and/or activating p53 proteins in cells. In its many embodiments, the present invention provides novel compounds having HDM2 or MDM2 antagonist activity, methods of preparing such compounds, pharmaceutical compositions comprising one or more of such compounds, methods of preparing pharmaceutical formulations comprising one or more of such compounds, methods of treatment or prevention of one or more diseases associated with HDM2, MDM2, p53, or p53 peptides by administering such compounds or pharmaceutical compositions.
Summary of the Invention
In its many embodiments, the present invention provides a novel class of substituted piperidine compounds, pharmaceutical compositions comprising bne or more said compounds, and methods for using5 said compounds for treating or preventing a disease associated with the HDM2 protein.
Accordingly, in one aspect the present invention provides a compound of Formul
Figure imgf000006_0001
Detailed description of the invention
In one embodiment, the present invention provides compounds illustrated as Formula I, as described above, or pharmaceutically acceptable salts or solvates thereof. Certain compounds of the invention unexpectedly demonstrate reduced CYP450 inhibitory liability (3A4) and/or good inhibition of HDM2 protein.
Accordingly, in one aspect the present invention provides a compound of Formula I:
Figure imgf000007_0001
wherein:
X is CR3 or N;
Y is CR3 or N;
Ring B is a 5 or 6-membered heteroaryl ring or phenyl;
R1 is independently selected from H, halo, CN, (CRa 2)nR8, -N(R8)2, (C3-
C6)cycloalkylCOOR8, (CRa 2)nCOOR8, (CRa 2)nC(0)NRaR8,
(CRa 2)nC(0)NRaS02R8, (CRa 2)nNRaC(O)R8, (CRa 2)nOR8, (CRa 2)nC(0)R8 arid
(CRa 2)nO(CRa 2)nCOORa;
R2 is independently selected from H, halo, CN, amide, aryl, heterocyclic,
(CRa 2)nCOOR8, -N(Ra)2 , (CRa 2)nORa, (CRa 2)nSRa and -S02Ra, wherein the aryl or heterocyclic is optionally subtituted with one to three substituents selected from cyano, hydroxy, amide, halo and methoxy;
Provided that R1 and R2 are not both H;
R3 is independently selected from the group consisting of: H, cyano, hydroxy, and alkoxy; R4 is heteroaryl which is optionally substituted with halo, halo-(Ci-C6)alkyl, (Ci- C6)alkyl, or -(Ci-C6)alkoxy;
R5 is H, (Ci-C6)alkyl, (CrC6)alkenyl, (d-Ce^lkynyl, (CRb 2)tCOOH, (CRb 2)tN(R9)2,
(CRb 2)tOR9 or (CRb 2)tR9 ;
R6 is independently (Ci-Ce)alkyl;
R7 is haloalkyl, -NRaC(0)Ra, or C(0)N(Ra)2;
R8 is independently selected from H, halo, OH, CN, (Ci-C6)alkyl, (C3-
C8)cycloalkyl, heterocylic, heterocyclenyl, heteroaryl, (Ci-C6)alkyiheterocyclic,
(Ci-C6)alkylheterocyclenyl and (Ci-C6)alkylheteroaryl, wherein said alkyi, cycloalkyl, heterocyclic, heterocyclenyl and heteroaryl is optionally substituted with (C C6)alkyl, (CRa 2)nORa, -N(Ra)2, (CRa 2)nCOORa, (CRa 2)nC(O)NRaRa, or
(CRa 2)nNRaC(O)Ra.
R9 is independently H, (Ci-C6)alkyl, (C3-C8)cycloalkyl, heteroaryl, heterocyclenyl or heterocyclic, wherein the alkyi, cycloalkyl, heteroaryl, heterocyclenyl and heterocyclic is optionally substituted with (CrC6)alkyl, (C3-C8)cycloalkyl,
(CRa 2)nCOOH, or (CRa 2)nORb;
R10 is independently (Ci-C6)alkyl;
Ra is independently H or (Ci-C6)alkyl, wherein the alkyi is optionally substituted with (C0-C6)alkyl-OH or -(C0-C6)alkylOMe; and
Rb is independently H or (Ci-Ce)alkyl;
m is 1 , 2, or 3;
n is independently 0, 1 , 2, 3, 4 or 5;
p is 0, 1 , or 2;
q is 0, 1 , 2, or 3;
r is 1 , 2 or 3;
t is O, 1 , 2 or 3 . or a pharmaceutically acceptable salt thereof.
In one embodiment,
X is CR3 or N;
Y is CR3 or N;
Ring B is a 5 or 6-membered heteroaryl ring or phenyl; R1 is independently selected from halo, CN, (CRa 2)nR8, -N(R8)2, (C3- C6)cycloalkylCOOR8, (CRa 2)nCOOR8, (CRa 2)nC(0)NRaR8,
(CRa 2)nC(0)NRaS02R8, (CRa 2)nNRaC(0)R8, (CRa 2)nOR8, (CRa 2)nC(0)R8 and (CRa 2)nO(CRa 2)nCOORa;
R2 is independently selected from H, halo, CN, amide, aryl, heterocyclic,
(CRa 2)nCOOR8, -N(Ra)2 , (CRa 2)nORa, (CRa 2)nSRa and -SO2Ra, wherein the aryl or heterocyclic is optionally subtituted with one to three substituents selected from cyano, hydroxy, amide, halo and methoxy;
R3 is independently selected from the group consisting of: H, cyano, hydroxy, and alkoxy;
R4 is heteroaryl which is optionally substituted with halo, halo-(Ci-C6)alkyl, (Gr Ce)alkyl, or -(Ci-C6)alkoxy;
R5 is H, (Ci-Ce)alkyl, (C C6)alkenyl, (C C6)alkynyl, (CRb 2)tCOOH, (CRb 2)tN(R9)2,
(CRb 2)tOR9 or (CRb 2)tR9 ;
R6 is independently (d-C6)alkyl;
R7 is haloalkyl, -NRaC(0)Ra, or C(0)N(Ra)2;
R8 is independently selected from H, halo, OH, CN, (Ci-C6)alkyl, (C3-
Ceicycloalkyl, heterocylic, heterocyclenyl, heteroaryl, (CrC6)alkylheterocyclic,
(Ci-C6)alkylheterocyclenyl and (Ci-C6)alkylheteroaryl, wherein said alkyl, cycloalkyl, heterocyclic, heterocyclenyl and heteroaryl is optionally substituted with (d-CeJalkyl, (CRa 2)nORa, -N(Ra)2, (CRa 2)nCOORa, (CRa 2)nC(O)NRaRa, or
(CRa 2)nNRaC(O)Ra.
R9 is independently H, (Ci-C6)alkyl, (C3-C8)cycloalkyl, heteroaryl, heterocyclenyl or heterocyclic, wherein the alkyl, cycloalkyl, heteroaryl, heterocyclenyl and heterocyclic is optionally substituted with (Ci-C6)alkyl, (C3-C8)cycloalkyl,
(CRa 2)nCOOH, or (CRa 2)nORb;
R10 is independently (Ci-Ce)alkyl;
Ra is independently H or (CrC6)alkyl, wherein the alkyl is optionally substituted with (C0-C6)alkyl-OH or -(C0-C6)alkylOMe; and
R is independently H or (C C6)alkyl;
m is 1 , 2, or 3;
n is independently 0, 1, 2, 3, 4 or 5;
p is 0, 1 , or 2; q is O, 1 , 2, 6r 3;
r is 1 , 2 or 3;
t is 0, 1 , 2 or 3 . In another embodiment,
X is CR3 or N;
Y is CR3 or N;
Ring B is a 5 or 6-membered heteroaryl ring or phenyl;
R1 is independently selected from H, halo, CN, (CRa 2)nR8, -N(R8)2l (C3- C6)cycloalkylCOOR8, (CRa 2)nCOOR8, (CRa 2)nC(0)NRaR8,
(CRa 2)nC(0)NRaS02R8, (CRa 2)nNRaC(0)R8, (CRa 2)nOR8, (CRa 2)nC(0)R8 and (CRa 2)nO(CRa 2)nCOORa;
R2 is independently selected from H, halo, CN, amide, aryl, heterocyclic,
(CRa 2)nCOOR8, -N(Ra)2 , (CRa 2)nORa, (CRa 2)nSRa and -S02Ra, wherein the aryl or heterocyclic is optionally subtituted with one to three substituents selected from cyano, hydroxy, amide, halo and methoxy;
R3 is independently selected from the group consisting: of: H, cyano, hydroxy, and alkoxy;
R4 is thienyl, optionally substituted with CFs, CBr3, CCI3, CH3, Br, CI, F, or -OCH3. R5 is H, ( i-Ce)alkyl, (Ci-C6)alkenyl, (Ci-C6)alkynyl, (CRb 2)tCOOH, (CRb 2)tN(R9)2,
(CRb 2)tOR9 or (CRb 2)tR9 ;
R6 is independently (Ci-Ce)alkyl;
R7 is haloalkyl, -NRaC(0)Ra, or C(0)N(Ra)2;
R8 is independently selected from H, halo, OH, CN, (Ci-C6)alkyl, (C3- C8)cycloalkyl, heterocylic, heterocyclenyl, heteroaryl, (Ci-Ce)alkylheterocyclic,
(CrC6)alkylheterocyclenyl and (C CeJalkylheteroaryl, wherein said alkyl, cycloalkyl, heterocyclic, heterocyclenyl and heteroaryl is optionally substituted with (CrC6)alkyl, (CRa 2)nORa, -N(Ra)2, (CRa 2)nCOORa, (CRa 2)nC(O)NRaRa, or
(CRa 2)nNRaC(O)Ra.
R9 is independently H, (C C6)alkyl, (C3-C8)cycloalkyl, heteroaryl, heterocyclenyl or heterocyclic, wherein the alkyl, cycloalkyl, heteroaryl, heterocyclenyl and heterocyclic is optionally substituted with (CrC6)alkyl, (C3-C8)cycloalkyl,
(CRa 2)nCOOH, or (CRa 2)nORb; R10 is independently (C C6)alkyl;
Ra is independently H or (Ci-C6)alkyl, wherein the aikyl is optionally substituted with (C0-C6)alkyl-OH or -(C0-C6)alkylOMe; and
Rb is independently H or (CrC^alkyl;
m is 1 , 2, or 3;
n is independently 0, 1, 2, 3, 4 or 5;
p is 0, 1 , or 2;
q is 0, 1 , 2, or 3;
r is 1 , 2 or 3;
t is 0, 1 , 2 or 3 .
In one embodiment, R4 is
thienyl, optionally substituted with CF3, CBr3, CCI3, CH3, Br, CI, F, or -OCH3.
In another embodiment, R4
Figure imgf000011_0001
The present invention also provides compounds under Formula II,
Figure imgf000011_0002
wherein:
X is CH and Y is N, or X is N and Y is CH;
Ring B is a 5 or 6-membered heteroaryl ring or phenyl;
R1 is independently selected from H, halo, CN, (CRa 2)nR8, -N(R8)2, C3-
CecycloalkylCOOR8, (CRa 2)nCOOR8, (CRa 2)nC(0)NRaR8,
(CRa 2)nC(0)NRaS02R8, (CRa 2)nNRaC(0)R8, (CRa 2)nOR8, (CRa 2)nC(0)R8 and
(CRa 2)nO(CRa 2)nCOORa; R2 is independently selected from H, halo, CN, amide, aryl, heterocyclic,
(CRa 2)nCOOR8, -N(Ra)2 , (CRa 2)nORa, (CRa 2)nSRa and -S02Ra, wherein the aryl or heterocyclic is optionally subtituted with one to three substituents selected from cyano, hydroxy, amide, halo and methoxy;
R5 is H, (Ci-Ce)alkyl, (d-C6)alkenyl, (CrC6)alkynyl, (CRb 2)tCOOH, (CRb 2)tN(R9)2, (CRb 2)tOR9 or (CRb 2)tR9 ;
R8 is independently selected from H, halo, OH, CN, (Ci-C6)aikyl, (C3- C8)cycloalkyl, heterocylic, heterocyclenyi, heteroaryl, (Ci-C6)alkylheterocyclic, (Ci-Ce)alkylheterocyclenyl and (Ci-Cejalkylheteroaryl, wherein said alkyl, cycloalkyl, heterocyclic, heterocyclenyi and heteroaryl is optionally substituted with (Ci-C6)alkyl, (CRa 2)nORa, -N(Ra)2, (CRa 2)nCOORa, (CRa 2)nC(O)NRaRa, or (CRa 2)nNRaC(O)Ra.
R9 is independently H, (Ci-C6)alkyl, (C3-C8)cycloalkyl, heteroaryl, heterocyclenyi or heterocyclic, wherein the alkyl, cycloalkyl, heteroaryl, heterocyclenyi and heterocyclic is optionally substituted with (Ci-C6)alkyl, (C3-C8)cycloalkyl,
(CRa 2)nCOOH, or (CRa 2)nORb;
Ra is independently H or (Ci-C6)alkyl, wherein the alkyl is optionally substituted with (C0-C6)alkyl-OH or (C0-C6)alkylOMe; and
Rb is independently H or (Ci-C6)alkyl;
m is 1 or 2;
n is independently 0, 1 , 2, 3 or 4;
r is 1 or 2 ;
t is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.
In one embodiment, R1 and R2 are not both H.
The present invention also provides compounds under Formula III:
Figure imgf000013_0001
and all other substituents are as defined above.
The present invention also provides compounds under Formula IV:
Figure imgf000013_0002
and all other substituents are as defined above.
The present invention also provides compounds under Formula V:
Figure imgf000013_0003
Wherein
R2 and R2' are independently H, Br or CI,
and all other substituents are as defined above.
The present invention also provides compounds under Formula VA:
Figure imgf000014_0001
R2 and R2' are independently H, Br or CI,
and all other substituents are as defined above.
The present invention also provides compounds under Formula VI:
Figure imgf000014_0002
In one aspect of the above invention, R1 is selected from (C3- C6)cycloalkylCOORa (CRa 2)nCOORa, (CRa 2)nO(CRa 2)nCOORa, and
(CRa 2)nC(0)NRaS02R8. In one embodiment, R1 is (CRa 2)nCOORa. In another embodiment, R1 is (CH2)nCOOH, and n is 2 or 3. In a futher embodiment, R1 is (CH2)nCOOH, and n is 2 . In yet another embodiment, R is-CH2C(CH3)2COOH, -CH(CH3)CH2COOH, -cyclopentyl-COOH^ or CH2OCH2COOH.
In yet another embodiment, R1 is H, -CH2C(CH3)2COOH,
CH2CH(CH(CH3)2)COOH, CH2CH(CH2(CH3))COOH, -CH2GH(0H3)COOH, - CH2CH(OH)COOH, -CH(CH3)CH2COOH, -cyclopentyl-COOH, CH2OCH2COOH, COOH, CH2COOH, CH2CH2COOH, CH2CH2CH2COOH, CH2CH2CH2CH2COOH, (CRa 2)nC(O)NRaSO2Ra, methoxymethyl, morpholinylmethyl, or C(O)NH2 . In yet another embodiment, R1 is -cyclopentyl-COOH, (dRa 2)nCO(lH,
(CRa 2)nO(CRa 2)nCOOH , (CRa 2)nC(O)NRaSO2Ra, methoxymethyl,
morpholinylmethyl, or C(O)NH2l wherein n is 0, 1 , 2, 3 or 4.
In another aspect of the above inventions2 is halo. In another
embodiment, R2 is CI or Br.
In a futher aspect of the above invention, R5 is methyl,
CH(CH3)COOH, CH2CH2COOH or 5-6 membered heterocyclic, said heterocyclic optionally substituted with (Ci-C3)alkyl, (C3-C5)cycloalkyl, (CRa 2)nCOOH, or (CRa 2)nORb. In one embodiment, the heterocyclic is morpholinyl, p l,
piperdinyl, or piperzinyl. In another embodiment, the heterocylic is
Figure imgf000015_0001
In a further aspect of the above invention, R8 is selected from H, halo, OH, CN, (CrC6)alkyl, (C3-C8)cycloalkyl, heterocylic, heteroaryl, (Ci- C6)alkylheterocyclic, and (Ci-C6)alkylheteroaryl, wherein said alkyl, cycloalkyl, heterocyclic and heteroaryl is optionally substituted with (Ci-C6)alkyl, (CRa 2)nORa, -N(Ra)2, (CRa 2)nCOORa, (CRa 2)nC(O)NRaRa, or (CRa 2)nNRaC(O)Ra.
In a further aspect of the above invention, R9 is independently H, (Ci- Ce)alkyl or heterocyclic, wherein the alkyl and heterocyclic is optionally substituted with (Ci-C6)alkyl, (C3-C8)cycloalkyl, (CRa 2)nCOOH, or (CRa 2)nORb;
In a further aspect of the above invention, X is CH and Y is N.
In a further aspect of the above invention, r is 1.
Specific examples of the compounds of the invention include, but not limited to:
2-[(2R,3S)-3-[(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]-1-{[4- (trifluoromethyl)pyridin-3-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3- yl]oxy}piperidin-2-yl]-N,N-bis(2-methoxyethyl)ethanamine; 2-[(2R,3S)-3-[(6-chloro-3,4-dihydroisoquinolin-2(1 H)-yl)carbonyl]-1-{[4-
(trifluoromethyl)pyridin-3-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3- yl]oxy}piperidin-2-yl]-N,N-bis(2-methoxyethyl)ethanamine;
7-chloro-2-{[(2R,3S)-2-(2-morpholin-4-ylethyl)-1-{[4-(trifluoromethyl)pyrid yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-
1 ,2,3,4-tetrahydroisoquinoline;
6-chloro-2-{[(2R,3S)-2-(2-morpholin-4-ylethyi)-1-{[4-(trifluoromethyl)pyridi yl]carbonyl}-3-{[5-(trifluoromethyl^
1 ,2,3,4-tetrahydroisoquinoline;
2-{[(2R,3S)-2-propyl-1-{[3-(trifluo^
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbohyl}-1 , 2,3,4- tetrahydroisoquinoline-7-carbbnitrile;
2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-i-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-7-carboxamide;
6-fluoro-2-{t(2R,3S)-2-(2-morpholin-4-ylethyl)-1-p-(trifluoromethyl)pyrid yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbbnyl}-
1 ,2,3,4-tetrahydroisoquinoline;
5-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yi]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4, 5,6,7- tetrahyd roth ieno[3 , 2-c]pyrid i ne ;
ethyl 5-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4, 5,6,7- tetrahyd roth ieno[3 , 2-c]pyrid i ne-2-carboxylate ;
5- {[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4, 5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid;
2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-6-amine;
6- chloro-1 -(morpholin-4-ylmethyl)-2-{[(2R,3S)-2-propyl-1 -{[3- (trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3- yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4-tetrahydroisoquinoline; 2-chloro-5-{t(2R,3S)-2-propyl-1-{[3-(trifluoromethy!)pyridin-2-y
(trifluor0methyl)thiophen-3-yl]oxy}piperidi -3-yl]carb0nyl}-4,5,6J-
Figure imgf000017_0001
yl]carbonyl}-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-2-yl]acetic acid;
2-chloro-6-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyHdin-2-yl]carbonyl}-3- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbohyl}-4, 5,6,7- tetrahydrothieno[2,3-c]pyridine-7-carboxylic acid;
2-(1 -{2-[(2R,3S)-3-{[6-chlorc~1 -(methoxymethyl)-3,4-dihydroisoquirlolin-2(1 hi)- yl]carbonyl}-1 -{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-2-yl]ethyl}piperidin-4-yl)eth
6-chloro-2-{[(2R,3S)-2-{2-[4-(2-methoxyethyl)piperazin-1 -yl]ethyl}-1 -{[3- (trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)ihiophen-3- yl]oxy}piperidin-3-yl]carbonyl}-1-(methoxymethyl)-1 ,2,3,4-tetrahydroisoquindline; N-{2-[(2R,3S)-3-{[6-chloro-1-(methoxymethyl)-3,4-dihydroisoquinoliri-2(1 H)- yl]carbonyl}-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-2-yl]ethyl}tetrahydro-2H-pyran-4- amine; 3-(2-chloro-5-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-^ (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4, 5,6,7- tetrahydrothieno[3,2-c]pyridin-4-yl)propanoic acid;
3-(2-chloro-5-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyi)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4, 5,6,7-
Figure imgf000018_0001
tetrahydrothieno[2,3-c]pyridin-7-yl)propanoic acid;
2,2-dimethyl-3-(6-{[(2R,3S)-2-propyl-1-{[3-^
{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4, 5,6,7^·
tetrahydrothieno[2,3-c]pyridin-7-yl)-N-(1 H-tetrazol-5-ylmethyl)propanamide 3-(2-chloro-6-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4,5,6,7- tetrahydrothieno[2,3-c]pyridin-7-yl)-2,2-dimethylpropanoic acid;
2-chloro-4-(3-morpholin-4-ylpropyI)-5-{[(2R,3S)-2-propyl-1-{[3- (trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3- y!]oxy}piperidin-3-yl]carbonyl}-4,5,6,7-tetrahydrothieno[3,2-c]pyridine;
2-chloro-5-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4-(3-pyrrolidin ylpropyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine; 2-chloro-N-methyl-5-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2- yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-
4,5,6,7-tetrahydrothieno[3,2-c]pyridine-4-darboxamide;
2- chloro-5-{[(2R,3S)-2-propyl-1-{[3-(trifluo methyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy
ylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine;
3- (2-chloro-5-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3^
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl
tetrahydrothieno[3,2-c]pyridin-4-yl)-N-(methylsulfonyl)propanamide;
3-(2-chloro-5-{[(2RI3S)-2-propyl-1-{[3-(trifiuoromethyi)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidih-3-yl]carbohyl}-4, 5,6,7- tetrahydrothieno[3,2-c]pyridin-4-yl)-N-(methylsulfonyl)propanamide;
{[(3R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]car^ {[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinolin-3-yl]methoxy}acetic acid;
3-(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluorometHyl)pyridin-2-yl]carbonyl^ (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinolin-1-yl)propanoic acid;
5-(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carb6nyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)pentanoic acid;
5-(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(t^
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinolin-1-yl)pentanoic acid;
3-(6-fluoro-2-{[(2R,3S)-2-propyM-{[3-(trifl^^
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)propanoic acid;
5-(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-^ (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)pentanoic acid;
3-(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)propanoic acid; 3-[(1 R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}- 3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl]propanoic acid;
2- {[(2R,3S)r2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4-
Figure imgf000020_0001
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline;
3- (6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(t^
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)propan-1-ol;
(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinolin-1-yl)acetic acid;
(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yi]carbonyl}-3-{^ (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1~yl)acetic acid;
3-(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}^ (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)propan-1-ol;
(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5^ (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)acetic acid; (6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifludromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)acetic acid;
3-(6-bromo-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1 -yl)propanoic acid;
3-(6-bromo-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridiri-2-yl]carbbnyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)propanoic acid;
3-(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbdhyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)-N-(2H-tetrazol-5-ylmethyi)propanamide;
3-(6-fluoro-2-{[(2R>3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yiicarbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)-N-(2H-tetrazol-5-ylmethyl)propanamide;
3-(6-chloro-2-{[(2 R, 3S)-2-propyM -{[3^
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)-N-(methylsulfonyl)propanamide;
6-phenyl-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline;
3-(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-^ (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyi}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)-N-(methylsulfonyl)propanamide;
3-(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3^
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)-2,2-dimethylpropanoic acid;
3-(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3^ (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)-2,2-dimethylpropanoic acid;
2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-6-thiophen-3-yl-1 ,2,3,4- tetrahydroisoquinoline; 3-(6-chloro-2-{[(2R,3S)-2-propyl-1^
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4-
Figure imgf000022_0001
tetrahydroisoquinoline-1-carbonitrile;
6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5^ (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinoline-1-carboxamide;
6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-^ (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-1-carbonitrile; 3-[(1 R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-
5- nS-itrifluoromethy thiophen-S-ylloxyJpiperidin-S-yllcarbonylJ-I ^.S^i
tetrahydroisoquinolin-1-yl]-N-cyanopropanamide;
3- [(1S)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}^ 3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4-
Figure imgf000023_0001
(trifluoromethy thiophen-S-ylloxyJpiperidin-i-yllcarbonyQ-l , 2,3,4- tetrahydroisoquinolin-1-yl)acetyl]piperidin-4-ol;
N,N-dimethyl-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yn^
{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]Carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-6-amine;
4-[(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)acetyl]piperazin-2-one;
1- [(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)acetyl]piperidin-4-ol;
5,6-dichloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbony^ {[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline;
6,7-dichloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3- {[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline;
6- (methylsulfanyl)-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2- yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}- 1 ,2,3,4-tetrahydroisoquinoline;
2- {[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-6-carboxamide; 6-(methylsulfonyl)-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2- yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}- 1 ,2,3,4-tetrahydroisoquinoline;
2-(4-{3-[(1 R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2- yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidiri-3-yl]carbonyl}- 1 ,2,3,4-tetrahydroisoquinolin-l -yl]propanoyl}piperazin-1 -yl)ethanol;
2-{4-[(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3- {[5-(trifluoromethyl)thiophen-3-yl]oxy}pipehdin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquin0lin-1-yl)carbonyl]piperaiin-1-yl}ethanol;
2-{4-[(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(thfiuoromethyl)pyrW
{[5-(trifluoromethyl)thiophen-3-yl]oxy}pipeHdin-3-yl]carbonyl}-i , 2,3,4- tetrahydroisoquinolin-1-yl)carbonyl]piperazin-1-yl}ethanol;
2- {4-[(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3- {[5-(trifluorornethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2;3,4- tetrahydroisoquinolin-1-yl)carbonyl]piperazin-1-yl}ethanol;
[(2R,3S)-3-[(1 -carbamoyl-6-chloro-3,4-dihydroisoquinolin-2(1 H)-yl)carbonylj-1 -{[3- (trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3- yl]oxy}piperidin-2-yl]acetic acid;
3- (6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridiri-2-yi]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,^,3,4- tetrahydroisoquinolin-1-yl)cyclopentanecarboxylic acid;
[(2R,3S)-3-[(1-carbamoyl-6-chloro-3,4-dihydroisoquinolin-2(1 H)-yl)carbonyl]-1-{[3- (trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3- yl]oxy}piperidin-2-yl]acetic acid;
1-{3-[(1 R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2- yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}- 1 ,2,3,4-tetrahydroisoquinolin-1-yl]propanoyl}piperidine-4-carboxylic acid;
1-{3-[(1 S)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2- yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}- 1 ,2,3,4-tetrahydroisoquinolin-1-yl]propanoyl}piperidine-4-carboxyiic acid;
6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-1-carboxyiic acid; 6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(t^
Figure imgf000025_0001
3-(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)-2,2-dimethylpropanoic acid;
6-chloro-1-(2-hydroxyethyl)-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2- yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}- 1 ,2,3,4-tetrahydroisoquinoline-1-carboxamide;
6-fluoro-2-[(2-propyl-3-[4-(trifluoromethoxy)phenoxy]-1-{[3-(trifluoromethyl)pyridin- 2-yl]carbonyl}piperidin-3-yl)carbonyl]-1 ,2,3,4-tetrahydroisoquinoline;
3-[(1 S)-6-chloro-2-{[(2R,3S)-2-propyl-3-[4-(trifluoromethoxy)phenoxy]-1 -{[3- (trifluoromethyl)pyridin-2-yl]carbonyl}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl]propanoic acid; N-{2-[(2R,3S)-3-[(6-chloro-3,4-dihydroisoquinolin-2(1 H)-yl)carbonyl]-1-{[3-
(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3- yl]oxy}piperidin-2-yl]ethyl}tetrahydro-2H-pyran-4-amine;
6-chloro-2-{[(2R,3S)-2-prop-2-en-1-yl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbo
3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinoline-1 -carboxylic acid;
6-chloro-2-{[(2R,3S)-2-[2-(4-ethylpiperazin-1-yl)ethyl]-i-{[3-
(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3- yl]oxy}piperidin-3-yl]carb0nyl}-1 ,2,3,4-tetrahydroisoquiholine;
6-chloro-2-{[(2R,3S)-2-[2-(4-methylpiperazin-1-yi)ethyl]-1-{[3-
(trifluoromethyl)pyridin-2-yl]carbon
yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4-tetrahydroisciquinoline;
6-chloro-2-{t(2R,3S)-2-{2-[4-(cyclopropylmethyl)piperazin-1-yl]ethyl}-1^
(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluorbmethyl)thioph
yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4-tetrahydroisoquinoline;
2-[(2R,3S)-3-[(6-chloro-3,4-dihydroisoquinolin-2(1 H)-yl)carbonyl]-1-{[3-
(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(triflu0romethyl)thiopheh-3- yl]oxy}piperidin-2-yl]-N-(2-methoxyethyl)-N-methylethanamine;
6-chloro-2-{[(2R,3S)-2-{2-[4-(2-methoxyethyl)piperazin-1-yl]ethyl}-1-{[3-
(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3- yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4-tetrahydroisoquinoline;
2-(1-{2-[(2R,3S)-3-[(6-chloro-3,4-dihydroisoquinolin-2(1 H)-yl)carbonyl]-1-{[3-
(trifluoromethyi)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3- yl]oxy}piperidin-2-yl]ethyl}piperidin-4-yl)-2-methylpropanoic acid;
[(3S)-2-{[(2R,3S)-2-propyl-1-{[4-(trifluoromethyl)pyridin-3-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3-yl]methanol;
2-{[(2R,3S)-2-propyl-1-{[4-(trifiuoromethyl)pyridin-3-yi]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-8-ol;
(2-{[(2R,3S)-2-propyl-1-{[4-(trifluoromethyl)pyridin-3-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoiin-1-yl)acetic acid; (3R)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbon
{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-3-carboxylic acid;
3-[(3S)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbon
3-{[5-(trifluoromethyl)tN^
tetrahydroisoquinolin-3-yl]propanoic acid;
(3S)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]Carbonyl}-3- {[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4'·
tetrahydroisoquinoline-3-carboxylic acid;
(3R)-7-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trif^
{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl)carbonyl}-1 ,2,3,4- tetrahydroisoquinoline-3-carboxylic acid;
3-[(3R)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yijcarbohyi}- 3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3-yl]propanoic acid;
(3S)-7-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyi}-3^ {[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yi]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-3-carboxylic acid;
(3R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-^^
{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-3-carboxylic acid;
3-[(3S)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl} 3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3-yl]propanoic acid;
5-[(3S)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}- 3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinolin-3-yl]pentanoic acid;
3-[(3S)-7-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}- 3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3-yl]propanoic acid;
3-[(3R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl} 3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinolin-3-yl]butanoic acid; (3R)-6-bromo-2-{[(2R,3S)-2-propyl-1^
{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-3-carboxylic acid;
3-[(3S)-6-chloro-2-{[(2R,3S)-2-propyl-1^
3-{[5-(trifluoromethyl)thiophen-3-yl]oxy
tetrahydroisoquinolin-3-yl]-N,N-dimethylpropanamide;
3-[(3S)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridiri-2-yl]carbonyl}-
3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3-yl]-N-methylpropanamide;
(2S)-3-[(3S)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifiuoromethyl)pyn
yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]barbonyl}-
1 ,2,3,4-tetrahydroisoquinolin-3-yl]-2-methylpropanoic acid;
7-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluorbmethyl)pyridin-2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carponyl}-1 , 2,3,4- tetrahydroisoquinoline;
7-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(^
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinoline;
7-methoxy-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoro^
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yi]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline;
(3S)-6-chloro-3-(3-fluoropropyl)-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-
2- yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}- 1 ,2,3,4-tetrahydroisoquinoline;
7-bromo-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinoline;
3- [(3R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}- 3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinolin-3-yl]propanoic acid;
[(3R)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyi}-3- {[5-(trifluoromethyl)thiophen-3-yi]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3-yl]acetic acid; 3-[(3S)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluor0methyl)pyridin-2-yl]carbonyl}^
3- {[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3-yl]-N-hydroxypropanamide;
4- [(3S)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoroiTiethyl)pyridin-2-yl]carbon 3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}pip6ridin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3-yl]butanoic acid;
3-[(3R)-7-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}- 3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3-yl]propanoic acid;
3-[(3S)-6-chloro-2-{[(2R,3S)-2-propyl-1^
3-{[5-(triflubromethyl)thiophen-3-yl]oxy}piperidin-3-yl]c
tetrahydroisoquinolin-3-yl]-N-(methylsulfonyl)propanamide;
1- {[(3R)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluor methyl)pyridin-2-yl]carbonyl}- 3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinolin-3-yl]carbonyl}piperidin-4-ol;
(3R)-6-fluoro-N-(2-hydroxyethyl)-2-{[(2R,3S)-2-propyl-1-{[3- (trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3- yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide; (2R)-N-{[(3R)-6-chloro-2-{[(2R,3S)-2-propyi-1-{[3-(trifluoromethyl)pyridin-2- yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}- 1 ,2,3,4-tetrahydroisoquinolin-3-yl]methyl}-2-methoxy-N-methylpropanamide; N-{[(3R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl^^ 3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3-yl]methyl}-N-methylpropanamide;
(2S)-2-{i(3R)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2- yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}- 1 ,2,3,4-tetrahydroisoquinolin-3-yl]methyl}-3-methylbutanoic acid;
2- {[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-4-carboxylic acid;
(3S)-6-chloro-3-(3-morpholin-4-ylpropyl)-2-{[(2R,3S)-2-propyl-1-{[3-
(trifluoromethyl)pyridin-2-yi]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3- yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4-tetrahydroisoquinoline; (3S)-6-chloro-3-{3-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]propyl}-2-{[(2R,3S)-2- propyl-1-{[3-(trifluoromethyl)pyridin-2-yi]carbonyl}-3-{[5-(trifluoromethyl)thio
Figure imgf000030_0001
yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}- 1 ,2,3,4-tetrahydroisoquinolin-3-yl]-2-hydroxypropanoic acid;
(2S)-2-{[(3S)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2- yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}- 1 ,2,3,4-tetrahydroisoquinolin-3-yl]methyl}butanoic acid;
(3R)-6-chloro-2-{[(2R,3S)-2-propyi-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-
{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-N-(tetrahydro-2H- pyran-4-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide; 4-[(3R)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}- 3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3-yl]butan-2-ol;
1- {[(3R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbony^ 3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yi]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3-yl]carbonyl}piperidin-4-ol;
(3R)-6-chloro-3-[(4-methoxypiperidin-1-yl)carbonyl]-2-{[(2R,3S)-2-propyl-1-{[3- (trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluorbmethyl)thiophen-3- yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4-tetrahydroisoquirioline;
(3R)-1 -{[(3R)-6-chloro-2-{[(2R,3S)-2-propyl-1 -{[3-(tHfluoromethyl)pyridin-2- yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]0arbonyl}- 1 ,2,3,4-tetrahydroisoquinolin-3-yl]carbonyl} iperidin-3-ol;
6-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbo yl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4, 5,6,7- tetrahydrothieno[2,3-c]pyridine-5-carboxylic acid;
2- chloro-6-{[(2R,3S)-2-propyl-1-{[3-(trifluoi-omethyl)pyridin-2-yl]carbdnVl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4, 5,6,7- tetrahydrothieno[2,3-c]pyridine-5-carboxylic acid;
6-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4, 5,6,7- tetrahydrothieno[2,3-c]pyridine-5-carboxylic acid;
2-chloro-6-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4, 5,6,7- tetrahyd roth ieno[2 , 3-c]pyrid i ne-5-carboxylic acid ;
(5S)-2-bromo-N-(methylsulfonyl)-6-{[(2R,3S)-2-prbpyl-1-{[3-
(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen
yl]oxy}piperidin-3-yl]carbonyl}-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5- carboxamide;
6-chloro-1-(2-methylpropyl)-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2- yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}- 1 ,2,3,4-tetrahydroisoquinoline; 2-[(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridih-2-yl]carb
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinolin-1-yl)methyl]-3-methylbutanoic acid;
2-[(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]cd
(trifluoromethy thiophen-S-ylloxyJpiperidin- -yllcarbonylJ-I ^.S^- tetrahydroisoquinolin-1-yl)methyl]-3-methylbutanbic acid;
2-[(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifiuoromeihyl)pyridin-2-yl]car^
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carboriyl}-1 , 2,3,4- tetrahydroisoquinolin-1 -yl)methyl]-3-methylbutanoic acid;
2-[(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinolin-1-yl)methyl]-3-methylbutanoic acid; and
[(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbori
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carboriyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)methoxy]acetic acid;
or a pharmaceutically acceptable salt thereof.
Chemical Definitions
As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, C1-C10, as in "C1-C10 alkyl" is defined to include groups having 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbons in a linear or branched arrangement. For example, "C1-C10 alkyl" specifically includes methyl, ethyl, n-propyl, /-propyl, n-butyl, i-butyl, /-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and so on.
When used in the phrases "alkylaryl", "alkylcycloalkyl" and
"alkylheterocyclyl" the term "alkyl" refers to the alkyl portion of the moiety and does not describe the number of atoms in the heterocyclyl portion of the moiety. In an embodiment, if the number of carbon atoms is not specified, the "alkyl" of "alkylaryl", "alkylcycloalkyl" and "alkylheterocyclyl" refers to C1-C12 alkyl and in a further embodiment, refers to C1-C6 alkyl.
The term "cycloalkyl" means a monocyclic saturated or unsaturated aliphatic hydrocarbon group having the specified number of carbon atoms. The cycloalkyi is optionally bridged (i.e., forming a bicyclic moiety), for example with a methylene, ethylene or propylene bridge. The cycloalkyi may be fused with an aryl group such as phenyl, and it is understood that the cycloalkyi substituent is attached via the cycloalkyi group. For example, "cycloalkyi" includes cyclopropyl, methyl-cyclop ropy I, 2,2-dimethyl-cyclobutyl, 2-ethyi-cyclopentyl, cyclohexyl, cyclopentenyl, cyclobutenyl and so on.
In an embodiment, if the number of carbon atoms is not specified, "alkyl" refers to C1-C12 alkyl and in a further embodiment, "alkyl" refers to C1-C6 alkyl. In an embodiment, if the number of carbon atoms is not specified,
"cycloalkyi" refers to C3-C10 cycloalkyi and in a further embodiment, "cycldalkyl" refers to C3-C7 cycloalkyi. In an embodiment, examples of "alkyi" include methyl, ethyl, /7-propyl, /"-propyl, n-butyl, i-butyl and /'-butyl.
The term "alkylene" means a hydrocarbon diradical group having the specified number of carbon atoms. For example, "alkylene" includes -CH2-, - CH2CH2- and the like. In an embodiment, if the number of carbon atoms is not specified, "alkylene" refers to C1-C12 alkylene and in a further embodiment, "alkylene" refers to C1-C6 alkylene.
If no number of carbon atoms is specified, the term "alkenyl" refers to a non-aromatic hydrocarbon radical, straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond.
Preferably one carbon to carbon double bond is present, and up to four non- aromatic carbon-carbon double bonds may be present. Thus, "C2-C6 alkenyl" means an alkenyl radical having from 2 to 6 carbon atoms. Alkenyl groups include ethenyl, propenyl, butenyl, 2-methylbutenyl and cyclohexenyl. The straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated.
"Alkenylene" means a diradical group of an alkenyl group that is defined above. For example, "alkenylene" includes -CH2-CH2-CH=CH-CH2, -CH=CH-CH2 and the like.
The term "alkynyl" refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present. Thus, "C2-C6 alkynyl" means an alkynyl radical having from 2 to 6 carbon atoms. Alkynyl groups include ethynyl, propynyl, butynyl, 3-methylbutynyl and so on. The straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated.
In certain instances, substittients ma'y be defined with a range of carbons that includes zero, such as (Co-C6)alkylene-aryl. If aryl is taken to be phenyl, this definition would include phenyl itself as well as -CH2Ph, - CH2CH2Ph, CH(CH3)CH2CH(CH3)Ph, and so on.
"Aryl" is intended to mean any stable monocyclic, bicyclic or tricyclic carbon ring of up to 7 atoms in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl and biphenyl. In cases where the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring.
In one embodiment, "aryl" is an aromatic ring of 6 to 14 carbon atoms, and includes a carbocyclic aromatic group fused with a 5-or 6-membered cycloalkyl group such as indan. Examples of carbocyclic arornatic groups include, but are not limited to, phenyl, naphthyl, e.g. 1 -naphthyl and 2-naphthyl; anthracenyl, e.g. 1-anthracenyl, 2-anthracenyl; phenanthrenyl; fluorenonyl, e.g. 9- fluorenonyl, indanyl and the like.
The term heteroaryl, as used herein, represents a stable monocyclic, bicyclic or tricyclic ring of up to 7 atoms ih each ring, wherein at least one ring is aromatic and contains carbon and from 1 to 4 heteroatoms selected from the group consisting of O, N and S. In another embodiment, the term heteroaryl refers to a monocyclic, bicyclic or tricyclic aromatic ring of 5- to 14-ring atoms of carbon and from one to four heteroatoms selected from O, N, or S. As with the definition of heterocycle below, "heteroaryl" is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl. In cases where the heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively.
Heteroaryl groups within the scope of this definition include but are not limited to acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinoline. Additional examples of heteroaryl include, but are not limited to pyridyl, e.g., 2-pyridyl (also referred to as a-pyridyl), 3-pyridyl (also referred to as β-pyridyl) and 4-pyridyl (also referred to as (γ- pyridyl); thienyl, e.g., 2-thienyl and 3-thienyl; furanyl, e.g., 2-furanyl and 3-furanyl; pyrimidyl, e.g., 2-pyrimidyl and 4-pyrimidyl; imidazolyl, e.g., 2-imidazolyl; pyranyl, e.g., 2-pyranyl and 3-pyranyl; pyrazolyl, e.g., 4-pyrazoiyl and 5-pyrazblyl;
thiazolyl, e.g., 2-thiazolyl, 4-thiazolyl and 5-thiazolyl; ihiadiazblyl; isothiazolyl; oxazolyl, e.g., 2-oxazoyl, 4-oxazoyl and 5-oxazoyl; isbxazoyl; pyrrolyl; pyridazinyl; pyrazinyl and the like.
In an embodiment, "heteroaryl" may also include a "fused polycyclic aromatic", which is a heteroaryl fused with one or more other heteroaryl or nonaromatic heterocyclic ring. Examples include, quinolinyl and isoquinolinyl, e.g. 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl and 8-quindlinyl, 1-isoquinolinyl, 3-quinolinyl, 4-iSocjuinolinyl, 5-isoquinolinyl, 6- isoquinolinyl, 7-isoquinolinyl and 8-isoquinolinyl; benzofUranyl, e.g. 2- benzofurahyl and 3-benzofuranyl; dibenzofuranyl, e.g. 2,3-dihydrobenzofurahy ; dibenzothiophenyl; benzothienyl, e.g. 2-benzothienyl and 3-benzothiehyl; indolyl, e.g. 2-indolyl and 3-ihdolyl; benzothiazolyl, e.g., 2-benzothiazolyl; benzooxazolyl, e.g., 2-benzooxazolyl; benzimidazolyl, e.g. 2-benzoimidazolyi; isoindolyl, e.g. 1- isoindolyl and 3-isoindolyl; benzotriazolyl; purinyl; thianaphthenyi, pyrazinyland the like.
"Heterocyclyl" means a non-aromatic saturated monocyclic, bicyclic, tricyclic or spirocyclic ring system comprising up to 7 atoms in each ring.
Preferably, the heterocyclyl contains 3 to 14, or 5 to 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example, nitrogen, oxygen, phosphor or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The heterocycle may be fused with an aromatic aryl group such as phenyl or heterocyclenyl. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N- oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl,
tetrahydrothiophenyl, lactam, lactone, and the like. "Heterocyclyl" also includes heterocyclyl rings as described above wherein =0 replaces two available hydrogens on the same ring carbon atom. An example of such a moiety is pyrrolidone:
Figure imgf000036_0001
In describing the heteroatoms contained in a specified heterocyclyl group, the expression, "having one to x heteroatoms selected from the groups of N, O, P and S" (wherein x is a specified integer), for example, means that each heteroatom in the specified heterocyclyl is independently selected fror l the specified selection of heteroatoms. Attachment of a heterocyclyl substituent can occur via a carbon atom or via a heteroatom.
"Heterocyclenyl" means a norvaromatic monocyclic, bicyclic, tricyclic or spirocyclic ring system comprising up to 7 atoms in each ring.
Preferably, the heterocyclenyl contains 3 to 14, or 5 to 10 ring atonhs, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen, phosphor or sulfur atom respectively is present as a ring atom. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable heterocyclenyl groups include 1 ,2,3,4- tetrahydropyridinyl, 1 ,2-dihydropyridinyl, 1 ,4-dihydropyridinyl, 1 ,2,3,6-tetrahydropyridinyl, 1 ,4,5,6- tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4- dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7- oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like. "Heterocyclenyl" also includes heterocyclenyl rings as described above wherein =0 replaces two available hydrogens on the same ring carbon atom. An example of such a moiety is pyrrolidinone:
Figure imgf000037_0001
In describing the heteroatoms contained in a specified heterocyclenyl group, the expression, "having one to x heterbatOrns selectel from the group of N, O, P and S" (wherein x is an a specified integer)) fbr example, means that each heteroatom in the specified heterocyclenyl is indepehdently selected from the specified selection of heteroatoms.
It should also be noted that tautomeric forms such as, for example, the moieties:
Figure imgf000037_0002
are considered equivalent in certain embodiments of this invention.
An "alkylaryl group" is an alkyl group substituted wit an aryl group, for example, a phenyl group. Suitable aryl groups are described herein and suitable alkyl groups are described herein. The bond to the parent moiety is through the aryl group.
An "alkylheteroaryl group" is an alkyl group substituted with a heteroaryl group. Suitable heteroaryl groups are described herein and suitable alkyl groups are described herein. The bond to the parent moiety is through the heteroaryl group.
An "alkylheterocyclyl group" is an alkyl group substituted with a heterocyclyl group. Suitable heterocyclyl groups are described herein and suitable alkyi groups are described herein. The bond to the parent moiety is through the heterocyclyl group.
An "alkylheterocyclenyl group" is an alkyi group substituted with a heterocyclenyl group. Suitable heterocyclenyl groups are described herein and suitable alkyi groups are described herein. The bond to the parent moiety is through the heterocyclenyl group.
An "alkylcycloalkyl group" is an alkyi group substituted with a cycloalkyl group. Suitable cycloalkyl groups are described herein and suitable alkyi groups are described herein. The bond to the parent moiety is through the cycloalkyl group.
An "arylalkyl group" is an aryl group substituted with an alkyi group. Suitable aryl groups are described herein and suitable alkyi groups are described herein. The bond to the parent moiety is through the alkyi group.
A "heteroarylalkyl group" is a heteroaryl group substituted with an alkyi group. Suitable heteroaryl groups are described herein and suitable alkyi groups are described herein. The bond to the parent moiety is through the alkyi group.
A "heterocyclylalkyl group" is a heterocyclyl group substituted with an alkyi group. Suitable heterocyclyl groups are described hereih arid suitable alkyi groups are described herein. The bond to the parent moiety is through the alkyi group.
A "heterocyclenylalkyl group" is a heterocyclenyl group substituted with an alkyi group. Suitable heterocyclenyl groups are described herein and suitable alkyi groups are described herein. The bond to the parent moiety is through the alkyi group.
A "cycloalkylalkyl group" is a cycloalkyl group substituted with an alkyi group. Suitable cycloalkyl groups are described herein and suitable alkyi groups are described herein. The bond to the parent moiety is through the alkyi group.
An "aryloxy group" is an aryl group that is attached to a compound via an oxygen (e.g., phenoxy).
An "alkoxy group" (alkyloxy), as used herein, is a straight chain or branched C1-C12 or cyclic C3-C12 alkyi group that is connected to a compound via an oxygen atom. Examples of alkoxy groups include but are not limited to methoxy, ethoxy and propoxy.
An "arylalkoxy group" (arylalkyloxy) is an arylalkyl group that is attached to a compound via an oxygen on the alkyl portion of the arylalkyl (e.g., phenylmethoxy).
An "arylamino group" as used herein, is an aryl group that is attached to a compound via a nitrogen.
An "alkylamino group" as used herein, is an alkyl group that is attached to a compound via a nitrogen.
As used herein, an "arylalkylamino group" is an arylalkyl group that is attached to a compound via a nitrogen on the alkyl portion of the arylalkyl.
An "alkylsulfonyl group" as used herein, is an alkyl group that is attached to a compound via the sulfur of a sulfonyl group.
When a moiety is referred to as "unsubstituted" or not referred to as "substituted" or "optionally substituted", it means that the moiety does not have any substituents. When a moiety is referred to as substituted, it denotes that any portion of the moiety that is known to one skilled in the art as being available for substitution can be substituted. The phrase "optionally substituted with one or more substituents" means, in one embodiment, one substituent, two substituents, three substituents, four substituents or five substituents. For example, the substitutable group can be a hydrogen atom that is replaced with a group other than hydrogen (i.e., a substituent group). Multiple substituent groups can be present. When multiple substituents are present, the substituents can be the same or different and substitution can be at any of the substitutable sites. Such means for substitution are well known in the art. For purposes of exemplification, which should not be construed as limiting the scope of this invention, some examples of groups that are substituents are: alkyl, alkenyl or alkynyl groups (which can also be substituted, with one or more substituents), alkoxy groups (which can be substituted), a halogen or halo group (F, CI, Br, I), hydroxy, nitro, oxo, -CN, -COH, -COOH, amino, azido, N-alkylamino or N,N-dialkylamino (in which the alkyl groups can also be substituted), N-arylamino or N,N-diarylamino (in which the aryl groups can also be substituted), esters (-C(O)-OR, where R can be a group such as alkyl, aryl, etc., which can be substituted), ureas (-NHC(O)- NHR, where R can be a group such as alkyl, aryl, etc., which can be substituted), carbamates (-NHC(O)-OR, where R can be a group such as alkyl, aryl, etc., which can be substituted), sulfonamides (-NHS(0)2R, where R can be a group such as alkyl, aryl, etc., which can be substituted), alkylsulfonyl (which can be substituted), aryl (which can be substituted), cyclbalkyi (which can be substituted) alkylaryl (which can be substituted), alkylheterocyciyl (which can be substituted), alkylcycloalkyl (which can be substituted), and arylbxy.
It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples Srid Tables herein is assumed to have the sufficient number of hydrogen atom(s) satisfy the valences.
When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude' undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinar skill ih the art as well as by reference to standard textbooks such as, for exahnple, T. W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York.
When any variable (e.g., aryl, heterocycle, R2, etc.) occurs more than one time in any constituent or in Formula I, its definition on each occurrence is independent of its definition at every other occurrence.
As used herein, "a," an" and "the" include singular and plural referents unless the context clearly dictates otherwise. Thus, for example, reference t6 "an active agent" or "a pharmacologically active agent" includes a single active agent as well a two or more different active agents in combination, reference to "a carrier" includes mixtures of two or more carriers as well as a single carrier, and the like.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
Isotopes In the compounds of generic Formula I, the atoms may exhibit their natural isotopic abundances, or one or more of thi atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I. For example, different isotopic forms of hydrogen (H) include protium (1 H) and deuterium (2H).
Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds within generic Formula I can be prepared without undue
experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
Certain isotopically-labelled compounds of Formula (I) (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Certain isotopically-labelled compounds of Formula (I) can be useful for medical imaging purposes. For instance those compounds labeled with positron-emitting isotopes like 11C or 18F can be useful for application in Positron Emission Tomography (PET) and those labeled with gamma ray emitting isotopes like 123l can be Useful for application in Single Photon Emission Computed Tomography (SPECT). Additionally, isotopic substitution of a compound at a site where epimerization occurs may slow or reduce the epimerization process and thereby retain the more active or efficacious form of the compound for a longer period of time.
Stereochemistry
When structures of the same constitution differ in respect to the spatial arrangement of certain atoms or groups, they are stereoisomers, and the considerations that are significant in analyzing their interrelationships are topological. If the relationship between two stereoisomers is that of an object and its nonsuperimposable mirror image, the two structures are enantiomeric, and each structure is said to be chiral. Stereoisomers also include diastereomers, cis-trans isomers and conformational isomers. Diastereoisomers can be chiral or achiral, and are not mirror images of one another. Cis-trans isomers differ only in the positions of atoms relative to a specified planes in cases where these atoms are, or are considered as if they were, parts of a rigid structure. Conformational isomers are isomers that can be interconverted by rotations about formally single bonds. Examples of such conformational isomers include cyclohexane
conformations with chair and boat conformers, carbohydrates, linear alkane conformations with staggered, eclipsed and gauche conformers, etc. See J. Org. Chem. 35, 2849 (1970).
Many organic compounds exist in optically active forms having the ability to rotate the plane of plane-polarized light. In describing ah optilally lictive compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The Prefixes d and I or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, enantiomers are identical except that they are non-superimposable mirroi' irriages of one another. A mixture of enantiomers is often balled an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racehnic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the Formulas of the invention, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the Formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines (bonds to atoms below the plane). The Cahn-lnglod-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon. When the compounds of the present invention contain one chiral center, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as a racemic mixtures. The enantiomers can be resolved by methods known to those skilled in the art, such as formation of diastereoisomeric salts which may be separated, for example, by crystallization (see, CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC Press, 2001)); formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with ari
enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
Designation of a specific absolute configuration at a chiral carbon of the compounds of the invention is understood to mean that the designated enantiomeric form of the compounds is in enantiomeric excess (ee) or in other words is substantially free from the other enantiomer. For example, the "R" forms of the compounds are substantially free from the "S" forms of the compounds and are, thus, in enantiomeric excess of the "S" forms. Conversely, "S" forms of the compounds are substantially free of "R" forms of the compounds and are, thus, in enantiomeric excess of the "R" forms. Enantiomeric excess, as used herein, is the presence of a particular enantiomer at greater than 50%. In a particular embodiment when a specific absolute configuration is designated, the
enantiomeric excess of depicted compounds is at least about 90%.
When a compound of the present invention has two or more chiral carbons it can have more than two optical isomers and can exist in
diastereoisomeric forms. For example, when there are two chiral carbons, the compound can have up to 4 optical isomers and 2 pairs of enantiomers
((S,S)/(R,R) and (R,S)/(S,R)). The pairs of enantiomers (e.g., (S,S)/(R,R)) are mirror image stereoisomers of one another. The stereoisomers that are not mirror-images (e.g., (S,S) and (R,S)) are diastereomers. The diastereoisomeric pairs may be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. The present invention includes each diastereoisomer of such compounds and mixtures thereof. Solvates
One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogeri- bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H2O.
One or more compounds of the invention may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical Sci., 93(3). 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient
temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
The active compounds disclosed can also be prepared in any solid or liquid physical form. For example, the compound can be in a crystalline form, in amorphous form, and have any particle size. Furthermore, the compound particles may be micronized, or may be agglomerated, particulate granules, powders, oils, oily suspensions or any other form of solid or liquid physical form.
The compounds of the present invention may also exhibit polymorphism. This invention further includes different polymorphs df the compounds of the present invention. The term "polymorph" refers to a particular crystalline state of a substance, having particular physical properties such as X-ray diffraction, IR spectra, melting point, and the like.
Phamaceuticallv acceptable Salts
The compounds of Formula I can form salts which are also within the scope of this invention. Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the Formula I may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of
Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 3 201-217; Anderson ef al, The
Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website).
Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, brganic amines) such as dicyclohexylamines, t-butyl amines, and salts with amiho acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be
quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, arid butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyi halides (e.g. benzyl and phenethyl bromides), and others.
All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention.
Compounds of Formula I, and salts, solvates thereof j may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.
Pharmaceutical Compositions
The term "pharmaceutical composition" is also intended to encompass both the bulk composition and individual dosage units comprised of more than one (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients. The bulk composition and each individual dosage unit can contain fixed amounts of the afore-said "more than one pharmaceutically active agents". The bulk composition is material that has hot yet been formed into individual dosage units. An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like. Similarly, the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.
Isolation of the compound at various stages of the reaction may be achieved by standard techniques such as\ f6r example, filtration, evapbration of solvent and the like. Purification of the product and the like, may also be performed by standard techniques such ds recryltaiiization, distillation, sublimation, chromatography, conversion to a suitable derivative. Such techniques are well known to those skilled in the art. The compounds of this invention may be analyzed for their composition and purity as well as
characterized by standard analytical techniques such as, for example, elemental analysis, NMR, mass spectroscopy, and IR spectra.
In another embodiment, this invention provides pharmaceutical
compositions comprising the compounds of the invention as an active ingredient. The pharmaceutical compositions generally additionally comprise a
pharmaceutically acceptable carrier diluent, excipient or carrier (collectively referred to herein as carrier materials).
In yet another embodiment, the present invention discloses methods for preparing pharmaceutical compositions comprising the compounds as an active ingredient. In the pharmaceutical compositions and methods of the present invention, the active ingredients will typically be administered in admixture with suitable carrier materials suitably selected with respect to the intended form of administration, i.e. oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional
pharmaceutical practices. For example, for oral administration in the form of tablets or capsules, the active drug component may be combined with any oral non-toxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like. Moreover, when desired or needed, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated in the mixture. Powders and tablets may be comprised of from about 5 to about 95 percent inventive composition. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Lubricants in these dosage forms include boric acid, sodium benzoate, sodium acetate, sodium chloride, and tt e like. Disintegrahts include starch, methylcellulose, guar gum and the like. Sweetening and flavoring agents and preservatives may also be included Where appropriate. Some of the terms noted above, namely disintegrants, diluents, lubricants, binders and the like, are discussed in more detail below.
Additionally, the compositions of the present invention may be formulated in sustained release form to provide the rite controlled release of any one or more of the components or active ingredients to optimize the therapeutic effects. Suitable dosage forms for sustained release include layered tablets containing layers of Varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated poroUs polymeric matrices.
Liquid form preparations include solutions, suspensions arid emulsions.
For example, water or water-propylene glycol solutions may be included for parenteral injections or sweeteners and pacifiers may be added for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier such as inert compressed gas, e.g. nitrogen.
For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides such as cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein by stirring or similar mixing. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool to solidify. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
The compounds of the invention may also be deliverable transdermally.
The transdermal compositions may take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
Preferably the compound is administered orally.
Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit dbses containing appropriate quantities of the active components, e.g., an effective amount td achieve the desired purpose.
The quantity of the inventive active composition in a unit dose of preparation may be generally varied or adjusted from about 1.0 milligram to about 1 ,000 milligrams, preferably from about 1.0 to about 500 milligrams, and typically from about 1 to about 250 milligrams, according to the particular application. The actual dosage employed may be varied depending upon the patient's age, sex, weight and severity of the condition being treated. Such techniques are well known to those skilled in the art.
The actual dosage employed may be varied depending upon the
requirements of the patient and the severity of the condition being treated.
Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
Generally, the human oral dosage form containing the active ingredients can be administered 1 or 2 times per day. The amount and frequency of the administration will be regulated according to the judgment of the attending clinician. A generally recommended daily dosage regimen for oral administration may range from about 1.0 milligram to about 1 ,000 milligrams per day, in single or divided doses.
Another aspect of this invention is a kit comprising a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.
Yet another aspect of this inventiori is a kit comprising an amount of at least one compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound and an amount df at least One anticancer therapy and /or anti-cancer agent described below, wherein the amounts of the two or more ingredients result in desired therapeutic effect.
Capsule - refers to a special container or enclosure made of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active ingredients. Hard shell capsules are typically made of blends of relatively high gel strength bone arid pork skin gelatins. The capsule itself may contain small amounts of dyes, opaquing agents, plasticizers and preservatives.
Tablet- refers to a compressed or molded solid dosage form containing the active ingredients with suitable diluents, the tablet can be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation or by compaction.
Oral gels- refer to the active ingredients dispersed or solubilized in a hydrophillic semi-solid matrix.
Powders for constitution refer to powder blends containing the active ingredients and suitable diluents which can be suspended in water or juices.
Diluent - refers to substances that usually rhake up the major portion of the composition or dosage form. Suitable diluents include but are not limited to sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corn, rice and potato; and celluloses such as microcrystalline cellulose.
The amount of diluent in the composition can range from about 10 to about 90% by weight of the total composition.
Disintegrants - refers to materials added to the composition to help it break apart (disintegrate) and release the medicaments. Suitable disintegrants include but are not limited to modified starches such as sodium carboxymethyl starch; methylcellulose, microcrystalline celluloses and sodium croscarmellose; and sodium alginate. The amount of disintegrant in the composition can range from about 2 to about 10% by weight of the composition. Lubricant - refers to a substance added to the dosage form to enable the tablet, granules, etc. after it has been compressed, to release from the mold or die by reducing friction or wear. Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting point waxes; and water soluble lubricants such as high molecular weight polyethylene glycols and d,l-leucine. Lubricants are usually added at the very last step before compression, since they must be present on the surfaces of the granules and in between them and the parts of the tablet press. The amount of lubricant in the composition can range from about 0.2 to about 5% by weight of the composition.
Glidents - materials that prevent caking arid improve the flow
characteristics of granulations, so that flow is smooth and uniform. Suitable glidents include silicon dioxide and talc. The amount of glident in the composition can range from about 0.1 % to about 5% by weight of the total composition.
Coloring agents - excipients that provide coloration to the composition or the dosage form. Such excipients can include food grade dyes and food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide. The amount of the coloring agent can vary from about 0.1 to about 5% by weight of the composition.
Conventional methods for preparing tablets are known. Such methods include dry methods such as direct compression and compression of granulation produced by compaction, or wet methods or other special procedures.
Conventional methods for making other forms for administration such as, for example, capsules, suppositories and the like are also well known.
Method of Treatment
HDM2, Hdm2, hDM2, and hdm2 are all equivalent representations of the Human Double Minute 2 protein. Likewise, MDM2, Mdm2, mDM2, and mdm2 are all equivalent representations mouse Double Minute 2 protein. The compounds of Formula I can be inhibitors or antagonists of the
Human or Mouse Double Minute 2 protein interaction with p53 protein and it can be activators of the p53 protein in cells. Furthermore, the pharmacological properties of the compounds of Formula I can be used to treat or prevent cancer, treat or prevent other disease states associated with abnormal cell proliferation, and treat or prevent diseases resulting from inadequate levels of p53 protein in cells.
Those skilled in the art will realize that the term "cancer" to be the name for diseases in which the body's cells become abnormal and divide without control.
Cancers that may be treated by the compounds, compositions and methods of the invention include, but are not limited to: Cardiac: sarcorha
(angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: brohchogehib carcinoma (squamous cell, undifferentiated small cell, undifferentiated large dell,
adenocarcinoma), alveolar (bronchiolar) carcinoma, brohchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;
Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma) colorectal; Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver:
hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma,
osteochronfroma (osteocartilaginous exostoses), benign chondroma,
chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous
cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial catcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinorna, squamous cell carcinoma, botryoid sarcoma (embrydnal rhabdomyosarcoma), fallopian tubes (carcinoma), breast; Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; Skin:
malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. Thus, the term "cancerous cell" as provided herein, includes a cell afflicted by any one of the above-identified conditions.
In one embodment, cancers that may be treated by the compounds, compositions and methods of the invention include, but are not limited to: lung cancer, pancreatic cancer, colon cancer, colorectal cancer, myeloid leukemias, acute myelogenous leukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, thyroid cancer, myelodysplastic syndrome, bladder carcinoma, epidermal carcinoma, melanoma, breast cancer, prostate cancer, head and neck cancers, ovarian cancer, brain cancers, cancers of mesenchymal origin, sarcomas, tetracarcinomas, neuroblastomas, kidney carcinomas, hepatomas, non-Hodgkin's lymphoma, multiple myeloma, and anaplastic thyroid carcinoma.
In another embodiment, cancers that may be treated by the compounds, compositions and methods of the invention include, but are not limited to: breast, prostate, colon, colorectal, lung, brain, testicular, stomach, pancrease, skin, small intestine, large intestine, throat, head and neck, oral, bone, liver, bladder, kidney, thyroid and blood.
In another embodiment, cancers that may be treated by the compounds, compositions and methods of the invention include breast, prostate, colon, ovary, endometrium and thyroid.
In another embodiment, cancers that may be treated by the compositions and methods of the invention include acute myeloid leukemia (AML),
liposarcoma, colorectal cancer, gastric cancer and melanoma.
In a further embodiment, cancers that may be treated by the compositions and methods of the invention include hematological malignancies, for example acute myeloid leukemia.
In a further embodiment, cancers that may be treated by the compositions and methods of the invention include acute lymphoblastic leukemia (ALL);
lymphoma, lung, breast and glioblastoma.
The compounds of the invention are also useful in preparing a
medicament that can be useful in treating cancer. In One embodiment, the compounds of the invention are for the potential treatment of cancer.
The compounds of Formula I can be useful to the treatment of a variety of cancers, including, but not limited to: carcinoma, including, but not limited to, of the bladder, breast, colon, rectum, endometrium, kidney, liver, lung, head and neck, esophagus, gall bladder, cervix, pancreas, prostrate, larynx, ovaries, stomach, uterus, sarcoma and thyroid cancer;
hematopoietic tumors of the lymphoid lineage, including leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non- Hodgkins lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma, and Burkett's lymphoma;
hematopoetic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and
rhabdomyosarcoma; tumors of the central and peripheral nervous system, including
astrocytoma, neuroblastoma, glioma, and schwannomas; and
other tumors, including melanoma, skin (non-melanomal) cancer, mesothelioma (cells), seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
Due to the key role of p53 in the regulation of cellular apoptosis (cell death), the compounds of Formula I could abt as agent to induce cell death which may be useful in the treatment of any disease process which features abnormal celllular proliferation eg, cancers of various origin and tissue types, inflammation, immunological disorders.
Due to the key role of HDM2 and p53 in the regulation of cellular proliferation, the compounds of Formula I could act as reversible cytostatic agents which may be useful in the treatment of any disease process which features abnormal celllular proliferation, inhibitors could act as reversible cytostatic agents which may be useful in the treatment of any disease process which features abnormal cell proliferation, e.g., benign prostrate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty, or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections.
Compounds of Formula I may also be useful in the chemoprevehtion of cancer. Chemoprevention is defined as inhibiting the development of invasive cancer by either blocking the initiating mutagenic event by blocking the progression of pre-malignant cells that have already suffered an insult or inhibiting tumor relapse.
Compounds of Formula I may also be useful in inhibiting tumor
angiogenesis and metastasis.
Another aspect of this invention is a potential method of treating a mammal (e.g., human) having a disease or condition associated with HDM2 by administering a therapeutically effective amount of at least one compound of
Formula I, or a pharmaceutically acceptable salt or solvate of said compound to the mammal. The invention also provides a method of inhibiting one or more HDM2 proteins in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.
Another aspect of the present invention is a potential method of treating, or slowing the progression of a disease associated with one or more HDM2 proteins in a patient, comprising administering to a patient in need thereof, a
therapeutically effective amount of at least one compound of the present invention or a pharmaceutically acceptable salt or solvate thereof;
Another aspect of the present invention is a potential method of treating, or slowing the progression of a disease associated with inadequate p53 levels in a patient, comprising administering to a patient in need thereof, a therapeutically effective amount of at least one compound of the present invention or a
pharmaceutically acceptable salt or solvate thereof.
Yet another aspect of the present invention is a potential method of treating one or more diseases associated with HDM2, comprising administering to a mammal in need of such treatment an amount of a first compound, which is a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof; and an amount of at least one second compound, the second compound being an anti-cancer agent, wherein the amounts of the first
compound and the second compound result in a therapeutic effect.
Another aspect of the present invention is a potential method of treating one or more diseases associated with inadequate p53 levels, comprising administering to a mammal in need of such treatment an amount of a first compound, which is a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof; and an amount of at least one second compound, the second compound being an anti-cancer agent, wherein the amounts of the first compound and the second compound result in a therapeutic effect.
Another aspect of the present invention is a potential method of treating, or slowing the progression of, a disease associated with a HDM2 protein comprising administering to a patient in need thereof, a therapeutically effective amount of a pharmaceutical composition comprising in combination at least one pharmaceutically acceptable carrier and at least one compound according to the present invention, or a pharmaceutically acceptable salt or solvate thereof.
Another aspect of the present invention is a potential method of treating, or slowing the progression of, a disease associated with inadequate p53 levels in a patient, comprising administering to a patieht in need thereof, a therapeutically effective amount of a pharmaceutical composition comprising in combination at least one pharmaceutically acceptable carrier and at least one compound according to the present invention, or a pharmaceutically acceptable salt or solvate thereof.
In one embodiment, the dosage is about 0.001 to 500 mg/kg of body weight/day of the compound of Formula I. In another embodiment, the dosage is about 0.01 to 25 mg/kg of body weight/day of a compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound.
"Effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
"Patient" includes both human and animals.
"Mammal" means humans and other mammalian animals.
Combination Therapy ;
The instant compounds are also useful in combination with therapeutic, chemotherapeutic and anti-cancer agents. Combinations of the presently disclosed compounds with therapeutic, chemotherapeutic and anti-cancer agents are within the scope of the invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V .T '. Devita and S. Hellman (editors), 6th edition (February 15, 2001 ), Lippincott Williams & Wilkins
Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved. Such agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor
modulators, cytotoxic/cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, inhibitors of cell proliferation and survival signaling, bisphosphohates, aromatase inhibitors, siRNA therapeutics, γ-secretase inhibitors, agents that interfere with receptor tyrosine kinases (RTKs) and agents that interfere with cell cycle checkpoints. The instant compounds are also useful when co-administered with radiation therapy. The compounds of the present invention can be present in the same dosage unit as the anticancer agent or in separate dosage units.
Another aspect of the present invention is a potential method of treating one or more diseases associated with HDM2, comprising administering to a mammal in need of such treatment an amount of a first compound, which is a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof; and an amount of at least oiie second compound, the second compound being an anti-cancer agent different from the compounds of the present invention, wherein the amounts of the first compound and the second compound result in a therapeutic effect.
Non-limiting examples of suitable anti-cancer agents include cytostatic [ agents, cytotoxic agents, targeted therapeutic agents (small molecules, biologies, siRNA and microRNA) against cancer and neoplastic diseases,
1) anti-metabolites (such as methoxtrexate, 5-fluorouracil, gemcitabine,
fludarabine, capecitabine);
2) alkylating agents, such as temozolomide, cyclophosphamide,
3) DNA interactive and DNA damaging agents, such as cisplatin, oxaliplatin, doxorubicin,
4) Ionizing irradiation, such as radiation therapy,
5) topoisomerase II inhibitors, such as etoposide, doxorubicin,
6) topoisomerase I inhibitors, such as irinotecan, topotecan,
7) tubulin interacting agents, such as paclitaxel, docetaxel, Abraxane,
epothilones,
8) kinesin spindle protein inhibitors,
9) spindle checkpoint inhibitors,
10) Poly(ADP-ribose) polymerase (PARP) inhibitors, such as olaparib, MK- 4827 and veliparib ) Matrix metalloprotease (MMP) inhibitors
) Protease inhibitors, such as cathepsin D and cathepsin K inhibitors
) Proteosome or ubiquitination inhibitors, such as bortezomib,
) Activator of mutant p53 to restore its wild-type p53 activity
) Adenoviral-p53
) Bcl-2 inhibitors, such as ABT-263
) Heat shock protein (HSP) modulators, such as geldanamycin and 17-AAG) Histone deacetylase (HDAC) inhibitors, such as vorinostat (SAHA),) sex hormone modulating agents,
a. anti-estrogens, such as tamoxifen, fulvestrant,
b. selective estrogen receptor modulators (SERM), such as raloxifene, c. anti-androgens, such as bicalutamide, flutamide
d. LHRH agonists, such as leuprolide,
e. 5 -reductase inhibitors, such as finasteride,
f. Cytochrome P450 C17 lyase (CYP450c17, also called 17a- hydroxylase/17,20 lysase) inhibitors, such as Abiraterone acetate, VN/124-1. TAK-700
g. aromatase inhibitors, such as letrozble, anastrozole, exemestane,) EGFR kinase inhibitors, such as geftinib, erlotinib, laptinib
) dual erbB and erbB2 inhibitors, such as Lapatinib
) multi-targeted kinases (serine/threonine and/or tyrosine kinase) inhibitors, a. ABL kinase inhibitors, imatiriib and nilotinib, dasatinib
b. VEGFR-1 , VEGFR-2, PDGFR, KDR, FLT, c-Kit, Tie2, Raf, MEK and ERK inhibitors, such as sunitinib, sorafenib, Vandetanib, pazopanib, PLX-4032, Axitinib, PTK787, GSK-1120212
c. Polo-like kinase inhibitors
d. Aurora kinase inhibitors
e. JAK inhibitor
f. c-MET kinase inhibitors
g. Cyclin-dependent kinase inhibitors, such as CDK1 and CDK2
inhibitor SCH 727965
h. PI3K and mTOR inhibitors, such as GDC-0941 , BEZ-235, BKM-120 and AZD-8055 i. Rapamycin and its analogs, such as Temsirolimus, everolimus, and
Figure imgf000060_0001
26) anti-erbB1 antibodies, such as cetuximab, panitumumab,
27) anti-erbB2 antibodies, such as trastuzumab,
28) anti-CD52 antibodies, such as Alemtuzumab,
29)anti-CD20 antibodies, such as Rituximab
30) anti-CD33 antibodies, such as Gemtuzumab ozogamicin
31) anti-VEGF antibodies, such as Avastin,
32) TRIAL ligands, such as Lexatumumab, mapatumumab, and AMG-655 33) Anti-CTLA-4 antibodies, such as ipilimumab
34) antibodies against CTA1 , CEA, CD5, CD19, CD22, CD30, CD44,
CD44V6, CD55, CD56, EpCAM, FAP, MHCII, HGF, IL-6, MUC1 , PSMA, TAL6, TAG-72, TRAILR, VEGFR, IGF-2, FGF,
35)anti-IGF-1 R antibodies, such as dalotuzumab (MK-0646) and
robatumumab (SCH 717454).
If formulated as a fixed dose such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent or treatment within its dosage rdnge.
Compounds of Formula I may also be administered sequentially with known anticancer or cytotoxic agents when a combination formulation is inappropriate. The invention is not limited in the sequence of administration; compoUrids Of Formula I may be administered either concurrent with, prior to or after
administration of the known anticancer or cytotoxic agent. Such techniques are within the skills of the persons skilled in the art as well as attending physicians.
Accordingly, in an aspect, this invention includes combinations comprisihg an amount of at least one compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and an amount of one or more anti-cancer treatments and anti-cancer agents listed above wherein the amounts of the compounds/treatments result in desired therapeutic effect.
"Estrogen receptor modulators" refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of mechanism.
Examples of estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381 , LY1 17081 , toremifene, fulvestrant, 4- [7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H- 1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate, 4,4'- dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.
"Androgen receptor modulators" refers to compounds which interfere or inhibit the binding of androgens to the receptor, regardless of mechanism.
Examples of androgen receptor modulators include finasteride and other 5a- reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and
abiraterone acetate. "Retinoid receptor modulators" refers to compounds which interfere or inhibit the binding of retinoids to the receptor, regardless of mechanism.
Examples of such retinoid receptor modulators include bexarotene, tretinoin, 13- cis-retinoic acid, 9-cis-retinoic acid, a-difluoromethylomithine, ILX23-7553, trans- N-(4'-hydroxyphenyl) retinamide, and N-4-carboxyphenyl retinamide.
"Cytotoxic/cytostatic agents" refer to compounds which cause cell death or inhibit cell proliferation primarily by interferihg directly with the cell's functioning or inhibit or interfere with cell myosis, including alkylating agents, tumor necrosis factors, intercalators, hypoxia activatable compounds, microtubule
inhibitors/microtubule-stabilizing agents, inhibitors of mitotic kinesins1, histone deacetylase inhibitors, inhibitors of kinases involved in mitotic progression, inhibitors of kinases involved in growth factor and cytokine signal transduction pathways, antimetabolites, biological response modifiers, hormonal/anti-hormonal therapeutic agents, haematopoietic growth factors, monoclonal antibody targeted therapeutic agents, topoisomerase inhibitors, proteosome inhibitors, ubiquitin ligase inhibitors, and aurora kinase inhibitors.
Examples of cytotoxic/cytostatic agents include, but are not limited to, platinum coordinator compounds, sertenef, cachectin, ifosfamide, tasonerrriih, lonidamine, carboplatin, altretamine, prednimustihe, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide, cis- aminedichloro(2-methyl-pyridine)platinum, benzylguanine, glufosfamide,
GPX100, (trans, trans, trans)-bis-mu-(hexane-1 ,6-diamine)-mu-[diamine- platinum(ll)]bis[diamine(chlor0)platinum (ll)]tetrachloride, diarizidinylspermine, arsenic trioxide, 1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin, pinafide, valrubicin, amrubicin, antineoplaston, 3'-deamino-3'-morpholino-13- deoxo-10-hydroxycarminomycin, annamycin, galarubicin, elinafide, MEN 10755, 4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunorubicin (see WO 00/50032).
An example of a hypoxia activatable compound is tirapazamine. Examples of proteosome inhibitors include but are not limited to lactacystin and MLN-341 (Velcade).
Examples of microtubule inhibitors/microtubule-stabilising agents include taxanes in general. Specific compounds include paclitaxel (Taxol®), vindesine sulfate, 3\4'-didehydro-4'-deoxy-8'-norvincaleukoblastine, docetaxol (Taxotere®),
Figure imgf000063_0001
hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbaz0le-1-carboxamide, asulacrine, (5a, 5aB, 8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4- hydro0xy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9- hexohydrofuro(3',4':6,7)naphtho(2,3-d)-1 ,3-dioxol-6-one, 2,3-(methylenedioxy)-5- methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium, 6,9-bis[(2- aminoethyl)amino]benzo[g]isoguinoline-5, 10-dione, 5-(3-aminopropylamino)- 7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5, 1 -de]acridin-6- one, N-[1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4- ylmethyl]formamide, N-(2-(dimethylamino)ethyl)acridine-4-carboxamide, 6-[[2- (dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2, 1 -c] quinolin-7-one, and dimesna.
Examples of inhibitors of mitotic kinesins, and in particular the human mitotic kinesin KSP, are described in Publications WO03/039460, WO03/050064, WO03/050122, WO03/049527, WO03/049679, WO03/049678, WO04/039774, WO03/079973, WO03/099211 , WO03/105855, WO03/106417, WO04/037171 , WO04/058148, WO04/058700, WO04/126699, WO05/018638, WO05/019206, WO05/019205, WO05/018547, WO05/017190, US2005/0176776. In an embodiment inhibitors of mitotic kinesins include, but are not limited to inhibitors of KSP, inhibitors of MKLP1 , inhibitors of CENP-E, inhibitors of MCAK and inhibitors of Rab6-KIFL.
Examples of "histone deacetylase inhibitors" include, but are hot limited to, SAHA, TSA, oxamflatin, PXD101 , MG98 and scriptaid. Further reference to other histone deacetylase inhibitors may be found in the following manuscript; Miller, T.A. et al. J. Med. Chem. 46(24):5097-5116 (2003).
"Inhibitors of kinases involved in mitotic progression" include, but are not limited to, inhibitors of aurora kinase, inhibitors of Polo-like kinases (PLK; in particular inhibitors of PL.K-1), inhibitors of bub-1 and inhibitors of bub-R1. An example of an "aurora kinase inhibitor" is VX-680.
"Antiproliferative agents" includes antisense RNA and DNA
oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 , and INX3001 , and antimetabolites such as enocitabine, carmofUr, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'- methylidenecytidine, 2'-fluoromethylene-2'-deoxycytidine, N-[5-(2,3-dihydro- benzofuryl)sulfonyl]-N'-(3,4-dichlorophenyl)urea, N6-[4-deoxy-4-[N2-[2(E),4(E)- tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine, aplidine, ecteinascidin, troxacitabine, 4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H- pyrimidino[5,4-b][1 ,4]thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamic acid, aminopterin, 5-flurouracil, alanosine, 11-acetyl-8-(carbamoyloxymethyl)-4-formyl- 6-methoxy-14-oxa-1 ,1 1-diazatetracyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-yl acetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase, 2'-cyano-2'- deoxy-N4-palmitoyl-1-B-D-arabino furanosyl cytosine, 3-aminopyridine-2- carboxaldehyde thiosemicarbazone and trastuzumab.
Examples of monoclonal antibody targeted therapeutic agents include those therapeutic agents which have cytotoxic agents or radioisotopes attached to a cancer cell specific or target cell specific monoclonal antibody. Examples include Bexxar. "HMG-CoA reductase inhibitors" refers to inhibitors of 3-hydroxy-3- methylglutaryl-CoA reductase. Examples of HMG-CoA reductase inhibitors that may be used include but are not limited to lovastatin (MEVACOR®; see U.S.
Patent Nos. 4,231 ,938, 4,294,926 and 4,319,039), simvastatin (ZOCOR®; see U.S. Patent Nos. 4,444,784, 4,820,850 and 4,916,239), pravastatin
(PRAVACHOL®; see U.S. Patent Nos. 4,346,227; 4,537,859, 4,410,629,
5,030,447 and 5,180,589), fluvastatin (LESCOL®; see U.S. Patent Nos.
5,354,772, 4,911 ,165, 4,929,437, 5,189,164, 5,1 18,853, 5,290,946 and
5,356,896), atorvastatin (LIPITOR®; see U.S. Patent Nos. 5,273,995, 4,681 ,893, 5,489,691 and 5,342,952) and cerivastatin (also kno h as rivastatin and
BAYCHOL®; see US Patent No. 5,177,080). The structural formulas of these and additional HMG-CoA reductase inhibitors that may be used in the instant methods are described at page 87 of M. Yalpani, "Cholesterol Lowering Drugs", Chemistry & Industry, pp. 85-89 (5 February 1996) and US Patent Nos;
4,782,084 and 4,885,314. The term HMG-CoA reductase inhibitor as Used herein includes all pharmaceutically acceptable lactdne and open-acid forms (i.e., where the lactone ring is opened to form the free acid) as well as salt and ester forms of compounds which have HMG-CoA reductase inhibitory activity, and therefor the use of such salts, esters, open-acid and lactone forms is included within the scope of this invention.
"Prenyl-protein transferase inhibitor" refers to a compound w iidh inhibits any one or any combination of the prenyl-protein transferase enzymes, including farnesyl-protein transferase (FPTase), geranylgeranyl-protein transferase type I (GGPTase-l), and geranylgeranyl-protein transferase type-ll (GGPTase-ll, also called Rab GGPTase).
Examples of prenyl-protein transferase inhibitors can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701 , WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S. Patent No. 5,420,245, U.S. Patent No. 5,523,430, U.S. Patent No. 5,532,359, U.S. Patent No. 5,510,510, U.S. Patent No. 5,589,485, U.S. Patent No.
5,602,098, European Patent Publ. 0 618 221 , European Patent Publ. 0 675 1 12, European Patent Publ. 0 604 181 , European Patent Publ. 0 696 593, WO 94/19357, WO 95/08542, WO 95/1 917, WO 95/12612, WO 95/12572, WO 95/10514, U.S. Patent No. 5,661 ,152, WO 95/10515, WO 95/10516, WO
95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO 96/06138, WO 96/06193, WO 96/16443, WO 96/21701 , WO 96/21456, WO 96/22278, WO 96/24611 , WO 96/24612, WO 96/05168, WO 96/05169, WO 96/00736, U.S. Patent No. 5,571 ,792, WO 96/17861 , WO 96/33159, WO 96/34850, WO
96/34851 , WO 96/30017, WO 96/30018, WO 96/30362, WO 96/30363, WO 96/31 1 11 , WO 96/31477, WO 96/31478, WO 96/31501 , WO 97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO 97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO 97/44350, WO 98/02436, and U.S. Patent No. 5,532,359. For an example of the role of a prenyl-protein transferase inhibitor on angiogenesis see European J. of Cancer, Vol. 35, No. 9, pp.1394- 1401 (1999).
"Angiogenesis inhibitors" refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism. Examples of angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFR1) and Flk-1/KDR
(VEGFR2), inhibitors of epidermal-derived, fibroblast-derived, or platelet derived growth factors, MMP (matrix metalloprotease) inhibitors, integrin blockers, interferon-oc, interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidal anti-inflammatories (NSAIDs) like aspirin a d ibUprofen as well as selective cyclooxy-genase-2 inhibitors like celecoxib and rofecoxib {PNAS, Vol. 89, p. 7384 (1992); JNCI, Vol. 69, p. 475 (1982); Arch. Opthalmol., Vol. 108, p.573 (1990); Anat. Rec, Vol. 238, p. 68 (1994); FEBS Letters, Vol. 372, p. 83 (1995); Clin, Orthop. Vol. 313, p. 76 (1995); J. Mol. Endocrinol., Vol 16, p.107 (1996); Jpn. J. Pharmacol., Vol. 75, p. 105 (1997); Cancer Res., Vol. 57, p. 1625 (1997); Cell, Vol. 93, p. 705 (1998); Intl. J. Mol. Med., Vol. 2, p. 715 (1998); J. Biol. Chem., Vol. 274, p. 9116 (1999)), steroidal anti-inflammatories (such as corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone, methylpred, betamethasone), carboxyamidotriazole,
combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1 , angiotensin II antagonists (see Fernandez et al., J. Lab. Clin. Med. 105:141-145 (1985)), and antibodies to VEGF (see, Nature Biotechnology, Vol. 17, pp.963-968 (October 1999); Kim et al., Nature, 362, 841- 844 (1993); WO 00/44777; and WO 00/61186).
Other examples of angiogenesis inhibitors include, but are not limited to, endostatin, ukrain, ranpirnase, IM862, 5-methoxy-4-[2-methyl-3-(3-methyl-2- butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate,
acetyldinanaline, 5-amino-1 -[[3,5-dichloro-4-(4-chl0robenzoy|)phenyl]methyl]-1 H- 1 ,2,3-triazole-4-carbox¾mide,CM101 , squalamine, cornbretastatin, RPI4610, NX31838, sulfated mannopentaose phosphate, 7,7-(carbonyl-bis[imino-N-methyl- 4,2-pyrrolocarbonylimino[N-methyl-4,2-pyrrole]-carbonylimino]-bis-(1 ,3- naphthalene disulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indoiinone (SU5416).
Other therapeutic agents that modulate or inhibit angiogenesis and may also be used in combination with the compounds of the5 instant invention include agents that modulate or inhibit the coagulation and fibrinolysis5 systems (see review in Clin. Chem. La. Med. 38:679-692 (2000)). Examples of such agents that modulate or inhibit the coagulation and fibrinblysis pathways include, but are not limited to, heparin (see Thromb. Haemost. 80:10-23 (1998)), low molecular weight heparins and carboxypeptidase U inhibitors (also known as inhibitors of active thrombin activatable fibrinolysis inhibitor [TAFIa]) (see Thrombosis Res. 101 :329-354 (2001)). TAFIa inhibitors have been described in U.S. Ser. Nos. 60/310,927 (filed August 8, 2001) and 60/349,925 (filed January 18, 2002).
"Agents that interfere with cell cycle checkpoints" refer to compounds that inhibit protein kinases that transduce cell cycle checkpoint signals, thereby sensitizing the cancer cell to DNA damaging agents. Such agents include inhibitors of ATR, ATM, the CHK1 1 and CHK12 kinases and cdk and cdc kinase inhibitors and are specifically exemplified by 7-hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.
"Agents that interfere with receptor tyrosine kinases (RTKs)" refer to compounds that inhibit RTKs and therefore mechanisms involved in oncogenesis and tumor progression. Such agents include inhibitors of c-Kit, Eph, PDGF, Flt3 and c-Met. Further agents include inhibitors of RTKs as described by Bume- Jensen and Hunter, Nature, 411 :355-365, 2001. "Inhibitors of cell proliferation and survival signalling pathway" refer to compounds that inhibit signal transduction cascades downstream of cell surface receptors. Such agents include inhibitors of serine/threonine kinases (including but not limited to inhibitors of Akt such as described in WO 02/083064, WO 02/083139, WO 02/083140, US 2004-0116432, WO 02/083138, US 2004-
0102360, WO 03/086404, WO 03/086279, WO 03/086394, WO 03/084473, WO 03/086403, WO 2004/041162, WO 2004/096131 , WO 2004/096129, WO
2004/096135, WO 2004/096130, WO 2005/100356, WO 2005/100344, US 2005/029941 , US 2005/44294, US 2005/43361 , 60/734188, 60/652737,
60/670469), inhibitors of Raf kinase (for example PLX-4032 ), inhibitors1 of ΙνίΐΞΚ (for example Arry-162, RO-4987655 and GSK-1 120212), inhibitors of mTOR (for example AZD-8055, BEZ-235 and everolimus), and inhibitors of PI3K (for example GDC-0941 , BKM-120).
As described above, the combinations with NSAID's are directed to the use of NSAID's which are potent COX-2 inhibiting agents. For purposes of this specification an NSAID is potent if it possesses an IC50 for the inhibitioh of COX-2 of 1μΜ or less as measured by cell or microsomal assays.
The invention also encompasses combinations with NSAID's which are selective COX-2 inhibitors. For purposes of this specification NSAID's which are selective inhibitors of COX-2 are defined as those which possess a specificity for inhibiting COX-2 over COX-1 of at least 100 fold as measured by the ratio of IC50 for COX-2 over IC50 for COX-1 evaluated by cell or microsomal assays. Such compounds include, but are not limited to those disclosed in U.S. Patent
5,474,995, U.S. Patent 5,861 ,419, U.S. Patent 6,001 ,843, U.S. Patent 6,020,343, U.S. Patent 5,409,944, U.S. Patent 5,436,265, U.S. Patent 5,536,752, U.S.
Patent 5,550,142, U.S. Patent 5,604,260, U.S. 5,698,584, U.S. Patent 5,710,140, WO 94/15932, U.S. Patent 5,344,991 , U.S. Patent 5,134,142, U.S. Patent 5,380,738, U.S. Patent 5,393,790, U.S. Patent 5,466,823, U.S. Patent 5,633,272 and U.S. Patent 5,932,598.
Inhibitors of COX-2 can be useful in the instant method of treatment are: 3- phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone; and 5-chloro-3-(4- methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine; or a pharmaceutically acceptable salt thereof. Compounds that have been described as specific inhibitors of COX-2 and are therefore useful in the present invention include, but are not limited to, the following: parecoxib, BEXTRA® and CELEBREX® or a pharmaceutically acceptable salt thereof.
As used above, "integrin blockers" refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the β3 integrin, to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the νβ5 integrin, to compounds which antagonize, inhibit or counteract binding of a physiological ligand to both the ανβ3 integrin and the ανβ5 integrin, and to compounds which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed oh capillary endothelial cells. The term also refers to antagonists of the ανβ6. «νβδ. «1 β1 > «2β1 , α5β1. «6β1 and α6β4 integrins. The term also refers to antagonists of any combination of ανβ3, ανβ5>ανβ6. ανβ8> <*1 β1 , α2β1 , δβΐ , 6β1 and 6β4 integrins.
Some specific examples of tyrosine kinase inhibitors include N-
(trifluoromethylphenyl)-5-methylisoxazol-4-carboxanriide, 3-[(2,4-dimethylpyrrol-5- yl)methylidenyl)indolin-2-one, 17-(allylamiho)-17-demethoxygeldanamycin, 4-(3- chloro-4 luorophenylamino)-7-methoxy-6-i3-(4-morpholinyl)propoxyl]qiiinaz0line, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, BIBX1382, 2,3,9,10,11 ,12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9-methyl-9,12-epoxy- 1 H-diindolo[1 ,2,3-fg:3',2',1 '-kl]pyrrolo[3,4-i][1 ,6]benzodiazocin-1-one, SH268, genistein, STI571 , CEP2563, 4-(3-chlorophenylamino)-5,6-dimethyl-7H- pyrrolo[2,3-d]pyrimidinemethane sulfonate, 4-(3-bromo-4-hydroxyphenyl)amino- 6,7-dimethoxyquinazoline, 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, SU6668, STI571A, N-4-chlorophenyl-4-(4-pyridylmethyl)-1-phthalazinamine, and EMD121974.
Combinations of the instantly claimed compounds with PPAR-γ (i.e., PPAR-gamma) agonists and PPAR-δ (i.e., PPAR-delta) agonists can be useful in the treatment of certain malignancies. PPAR-γ and PPAR-δ are the nuclear peroxisome proliferator-activated receptors γ and δ. The expression of PPAR-γ on endothelial cells and its involvement in angiogenesis has been reported in the literature (see J. Cardiovasc. Pharmacol. 1998; 31 :909-913; J. Biol. Chem. 1999;274:9i 16-9121 ; Invest. Ophthalmol Vis. Sci. 2000; 41 :2309-2317). More recently, PPAR-γ agonists have been shown to inhibit the angiogenic response to VEGF in vitro; both troglitazone and rosiglitazone maleate inhibit the
Figure imgf000070_0001
2000;164:217-222).
The compounds of the instant invention rriay also be administered in , combination with an inhibitor Of inherent multidrug resistance (MDR), in partibular MDR associated with high levels of expression of transporter proteins. Such MDR inhibitors include inhibitors of p-glycoprotein (P-gp), such as LY33597¾, XR9576, OC144-093, R101922, VX853 and PSC833 (valspodar).
A compound of the present invention may be employed in conjunction with anti-emetic agents to treat nausea or emesis, including acute, delayed, late- phase, and anticipatory emesis, which may result from the use of a compound of the present invention, alone or with radiation therapy. For the prevention or treatment of emesis, a compound of the present invention may be used in conjunction with other anti-emetic agents, especially neurokinin-1 receptor antagonists, 5HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron, and zatisetron, GABAB receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S. Patent Nos. 2,789,118, 2,990,401 , 3,048,581 , 3,126,375, 3,929,768, 3,996,359, 3,928,326 and
3,749,712, an antidopaminergic, such as the phehothiazines (for example prochlorperazine, fluphenazine, thioridazine and mesoridazine), metoclopramide or dronabinol. In another embodiment, conjunctive therapy with an anti-emesis agent selected from a neurokinin-1 receptor antagonist, a 5HT3 receptor antagonist and a corticosteroid is disclosed for the treatment or prevention of emesis that may result upon administration of the instant compounds.
Neurokinin-1 receptor antagonists of Use in conjunction with the
compounds of the present invention are fully described, for example, in U.S.
Patent Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, 5,637,699, 5,719,147; European Patent Publication Nos. EP 0 360 390, 0 394 989, 0 428 434, 0 429 366, 0 430 771 , 0 436 334, 0 443 132, 0 482 539, 0 498 069, 0 499 313, 0 512 901 , 0 512 90 , 0 514 273, 0 514 274, 0 514 275, 0 514 276, 0 515 681 , 0 517 589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0 545 478, 0 558 156, 0 577 394, 0 585 913,0 590 152, 0 599 538, 0 610 793, 0 634 402, 0 686 629, 0 693 489,
0 694 535, 0 699 655, 0 699 674, 0 707 006, 0 708 101 , 0 709 375, 0 709 376, 0 714 891 , 0 723 959, 0 733 632 and 0 776 893; PCT International Patent Publication Nos. WO 90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151 , 92/15585, 92/17449, 92/20661 , 92/20676, 92/21677, 92/22569, 93/00330, 93/00331 , 93/01159, 93/01 165, 93/01169, 93/01170, 93/06099, 93/091 16, 93/10073, 93/14084, 93/14113, 93/18023, 93/19064, 93/21 155, 93/21181 , 93/23380, 93/24465, 94/00440, 94/01402, 94/02461 , 94/02595, 94/03429, 94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/08997, 94/10165, 94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767, 94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, 94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549, 95/11880, 95/14017, 95/1531 1 , 95/16679, 95/17382, 95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 95/22525, 95/23798, 95/26338, 95/28418, 95/30674, 95/30687, 95/33744, 96/05181 , 96/05193, 96/05203, 96/06094, 96/07649, 96/10562, 96/16939; 96/18643, 96/20197, 96/21661 , 96/29304, 96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553, 97/01554, 97/03066, 97/08144, 97/14671 , 97/17362, 97/18206, 97/19084, 97/19942 and 97/21702; and in British Patent Publication Nos. 2 266 529, 2 268 931 , 2 269 170, 2 269 590, 2 271 774, 2 292 144,
2 293 168, 2 293 69, and 2 302 689. The preparation of such compounds is fully described in the aforementioned patents and publications.
In an embodiment, the neurokinin-1 receptdr antagonist for use in conjunction with the compounds of the present invention is selected from: 2-(R)- (1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo- 1 H,4H-1 ,2,4-triazolo)methyl)morpholine, or a pharmaceutically acceptable salt thereof, which is described in U.S. Patent No. 5,719,147,
A compound of the instant invention may also be administered with ah agent useful in the treatment of anemia. Such an anemia treatmeht agent is, for example, a continuous eythropoiesis receptor activator (such as epoetin alfa).
A compound of the instant invention may also be administered with an agent useful in the treatment of neutropenia. Such a neutropenia treatment agent is, for example, a hematopoietic growth factor which regulates the production and function of neutrophils such as a human granulocyte colony stimulating factor, (G-CSF). Examples of a G-CSF include filgrastim.
A compound of the instant invention may also be administered with art immunologic-enhancing drug, such as levamisole, isoprinosine and Zadaxin.
A compound of the instant invention may also be useful for treating or preventing cancer in combination with P450 inhibitors including: xenobiotics, quinidine, tyramine, ketoconazole, testosterone, quinine, methyrapone, caffeine, phenelzine, doxorubicin, troleandomycin, cyclobenzaprine, erythromycin, cocaine, furafyline, cimetidine, dextromethorphan, ritonavir, indinavir, amprenavir, diltiazem, terfenadine, verapamil, Cortisol, itraconazole, mibefradil, nefazodone and nelfinavir. A compound of the instant invention may also be useful for treating or preventing cancer in combination with Pgp and/or BCRP inhibitors including: cyclosporin A, PSC833, GF120918, cremophorEL, fumitremorgin C, Ko132, Ko134, Iressa, Imatnib mesylate, EKI-785, CM 033, novobiocin, diethylstilbestrol, tamoxifen, resperpine, VX-710, tryprostatin A, flavonoids, ritonavir,, saquinavir, nelfinavir, omeprazole, quinidine, verapamil, terferiadine, ketoconazole, nifidepine, FK506, amiodarone, XR9576, indinavir, amprenavir, Cortisol, testosterone, LY335979, OC144-093, erythromycin, vincristine, digoxin and talinolol.
A cbmpound of the instant invention may also be useful for treating or preventing cancer, including bone cancer, in combination with bisphosphonates (understood to include bisphosphonates, diphosphonates, bisphosphonic acids and diphosphonic acids). Examples of bisphosphonates include but are not limited to: etidronate (Didronel), pamidronate (Aredia), alendronate (Fbsamax), risedronate (Actonel), zoledronate (Zometa), ibahdronate (Boniva), incadronate or cimadronate, clodronate, EB-1053, minodronate, neridronate, piridronate and tiludronate including any and all pharmaceutically acceptable salts, derivatives, hydrates and mixtures thereof.
A compound of the instant invention may also be useful for treating or preventing breast cancer in combination with aromatase inhibitors. Examples of aromatase inhibitors include but are not limited to: anastrozole, letrozole and exemestane.
A compound of the instant invention may also be useful for treating or preventing cancer in combination with siRNA therapeutics.
The compounds of the instant invention may also be administered in combination with γ-secretase inhibitors and/or inhibitors of NOTCH signaling. Such inhibitors include compounds described in WO 01/90084, WO 02/30912, WO 01/70677, WO 03/013506, WO 02/36555, WO 03/093252, WO 03/093264, WO 03/093251 , WO 03/093253, WO 2004/039800, WO 2004/039370, WO 2005/030731 , WO 2005/014553, USSN 10/957,251 , WO 2004/08991 1 , WO 02/081435, WO 02/081433, WO 03/018543, WO 2004/031137, WO
2004/031 139, WO 2004/031 138, WO 2004/101538, WO 2004/101539 and WO 02/47671 (including LY-450139). Inhibitors of Akt, as disclosed in the following publications; WO 02/083064, WO 02/083139, WO 02/083140, US 2004-0116432, WO 02/083138, US 2004- 0102360, WO 03/086404, WO 03/086279, WO 03/086394, WO 03/084473, WO 03/086403, WO 2004/041162, WO 2004/096131 , WO 2004/096129, WO
2004/096135, WO 2004/096130, WO 2005/100356, WO 2005/100344, US 2005/029941 , US 2005/44294, US 2005/43361 , 60/734188, 60/652737,
60/670469, and including compounds of the instant invention, are also useful in combination with potassium salts, magnesium salts, beta-blockers (such as atenolol) and endothelin-a (ETa)antagonists with the goal of maintaihing cardiovascular homeostasis.
Inhibitors of Akt, as disclosed in the following publications; WO 02/083064, WO 02/083139, WO 02/083140, US 2004-01 16432, WO 02/083 38, US 2004- 0102360, WO 03/086404, WO 03/086279, WO 03/086394, WO 03/084473, WO 03/086403, WO 2004/041 162, WO 2004/096131 , WO 2004/096129, WO
2004/096135, WO 2004/096130, WO 2005/100356, WO 2005/100344, US 2005/029941 , US 2005/44294, US 2005/43361 , 60/734188, 60/652737,
60/670469, and including compounds of the instant invention, are also useful in combination with insulin, insulin secretagogues, PPAR-gamma agonists, metformin, somatostatin receptor agonists such as octreotide, bPP4 inhibitors, sulfonylureas and alpha-glucosidase inhibitors with the goal of maintaihing glucose homeostasis.
A compound of the instant invention may also be useful for treating or preventing cancer in combination with PARP inhibitors: olaparib, MK 827 and veliparib.
A compound of the instant invention may also be useful for treating cancer in combination with the following chemotherapeutic agents: abarelix (Plenaxis depot®); aldesleukin (Prokine®); Aldesleukin (Proleukin®); Alemtuzumabb (Campath®); alitretinoin (Panretin®); allopurinol (Zyloprim®); altretamine
(Hexalen®); amifostine (Ethyol®); anastrozole (Arimidex®); arsenic trioxide (Trisenox®); asparaginase (Elspar®); azacitidine (Vidaza®); bendamustine hydrochloride (Treanda®); bevacuzimab (Avastin®); bexarotene capsules
(Targretin®); bexarotene gel (Targretin®); bleomycin (Blenoxane®); bortezomib (Velcade®); brefeldin A; busulfan intravenous (Busulfex®); busulfan oral
(Myleran®); calusterone (Methosarb®); capecitabine (Xeloda®); carboplatin (Paraplatin®); carmustine (BCNU®, BiCNU®); carmustine (Gliadel®); carmustine with Polifeprosan 20 Implant (Gliadel Wafer®); celecoxib (Celebrex®); cetuximab (Erbitux®); chlorambucil (Leukeran®); cispiatin (PlatiHbl®); cladribine
(Leustatin®, 2-CdA®); clofarabine (Clolar®); cyclophosphamide (Cytoxan®, Neosar®); cyclophosphamide (Cytoxan Injection®); cyclophosphamide (Cytoxan Tablet®); cytarabine (Cytosar-U®); cytarabine liposomal (DepoCyt®);
dacarbazine (DTIC-Dome®); dactinomyciri, actinorriycin D (Coimegeh®);
dalteparin sodium injection (Fragmin®); Darbepoetin alfa (Aranesp®); dasatinib (Sprycel®); daunorubiciri liposomal (DanuoXome®); daVnorubiciri, daunornycin (Daunorubicin®); daunorubicin, daunornycin (Cerubidjrie®); degarel!x
(Firmagon®); Denileukin diftitox (Ontak®); dexrazoxane (Zinecard®);
dexrazoxane hydrochloride (Totect®); didemnin B; 17-DMAG; docetaxel
(Taxotere®); doxorubicin (Adriamycin PFS®); doxorubicin (Adriamycln®, .
Rubex®); doxorubicin (Adriamycin PFS Injection®); doxorubicin liposomal (Doxil®); dromostanolone propionate (Dromostanolohe ®); dromostanolone propionate (Masterone Injection®); eculizumab injection (Soiiris®); Elliott's B; Solution (Elliott's B Solution®); eltrombopag (Promacta®); epirubiciri (Ellence®); Epoetin alfa (epogen®); erlotinib (Tarceva®); estramustine (Emcyt®); ethinyl estradiol; etoposide phosphate (Etopophos®); etoposide, VP-16 (Vepesid®); everolimus tablets (Afinitor®); exemestane (Aromasin®); ferumoxytol (Feraheme Injection®); Filgrastim (Neupogen®); floxuridine (intraarterial) (FUDR®);
fludarabine (Fludara®); fluorouracil, 5-FU (Adrucil®); fulvestrant (Faslodex®); gefitinib (Iressa®); geldanamycin; gemcitabine (Gemzar®); gemtuzumab ozogamicin (Mylotarg®); goserelin acetate (Zoladex Implant®); goserelin acetate (Zoladex®); histrelin acetate (Histrelin implant®); hydroxyurea (Hydrea®);
Ibritumomab Tiuxetan (Zevalin®); idarubicin (Idamycin®); ifosfamide (IFEX®); imatinib mesylate (Gleevec®); interferon alfa 2a (Roferon A®); Interferon alfa-2b (Intron A®); iobenguane I 123 injection (AdreView®); irinotecan (Camptosar®); ixabepilone (Ixempra®); lapatinib tablets (Tykerb®); lenalidomide (Revlimid®); letrozole (Femara®); leucovorin (Wellcovorin®, Leucovorin®); Leuprolide Acetate (Eligard®); levamisole (Ergamisol®); lomustine, CCNU (CeeBU®);
meclorethamine, nitrogen mustard (Mustargen®); megestrol acetate (Megace®); melphalan, L-PAM (Alkeran®); mercaptopurine, 6-MP (Purinethol®); mesna
(Mesnex®); mesna (Mesnex tabs®); methotrexate (Methotrexate®); rriethoxsalen (Uvadex®); 8-methoxypsoralen; mitomycin C (Mutamycin®); mitotane
(Lysodren®); mitoxantrone (Novantrone®); mitramycin; nandroione
phenpropionate (Durabolin-50®); nelarabine (Arranon®); nilotinib (Tasigna®); Nofetumomab (Verluma®); ofatumumab (Arzerra®); Oprelvekin (Neumega®); oxaliplatin (Eloxatin®); paclitaxel (Paxene®); paclitaxei (Taxol®); paclitaxel protein-bound particles (Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®); panitumumab (Vectibix®); pazopanib tablets (Votrienttm®);
pegademase (Adagen (Pegademase Bovine)®); pegasparga e (Oncaspar®); Pegfilgrastim (Neulasta®); pemetrexed disodium (Alimta®); pentostatiri
(Nipent®); pipobroman (Vercyte®); plerixafor (Mozobil®); plicamycirt,
mithramycin (Mithracin®); porfimer sodium (Photofrin®); pralatrexate injection (Folotyn®); procarbazine (Matulane®); quinacrine (Atabrine®); rapamycin;
Rasburicase (Elitek®); raloxifene hydrochloride (Evista®); Rituximab (Rituxan®); romidepsin (Istodax®); romiplostim (Nplate®); sargramostim (Leukine®);
Sargramostim (Prokine®); sorafenib (Nexavar®); streptozocin (Zanosar®);
sunitinib maleate (Sutent®); talc (Sclerosol®); tamoxifen (Nolvadex®);
temozolomide (Temodar®); temsirolimus (Torisel®); teniposide, VM-26
(Vumon®); testolactone (Teslac®); thioguanine, 6-TG (Thioguanine®); thiopurine; thiotepa (Thioplex®); topotecan (Hycamtin®); toremifene (Fareston®);
Tositumomab (Bexxar®); Tositumomab/l-131 tositumomab (Bexxar®); trans- retinoic acid; Trastuzumab (Herceptin®); tretinoin, ATRA (Vesanoid®);
triethylenemelamine; Uracil Mustard (Uracil Mustard Capsules®); valrubicin (Valstar®); vinblastine (Velban®); vincristine (Oncovin®); vinorelbine
(Navelbine®); vorinostat (Zolinza®); wortmannin; and zoledronate (Zometa®). Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature. For example, the
administration of many of the chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR), e.g., 1996 edition (Medical Economics Company, Montvale, NJ 07645-1742, USA), the Physician's Desk Reference, 56th Edition, 2002 (published by Medical Economics company, Inc. Montvale, NJ 07645-1742), and the Physician's Desk Reference, 57th Edition, 2003 (published by Thompson PDR, Montvale, NJ 07645-1742).
The invention disclosed herein is exemplified by the following preparations and examples which should not be construed to limit the scope of the disclbsure.
Examples
The following abbreviations have the followihg meanings unless defined otherwise:
ACN Acetonitrile
AcOH Acetic acid
DAST (diethylamino)sulfur trifluoride
DCC Dicyclohexylcarbodiimide
DCU Dicyclohexylurea
DCM Dichloromethane
Dl Deionized water
DIAD Diisopropylazodicarboxylate
DIEA Diisopropylethylamine
DMAP 4-Dimethylaminopyridine
DME Dimethoxyethane
DMF Dimethylformamide
DMFDMA Ν,Ν-Dimethylformamide dimethylacetal
DMSO Dimethyl sulfoxide
DTT Dithiothreitol
EDCI 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide
hydrochloride EtOAc Ethyl acetate
EtOH Ethanol
HATU N , N , N', N'-Tetramethyl-0-(7-Azabenzotriazol- 1 -yl) U ronium hexafluorophosphate Hex hexanes
HOBt 1-Hydroxylbenzotriazole
HPLC High pressure liquid chromatography
LCMS Liquid chromatography mass spectrometry
LDA Lithium diisopropylamide mCPBA /nefa-Chloroperoxybenzoic acid
MeOH Methanol
MTT (3-[4 , 5-dimethyl-thiazol-2-yl]-2 , 5-d iphenyltetrazolium
bromide, Thiazolyl blue)
NMR Nuclear magnetic resonance
PFP Pentafluorophenol
PMB p-methoxybenzyl
Pyr Pyridine
Rb Round bottom flask
Rbt Round bottom flask
RT Room temperature
SEMCI 2-(Trimethylsily)ethoxy methyl chloride
TBTU O-iBenzotriazol-l-y -N.N.N'.N'-tetramethyluronium
tetrafluoroborate
TEA Triethylamine
Tr Triphenyl methane
Trt Triphenyl methane
TrCI Triphenyl methane chloride
TFA Trifluoroacetic acid
THF Tetrahydrofuran
TLC Thin layer chromatography
TMS Trimethylsilyl Example 1: Representative procedures to prepare substituted tetrahydroisoquinolines The following common intermediates were prepared according to previous
Figure imgf000079_0001
Na2CO3 (2.12 g, 20.04 mmol) was added to a suspension of 3-chloro-D- phenylalanine 9 (2.5 g, 10.02 mmol) in MeOH/H2O (8.3 mL/8.3 mL) at room temperature. Ethyl chloroformate (1.44 mL, 15.03 mmol) was added drop wise over 20 min via syringe pump and the reaction was stirred overnight. The reaction mixture was washed with Et2O (1 x 15 mL) and the aqueous layer was acidified to pH ~ 5 with 2 M HCI (aq). The aqueous layer was extracted with EtOAc (2 x 30 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to obtain the ethyl carbamate.
The crude ethyl carbamate (1.62 g, 6.35 mmol) was dissolved in AcOH/conc. H2SO4 (3. , 6.0 mL/2.0 mL). Paraformaldehyde (200 mg, 6.67 mmol) was added and the reaction was stirred at room temperature overnight. EtOAc (15 mL) and H20 (15 mL) were added to the reaction mixture. The layers were separated and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organics were dried over MgS04, filtered and concentrated to obtain (R)-6-chloro-2- (ethoxycarbonyl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 10 (2.3 g, 8.13 mmol, 81 % overall yield).
Synthesis of (R)-2-tert-butyl 3-methyl 6-chloro-3,4-dihydroisoquinoline-
Figure imgf000080_0001
CH2CI2 (4 mL) was added to the reaction mixture and was stirred overnight at room temperature. The reaction was diluted with H2O and was extracted with CH2CI2 (2 x 20 mL). The organic layers were dried over MgSO4, filtered and concentrated. The crude product 11 was purified by silica gel chromatography (30% EtOAc/hexanes).
Synthesis of (R)-6-chloro-2-((2 ?,3S)-2-propyl-1-(3-
(trifluoromethyl)picolinoyl)-3-(5-(trifluoromethyl)thiophen-3- yloxy)piperidine-3-carbonyl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (A129)
Figure imgf000081_0001
The acid chloride 6 (40 mg, 75.6 pmolj was dissolved in CH2CI2 (0.8 mL). A solution of tetrahydroisoquinoline amine (30 mg, 11.3 μιηοΙ, obtained from the treatment of purified 11 with 4N HCI in dioxane) and DIPEA (40 pL, 22.7 μιτιοΙ) in CH2CI2 (0.5 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 3 h. The reaction was concentrated and was purified by silica gel chromatography (EtOAc/hexanes* , gradient, 30% to 50%).
LiOH (9 mg, 37.8 pmol) was added to a stirred solution of the ester (54 mg, 75.6 μΐηοΙ) in EtOH/h^O (0.8 mL/2 drops). The reaction mixture was stirred at 50 °C for 1 h. The reaction was concentrated and was acidified to pH ~4 with 1 M HCI (aq). The mixture was extracted with EtOAc (3 x 15 mL). The organic layers were dried over Na2S04 and concentrated. The crude product was purified by reverse phase preparative HPLC to yield A129.
Synthesis of (f?,£)-tert-butyl 6-chloro-3-(3-ethoxy-3-oxoprop-1-enyl)-3,4- dihydroisoquinoline-2(1 H)-carboxylate (12)
Figure imgf000081_0002
LAH/THF (1 M, 2.59 mL, 2.59 mmol) was added to a stirred solution of ester tetrahydroisoquinoline 11 (767 mg, 2.35 mmol) in THF (15 mL) at -30 °C under N2. The reaction was stirred at this temperature for 45 min, then was warmed to room temperature and was stirred for 15 min. The reaction mixture was quenched with MeOH (2.0 mL). Sat'd aqueous Rochelle's salt solution (20 mL) and EtOAc (20 mL) were added and was stirred for 30 min. The layers were separated and the aqueous layer was extracted with EtOAc (3 x 20 mL). The organic layers were dried over Na2S04, and concentrated to obtain the corresponding alcohol.
Oxalyl chloride (388 μί, 4.08 mmol) was added to a stirred solution of DMSO (580 μΐ, 8.16 mmol) in CH2CI2 (18 mL) ai -78 °C under N2 and was stirred for 5 min. A solution of the alcohol (608 mg, 2.54 mmol) in CH2CI2 (2.0 mL) was added to the reaction mixture and was stirred at -78 °C for 1 h. 3N (1,42 mL, 10.2 mmol) was added and the solution was warmed to room temperature and was stirred for 1 h. The reaction mixture was quenched with sat'd aqueous NaHC03. The layers were separated and the aqueous layers was extracted with CH2CI2 (2 x 20 mL). The organic layers were washed with brine, dried over gS04, filtered and concentrated to obtain the corresponding aldehyde.
NaH (60% in oil, 92 mg, 2.31 mmol) was washed with hexanes (2 x 3 mL). THF (15 mL) was added under N2. The solution was cooled to 0 °C and triethylphosphonoacetate (499 μΐ, 2.52 mmol) was added drop wise and was stirred for 20 min. A solution of the aldehyde (620 mg, 2.10 mmol) in THF (5 mL) was added to the reaction mixture at 0 °C. The reaction was warmed to room temperature and was stirred overnight. The reaction mixture was quenched with sat'd aqueous NH4CI (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 20 mL). The organic layers were washed with brine (1 x 30 mL), dried over MgSO4, filtered and concentrated to obtain the desired product, 12. The crude product 12 was purified by silica gel chromatography (EtOAc/hexanes, gradient, 10% to 30%).
Synthesis of (S)-ethyl 3-(6-chloro-1,2,3,4-tetrahydroisoquinolin-3- yl)propanoate (13)
Figure imgf000082_0001
ZnBr2 (13 mg, 58.6 μηιοΙ) was added to a stirred solution of the 12 (107 mg, 0.293 mmol) in MeOH. The solution was degassed with N2 for a few minutes. Pd(OH)2/C (20%, 20 mg) was added and then H2 was bubbled into the mixture for a few minutes. The reaction was stirred under a H2 balloon overnight at room temperature. The solution was filtered through Celite, washed with EtOAc and concentrated to obtain the hydrogenated product and dechlorinated product (<10%). The crude product was purified by silica gel chromatography (EtOAc/hexanes, gradient, 10% to 20%).
HCI/dioxane (4 M, 511 μΙ_, 2.04 mmol) was added to neat Boc- tetrahydroisoquinoline (75 mg, 0.204 mmol) at room temperature and was stirred for 2 h. The reaction mixture was concentrated to obtain (S)-ethyl 3-(6-chloro- 1 ,2,3,4-tetrahydroisoquinolin-3-yl)propanoate 13.
Synthesis of 3-((S)-6-cHloro-2-((2R,3S)-i*-propyl-1-(3-
(trifluoromethyl)picolinoyl)-3-(5-(trifluoromethyl)thiophen-3- yloxy)piperidine-3-carbonyl)-1 ,2,3,4-tetrahydroisoquinolin-3-yl)pi-opanoic acid, A130
Figure imgf000083_0001
A130
The acid chloride 6 (87 mg, 0.165 mmol) was dissolved in CH2CI2 (1.15 mL). A solution of (S)-ethyl 3-(6-chloro-1 ,2,3,4-tetrahydroisoquinolin-3-yl)propanoate 13 (60 mg, 0.198 mmol) and DIPEA (88 μΙ_, 0.495 mmol) in CH2CI2 (0.5 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 2.5 h. The reaction was concentrated and was purified by silica gel chromatography (EtOAc/hexanes, gradient, 30% to 50%).
KOH (18 mg, 0.32 mmol) was added to a stirred solution of the ester (49 mg, 64.5 μΐηοΙ) in EtOH/H20 (0.7 mL/2 drops). The reaction mixture was stirred at 60 °C for 1 h. The reaction was concentrated and was acidified to pH ~4 with 1 M HCI (aq). The mixture was extracted with EtOAc (3 x 15 mL). The organic layers were dried over Na2S04 and concentrated. The crude product was purified by reverse phase preparative HPLC to yield 3-((S)-6-chloro-2-((2R,3S)-2-propyl-1- (3-(trifluoromethyl)picolinoyl)-3-(5-(trifluor0methyl)thiophen-3-yloxy)piperidine-3- carbonyl)-1 ,2,3,4-tetrahydroisoquinolin-3-yl)propanoic acid, A130. LC/MS RT (10 min method) = 4.315 min.
Two representative routes to modify the substituted
tetrahydroisoquinolines: preparation of A45
Route A
Figure imgf000084_0001
Route A
To a solution of 14 (6.4mmol, 2.0g) in tetrahydrofuran at 0°C was added borane- THF complex (1.0M in THF, 8mmol, 8.0ml). The reaction mixture was stirred at rt for 4h. The reaction was quenched with water, extracted with EtOAc. The combined organic layer was washed with brine, dried (MgSO4), and concentrated. The crude product 15 was obtained as colorless oil (~2.0g) and used in the next step without further purification.
To a stirring solution of 15 (~2.0g) in DCM (30ml) at room temperature was added Dess-Martin Periodinane and the reaction mixture was stirred at rt for 1h. The solvent was removed in vacuo. The reaction was quenched with water, extracted with EtOAc. The combined organic layer was washed with brine, dried (MgS04), and concentrated. The crude product 16 was obtained as colorless oil (1.8 g) and used in the next step without further purification.
To a stirring solution of 16 (1.8g) in DCM (30ml) at room temperature was added (carbethoxymethylene) triphenylphosphorane and the reaction mixture was stirred at rt for 3 days. The solvent was removed in vacuo. The crude product was purified on Biotage (EtOAc in hexahe: 10~25%) to give 17 as yellowish oil (1.0g). 17 (50mg, 0.14mmol) was treated with 4M HC| for 1 h. Then the solvent was removed in vacuo. To the residue in MeOH was added catalytical amount of 10% Pd/C followed by Zinc Bromide (0.2eq) and the mixture was subjected to hydrogenation (55psi) on Parr Shaker. After stirring at room temperature overnight, the mixture was filtered through Celite. The filtrate was concentrated in vacuo, to give the residue that was protected ith Boc by following standard conditions. After work-up, the crude product Boc-protected amine was purified on Biotage (EtOAc in hexane: 5~10%) to give 18 as colorless oil (30 mg).
To a solution of 18 in acetonitrile at room temperature was added 4.0 M hydrochloride in 1 ,4-dioxane. After 1 h, the solvent was removed by lyophilization, to give 19 as white solid.
To a stirring; mixture of acid intermediate 6 and Ϊ9 in DCM at room temperature was added followed by DIEA. The reaction was stirred at room temperature overnight. The solvent was removed in vacuo. The crude product was purified on
Biotage (EtOAc in hexane: 25~50%), to give 20 as white solid.
To 20 in ethanol was added 2.0 M NaOH aqueous solution and the mixture was stirred at 70 °C for 1 h. Then the solvent was removed in vacuo. The residue was redissolved in water, acidified with 6N HCI to pH ~4, then extracted with EtOAc
(2x30ml), dried (MgSO4), concentrated, purified on Gilson, to give two isomers with both as white solids. The 1st one obtained was A45.
Route B
To a solution of 2-(3-chlorophenyl)-ethylamine 21 (24g, 0.15mol) in DCM (500ml) and triethylamine (23ml, 0.165mmol) at 0°C was added dropwise benzyl chloroformate and the resulting solution was stirred at 0°C for 30min and then at rt overnight. The reaction mixture was washed with saturated NaHCO3, brine, and then concentrated. The crude product was purified on Biotage (EtOAc in hexane: 10~25%) to give 22 (35g) as light yellow oil.
To a stirring mixture of 22 (5.9g, 20mmol) arid methyl-4-oxobutyrate (3.4ml, 30mmol) at 0°C was added the premixed solvent H2S04:AcOH (1 :3, 40ml) and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into ice, extracted with DCM (4x75ml). The organic phase was concentrated. The crude product 18 was obtained as reddish oil (~6.0g), which was subjected the Boc-protection by following standard condition. After work-up and purification on Biotage (EtOAc in hexane: 5~10%) to give the pure product 19 as pinky oil (0.8g).
Synthesis of A73 and A74
Figure imgf000086_0001
To a stirring solution of 23 (1 mmol, 200mg) in dichloromethane and triethylamine (2mmol, 0.3ml) at room temperature was added N-bromosuccinimide (Hrhmol, 200mg). The reaction mixture was stirred at room temperature for 30min. Then 2.0 M NaOH aqueous solution was added and the reaction mixture was stirred at rt for another 1 h. The reaction mixture as extracted with DCM. The combined organic layer was over MgSO4. The solvent was removed in vacuo. The crude product 24 was used in the next step without further purification. The crude material 24 (1 mmol) and Malonic acid were mixed well at room temperature. The mixture was immersed in an oil bath that was preheated to 120°C and stirred for 1h. After cooling down, the residue 25 was used in the next step without further purification.
Thionyl chloride (1.1 mmol, 80 ul) was added dropwise with stirring to methanol at -10°C. Stirring was continued for 30min at -10°C. A solution of 25 in MeOH was then added and the reaction mixture was stirred at rt overnight. The solvent was removed in vacuo. The residue was dissolved in DCM and added with 3 drops of triethylamine, then diluted with EtOAc, washed with saturated NaHC03 twice, then brine and then dried over MgS04. The solvent was removed in vacuo. The crude product 26 was obtained as brownish oil (~0.2g).
To a stirring solution of 26 in dichloromethane and triethylamine at room temperature was added di-t-butyl dicarbohate followed by DMAP. the reaction mixture was stirred at room temperature overnight and then diluted with EtOAc, washed with water, brine, then dried (MgSO4). The solvent Was removed in vacuo. The crude product 27 was obtained as brownish oil, which was used in the next step without further purification.
To a solution of 27 in dichloromethane was added diisobutylaluminum and the reaction mixture was stirred at -78°C for 1 h. Then Rochelle salt solution was added, and the mixture was stirred vigorously for 30min and then extracted with EtOAc. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over MgSO4, concentrated. The crude product 28 was used in the next step without further purification.
To a stirring solution of 28 in DCM at room temperature was added (carbothoxymethylene) triphenylphosphorane and the reaction mixture was stirred at reflux overnight. The solvent was removed in vacuo. The crude product was purified on Biotage (EtOAc in hexane: 10~25%) to give 29 as colorless oil. To a stirring solution of 29 in EtOAc was added catalytical amount of 10% palladium on carbon and the reaction mixture was purged with Hydrogen balloon. After stirring at room temperature overnight, the mixture was filtered through celite and concentrated in vacuo, to give 30 as colorless oil, which was used in the next step without further purification. To a solution of 30 in acetonitrile at room temperature was added 4.0 M hydrochloride in 1 ,4-dioxane. After 1h, the solvent was removed by lyophilization, to give 31 as yellowish oil.
To a stirring mixture of acid intermediate 6 (0.1 mmol, 50 mg) and 31 (0.2 mmol, 70 mg) in DCM at room temperature was added HATU (0.15 mmol, 57 mg) followed by DIEA (0.1 ml). The reaction was stirred at room temperature overnight. The solvent was removed in vacuo. The crude product was purified on Biotage (EtOAc in hexane: 25-50%), to give 32 as white solid.
To 32 in ethanol was added 2.0 M NaOH aqueous solution and the mixture was stirred at 70 °C for 1 h. Then the solvent was removed in vacuo. The residue was redissolved in water and acidified with 6N HCI to pH~4, then extracted with EtOAc(2x30ml), dried (MgSO4), concentrated, purified on HPLC, treated with 4.0 M HCI in dioxane (2-3 drops), lyophilized, give the two separated isomers A73 and A74, both of which are white solid.
Using analogous methods as described above, the following compounds in Table 1 can be synthesized.
Figure imgf000088_0001
Figure imgf000089_0001
A8 5-{[(2R,3S)-2-propyl-1- Calc'd B
{[3- 632.1 , found
(trifluoromethyl)pyridin- 632
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-4, 5,6,7- tetrahydrothieno[3,2- c]pyridine
A9 0 ethyl 5-{[(2R,3S)-2- Calc'd B
propyl-1-{[3- ; | 704.2, found
(trifluoromethyl)pyridin- 704.2
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidih-3- yl]carbonyl}-4, 5,6,7- tetrahydrothieno[3,2- c]pyridine-2- carboxylate
A10 0 5-{[(2R,3S)-2-propyl-1- Cald'd B
{[3- 676.1, found
(trifluoromethyl)pyridin- 676
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-S-ylloxyJpiperidin^- yl]carbonyl}-4, 5,6,7- tetrahydrothieno[3,2- c]pyridine-2-carboxylic
acid
A11 2-{[(2R,3S)-2-propyl-1- Calc'd B
< o rO-NH! {[3- 641.2, found
(trifluoromethyl)pyridin- 641
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
0 n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-6- amine
A12 6-chloro-1 -(morpholin- Calc'd A
4-ylmethyl)-2-{[(2R,3S)- 759.2, found
2-propyl-1-{[3- 759
(trifluoromethyl)pyridin-
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
A57 Br 3-(6-bromo-2-{[(2R,3S)- Calc'd A
2-propyl-1-{[3- 776.1 , found
(trifluoromethyl)pyridin- 776
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinolin-1- yl)propanoic acid
A58 Br 3-(6-bromo-2-{[(2R,3S)- Calc'd A
2-propyl-1-{[3- 776.1 , found (trifluoromethyl)pyridin- 776
2-yl]carbonyl}-3-{[5- :
(trifluoromethyOthiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 ,2,3,4- tetrahydroisoquiriolin-1 - yl)propanoic acid
A59 3-(6-fluoro-2-{[(2R,3S)- Calc'd A
2-propyl-1-{[3- ■ 797.2, found
(trifluoromethyl)pyridin- 797
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1- yl)-N-(2H-tetrazol-5- ylmethyl)propanamide
A60 3-(6-fluoro-2-{[(2R,3S)- Calc'd A
2-propyl-1-{[3- j 797.2, found
(trifluoromethyl)pyridin- 797.1
2-yl]carbonyl}-3-{[5-
• ί>· ¼8... (trifluoromethyl)thi0phe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinolin- - yl)-N-(2H-tetrazol-5- ylmethyl)propanamide
A61 CI 3-(6-chloro-2-{[(2R,3S)- Calc'd A
2-propyl-1-{[3- 809.2, found
(trifluoromethyl)pyridin- 808.9
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 , 2,3,4- ½F tetrahydroisoquinolin-1- yl)-N-
(methylsulfonyl)propan
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
A75 CI 6-chloro-2-{[(2R,3S)-2- Calc'd A
propyl-1-{[3- 703.2, found
(trifluoromethyi)pyridin- 703
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-
1-carboxamide
A76 CI 6-chloro-2-{[(2R,3S)-2- Calc'd B
propyl-1-{[3- 685.1 , found
(trifluorom thyl)pyridin- 684.9
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}pipehdin-3- yl]carbonyl}-1 , 2,3,4- tetra hyd roisoq Uinoline-
1-carbonitrile
A77 CI 6-chloro-2-{[(2R,3S)-2- Calc'd A
propyl-1-{[3- 703.2, found
(trifluorbmethyljpyridih- 703
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidih-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-
1-carboxamide
A78 CI 6-chioro-2-{[(2R,3S)-2- Calc'd B
propyl-1-{[3- 685.1 , found
(trifluoromethyl)pyridin- 684.9
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-
1-carbonitrile
A79 CI 3-[(1 R)-6-chloro-2- Calc'd A
{[(2R,3S)-2-propyl-1- 756.2, found
{[3- 756
F (trifluoromethyl)pyridin-
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinolin-1- yl]-N-
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
A100 CI 6-chloro-2-{[(2R,3S)-2- Calc'd A
propyl-1-{[3- 704.1 , found
(trifluoromethyl)pyridin- 704
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-
1-carboxylic acid
A101 6-fluoro-2-{[(2R,3S)-2- Calc'd A
propyl-1-{[3- 688.2, found
(trifluoromethyi)pyridin- 688.2
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3~
yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-
1-carboxylic acid
A102 CI 6-chloro-2-{[(2R,3S)-2- Calc'd A
propyl-1-{[3- 704.1 , found
(trifluoromethyl)pyridin- 704
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-
1-carboxylic acid
A103 CI (6-chloro-2-{[(2R,3S)-2- Calc'd B
propyl-1-{[3- 690.2, found
(trifluoromethyl)pyridin- 690.2
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-
N Y > yl)methanol
A104 6-fluoro-2-{[(2R,3S)-2- Calc'd A
propyl-1-{[3- 688.2, found
(trifluoromethyl)pyridin- 688.2
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-
1 -carboxylic acid
Figure imgf000112_0001
tetrahydroisoquinoline- 1-carboxamide
A110 6-fluoro-2-[(2-propyl-3- Calc'd B
[4- 654.2, found
(trifluoromethoxy)pheno 654
xy]-1-{[3-
(trifluoromethyl)pyridin-
2- yl]carbonyl}piperidin-
3- yl)carbonyl]-1 , 2,3,4- tetrahydroisoquinoline
A111 OH 3-[(1S)-6-chloro-2- Calc'd A
{[(2R,3S)-2-propyl-3-t4- 742.2, found (trifluoromethoxy)pheno 741.8 xy]-1-{[3-
(trifluoromethyl)pyndin-
& 2- yl]carbonyl}piperidin-
3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1 - yl]propanoic acid
A112 CI N-{2-[(2R,3S)-3-[(6- Calc'd A
chloro-3,4- 745.2, found dihydroisoquinolin- 745.2
2(1 H)-yl)carbonyl]-1-
{[3-
(trifluoromethyl)pyridin-
5*·' 2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-2- yl]ethyl}tetrahydro-2H- pyran-4-amine
A113 6-chloro-2-{[(2R,3S)-2- Calc'd A
prop-2-en-1-yl-1-{[3- 702.1 , found
(trifluoromethyl)pyridin- 702
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-
1-carboxylic acid
A114 6-chloro-2-{[(2R,3S)-2- Calc'd A
[2-(4-ethylpiperazin-1 - 758.2, found yl)ethyl]-1-{[3- 758.2
(trifluoromethyl)pyridin-
2-y!]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3-
N yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline
Figure imgf000114_0001
Figure imgf000115_0001
A125 (3S)-6-fluoro-2- Calc'd A
{[(2R,3S)-2-propyl-1- 688.2, found
{[3- 688
(trifluoromethyl)pyridin-
2- yl]carbonyl}-3-{[5- (trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-
3- carboxylic acid
A126 (3R)-7-fluoro-2- Calc'd A
{[(2R,3S)-2-propyl-1- 688.2, found
{[3- 688
(trifluoromethyl)pyridin-
2- yl]carbonyl}-3-{[5- (trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbohyl}-1 , 2^3,4- tetrahydroisoquinoline-
3- carboxylic acid
A127 3-[(3R)-6-fluoro-2- Calc'd A
{[(2R,3S)-2-propyl-1- 716.2, found
{[3- 716
o (trifluoromethyl)pyridin-
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidin- - yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3- yl]propanoic acid
A128 (3S)-7-fluoro-2- Calc'd A
{[(2R,3S)-2-propyl-1- 688.2, found
{[3- 688
(trifluoromethyl)pyridin-
2- yl]carbonyl}-3-{[5- (trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-
3- carboxylic acid
Figure imgf000117_0001
yl]butanoic acid
A134 Br (3R)-6-bromo-2- Calc'd A
{[(2R,3S)-2-propyl-1- 748.1 , found
{[3- 748
(trifluoromethyl)pyridin-
2- yl]carbonyl}-3-{[5- (trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-
3- carboxylic acid
A135 CI 3-[(3S)-6-chloro-2- Calc'd A
is {[(2R,3S)-2-propyl-1- 759.2, found
- 759
(trifluoromethyl)pyridin-
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoqUinolin-3- yl]-N,N- dimethylpropanamide
A136 CI 3-[(3S)-6-chloro-2- Calc'd A
{[(2R,3S)-2-propyl-1- 745.2, found
{[3- 745
(trifluoromethyl)pyridin-
2-yl]carbonyl}-3-{[5-
L.NY0F (trifluoromethyi)thiophe
'i ' n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3- yl]-N- methylpropanamide
A137 (2S)-3-[(3S)-6-chloro-2- Calc'd A
{[(2R,3S)-2-propyl-1- 746.2, found
{[3- 746
(trifluoromethyl)pyridin-
2-yl]carbonyl}-3-{[5- NYO F (trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3- yl]-2-methylpropanoic
acid A138 7-fluoro-2-{[(2R,3S)-2- Calc'd B
propyl-1-{[3- 644.2, found
F N (trifluoromethyl)pyridin- 644
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinoline
A139 7-chloro-2-{[(2R,3S)-2- Calc'd B
propyl-1-{[3- 660.2, found
(trifluoromethyl)pyridin- 660
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3-
0"' yl]carbonyi}-1 , 2,3,4- tetrahydroisoc!juinoline
A140 7-methoxy-2-{[(2R,3S)- Calc'd B
2-propyl-1-{[3- 656.2, found
(trifluoromethyl)pyridin- 656
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinoline
A141 CI (3S)-6-chloro-3-(3- Calc'd B
fluoropropyl)-2- 720.2, found {[(2R,3S)-2-propyl-1- 720
{[3-
(trifluoromethyl)pyridin-
2-yl]carbonyl}-3-{[5-
LNTOF (trifluoromethyl)tniophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinoline
A142 7-bromo-2-{[(2R,3S)-2- Calc'd B
propyl-1-{[3- 704.1 , found
(trifluoromethyl)pyridin- 704
2-yl]carbonyl}-3-{[5-
LYOF (trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline
Figure imgf000120_0001
tetrahydroisoquinolin-3- yl]propanoic acid
A148 3-[(3S)-6-chloro-2- Calc'd A
{[(2R,3S)-2-propyl-1- 809.2, found
{[3- 809
(trifluoromethyl)pyridin-
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinolin-3- yl]-N-
(methylsulfonyl)propan
amide
A149 1- {[(3R)-6-fluoro-2- Calc'd A
{[(2R,3S)-2-propyl-1- 771.2, found {[3- 771
(trifluoromethyl)pyridin-
2- yl]carbonyl}-3-{[5- (trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3- yl]carbonyl}piperidin-4- ol
A150 (3R)-6-fluoro-N-(2- Calc'd A hydroxyethyl)-2- 731.2, found {[(2R,3S)-2-propyl-1- 731
{[3-
(trifluoromethyl)pyridin-
2- yl]carbonyl}-3-{[5- (trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-
3- carboxamide
A151 (2R)-N-{[(3R)-6-chloro- Calc'd A
2-{[(2R,3S)-2-propyl-1- 789.2, found {[3- 789
• N 0 (trifluoromethyl)pyridin-
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3- yl]methyl}-2-methoxy-
N-methylpropanamide A152 N-{[(3R)-6-chlorc~2- Calc'd A
{[(2R,3S)-2-propy!-1- 759.2, found
{[3- 759
• 0 (trifluoromethyl)pyridin-
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3- yl]methyl}-N- methylpropanamide
A153 (2S)-2-{[(3R)-6-fluoro- Calc'd A
2-{[(2R,3S)-2-propyl-1- 758.2, found
{[3- 758
0 (trifluoromethyl)pyridln- 2-yl]carbohyl}-3-{[5- (trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinbliH-3- yl]methyl}-3- methylbutanoic acid
A154 2-{[(2R,3S)-2-prbpyl-1- Calc'd B
{[3- 670.2, found
(trifluoromethyl)pyridin- 670
2-yl]carbonyl}-3-{[5-
(trifluorofaethyljthiophe
C YO F n-3-yl]oxyjpiperidin-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquifioline-
4-carboxylic acid
A155 (3S)-6-chloro-3-(3- Calc'd A morpholin-4-yipropyl)- 787.3, found 2-{[(2R,3S)-2-propyl-1- 787
{[3-
(trifluoromethyl)pyridin- TO F 2-yl]carbonyl}-3-{[5- a (trifluoromethyl)thiophe
n-3-yl]oxy}pipehdin-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline A156 (3S)-6-chloro-3-{3- Calc'd A
[(2S)-2- 815.3, found
(methoxymethyl)pyrroli 815
Λ Ν din-1-yl]propyl}-2- {[(2R,3S)-2-propyl-1- {[3-
(trifluoromethyl)pyridin-
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)tniophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinoline
A157 3-[(3R)-6,7-difluoro-2- Calc'd A
{[(2R,3S)-2-propyl-1- 734.2, found
{[3- 734
(trifluoromethyl)pyridin-
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3- yl]propanoic acid
A158 (2R)-N-{[(3S)-6-fluoro- Calc'd B
2-{[(2R,3S)-2-propyl-1- 759.2, found {[3- 759
■ Ν 0 (trifluoromethyl)pyridin-
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3- yl]methyl}-2-hydroxy-N- methylpropanamide
A159 2,2-difluoro-N-{[(3S)-6- Calc'd B
fluoro-2-{[(2R,3S)-2- 765.2, found propyl-1-{[3- 765
F 0 (trifluoromethyl)pyridin-
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3-
Cv yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3- yl]methyl}-N- methylacetamide A160 (3S)-6-fluoro-3-[(4- Calc'd B
methylpiperazin-1- 770.3, found yl)carbonyl]-2- 770
{[(2R,3S)-2-propyl-1-
{[3-
(trifluoromethyl)pyridin-
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinoline
A161 (2R)-3-[(3S)-6-chloro-2- Calc'd A
{[(2R,3S)-2-propyl-1- 776.2, found
{[3- 776
■ N 0 (trifluoromethyl)pyridin-
2-yl]carbonyl}-3-{[5-
LNYOF (trifluoromethyi)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinolin-3- yl]-2-
(methoxymethyl)propan
oic acid
A162 1- {[(3S)-6-fluoro-2- Calc'd B
{[(2R,3S)-2-propyl-1- 757.3, found {[3- 757
(trifluoromethyl)pyridin-
2- yl]carbonyl}-3-{[5- (trifluoromethyl)thiophe
n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3- yl]methyl}piperidin-4-ol
A163 (2R)-N-{2-[(3R)-6- Calc'd A
fluoro-2-{[(2R,3S)-2- 773.3, found propyl-1-{[3- 773
(trifluoromethyl)pyridin-
2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophe
5 n-3-yl]oxy}piperidin-3- yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3- yl]ethyl}-2-hydroxy-N- methylpropanamide
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
n cates 50 o - n , n cates 50 o n - u .
Example 2: HDM2 Activity
The compounds were evaluated to determine activity at the HDM2 protein by known methods such as the fluorescence polarization screening assay that measures the inhibitory concentration that achieves 50% of maximal activity (FP IC5o) and the dissociation constant for inhibitor binding (FP Ki). [Zhang et al., J. Analytical Biochemistry 331 : 138-146 (2004)].
Additionally, compounds can be tested for activity at the HDM2 protein using the Cell Viability Assay, which measures the number of viable cells in culture after treatment with the inventive compound for a certain period of time e.g. 72 hours based on quantitation of the ATP present (Cell Viability. IC5o). [CellTiter-Glo® Luminescent Cell Viability Assay from Promega].
Example 3: CYP Inhibition
In order to assess the potential for inhibition of CYP3A4, human liver microsomes were incubated with several concentrations of the compounds of the invention (0 to 30 mM), 1 mM reduced nicotinamide adenine dinucleotide phosphate (NADPH) and probe substrate testosterone (100 mM) at 37°C for 13 min. The CYP3A4 activity was measured by the formation of the specific metabolite, 6b-hydroxy-testosterone. The concentrations of the metabolite formed after incubation were determined by LC-MS/MS using a standard curve. The concentrations at which 50% of the initial enzyme activity was inhibited (IC50) were determined from the graph of compound concentrations versus percent of inhibition.
Figure imgf000130_0001
compound concentrations versus percent o inh bit on.
To evaluate time-dependent inhibition, compounds at the stated concentrations were pre-incubated with human liver microsomes for 30 min at 37°C in the presence of NADPH and in the absence of substrates. After the preincubation step, the CYP substrates were added at the previously stated concentrations and the reactions were allowed to proceed as indicated in the previous paragraph.

Claims

What is claimed is:
1. A compoun
Figure imgf000131_0001
I
wherein:
X is CR3 or N;
Y is CR3 or N;
Ring B is a 5 or 6-membered heteroaryl ring or phenyl;
R1 is independently selected from H, halo, CN, (CRa 2)nR8, -N(R8)2, (C3- C6)cycloalkylCOOR8, (CRa 2)nCOOR8, (CRa 2)nC(0)NRaR8,
(CRa 2)nC(0)NRaS02R8, (CRa 2)nNRaC(0)R8, (CRa 2)nOR8, (CRa 2)nC(0)R8 and (CRa 2)nO(CRa 2)nCOORa;
R2 is independently selected from H, halo, CN, amide, aryl, heterocyclic,
(CRa 2)nCOOR8, -N(Ra)2 , (CRa 2)nORa, (CRa 2)nSRa and -S02Ra, wherein the aryl or heterocyclic is optionally subtituted with one to three substituents selected from cyano, hydroxy, amide, halo and methoxy;
Provided that R1 and R2 are not both H;
R3 is independently selected from the group consisting of: H, cyano, hydroxy, and alkoxy; R4 is heteroaryl which is optionally substituted with halo, halo-(Ci-C6)alkyl, (Cr C6)alkyl, or -(Ci-C6)alkoxy;
R5 is H, (Ci-C6)alkyl, (Ci-Ce)alkenyl, (Ci-C6)alkynyl, (CRb 2)tCOOH, (CRb 2)tN(R9)2, (CRb 2)tOR9 or (CRb 2)tR9 ;
R6 is independently (Ci-C6)alkyl;
R7 is haloalkyl, -NRaC(O)Ra, or C(0)N(Ra)2;
R8 is independently selected from H, halo, OH, CN, (Ci-C6)alkyl, (C3- Cejcycioalkyl, heterocylic, heterocyclenyl, heteroaryl, (Ci-Ce)alkylheterocyclic, (Ci-C6)alkylheterocyclenyl and (Ci-C6)alkylheteroaryl, wherein said alkyl, cycloalkyl, heterocyclic, heterocyclenyl and heteroaryl is optionally substituted with (Ci-C6)alkyl, (CRa 2)nORa, -N(Ra)2, (CRa 2)nCOORai (CRa 2)nC(O)NRaRa, or (CRa 2)nNRaC(O)Ra.
R9 is independently H, (CrC6)alkyl, (C3-C8)cycloalkyl, heteroaryl, Heterocyclenyl or heterocyclic, wherein the alkyl, cycloalkyl, heteroaryl, heterocyclenyl and heterocyclic is optionally substituted with (C C6)alkyl, (C3-C8)cyclbaikyl,
(CRa 2)nCOOH, or (CRa 2)nORb;
R10 is independently (d-C6)alkyl;
Ra is independently H or (CrC6)alkyl, wherein the alkyl is optionally substituted with (Co-C6)alkyl-OH or -(C0-C6)alkylOMe; and
Rb is independently H or (Ci-C6)alkyl;
m is 1 , 2, or 3;
n is independently 0, 1 , 2, 3, 4 or 5;
p is 0, 1 , or 2;
q is 0, 1 , 2, or 3;
r is 1 , 2 or 3;
t is 0, 1 , 2 or 3 . or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 , wherein
X is CR3 or N;
Y is CR3 or N; Ring B is a 5 or 6-membered heteroaryl ring or phenyl;
R1 is independently selected from halo, CN, (CRa 2)nR8, -N(R8)2, (C3- C6)cycloalkylCOOR8, (CRa 2)nCOOR8, (CRa 2)nC(0)NRaR8,
(CRa 2)nC(0)NRaS02R8, (CRa 2)nNRaC(0)R8, (CRa 2)nOR8, (CRa 2)nC(O)R8 and (CRa 2)nO(CRa 2)nCOORa;
R2 is independently selected from H, halo, CN, amide, aryl, heterocyclic,
(CRa 2)nCOOR8, -N(Ra)2 , (CRa 2)nORa, (CRa 2)nSRa and -S02Ra, wherein the aryl or heterocyclic is optionally subtituted with one to three substituents selected from cyano, hydroxy, amide, halo and methoxy;
R3 is independently selected from the group consisting of: H, cyano, hydroxy, and alkoxy;
R4 is heteroaryl which is optionally substituted with halo, halo-(Ci-C6)alkyl, (Cr C6)alkyl, or -(Ci-C6)alkoxy;
R5 is H, (C C6)alkyl, (CrCeJalkenyl, (d-Ceialkynyl, (CRb 2)tCOOH, (CRb 2)tN(R9)2, (CRb 2)tOR9 or (CRb 2)tR9 ;
R6 is independently (Ci-C6)alkyl;
R7 is haloalkyl, -NRaC(0)Ra, or C(0)N(Ra)2;
R8 is independently selected from H, halo, OH, CN, (Ci-C6)alkyl, (C3-
C8)cycloalkyl, heterocylic, heterocyclenyl, heteroaryl, (Ci-C6)alkylheterocyclic, (Ci-C6)alkylheterocyclenyl and (Ci-C6)alkylheteroaryl, wherein said alkyl, cycloalkyl, heterocyclic, heterocyclenyl and heteroaryl is optionally substituted with (Ci-C6)alkyl, (CRa 2)nORa, -N(Ra)2, (CRa 2)nCOORa, (CRa 2)nC(O)NRaRa, or
(CRa 2)nNRaC(O)Ra.
R9 is independently H, (CrC6)alkyl, (C3-C8)cycloalkyl, heteroaryl, heterocyclenyl or heterocyclic, wherein the alkyl, cycloalkyl, heteroaryl, heterocyclenyl and heterocyclic is optionally substituted with (Ci-C6)alkyl, (C3-C8)cycloalkyl,
(CRa 2)nCOOH, or (CRa 2)nORb;
R10 is independently (C^C6)a\Wy\;
Ra is independently H or (Ci-C6)alkyl, wherein the alkyl is optionally substituted with (C0-C6)alkyl-OH or -(C0-C6)alkylOMe; and
Rb is independently H or (Ci-C6)alkyl;
m is 1 , 2, or 3;
n is independently 0, 1 , 2, 3, 4 or 5; p is 0, 1 , or 2;
q is 0, 1 , 2, or 3;
r is 1 , 2 or 3;
t is 0, 1 , 2 or 3 .
3. The compound of claim 1 , wherein R4 is
thienyl, optionally substituted with CF3, CBr3, CCI3, CH3, Br, CI, F, or -OCH3.
4. The compound of claim 1 , wherein R4
Figure imgf000134_0001
5. The compound of claim 1 under Formula II,
Figure imgf000134_0002
wherein:
X is CH and Y is N, or X is N and Y is CH;
Ring B is a 5 or 6-membered heteroaryl ring or phenyl;
R1 is independently selected from H, halo, CN, (CRa 2)nR8, -N(R8)2, C3- CecycloalkylCOOR8, (CRa 2)nCOOR8, (CRa 2)nC(0)NRaR8,
(CRa 2)nC(0)NRaS02R8, (CRa 2)nNRaC(0)R8, (CRa 2)nOR8, (CRa 2)nC(0)R8 and (CRa 2)nO(CRa 2)nCOORa;
R2 is independently selected from H, halo, CN, amide, aryl, heterocyclic,
(CRa 2)nCOOR8, -N(Ra)2 , (CRa 2)nORa, (CRa 2)nSRa and -S02Ra, wherein the aryl or heterocyclic is optionally subtituted with one to three substituents selected from cyano, hydroxy, amide, halo and methoxy;
Provided that R1 and R2 are not both H;
R5 is H, (CrC6)alkyl, (Ci-C6)alkenyl, (CrC6)alkynyl, (CRb 2)tCOOH, (CRb 2)tN(R9)2, (CRb 2)tOR9 or (CRb 2)tR9 ; R8 is independently selected from H, halo, OH, CN, (d-C6)alkyl, (C3- C8)cycloalkyl, heterocylic, heterocyclenyl, heteroaryl, (Ci-C6)alkylheterocyclic, (Ci-C6)alkylheterocyclenyl and (CrC6)alkylheteroaryl, wherein said alkyl, cycloalkyl, heterocyclic, heterocyclenyl and heteroaryl is optionally substituted with (Ci-Ce)alkyl, (CRa 2)nORa, -N(Ra)2, (CRa 2)nCOORa, (CRa 2)nC(O)NRaRa, or (CRa 2)nNRaC(O)Ra.
R9 is independently H, (Ci-C6)alkyl, (C3-C8)cycloalkyl, heteroaryl, heterocyclenyl or heterocyclic, wherein the alkyl, cycloalkyl, heteroaryl, heterocyclenyl and heterocyclic is optionally substituted with (Ci-C6)alkyl, (C3-C8)cycloalkyl,
(CRa 2)nCOOH, or (CRa 2)nORb;
Ra is independently H or (Ci-C6)alkyl, wherein the alkyl is optionally substituted with (Co-C6)alkyl-OH or (C0-C6)alkylOMe; arid
Rb is independently H or (Ci-C6)alkyl;
m is 1 or 2;
n is independently 0, 1 , 2, 3 or 4;
r is 1 or 2 ;
t is 0, 1 or 2.
Figure imgf000135_0001
wherein
R1 is selected from (C3-C6)cycloalkylCOORa (CRa 2)nCOORa,
(CRa 2)nO(CRa 2)nCOORa, and (CRa 2)nC(O)NRaSO2R8;
and all other substituents are as defined in claim 5.
7. The compound of claim 5 under Formula III:
Figure imgf000136_0001
wherein
R1 is -cyclopentyl-COOH, (CRa 2)nCOOH, (CRa 2)nO(CRa 2)nCOOH ,
(CRa 2)nC(0)NRaS02Ra, methoxymethyl, hnorpholinylmethyl, or C(0)NH2, wherein n is 0, 1 , 2, 3 or 4, and all other substituents are as defined in claim 5.
8. The compound of any one of claims 1-7, wherein R1 is
(CRa 2)nCOORa.
9. The compound of claim 7, wherein R1 is (CH2)nCOOH, and n is 2 or
3.
10. The compound of any one of claims 1-9, wherein R2 is halo.
11. The compound of claim 10, wherein R2 is CI or Br. 5 under Formula VA:
Figure imgf000136_0002
Wherein R is selected from (C3-C6)cycloalkylCOORa (CRa 2)nCOORa,
(CRa 2)nO(CRa 2)nCOORa, and (CRa 2)nC(0)NRaS02R8;
R2 and R2' are independently H, Br or CI.
and all other substituents are as defined in claim 5.
13. The compound of any one of claims 1-12, wherein R5 is methyl, CH(CH3)COOH, CH2CH2COOH or heterocyclic, said heterocyclic optionally substituted with (C C3)alkyl, (C3-C5)cycloalkyl, (CRa 2)npOOH, or (CRa 2)nORb .
14. The compound of claim 1 selected from the group consisting of:
2-[(2R,3S)-3-[(7-chloro-3,4-dihydroisoqum
(trifluoromethyl)pyridin-3-yl]carbonyl}-3-{[5-(trifluoromethyl)thi6phen-3- yl]oxy}piperidin-2-yl]-N,N-bis(2-methoxyethyl)ethihamine;
2-[(2R,3S)-3-[(6-chloro-3,4-dihydroisoquinolin-2(iH)-yl)carbonyl]-1-{t4-
(trifluoromethyl)pyridin-3-yl]carbonyl}-3-{[5-(triflubrbmethyl)thiophen-3- yl]oxy}piperidin-2-yl]-N,N-bis(2-methoxyethyl)ethanamine;
7-chloro-2-{t(2R,3S)-2-(2-morpholin-4-ylethyl)-1-i[4-(trifluoromethyl)pyridin-3- yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-
1 ,2,3,4-tetrahydroisoquinoline;
6-chloro-2-{[(2R,3S)-2-(2-morpholin-4-ylethyl)-1-{[4-(trifluoromethyl)pyridin-3- yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}- 1 ,2,3,4-tetrahydroisoquinoline;
2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinoline-7-carbonitrile;
2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinoline-7-carboxamide;
6-fluoro-2-{[(2R,3S)-2-(2-morpholin-4-ylethyl)-1-{[3-(trifluoromethyl)pyridin-2- yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}- 1 ,2,3,4-tetrahydroisoquinoline; 5-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4, 5,6,7- tetrahydrothieno[3,2-c]pyridine;
ethyl 5-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidiri-3-yl]carbonyl}-4, 5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxylate;
5- {[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidiri-3-yl]carbonyl}-4,5,6,7- tetrahydrothleno[3,2-c]pyridine-2-carboxylic acid;
2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-6-amine;
6- chloro-1-(morpholin-4-ylmethyl)-2-{[(2R,3S)-2-propyl-1-{[3- (trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluor0methyl)thiophen-3- yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4-tetrahydroisoqUinoline;
2-chloro-5-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2^yi]carbonyi}- (triTluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4, 5,6,7- tetrahydrothieno[3,2-c]pyridine-4-carboxylic acid;
2-chloro-5-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4, 5,6,7- tetrahyd roth ieno[3 , 2-c]py rid i ne-4-carboxyl ic acid ;
6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1-(pyrrolidin-1- ylmethyl)-1 ,2,3,4-tetrahydroisoquinoline;
6-chloro-1-(methoxymethyl)-2-{[(2R,3S)-2-(2-pyrrolidin-1-ylethyl)-1-{[3-
(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3- yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4-tetrahydroisoquinoline;
6-chloro-1-(methoxymethyl)-2-{[(2R,3S)-2-(2-morpholin-4-ylethyl)-1-{[3-
(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3- yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4-tetrahydroisoquinoline;
[(2R,3S)-3-{[6-chloro-1-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)- yl]carbonyl}-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-2-yl]acetic acid; 2-chloro-6-{[(2R,3S)-2-propyl-1-{[3-(trifl^^
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4, 5,6,7- tetrahydrothieno[2,3-c]pyridine-7-carboxylic acid;
2- (1 -{2-[(2R,3S)-3-{[6-chloro-1 -(methoxymethyl)-3,4-dihydroisoquinolin-2(1 H)- yl]carbonyl}-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-2-yl]ethyl}piperidin-4-y^
6-chloro-2-{[(2R,3S)-2-{2-[4-(2-methoxyethyl)piperazin-1-yl]ethyl}-1-{[3- (trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3- ylloxyJpiperidin-S-yllcarbonylJ-l-imethoxymethy -I ^.S^-tetrahydroisoquinoline; N-{2-[(2R,3S)-3-{[6-chloro-1-(methoxymethyl)-3,4-dihydroisoquinolin-2(1 H)- yl]carbonyl}-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-2-yl]ethyljtetrahydro-2H-pyran-4- amine;
3- (2-chloro-5-{[(2R,3S)-2-propyl-1-{[3-(triflu0romethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4, 5,6,7- tetrahydrothieno[3,2-c]pyridin-4-yl)propanoic acid;
3-(2-chloro-5-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4,5,6,7- tetrahydrothieno[3,2-c]pyridin-4-yl)propanamide;
3-(2-chloro-5-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yi]carbonyl}-4, 5,6,7- tetrahydrothieno[3,2-c]pyridin-4-yl)-2,2-dimethylpropanoic acid;
3-(2-chloro-5-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-^ (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4, 5,6,7- tetrahydrothieno[3,2-c]pyridin-4-yl)-2,2-dimethylpropanoic acid;
3-(2-chloro-5-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{^
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4, 5,6,7- tetrahydrothieno[3,2-c]pyridin-4-yl)-N-methylpropanamide;
ethyl 2,2-dimethyl-3-(6-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2- yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}- 4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)propanoate; 2,2-dimethyl-3-(6-{[(2R,3S)-2-propy^
{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonylH
Figure imgf000140_0001
2-chloro-N-methyl-5-{[(2R,3S)-2-propyl-1-{[3-(trif uorbmethyl)pyrid n- - yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]0xy}piperidin-3-yi]carbonyl}'-
4,516 -tetrahydrothieno[3,2-c]pyridine-4-carboxamide;
2- chloro-5-{[(2R,3S)-2-propyl-1-{[3-(trifl^^
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbohyl}-4-(pyrroiidi
ylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine;
3- (2-chloro-5-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl^ (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4, 5,6,7- tetrahydrothieno[3,2-c]pyridin-4-yl)-N-(methylsulfonyl)propanamide;
3-(2-chloro-5-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4, 5,6,7- tetrahydrothieno[3,2-c]pyridin-4-yl)-N-(methylsulfonyl)propanamide;
{[(3R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridih-2-yi]carb^ {[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3-yl]methoxy}acetic acid;
3-(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[ (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinolin-1-yl)propanoic acid; 5-(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yi]carbonyl}-3- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)pentanoic acid;
5-(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5 (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)pentanoic acid;
3-(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5 (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)propanoic acid;
5- (6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3^ (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbohyl}-1 ,2,3,4- tetrahydroisoquinolin-1-yl)pentanoic acid;
3-(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5 (trifluoromethyl)thiophen-3-yl]oxy}piperidih-3-yl]cai-bonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)propanoic acid;
3-[(1 R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbon 3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl]propanoic acid;
2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-6-carbonitrile;
6- methoxy-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5 (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline;
6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline;
6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline;
6-bromo-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline; 3-(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4-
Figure imgf000142_0001
tetrahydroisoquinolin-1-yl)acetic acid;
3-(6-bromo-2-{[(2R,3S)-2-propyl-1-{[3-(t^
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbohyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)propanoic acid;
3-(6-bromo-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridih-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)propanoic acid;
3-(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)-N-(2H-tetrazol-5-ylmethyl)propanamide;
3-(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinolin-1-yl)-N-(2H-tetrazol-5-ylmethyl)propanamide;
3-(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)-N-(methylsulfonyl)propanamide; 6-phenyl-2-{[(2R,3S)-2-propyl-1-{[3-(trifl^^
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline;
3-(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(^
(trifluoromethyl)thiophen-3-yl]oxy}piperidiri-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)-N-(methylsulfonyl)propanamide;
3-(6-chloro-2-{[(2R,3S)-2-propyM-{[3-(trffl^
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)-2,2-dimethylpropanoic acid;
3-(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoi m
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbbnyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)-2,2-dimethylpropanoic acid;
2- {[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridiri-2-yljcarbonyl}-3-n
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-6-thiophen-3^^ tetrahydroisoquinoline;
3- (6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trffl^
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)-N-(2H-tetrazol-5-ylmethyl)propanamide;
3- (6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl^ (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)-2,2-dimethyl-N-(methylsulfonyl)propanamide;
(6-bromo-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)acetic acid;
3-(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-n (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)-2,2-dimethylpropanenitrile;
(6-bromo-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinolin-1-yl)acetic acid;
4- (6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyi}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)butanoic acid; 4-(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbony^
Figure imgf000144_0001
tetrahydroisoquinolin-1-yl)butanoic acid;
6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{ (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carb0nyl}-1 ,2,3,4- tetrahydroisoquinoline-1 -carboxamide;
6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoror†iethyl)pyridin-2-yl]carbonyl^
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carb0hyl}-1 , 2,3,4-
Figure imgf000144_0002
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-1 -carboxamide;
6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluorometHyl)pyridin-2-yl]carb
(trifluoromethyl)thiophen-3-yl]oxy}piperidiri-3-yi]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-1-carbonitrile;
3-[(1 R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{^
3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinolin-1-yl]-N-cyanopropanamide;
3- [(1 S)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]c
3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,^
tetrahydroisoquinolin-1 -yl]-N-cyanopropanamide;
4- [(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-^
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)acetyl]piperazin-2-one;
1 -[(6-chloro-2-{[(2R,3S)-2-propyl-1 -{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-i , 2,3,4- tetrahydr0isoquinolin-1-yl)acetyl]piperidin-4-ol;
N,N-dimethyl-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3- {[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-6-amine;
4-[(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3^ (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)acetyl]piperazin-2-one; 1- [(6-chloro-2-{[(2R,3S)-2-propyl-1^
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4-
Figure imgf000145_0001
y car ony - - - r uorome y op en- -y oxy p pfer n- -y car on
1 ,2,3,4-tetrahydroisoquinoline;
2-(4-{3-[(1 R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifiuoromem^^^
yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-
1 ,2,3,4-tetrahydroisoquinolin-1-yl]propanoyl}piperazlri-1-yl)ethan0i;
2-{4-[(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yijcarbonyl}-3-
{[5-(triflUoromethyl)thi0phen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3^
tetrahydroisoquinolin-1-yl)carbonyl]piperazin-1-yl}ethanol;
2-{4-[(6-fluoro-2-{[(2R,3S)-2-propyl-1-^
{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)carbonyl]piperazin-1-yl}ethanol;
2-{4-[(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbony^
{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)carbonyl]piperazin-1-yl}ethanol;
[(2R,3S)-3-[(1-carbamoyl-6-chloro-3,4-dihydroisoquinolin-2(1 H)-yl)carbonyl]-1-{[3-
(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3- yi]oxy}piperidin-2-yl]acetic acid; 3-(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)cycl6pentanecarboxylic acid;
[(2R,3S)-3-[(1-carbamoyl-6-chloro-3,4-dihydroisoquinolin-2(1 H)-yl)carbonyl]-1-{[3- (trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3- yl]oxy}piperidin-2-yl]acetic acid;
1-{3-[(1R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2- yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy} iperidin-3-yl]carbonyl}- 1 ,2,3,4-tetrahydroisoquinolin-1-yl]propanoyl}piperidine-4-carboxylic acid;
1-{3-[(1S)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluorbmethyl)pyridi
yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oXy}piperidin-3-yl]carbonyl}- 1 ,2,3,4-tetrahydroisoquinolin-l -yl]propanoyl}piperidihe-4-carboxylic acid;
6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]car^
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbcinyl}-1 , 2,3,4- tetrahydroisoquinoline-1-carboxylic acid;
6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-^
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinoline-1-carboxylic acid;
6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(^
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-1-carboxylic acid;
(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3^ (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)methanol;
6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahyd roisoq u i nol i ne- 1 -carboxyl ic acid ;
(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyi)pyridin-2-yl]carbonyl}-3-n (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)methanol;
6-chloro-1-(methoxymethyl)-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2- yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}- 1 ,2,3,4-tetrahydroisoquinoline; 6-chloro-1-(methoxymethyl)-2-{[(2R^
yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}- 1 ,2,3,4-tetrahydroisoquinoline;
3-(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinolin-1-yl)-2,2-dimethylpropanoic acid;
6-chloro-1-(2-hydroxyethyl)-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2- yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}- 1 ,2,3,4-tetrahydroisoquinoline-l -carboxamide;
6-fluoro-2-[(2-propyl-3-[4-(trifluoromethoxy)phenoxy]-1-{[3-(trifluor0methyl)pyridm
2- yl]carbonyl}piperidin-3-yl)carbonyl]-1 ,2,3,4-tetrahydroisoquinoline;
3- [(1S)-6-chloro-2-{[(2R,3S)-2-propyl-3-[4-(trifluordmethoxy)phenoxy]-^
(trifluoromethyl)pyridin-2-yl]carbonyl}piperidin-3-yl]carbbnyl}-1 , 2,3,4- tetrahydroisoquinolin-1 -yl]propanoic acid;
N-{2-[(2R,3S)-3-[(6-chloro-3,4-dihydroisoquinolin-2(1 H)-yl)carbonyl]-1-{[3-
(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3- yl]oxy}piperidin-2-yl]ethyl}tetrahydro-2H-pyran-4-amine;
6-chloro-2-{[(2R,3S)-2-prop-2-en-1-yl-1-{[3-(trifluorbmethyl)pyridin-2-yi]carbonyl}-
3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-1-carboxylic acid;
6-chloro-2-{[(2R,3S)-2-[2-(4-ethylpiperazin-1-yl)ethyl]-1-{[3-
(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3- yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline;
6-chloro-2-{[(2R,3S)-2-[2-(4-methylpiperazin-1-yl)ethyl]-1-{[3-
(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3- yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4-tetrahydroisoquinoline;
6-chloro-2-{[(2R,3S)-2-{2-[4-(cyclopropylmethyl)piperazin-1-yl]ethyl}-1-{[3-
(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3- yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4-tetrahydroisoquinoline;
2-[(2R,3S)-3-[(6-chloro-3,4-dihydroisoquinolin-2(1 H)-yl)carbonyl]-1-{[3-
(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3- yl]oxy}piperidin-2-yl]-N-(2-methoxyethyl)-N-methylethanamine; 6-chloro-2-{[(2R,3S)-2-{2-[4-(2-methoxyethyl)piperazin-1-yl]ethyl}-1-{[3-
(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3- yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4-tetrahydroisoquinoline;
2-(1 -{2-[(2R,3S)-3-[(6-chloro-3,4-dihydroisoquinolin-2(1 H)-yl)carbonyl]-1 -{[3-
(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3- yl]oxy}piperidin-2-yl]ethyl}piperidin-4-yl)-2-methylpropanoic acid;
[(3S)-2-{[(2R,3S)-2-propyl-1-{[4-(trifluoromethyl)pyridin-3-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophen-3-yl]oxy}piperidiri-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3-yl]methanol;
2- {[(2R,3S)-2-propyl-1-{[4-(trifluoromethyl)pyridin-3-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisbquinolin-8-ol;
(2-{[(2R,3S)-2-propyl-1-{[4-(trifluoromethyl)pyridin-3-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinolin-1-yl)acetic acid;
(3R)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(triflUoromethyl)pyridin-2-yl]carbonyl}-3- {[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-3-carboxylic acid;
3- [(3S)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}- 3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3-yl]propanoic acid;
(3S)-6-fluorb-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3- {[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4- tetra hyd roisoq u inol i ne-3-carboxy I ic acid ;
(3R)-7-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3- {[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-3-carboxylic acid;
3-[(3R)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}- 3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3-yl]propanoic acid;
(3S)-7-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3- {[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-3-carboxylic acid; (3R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl^ {[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline-3-carboxylic acid;
3-[(3S)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbon 3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}pipeHdin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3-yl]propanoic acid;
5-[(3S)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}- 3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinolin-3-yl]pentanoic acid;
3-[(3S)-7-fluoro-2-{[(2R,3S)-2-propyl-1-{^
3-{[5-(trifluoromethyi)thiophen-3-yl]oxy}piperidin-3-yl]carbonyi}-1 , 2,3,4- tetrahydroisoquinolin-3-yl]propanoic acid;
3-[(3R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yO^
3-{[5-(trifluoromethyl)thio^
tetrahydroisoquinolin-3-yl]butanoic acid;
(3R)-6-bromo-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyi}^ {[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinoline-3-carboxylic acid;
3-[(3S)-6-chloro-2-{[(2R,3S)-2-propy 1-{[3-(trifluoromethyl)pyndin-2-ylj
3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3-yl]-N,N-dimethylpropanamide;
3-[(3S)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}- 3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3-yl]-N-methylpropanamide;
(2S)-3-[(3S)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2- yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}- 1 ,2,3,4-tetrahydroisoquinolin-3-yl]-2-methylpropanoic acid;
7-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline;
7-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinoline; 7-methoxy-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carb6nyl}-1 , 2,3,4-
Figure imgf000150_0001
3- {[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yljcarbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3-yl]-N-hydroxypropanamide;
4- [(3S)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoroHethyl)pyridin-2-yi]barb0hyl}- 3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yi]carbonyl}-1 ,2,3j4- tetrahydroisoquinolin-3-yl]butanoic acid;
3-[(3R)-7-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yi]carb6nyl}- 3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3-yl]propanoic acid;
3-[(3S)-6-chloro-2-{[(2R,3S)-2-propyl-H^
3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3-yl]-N-(methylsulfonyl)propanamide;
1-{[(3R)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}- 3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3-yl]carbonyl}piperidin-4-ol;
(3R)-6-fluoro-N-(2-hydroxyethyl)-2-{[(2R,3S)-2-propyl-1-{[3-
(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3- yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide; (2R)-N-{[(3R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2- yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-
1 ,2,3,4-tetrahydroisoquinolin-3-yl]methyl}-2-methoxy-N-methylpropanamide;
N-{[(3R)-6-chloro-2-{[(2R>3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl^
3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,^
Figure imgf000151_0001
yl]carbonyl -3- [5- tr uoromet y t op en- -y oxy p per n- -y car ny - 1 ,2,3,4-tetrahydroisoquiholin-3-yl]propanoic acid;
(2R)-N-{[(3S)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifiuoromethyl)pyridin-2- yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyi}- 1 ,2,3,4-tetrahydroisoquinolin-3-yl]methyl}-2-hydroxy-N-methylpropanamide; 2,2-difluoro-N-{[(3S)-6-fluoro-2^
yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-
1 ,2,3,4-tetrahydroisoquinolin-3-yl]methyl}-N-methyiacetamide;
(3S)-6-fluoro-3-[(4-methylpiperazin-1-yl)carbonyl]-2-{[(2R,3S)-2-propyl-1-{[3-
(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3- yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4-tetrahydroisoquinoline;
(2R)-3-[(3S)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2- yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-
1 ,2,3,4-tetrahydroisoquinolin-3-yl]-2-(methoxymethyl)propanoic acid; 1-{[(3S)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]ca^
Figure imgf000152_0001
tetrahydroisoquinolin-3-yl]butan-2-ol;
1- {[(3R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-^
3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-3-yl]carbonyl}piperidin-4-ol;
(3R)-6-chloro-3-[(4-methoxypiperidin-1-yl)carbonyl]-2-{[(2R,3S)-2-propyl-1-{[3-
(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3- yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4-tetrahydroisoquinoline;
(3R)-1-{[(3R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2- yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}- 1 ,2,3,4-tetrahydroisoquinolin-3-yl]carbonyl}piperidin-3-ol;
6-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-y!]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4, 5,6,7- tetrahydrothieno[2,3-c]pyridine-5-carboxylic acid;
2- chloro-6-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4, 5,6,7- tetrahydrothieno[2,3-c]pyridine-5-carboxylic acid; 6-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5- (trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4, 5,6,7- tetrahydrothieno[2,3-c]pyridine-5-carboxylic acid;
2-chloro-6-{[(2R,3S)-2-propyl-1-{[3-(trifluo
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-5-carboxyiic acid;
(5S)-2-bromo-N-(methylsulfonyl)-6-{[(2R,3S)-2-propyl-1-{[3- (trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3- yl]oxy}piperidin-3-yl]carbonyl}-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5- carboxamide;
6-chloro-1-(2-methylpropyl)-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-^ yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}- 1 ,2,3,4-tetrahydroisoquinoline;
2-[(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]ca^
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydrois0quinolin-1-yl)methyl]-3-methylbutanoic acid;
2-[(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifl^^
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 ,2,3,4- tetrahydroisoquinolin-1-yl)methyl]-3-methylbutanoic acid;
2-[(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyi}-3
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)methyl]-3-methylbutanoic acid;
2-[(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)methyl]-3-methylbutanoic acid; and
[(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(t^
(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1 , 2,3,4- tetrahydroisoquinolin-1-yl)methoxy]acetic acid;
or a stereoisomer thereof;
or a pharmaceutically acceptable salt thereof;
or a pharmaceutically acceptable salt of the stereoisomer thereof.
15. A pharmaceutical composition comprising a therapeutically effective amount of at least one corhpound of any one of claims 1- 14 or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable carrier.
16. A compound according to any one of claims 1 -14 for the treatment of a cancer selected from the group consisting of cancer of bladder, breast, colon, rectum, endometrium, kidney, li er/ lung, head and neck, esophagus, gall bladder, cervix, pancreas, prostrate, larynx, ovaries, stomach, uterus, sarcoma, osteosarcoma, liposarcoma, thyroid cancer, hematopoietic tumors of the lymphoid lineage, hematopoetic tumors of myeloid lineage, myelogenous leukemias, myelodysplasia syndrome, promyelocytic leukemia, tumors of mesenchymal origin, tumors of the central and peripheral nervous system, melanoma, skin (non-melanomal) cancer, mesothelioma (cells), seminoma, teratocarcinoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
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