WO2008016534A1 - Urotensin ii receptor antagonists - Google Patents

Urotensin ii receptor antagonists Download PDF

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Publication number
WO2008016534A1
WO2008016534A1 PCT/US2007/016806 US2007016806W WO2008016534A1 WO 2008016534 A1 WO2008016534 A1 WO 2008016534A1 US 2007016806 W US2007016806 W US 2007016806W WO 2008016534 A1 WO2008016534 A1 WO 2008016534A1
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WIPO (PCT)
Prior art keywords
ethyl
βalkyl
oxo
carbonyl
oxazin
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PCT/US2007/016806
Other languages
French (fr)
Inventor
Shyamali Ghosh
William A. Kinney
Edward C. Lawson
Diane K. Luci
Bruce E. Maryanoff
Francois Maria Sommen
Yongchun Pan
Original Assignee
Janssen Pharmaceutica, N.V.
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Application filed by Janssen Pharmaceutica, N.V. filed Critical Janssen Pharmaceutica, N.V.
Priority to JP2009522801A priority Critical patent/JP5379000B2/en
Priority to CA002659412A priority patent/CA2659412A1/en
Priority to BRPI0714804-6A priority patent/BRPI0714804A2/en
Priority to AU2007281591A priority patent/AU2007281591A1/en
Priority to CN200780036393XA priority patent/CN101522197B/en
Priority to EP07836257A priority patent/EP2049120A4/en
Publication of WO2008016534A1 publication Critical patent/WO2008016534A1/en
Priority to IL196758A priority patent/IL196758A0/en
Priority to HK10102146.7A priority patent/HK1137353A1/en

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Definitions

  • the present invention relates to certain novel compounds, methods for preparing compounds, compositions, intermediates and derivatives thereof and methods for treating or ameliorating a Urotensin-ll mediated disorder. More particularly, the compounds of the present invention are Urotensin-ll receptor antagonists useful for treating or ameliorating Urotensin-ll mediated disorders.
  • Urotensin-ll (U-Il) is a cysteine-linked cyclic peptide, which exerts potent effects on the cardiovascular, renal, pancreatic, and central nervous systems.
  • this substance was isolated from the urophysis (a caudal neurosecretory organ) of the goby fish (GiHichthys mirabilis) as a 12-mer, AGTAD- cyclo(CFWKYC)-V (D. Pearson. J. E. Shively, B. R. Clark, 1. 1. Geschwind, M. Barkley, R. S. Nishioka, H. A. Bern, Proc. Natl. Acad. Sci.
  • U-Il ranges from 11 amino acids in humans to 14 amino acids in mice, always with a conserved cysteine-linked macrocycle, CFWKYC.
  • CFWKYC cysteine-linked macrocycle
  • U-Il receptor was identified (R. S. Ames, H. M. Sarau, J. K. Chambers, R. N. Willette, N. V. Aiyar, A. M. Romanic, C. S. Louden, J. J. Foley, C. F. Sauermelch, R. W. Coatney, Z. Ao, J. Disa, S. D. Holmes, J. M. Stadel, J. D. Martin, W.-S.
  • GPCR G-protein-coupled receptor
  • Kikkawa, H. and Kushida, H. in International Publication WO 2005/072226 disclosed the use of Urotensin-ll antagonists for the prevention and/or treatment of inflammatory bowel diseases including, but not limited to, Crohn's disease, ulcerative colitis, and inflammatory colitis caused by bacteria, ischemia, radiation, drugs, or chemical substances.
  • U-Il has been described as a potential mediator in diabetes. For instance, U-Il was shown to inhibit the release of insulin in the perfused rat pancreas in response to increasing glucose levels (R. A. Silvestre, J. Rod ⁇ guez-Gallardo, E. M. Egido, J. Marco, Horm. Metab. Res. 2001, 33, 379-381). Elevated U-H levels were seen in patients with diabetis mellitus (K. Totsune, K. Takahashi, Z. Arihara, M. Sone,.S. Ito, O. Murakami, Clin. Sci. 2003, 104, 1-5) even without renal failure.
  • Haplotypes in the urotensin Il gene and urotensin Il receptor gene are reported to be associated with insulin resistance and impaired glucose tolerance (K. Ong, L. Wong, Y. Man, R. Leung, Y. Song, K. Lam, B. Cheung, Peptides, 2006, 27(7), 1659-1667).
  • a U-Il antagonist may be useful for the treatment of pain, neurological and psychiatric conditions, migraine, neuromuscular deficit, anxiety disorders and cardiovascular disorders.
  • ICV intracerebroventricular
  • administration of U-Il increases rearing, grooming, and motor activity suggesting a CNS stimulatory activity (J. Gartlon, F. Parker, D. C. Harrison, S. A. Douglas, T. E. Ashmeade, G. J. Riley, Z. A. Hughes, S. G. Taylor, R. P. Munton, J. J. Hagan, J. A. Hunter, D. N. C. Jones, Psychopharmacology 2001 , 155, 426-433).
  • U-M increases Fos expression in the cingulate cortex and periaqueductal grey brain regions important in cognitive, emotional, and motor responses; the perceptions of pain; and panic responses (J. E. Gartlon, T. Ashmeade, M. Duxon, J. J. Hagan, D. N. C. Jones, Eur. J. of Pharmacol. 2004, 493, 95-98).
  • U-Il induces anxiogenic-like responses in rodents in the elevated plus maze and hole-board tests (Y. Matsumoto, M. Abe, T. Watanabe, Y. Adachi, T. Yano, H. Takahashi, T. Sugo, M. Mori, C. Kitada, T. Kurokawa, M.
  • JP 07242662 (also referred to as JP1995242662) describes substituted 4H-benzo[1 ,4]oxazin-3-ones as phospholipase A2 and interleukin 1 inhibitors.
  • PCT Application WO 03/091248 describes 7-fluoro-6- ⁇ 1-[2-(7-fluoro-2- methyl-quinolin-5-yloxy)-ethyl]-piperidin-4-ylmethyl ⁇ -4H-benzo[1 ,4]oxazin-3-one as a 5-HTIA receptor inhibitor.
  • the present invention is directed to a compound of Formula (I):
  • Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I).
  • a process for making a pharmaceutical composition comprising mixing a compound of Formula (I) and a pharmaceutically acceptable carrier.
  • the present invention is further directed to methods for treating or ameliorating a Urotensin ll-mediated disorder.
  • the method of the present invention is directed to treating or ameliorating a Urotensin ll-mediated disorder including, but not limited to, chronic vascular disease, vascular hypertension, heart failure, atherosclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, inflammatory colitis, renal dysfunction, renal failure, renal failure caused by drug induced toxicity, nephrotoxicity and diarrhea caused by anti-neoplastic agents, nephrotoxicity caused by radiocontrast agents and aminoglycosides, post-myocardial infarction, pulmonary hypertension, pulmonary fibrosis, insulin resistance and impaired glucose tolerance, diabetes, diabetic complications, diabetic nephropathy, pain, Alzheimer's disease, convulsions, depression, migraine, psychosis, anxiety, neuromuscular deficit and stroke.
  • the present invention is also directed to methods for producing the instant compounds and pharmaceutical compositions and medicaments thereof.
  • the present invention is directed a compound of Formula (I):
  • Ring A is selected from the group consisting of piperidinyl, 8-aza-bicyclo[3.2.1]oct-2- enyl, 8-aza-bicyclo[3.2.1]octyl and 1,2,3,6-tetrahyclro-pyridinyl;
  • Y is selected from the group consisting of CH 2 , O and S; Li is absent or is selected from the group consisting of -C(O)O-Ri , -C(O)N(Rs)-Ri and -NHC(O)-Ri; l_2 is d- ⁇ alkyl;
  • L 3 is absent or is -C(O)N(Rs)-R 7 ;
  • Ri is selected from the group consisting of Ci ⁇ alkyl, Ci ⁇ alkoxy, aryl, aryl-Ci ⁇ alkyl, C 3 -i4cycloalkyl, heterocyclyl, heterocyclyl-Ci- ⁇ alkyi, heteroaryl and heteroaryl-Ci- ⁇ alkyl, wherein C h alky!
  • Ci- 8 alkoxy is optionally substituted with one, two or three substituents each selected from the group consisting of Ci- 8 alkoxy, halogen, hydroxy and -NHR 6
  • Ci ⁇ alkoxy is optionally substituted with one, two or three substituents each selected from the group consisting of Ci- ⁇ alkoxy, halogen, hydroxy and -NHR 6
  • each instance of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of Ci- ⁇ alkyI, Ci.
  • R 2 is one, two or three substituents each selected from the group consisting of hydrogen, C 1-8 alkyl, Ci- ⁇ alkoxy and halogen;
  • R 3 is one, two or three substituents each selected from the group consisting of hydrogen and C ⁇ alkyl;
  • R4 is one, two or three substituents each selected from the group consisting of hydrogen, C h alky!, Ci- ⁇ alkoxy, hydroxy and halogen;
  • R 5 is selected from the group consisting of hydrogen and Ci-4alkyl
  • Re is selected from the group consisting of Ci- ⁇ alkyl-carbonyl, C-i- ⁇ alkoxy-carbonyl, C M - ⁇ alkyl-NfRsJ-carbonyl, aryl-carbonyl, aryl-Ci- ⁇ alkyl-carbonyl, aryl-Ci- ⁇ alkoxy-carbonyl, aryl-N(Rs)-carbonyl, aryl-Ci- ⁇ alkyl-NfRsVcarbonyl and aryl-Ci- ⁇ alkyl-sulfonyl; and,
  • R7 is selected from the group consisting of Chalky!, aryl, aryl-Ci- ⁇ alkyl,
  • C 3 -i4cydoalkyl Cs-ucycloalkyl-d-ealkyl, heterocyclyl, heterocyclyl-d- ⁇ a'kyl, heteroaryl and heteroaryl-Ci- ⁇ alkyl.
  • An example of the present invention includes a compound of Formula (I) and forms thereof, wherein Ring A is piperidinyl.
  • An example of the present invention includes a compound of Formula (I) and forms thereof, wherein Ring A is 8-aza-bicyclo[3.2.1]oct-2-enyl.
  • An example of the present invention includes a compound of Formula (I) and forms thereof, wherein Ring A is 8-aza-bicyclo[3.2.1]octyl.
  • An example of the present invention includes a compound of Formula (I) and forms thereof, wherein Ring A is 1,2,3,6-tetrahydro-pyridinyl.
  • An example of the present invention includes a compound of Formula (I) and forms thereof, wherein Ring A is substituted with one or two d ⁇ alkyl.
  • An example of the present invention includes a compound of Formula (I) and forms thereof, wherein Y is CH 2 .
  • An example of the present invention includes a compound of Formula (I) and forms thereof, wherein Y is O.
  • An example of the present invention includes a compound of Formula (I) and forms thereof, wherein Y is S.
  • An example of the present invention includes a compound of Formula (I) and forms thereof, wherein
  • Ri is selected from the group consisting of C h alky!, Ci ⁇ alkoxy, aryl-Ci- ⁇ alkyl,
  • Ci- ⁇ alkoxy is optionally substituted with a substituent selected from the group consisting of Ci- ⁇ alkoxy, hydroxy and -NHRe, wherein Ci- ⁇ alkoxy is optionally substituted with -NHR 6 , wherein each instance of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of C 1-8 alkoxy, halogen wherein each instance of heterocyclyl is optionally substituted with oxo, Ci- ⁇ alkyl-carbonyl, Ci- ⁇ alkoxy-carbonyl, aryl-carbonyl, aryl-Ci- ⁇ alkoxy-carbonyl, aryl-Ci ⁇ alkyl-N(R 5 )-carbonyl or aryl-Ci- ⁇ alkyl-sulfonyl.
  • An example of the present invention includes a compound of Formula (I) and forms thereof, wherein Ri is selected from the group consisting of Ci -8 alkyl, C 1- ⁇ alkoxy, phenyl-d- ⁇ alkyl, naphthyl-d- ⁇ alkyl, indanyl, cyclopropyl-d- ⁇ alkyl, cyclohexyl-Ci- ⁇ alkyl, 1 ,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-d- ⁇ alkyi, piperidinyl-d- ⁇ alkyl, piperazinyl-Ci -8 alkyl, furanyl-d- ⁇ alkyl, thienyl-Ci -8 alkyl, imidazolyl-d- ⁇ alkyl, pyridinyl-C 1-8 alkyl and indolyl-d- ⁇ alkyl, wherein d- ⁇ alkyl is optionally substituted with a substituent selected from the
  • d- ⁇ alkoxy is optionally substituted with -NHR 6
  • each instance of phenyl is optionally substituted with one, two or three substituents each selected from the group consisting of d- ⁇ alkoxy, chloro, fluoro, bromo and halo-d- ⁇ alkyl, and wherein each instance of 1 ,2.3,4-tetrahydro-isoquinolinyl, pyrrol idinyl-Ci- 8 alkyl, piperidinyl-d- ⁇ alkyl, piperazinyl-d- ⁇ alkyl is optionally substituted with oxo, Ci- ⁇ alkyl-carbonyl, d- ⁇ alkoxy-carbonyl, aryl-carbonyl, aryl-Ci- ⁇ alkoxy-carbonyl, aryl-d- 8 alkyl-N(R 5 )-carbonyl or aryl-C 1-8 alkyl-sulfonyl.
  • An example of the present invention includes a compound of Formula (I) and forms thereof, wherein R 2 is one substituent selected from the group consisting of hydrogen, d- ⁇ alkyl, Ci- ⁇ alkoxy and halogen.
  • An example of the present invention includes a compound of Formula (I) and forms thereof, wherein R 3 is one or two substituents each selected from the group consisting of hydrogen and d-4alkyl.
  • An example of the present invention includes a compound of Formula (I) and forms thereof, wherein R 4 is one substituent selected from the group consisting of hydrogen, Ci -8 alkyl and halogen.
  • An example of the present invention includes a compound of Formula (I) and forms thereof, wherein R 5 is hydrogen.
  • An example of the present invention includes a compound of Formula (I) and forms thereof, wherein R 5 is C ⁇ alkyl.
  • An example of the present invention includes a compound of Formula (I) and forms thereof, wherein R 6 is selected from the group consisting of Ci- ⁇ alkyl-carbonyl, Ci- ⁇ alkoxy-carbonyl, Ci- ⁇ alkyl-N(Rs)-carbonyl, aryl-Ci- ⁇ alkoxy-carbonyl, aryl-N(R 5 )-carbonyl, aryl-Ci- 8 alkyl-N(R5)-carbonyl and aryl-Ci- ⁇ alkyl-sulfonyl.
  • R 6 is selected from the group consisting of Ci- ⁇ alkyl-carbonyl, Ci- ⁇ alkoxy-carbonyl, Ci- ⁇ alkyl-N(Rs)-carbonyl, aryl-Ci- ⁇ alkoxy-carbonyl, aryl-N(R 5 )-carbonyl, aryl-Ci- 8 alkyl-N(R5)-carbonyl and aryl-Ci- ⁇ alky
  • An example of the present invention includes a compound of Formula (I) and forms thereof, wherein R 6 is selected from the group consisting of Ci- ⁇ alkyl-carbonyl. Ci.8alkoxy-carbonyl, Ci-8alkyl-N(R 5 )-carbonyl, phenyl-Ci- ⁇ aikoxy-carbonyl, phenyl-N(R 5 )-carbonyl, phenyl-Ci- 8 alkyl-N(R 5 )-carbonyl and phenyl-Ci- ⁇ alkyl-sulfonyl.
  • An example of the present invention includes a compound of Formula (I) and forms thereof, wherein R 7 is selected from the group consisting of Ci- ⁇ alkyI and aryl-Ci- ⁇ alkyl.
  • An example of the present invention includes a compound of Formula (I) and forms thereof, wherein R 7 is selected from the group consisting of Ci- ⁇ alkyl and phenyl-Ci- ⁇ alkyl.
  • An example of the present invention includes a compound of Formula (I) and forms thereof, wherein
  • Ring A is selected from the group consisting of piperidinyl, 8-aza-bicyclo[3.2.1]oct-2- enyl, 8-aza-bicyclo[3.2.1]octyl and 1,2,3,6-tetrahydro-pyridinyl;
  • Y is selected from the group consisting of CH 2 , O and S;
  • Li is absent or is selected from the group consisting of -C(O)ORi, -C(O)N(R 5 )-Ri and -NHC(O)-Ri; l_2 is Ci- ⁇ alkyl; L 3 is absent or is -C(O)N(R 5 )-R 7 ;
  • Ri is selected from the group consisting of Ci ⁇ alkyi, Ci- ⁇ alkoxy, aryl-Ci-ealkyl, Ca-ucycloalkyl, and heteroaryl-Ci- ⁇ alkyl, wherein C 1-8 alky1 is optionally substituted with a substituent selected from the group consisting of Ci- ⁇ alkoxy, hydroxy and -NR 6 , wherein Ci- ⁇ alkoxy is optionally substituted with -NHR 6 , wherein each instance of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of Ci- ⁇ alkoxy, halogen and halo-Ci- 8 alkyl, and wherein each instance of heterocyclyl is optionally substituted with oxo,
  • R 2 is one substituent selected from the group consisting of hydrogen, Ci- ⁇ alkyI, Ci- ⁇ alkoxy and halogen;
  • R 3 is one or two substituents each selected from the group consisting of hydrogen and d ⁇ alkyl
  • R 4 is one substituent selected from the group consisting of hydrogen, C h alky! and halogen;
  • Rs is selected from the group consisting of hydrogen and C h alky!
  • Re is selected from the group consisting of Ci- ⁇ alkyt-carbonyl, Ci-8alkyl-N(R5)-carbonyl, aryl-Ci- ⁇ alkoxy-carbonyl, aryl-NfRsJ-carbonyl, aryl-Ci-8alkyl-N(R 5 )-carbonyl and and F? 7 is selected from the group consisting of Ci- ⁇ alkyI and
  • An example of the present invention includes a compound of Formula (I) and forms thereof, wherein
  • Y is selected from the group consisting of CH 2 , O and S;
  • Li is absent or is selected from the group consisting of -C(O)O-Ri, -C(O)N(Rs)-Ri and -NHC(O)-Ri;
  • Re is selected from the group consisting of Ci- ⁇ alkyl-carbonyl, Ci- ⁇ alkoxy-carbonyl,
  • R 7 is selected from the group consisting of C h alky! and phenyl-Ci- ⁇ alkyl.
  • the present invention is directed a compound of Formula (Ia):
  • Y is selected from the group consisting of CH2, 0 and S;
  • Ri is selected from the group consisting of Ci- ⁇ alkyI, Ci- ⁇ alkoxy, aryl, aryl-d- ⁇ alkyl, C 3 -i 4 cycloalkyl, CVi-tcycloalkyl-Ci- ⁇ alkyl, heterocyclyl, heterocyclyl-Ci-ealkyl, heteroaryl and wherein C h alky!
  • Ci- ⁇ alkoxy is optionally substituted with one, two or three substituents each selected from the group consisting of Ci- ⁇ alkoxy, halogen, hydroxy and -NHR 6
  • C-i- ⁇ alkoxy is optionally substituted with one, two or three substituents each selected from the group consisting of Ci-8alkoxy, halogen, hydroxy and -NHR 6
  • each instance of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of Ci- ⁇ alkyl, d- ⁇ alkoxy, halogen and halo-Ci-ealkyl
  • heterocyclyl is optionally substituted with oxo, Ci- 8 alkyl-carbonyl, d- ⁇ alkoxy-carbonyl, Ci.
  • R4 is one, two or three substituents each selected from the group consisting of hydrogen, d- ⁇ alkyl, Ci-aalkoxy, hydroxy and halogen;
  • R 5 is selected from the group consisting of hydrogen and C ⁇ alkyl
  • Re is selected from the group consisting of d- ⁇ alkyl-carbonyl, Ci- ⁇ alkoxy-carbonyl, Ci- ⁇ alkyl-N(R 5 )-carbonyl, aryl-carbonyl, aryl-d- ⁇ alkyl-carbonyl, aryl-d- ⁇ alkoxy-carbonyl, aryl-N(R 5 )-carbonyl, aryl-C 1 - 8 alkyl-N(R 5 )-carbonyl and aryl-Ci- ⁇ alkyl-sulfonyl; and,
  • C 3 -i 4 cycloalkyl Ca- ⁇ cycloalkyl-Ci-ealkyl, heterocyclyl, heterocyclyl-Ci- ⁇ alkyl, heteroaryl and heteroaryl-Ci- ⁇ alkyl.
  • An example of the present invention includes a compound of Formula (Ia) and forms thereof, wherein
  • Y is selected from the group consisting of CH 2 , O and S;
  • Ri is selected from the group consisting of Ci- ⁇ alkyl, Ci- ⁇ alkoxy, phenyl-Ci- ⁇ alkyl, naphthyl-Ci- ⁇ alkyl, indanyl, cyclohexyl-Ci- ⁇ alkyl, 1 ,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-Ci- ⁇ alkyl, piperidinyl-Ci- ⁇ alkyl, piperazinyl-Ci-ealkyl, imidazolyl-Cv ⁇ alkyl.
  • pyridinyl-Ci- ⁇ alkyl an wherein is optionally substituted with a substituent selected from the group consisting of hydroxy and -NRe, wherein is optionally substituted with -NHRe, wherein each instance of phenyl is optionally substituted with one, two or three substituents each selected from the group consisting of chloro, fluoro, bromo and halo-C h alky!, and wherein each instance of 1,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-Ci.
  • R 2 is one substituent selected from the group consisting of hydrogen, C 1-8 alkyl, d- ⁇ alkoxy and halogen;
  • R 3 is one or two substituents each selected from the group consisting of hydrogen and d ⁇ alkyl
  • R4 is one substituent selected from the group consisting of hydrogen, Ci- ⁇ alkyI and halogen;
  • R 5 is selected from the group consisting of hydrogen and C 1-4 alkyl
  • R 6 is selected from the group consisting of C 1-8 alkyl-carbonyl, Ci- ⁇ alkoxy-carbonyl, Ci-8alkyl-N(R 5 )-carbonyl, phenyl-Ci- ⁇ alkoxy-carbonyl, phenyl-N(Rs)-carbonyl, phenyl-Ci- 8 alkyl-N(R 5 )-carbonyl and phenyl-Ci- ⁇ alkyl-sulfonyl; and
  • R 7 is selected from the group consisting of C h alky! and phenyl-Ci- ⁇ alkyl.
  • the present invention is directed a compound of Formula (Ib):
  • Li is absent or is selected from the group consisting of -C(O)O-Ri, -C(O)N(R 5 )-Ri and -NHC(O)-R 1 ;
  • L 2 is Ci- ⁇ alkyl;
  • L 3 is absent or is -C(O)N(R 5 J-R 7 ;
  • Ri is selected from the group consisting of Ci- ⁇ alkyI, Ci- ⁇ alkoxy, aryl, aryi-Ci-ealkyl, C 3 -i 4 cycloalkyl, C3-i4cycloalkyl-Ci-ealkyl, heterocyclyl, heterocyclyl-Ci- ⁇ alkyl, heteroaryl and heteroaryl-d- ⁇ alkyl, wherein Ci- ⁇ alkyl is optionally substituted with one, two or three substituents each selected from the group consisting of Ci- ⁇ alkoxy, halogen, hydroxy and -NHR 6 , wherein Ci- ⁇ alkoxy is optionally substituted with one, two or three substituents each selected from the group consisting of Ci- ⁇ alkoxy, halogen, hydroxy and
  • each instance of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of Chalky!, Ci- ⁇ alkoxy, halogen and halo-C h alky!, and wherein each instance of heterocyclyl is optionally substituted with oxo, C 1-8 alkyl-carbonyl, d- ⁇ alkoxy-carbonyl, Ci- 8 alkyl-N(R 5 )-carbonyl, aryl-carbonyl, aryl-Ci- ⁇ alkyl-carbonyl, aryl-Ci- ⁇ alkoxy-carbonyl, aryl-N(R 5 )-carbonyl, aryl-Ci- 8 alkyl-N(R 5 )-carbonyl or aryl-Ci- ⁇ alkyl-sulfonyl;
  • R2 is one, two or three substituents each selected from the group consisting of hydrogen, Ci- ⁇ alkyI, d- ⁇ alkoxy and halogen;
  • R3 is one, two or three substituents each selected from the group consisting of hydrogen and d ⁇ alkyl;
  • R4 is one, two or three substituents each selected from the group consisting of hydrogen, Ci- ⁇ alkyI, d- ⁇ alkoxy, hydroxy and halogen;
  • R 5 is selected from the group consisting of hydrogen and d ⁇ alkyl;
  • R 7 is selected from the group consisting of C h alky!, aryl, aryl-Ci- ⁇ alkyl, C 3 -i 4 cycloalkyl, C 3 -i 4 Cycloalkyl-Ci -8 alkyl, heterocyclyl, heterocyclyl-Ci- ⁇ alkyl, heteroaryl and heteroaryl-Ci- ⁇ alkyl.
  • Y is selected from the group consisting of CH 2 , O and S; Li is absent or is selected from the group consisting of -C(O)O-Ri, -C(O)N(Rs)-Ri and -NHC(O)-Ri; l_2 is Ci- ⁇ alkyl;
  • R 3 is one or two substituents each selected from the group consisting of hydrogen and Ci- 4 alkyl;
  • R7 is selected from the group consisting of Ci- ⁇ alkyI and phenyl-Ci- ⁇ alkyl.
  • the present invention is directed a compound of Formula (Ic):
  • Y is selected from the group consisting of CH 2 , O and S; Li is absent or is selected from the group consisting of -C(O)O-Ri, -C(O)N(R 5 )-Ri and -NHC(O)-Ri;
  • L 2 is Ci- ⁇ alkyl
  • R 7 is selected from the group consisting of C h alky!, aryl, aryl-Ci-ealkyl,
  • Y is selected from the group consisting of CH2, O and S;
  • L_2 is Ci- ⁇ alkyl; L 3 is absent or is -C(O)N(R 5 J-R 7 ;
  • R I is selected from the group consisting of Ci- ⁇ alkyI, C 1 ⁇ aIkOXy, phenyl-Ci-ealkyl, naphthyl-Ci- ⁇ alkyI, indanyl, cyclopropyl-Ci-ealkyl, cyclohexyl-d- ⁇ alkyl, 1 ,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-Ci-ealkyl, furanyl-Ci-ealkyl, imidazolyl-Ci-ealkyl, pyridinyl-Ci-ealkyl and indolyl-Ci ⁇ alkyl, wherein is optionally substituted with a substituent selected from the group consisting of Ci -8 alkoxy, hydroxy and -NR 6 , wherein d- ⁇ alkoxy is optionally substituted with -NHRe, wherein each instance of phenyl is optionally substituted with one, two
  • R3 is one or two substituents each selected from the group consisting of hydrogen and Ci-4alkyl
  • R 4 is one substituent selected from the group consisting of hydrogen, C h alky! and halogen
  • R 5 is selected from the group consisting of hydrogen and C h alky!
  • Re is selected from the group consisting of Ci- ⁇ alkyl-carbonyl, Ci- ⁇ alkoxy-carbonyl,
  • R 7 is selected from the group consisting of C h alky! and phenyl-Ci- ⁇ alkyl.
  • the present invention is directed a compound of Formula (Id):
  • L 1 is absent or is selected from the group consisting of -C(O)O-R 1 , -C(O)N(Rs)-R 1 and -NHC(O)-R 1 ;
  • L 2 is Ci- ⁇ alkyl
  • L 3 is absent or is -C(O)N(Rs)-R 7 ;
  • R 1 is selected from the group consisting of d- ⁇ alkyl, d- ⁇ alkoxy, aryl, aryl-Ci-ealkyl, C 3 - 14 cycloalkyl, Cj-ucycloalkyl-d- ⁇ alkyl, heterocyclyl, heterocyclyl-d- ⁇ alkyl, heteroaryl and heteroaryl-d- ⁇ alkyl, wherein Chalky! is optionally substituted with one, two or three substituents each selected from the group consisting of d- ⁇ alkoxy, halogen, hydroxy and
  • R4 is one, two or three substituents each selected from the group consisting of hydrogen, Ci- ⁇ alkyI, Ci- ⁇ alkoxy, hydroxy and halogen;
  • R 5 is selected from the group consisting of hydrogen and C 1-4 alkyl;
  • R7 is selected from the group consisting of Ci -8 alkyl, aryl, aryl-C 1-8 alkyl,
  • C 3 -i 4 cycloalkyl Ca- ⁇ cycloalkyl-Ci-ealkyl, heterocyclyl, heterocydyl-Ci- ⁇ alkyl, heteroaryl and heteroaryl-Ci- ⁇ alkyl.
  • An example of the present invention includes a compound of Formula (Id) and forms thereof, wherein
  • Y is selected from the group consisting of CH2, O and S;
  • Li is absent or is selected from the group consisting of -C(O)O-Ri, -C(O)N(Rs)-Ri L 2 is Ci- 8 alkyl;
  • Ri is selected from the group consisting of Ci- ⁇ alkyl, Ci- ⁇ alkoxy, naphthyl-Ci- ⁇ alkyl, indanyl, cyclopropyl-Ci- ⁇ alkyl, cyclohexyl-Ci-ealkyl, 1 ,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-Ci- ⁇ alkyl, piperidinyl-Ci- ⁇ alkyl, piperazinyl-Ci- ⁇ alkyl, furanyl-Ci. ⁇ alkyl, thienyl-d- ⁇ alkyl, imidazolyl-Ci -8 alkyl, pyridinyl-Ci-ealkyl and indolyl-Ci- ⁇ alkyl, wherein d- ⁇ alkyl is optionally substituted with a substituent selected from the group consisting of Ci- ⁇ alkoxy, hydroxy and -NR 6 , wherein Ci- ⁇ al
  • R 2 is one substituent selected from the group consisting of hydrogen, Ci-aalkyl, Ci- ⁇ alkoxy and halogen;
  • R 3 is one or two substituents each selected from the group consisting of hydrogen and Oi ⁇ alkyl
  • R4 is one substituent selected from the group consisting of hydrogen, Ci- ⁇ alkyI and halogen;
  • Re is selected from the group consisting of Ci- ⁇ alkyl-carbonyl, Ci- ⁇ alkoxy-carbonyl, Ci- 8 alkyl-N(R 5 )-carbonyl, phenyl-Ci- ⁇ alkoxy-carbonyl, phenyl-N(R 5 )-carbonyl, phenyl-Ci- 8 alkyl-N(R 5 )-carbonyl and phenyl-C 1-8 alkyl-sulfonyl; and
  • Bond lines drawn into a ring system from a substituent variable indicate that the substituent may be attached to any of the substitutable ring atoms.
  • C h alky refers to straight and branched carbon chains having 1 to 8 carbon atoms or any number within this range. Therefore, designated numbers of carbon atoms (e.g. Ci- ⁇ ) shall refer independently to the number of carbon atoms in the chain.
  • Cycloalkyl may be attached to a core molecule and further substituted on any atom when allowed by available valences.
  • heterocyclyl groups include, and are not limited to, azetidinyl, 2H-pyrrole, 2-pyrrolinyl, 3-pyrrolinyl, pyrrol idinyl, 1 ,3-dioxolanyl, 2-imidazolinyl (also referred to as 4,5-dihydro-1H-imidazolyl), imidazolidinyl, 2-pyrazolinyl, pyrazol idinyl, tetrazolyl, tetrazolidinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1 ,4- dithianyl, thiomorpholinyl, piperazinyl, azepanyl, hexahydro-1,4-diazepinyl, hexahydro-1,4-oxazepanyl, tetrahydro-furanyl, tetrahydro-thienyl, a
  • heterocyclyl also includes a benzofused-heterocyclyl ring system radical and the like, such as indolinyl (also referred to as 2,3-dihydro- indolyl), benzo[1 ,3]dioxolyl, 2,3-dihydro-1 ,4-benzodioxinyl, 2,3-dihydro- benzofuranyl, 1,2-dihydro-phthalazinyl and the like.
  • a heterocyclyl radical may be attached to a core molecule and further substituted on any atom when allowed by available valences.
  • aryt refers to an unsaturated, aromatic monocyclic ring of 6 carbon members or to an unsaturated, aromatic polycyclic ring of from 10 to 14 carbon members. Examples of such aryl rings include, and are not limited to, phenyl, naphthalenyl or anthracenyl.
  • heteroaryl refers to an aromatic ring of 5 or 6 members wherein the ring consists of carbon atoms and has at least one heteroatom member. Suitable heteroatoms include nitrogen, oxygen or sulfur. In the case of 5 membered rings, the heteroaryl ring contains one member of nitrogen, oxygen or sulfur and, in addition, may contain up to three additional nitrogens. In the case of 6 membered rings, the heteroaryl ring may contain from one to three nitrogen atoms. For the case wherein the 6 membered ring has three nitrogens, at most two nitrogen atoms are adjacent.
  • heteroaryl groups include, and are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyi, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and the like.
  • heteroaryl also includes a benzofused-heteroaryl ring system radical and the like, such as indolizinyl, indolyl, azaindolyl, isoindolyl, benzofuranyl, benzothienyl, indazolyl, azaindazolyl, benzoimidazolyl, benzothiazolyl, benzoxazolyl, benzoisoxazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl and the like.
  • a heteroaryl radical may be attached to a core molecule and further substituted on any atom when allowed by available valences.
  • benzofused-heteroaryl means a heteroaryl ring system radical having a benzene ring fused on the ring system on adjacent carbons.
  • a benzofused-heteroaryl radical may be attached to a core molecule and further substituted on any atom when allowed by available valences.
  • Cs-ucycloalkyl-Ci-ealkyl means a radical of the formula: -Ci- ⁇ alkyl-Cs-ucycloalkyl.
  • heterocyclyl-Ci-ealkyl means a radical of the formula: -Ci- ⁇ alkyl-heterocyclyl.
  • heteroaryl-Ci-ealkyl means a radical of the formula:
  • d- ⁇ alkoxy-carbonyl means a radical of the formula: -C(O)-C 1-8 alkoxy.
  • aryl-carbonyl means a radical of the formula: -C(O)-aryl.
  • aryl-Ci-ealkyl-carbonyl means a radical of the formula: -C(O)-Ci- 8 alkyl-aryl.
  • aryl-Ci- ⁇ alkoxy-carbonyl means a radical of the formula: -C(O)-C 1-8 alkoxy-aryl.
  • aryl-Ci- 8 alkyl-N(R 5 )-carbonyr means a radical of the formula: -C(O)-N(R5)-Ci.8alkyl-aryl.
  • aryl-C-i-ealkyl-sulfonyl means a radical of the formula: -SOa-Ci- ⁇ alkyl-aryl.
  • Ci -8 alkyl-N(R 5 )-carbonyl means a radical of the formula:
  • aryl-N(R 5 )-carbonyl means a radical of the formula: -C(O)-N(R 5 )-aryl.
  • halogen or halo means the group chloro, bromo, fluoro or iodo.
  • halo-Chalky means a radical of the formula: -Ci- 8 alkyl-(halo)n, wherein one or more halogen atoms may be substituted on d- ⁇ alkyl when allowed by available valences (wherein n represents that amount of available valences based on the number of carbon atoms in the chain), and includes monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl and the like.
  • substituted means the independent replacement of one or more hydrogen atoms within a radical with that amount of substitutents allowed by available valences.
  • form means, in reference to compounds of the present invention, such may exist as, without limitation, a salt, stereoisomer, tautomer, crystalline, polymorph, amorphous, solvate, hydrate, ester, prodrug or metabolite form.
  • the present invention encompasses all such compound forms and mixtures thereof.
  • isolated form means, in reference to compounds of the present invention, such may exist in an essentially pure state such as, without limitation, an enantiomer, a racemic mixture, a geometric isomer (such as a cis or trans stereoisomer), a mixture of geometric isomers, and the like.
  • the present invention encompasses all such compound forms and mixtures thereof.
  • the compounds of the invention may be present in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts for use in medicines, refer to non-toxic acidic/anionic or basic/cationic salt forms.
  • Suitable salt forms include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of an acid such as acetic acid, adipic acid, benzoic acid, carbonic acid, citric acid, fumaric acid, glycolic acid, hydrochloric acid, maleic acid, malonic acid, phosphoric acid, saccharinic acid, succinic acid, sulphuric acid, tartaric acid, trifluoroacetic acid and the like.
  • an acid such as acetic acid, adipic acid, benzoic acid, carbonic acid, citric acid, fumaric acid, glycolic acid, hydrochloric acid, maleic acid, malonic acid, phosphoric acid, saccharinic acid, succinic acid, sulphuric acid, tartaric acid, trifluoroacetic acid and the like.
  • suitable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
  • alkali metal salts e.g. sodium or potassium salts
  • alkaline earth metal salts e.g. calcium or magnesium salts
  • suitable organic ligands e.g. quaternary ammonium salts.
  • representative salts include the following: acetate, adipate, ammonium, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, camsylate (or camphosulphonate), carbonate, chloride, clavulanate, citrate, di hydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluconate, gluceptate, glutamate, glyconate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate
  • acids and bases which may be used in the preparation of pharmaceutically acceptable salts include the following: acids including acetic acid, 2,2-dichloroactic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, A- acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)- camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid, L
  • the present invention includes within its scope prodrugs of the compounds of this invention.
  • prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the required compound.
  • the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • the compounds according to this invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
  • compounds of the present invention may have one or more crystalline polymorph or amorphous forms and, as such, are intended to be included in the scope of the invention.
  • some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents (e.g., organic esters such as ethanolate and the like) and, as such, are also intended to be encompassed within the scope of this invention..
  • the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers
  • these isomers may be separated using various well known chromatographic methods such as preparative chromatography.
  • the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
  • any of the processes for preparation of the compounds of the present invention it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • the compounds of the present invention can be administered alone, they will generally be administered in admixture with a pharmaceutical carrier, excipient or diluent selected with regard to the intended route of administration and standard pharmaceutical or veterinary practice.
  • a pharmaceutical carrier excipient or diluent selected with regard to the intended route of administration and standard pharmaceutical or veterinary practice.
  • the present invention is directed to pharmaceutical and veterinary compositions comprising compounds of Formula (I) and one or more pharmaceutically acceptable carriers, excipients or diluents.
  • the compounds of the present invention may be admixed with any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), and/or solubilising agent(s).
  • Tablets or capsules of the compounds may be administered singly or two or more at a time, as appropriate. It is also possible to administer the compounds in sustained release formulations.
  • the compounds of the general Formula (I) can be administered by inhalation or in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
  • An alternative means of transdermal administration is by use of a skin patch.
  • they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. They can also be inco ⁇ orated, at a concentration of between 1 and 10% by weight, into an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and preservatives as may be required.
  • compositions are administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavoring or coloring agents.
  • excipients such as starch or lactose
  • capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavoring or coloring agents.
  • compositions can also be injected parenterally, for example intracavernosally, intravenously, intramuscularly or subcutaneously.
  • the compositions will comprise a suitable earner or diluent.
  • compositions are best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or monosaccharides to make the solution isotonic with blood.
  • compositions may be administered in the form of tablets or lozenges which can be formulated in a conventional manner.
  • compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral).
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
  • Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate the major site of absorption.
  • the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation.
  • injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those skilled in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. It is also apparent to one skilled in the art that the therapeutically effective dose for active compounds of the invention or a pharmaceutical composition thereof will vary according to the desired effect.
  • optimal dosages to be administered may be readily determined and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease condition.
  • factors associated with the particular subject being treated including subject age, weight, diet and time of administration, will result in the need to adjust the dose to an appropriate therapeutic level.
  • the above dosages are thus exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • compositions and dosage regimens may be administered in any of the foregoing compositions and dosage regimens or by means of those compositions and dosage regimens established in the art whenever use of the compounds of the invention as analgesics is required for a subject in need thereof.
  • the invention also provides a pharmaceutical or veterinary pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical and veterinary compositions of the invention.
  • Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • the present invention is also directed to a method for treating or ameliorating a Urotensin-ll mediated disorder.
  • An example of the method of the present invention is a method for treating or ameliorating a disease or condition in a mammal which disease or condition is affected by antagonism of a Urotensin Il receptor, which method comprises administering to the mammal in need of such treatment or prevention an effective amount of a compound of Formula (I):
  • Ring A is selected from the group consisting of piperidinyl, 8-aza-bicyclo[3.2.1]oct-2- enyl, 8-aza-bicyclo[3.2.1]octyl and 1.2,3,6-tetrahydro-pyridinyl;
  • Y is selected from the group consisting of CH 2 , O and S; Li is absent or is selected from the group consisting of -C(O)O-Ri, -C(O)N(Rs)-Ri and -NHC(O)-Ri;
  • L 2 is Ci- ⁇ alkyI
  • L 3 is absent or is -C(O)N(R 5 J-R?;
  • Ri is selected from the group consisting of Ci. 8 alkyl, d- ⁇ alkoxy, aryl, aryl-Ci-ealkyl, C 3 -i 4 cycloalkyl, Ca- ⁇ cycloalkyl-d-ealkyl, heterocyclyl, heterocyclyl-d- ⁇ alkyl, heteroaryl and heteroaryl-Ci- ⁇ alkyl, wherein d- ⁇ alkyl is optionally substituted with one, two or three substituents each selected from the group consisting of d- ⁇ alkoxy, halogen, hydroxy and -NHR 6 , wherein d- ⁇ alkoxy is optionally substituted with one, two or three substituents each selected from the group consisting of d- ⁇ alkoxy, halogen, hydroxy and -NHR 6 , wherein each instance of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of Chalky!, d- ⁇ alkoxy, halogen and
  • R 2 is one, two or three substituents each selected from the group consisting of hydrogen, d- ⁇ alkyl, d- ⁇ alkoxy and halogen;
  • R 3 is one, two or three substituents each selected from the group consisting of hydrogen and d- ⁇ alkyl
  • R 4 is one, two or three substituents each selected from the group consisting of hydrogen, d -8 alkyl, d ⁇ alkoxy, hydroxy and halogen;
  • R 5 is selected from the group consisting of hydrogen and d ⁇ alkyl
  • R 6 is selected from the group consisting of d- ⁇ alkyl-carbonyl, d- ⁇ alkoxy-carbonyl,
  • R7 is selected from the group consisting of d- ⁇ alkyl, aryl, aryl-d- ⁇ alkyl, Ca- M cycloalkyl, C 3 .14cycloalkyl-C 1 .ea I kyl, heterocyclyl, heterocyclyl-d- ⁇ alkyl, heteroaryl and heteroaryl-Ci- ⁇ alkyl.
  • Another example of the method of the present invention is a method for treating or ameliorating a Urotensin-ll mediated disorder in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I) or a form thereof.
  • a Urotensin ll-mediated disorder includes, and is not limited to, chronic vascular disease, vascular hypertension, heart failure, atherosclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, inflammatory colitis (caused by bacteria, ischemia, radiation, drugs or chemical substances), renal dysfunction, renal failure, renal failure caused by drug induced toxicity, nephrotoxicity and diarrhea caused by anti-neoplastic agents, nephrotoxicity caused by radiocontrast agents and aminoglycosides, post-myocardial infarction, pulmonary hypertension, pulmonary fibrosis, insulin resistance and impaired glucose tolerance, diabetes, diabetic complications, diabetic nephropathy, pain, Alzheimer's disease, convulsions, depression, migraine, psychosis, anxiety, neuromuscular deficit and stroke.
  • the present invention also includes the use of the compound of formula (I) or a form thereof for the manufacture of a medicament for treating or ameliorating a Urotensin-ll mediated disorder in a subject in need thereof.
  • An example of the present invention includes a method for treating or ameliorating a Urotensin-ll mediated disorder, wherein the disorder is heart failure.
  • the term “medicament” refers to a product for use in treating or ameliorating a Urotensin-ll mediated disorder.
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been a patient or the object of treatment, observation or experiment.
  • an effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • the effective amount of said compound or form thereof is from about 0.001 mg/kg/day to about 300 mg/kg/day.
  • 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 combinations of the specified ingredients in the specified amounts.
  • neoplasm refers to an abnormal growth of cells or tissue and is understood to include benign, i.e., non-cancerous growths, and malignant, i.e., cancerous growths.
  • neoplastic means of or related to neoplasm.
  • the term "agent” is understood to mean a substance that produces a desired effect in a tissue, system, animal, mammal (in particular human), or other subject. Accordingly, the term “antineoplastic agent” is understood to mean a substance producing an anti-neoplastic effect in a tissue, system, animal, mammal (in particular human), or other subject. It is understood that an “agent” may be a single compound or a combination or composition of two or more compounds.
  • Some of the typical anti-neoplastic agents include alkylating agents such as melphalan, chlorambucil, cyclophosphamide, mechlorethamine, hexamethylmelamine, busulfan, carmustine, lomustine, and dacarbazine; antimetabolites such as 5-fluorouracil, methotrexate, cytarabine, mecaptopurine, and thioguanine; antimitotic agents such as paclitaxel, docetaxel, vinblastine, vincristine; topoisomerase I inhibitors such as irinotecan, campthothecin and camptothecin derivatives, for example topotecan; topoisomerase Il inhibitors such as doxorubicin; and platinum coordination complexes such as cisplatin and carboplatin.
  • alkylating agents such as melphalan, chlorambucil, cyclophosphamide, mechlorethamine, hexa
  • An embodiment of the present invention is a method for treating a U-Il mediated disorder including, but not limited to, vascular hypertension, heart failure, atherosclerosis, renal failure, renal failure caused by drug induced toxicity, nephrotoxicity and diarrhea caused by anti-neoplastic agents, nephrotoxicity caused by radiocontrast agents and aminoglycosides, post-myocardial infarction, pulmonary hypertension, pulmonary fibrosis, insulin resistance and impaired glucose tolerance, diabetes, diabetic complications, diabetic nephropathy, depression, psychosis, anxiety and stroke.
  • vascular hypertension including, but not limited to, vascular hypertension, heart failure, atherosclerosis, renal failure, renal failure caused by drug induced toxicity, nephrotoxicity and diarrhea caused by anti-neoplastic agents, nephrotoxicity caused by radiocontrast agents and aminoglycosides, post-myocardial infarction, pulmonary hypertension, pulmonary fibrosis, insulin resistance and impaired glucose tolerance, diabetes, diabetic complications
  • the present method of using Urotensin Il receptor antagonists to reduce anti-neoplastic agent induced diarrhea and nephrotoxicity is applicable in any situation when anti-neoplastic agents (such as cisplatin, cis- diaminedichloroplatinum) are being administered to treat cancers or tumors.
  • anti-neoplastic agents such as cisplatin, cis- diaminedichloroplatinum
  • UII antagonists are used when tumors or cancers being treated are those of solid malignancies, notably those of the bladder, cervix, lung, ovary, and testis such as testicular tumor, bladder cancer, ureterpyelonephritic tumor, prostatic cancer, ovarian cancer, head and neck cancer, non-small-cell lung cancer, esophageal cancer, cervical cancer, neuroblastoma, gastric cancer, small cell lung cancer, bone cancer, non-Hodgkin's lymphomas, tumors of brain, endometrium, upper gastrointestinal tract, head and neck and thymus, neuroblastoma and sarcoma of bone and soft tissue.
  • Urotensin Il receptor antagonists may be useful for improving cardiac function and for cardiac remodeling associated with chronic heart failure (CHF)
  • CHF chronic heart failure
  • N. Bousette, F. Hu 1 E. H. Ohlstein, D. Dhanak, S. A. Douglas, A. Giaid, Journal of Molecular and Cellular Cardiology 2006, In Press Long-term treatment of streptozotocin-induced diabetic rats with palosuran improved survival, increased insulin, and slowed the increase in glycemia, glycosylated hemoglobin, and serum lipids.
  • palosuran increased renal blood flow and delayed the development of proteinuria and renal damage (M. Clozel, P. Hess, C. Qiu, S. S. Ding, M. Rey, J.
  • a therapeutically effective amount for use of the instant compounds or a pharmaceutical composition thereof comprises a dose range from about 0.1 mg to about 3000 mg, in particular from about 1 mg to about 1000 mg or, more particularly from about 10 mg to about 500 mg of active ingredient in a regimen of about 1 to 4 times per day for an average (70 kg) human; although, it is apparent to one skilled in the art that the therapeutically effective amount for active compounds of the invention will vary as will the conditions being treated.
  • Optimal dosages of the compounds of Formula (I) to be administered for the treatment of or prevention of Urotensin Il mediated disorders may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
  • a pharmaceutical composition is preferably provided in the form of tablets containing 0.01 , 10.0, 50.0, 100, 150, 200, 250, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
  • a representative compound of Formula (I) or a form thereof includes a compound selected from the group consisting of:
  • a compound of Formula (I) or a form thereof further includes a compound selected from the group consisting of:
  • Representative compounds of the present invention can be synthesized in accordance with the general synthetic schemes described below and are illustrated more particularly in the specific synthetic examples that follow.
  • the general schemes and specific examples are offered by way of illustration; the invention should not be construed as being limited by the chemical reactions and conditions expressed.
  • the methods for preparing the various starting materials used in the schemes and examples are well within the skill of persons versed in the art. No attempt has been made to optimize the yields obtained in any of the example reactions. One skilled in the art would know how to increase such yields through routine variations in reaction times, temperatures, solvents and/or reagents.
  • Electrospray mass spectra (MS-ES) were recorded on a Hewlett Packard 59987A spectrometer.
  • HRMS High resolution mass spectra
  • E spectrometer by fast atom bombardment (FAB) technique.
  • Formula (l)-1 A commercially available heterocycle of Compound A1 may be reacted with a strong base such as sodium hydride and a commercially available or readily accessible electropile Compound A2 in which an appropriate leaving group (LG) is displaced.
  • a strong base such as sodium hydride
  • a commercially available or readily accessible electropile Compound A2 in which an appropriate leaving group (LG) is displaced.
  • LG an appropriate leaving group
  • appropriate leaving groups include fluoride, bromide, iodide, triflate, mesylate, and the like.
  • the leaving group of Compound A2 may be displaced to give a Compound A3.
  • the terminal olefin in Compound A3 can be converted to a carbonyl of Compound A5 directly or through the intermediate Compound A4.
  • oxidation of Compound A3 with potassium osmate (Vl) can deliver diol Compound A4, which may be decomposed to Compound A5 with sodium metaperiodate.
  • ozone will convert Compound A3 to Compound A5 directly after a reductive workup with a reductant such as dimethylsulfide or triphenylphosphine.
  • the carbonyl of Compound A5 may be coupled to Compound A6 under reductive amination conditions to afford compounds of Formula (l)-1 , representative of a compound of Formula (I).
  • Reductive amination conditions would include a reducing agent such as borane-pyridine, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like. Use of Br ⁇ nsted or Lewis acids and a dehrydating agent may also be beneficial.
  • a reducing agent such as borane-pyridine, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like.
  • Scheme B describes the synthesis of compounds of the present invention wherein Ring A is piperidinyl and L 3 is -C(O)N (Rs)-Rz.
  • a commercially available or readily prepared carboxylic acid Compound B1 may be converted to a corresponding carboxamide Compound B3 by coupling to an amine Compound B2 by standard amide coupling methods.
  • HBTU may be utilized.
  • the Boc-group of Compound B3 can be removed with an acid such as hydrogen chloride or trifluoroacetic acid to afford the free amine of Compound B4.
  • Reductive coupling of Compound B4 and Compound A5 by the methods described in general Scheme A for coupling of A6 and A5 may afford compounds of Formula (l)-2, representative of a compound of Formula (I).
  • Scheme C describes the synthesis of certain compounds of the present invention in which L t is a carboxamide substituent.
  • An ester Compound C1 is prepared by the methods described in general Scheme A.
  • Compound C1 can be hydrolyzed to the carboxylic acid Compound C2 with a base such as lithium hydroxide.
  • Coupling of Compound C2 to the amine Compound C3 by methods described in general Scheme B for the coupling of Compound B1 and Compound B2 provides compounds of Formula (l)-3, representative of a compound of Formula (I).
  • a subset of amine Compound C3 are the primary amines of Compound C5.
  • Compound C5 can be prepared by reduction of the corresponding nitrile Compound C4 by a reagent such as a borane-tetrahydrofuran complex.
  • Scheme D describes the synthesis of compounds of the present invention wherein the phenylpiperidine group is not commercially available.
  • boronate Compound D1 can be coupled with a Compound D2, in which LG may be a leaving group as previously defined or, for the reaction illustrated in this Scheme, when LG is bromide or triflate.
  • the Suzuki Miyaura coupling (P. R. Eastwood, Tetrahedron Lett., 2000, 41, 3705) is facilitated by a palladium catalyst such as PdCl 2 dppf-CH 2 Cl 2 .
  • Reduction of the double bond in Compound D3 may be accomplished with hydrogen and a catalyst such as platinum (IV) oxide.
  • Deprotection of the Boc- group on Compound D4 can be done as described in general Scheme B for Compound B3.
  • Reductive coupling of Compound D5 and Compound A5 is achieved by the methods described in general Scheme A for Compound A6 and Compound A5.
  • Conversion of Compound C1 to the structures of Formula (l)-3 is accomplished by the sequence described in general Scheme C.
  • Scheme E describes the synthesis of compounds in which the vinyl boronate within Ring A needs to be prepared.
  • a Boc-protected Compound E1 may be converted to the vinyl boronate Compound E2 (as described in P. R. Eastwood, Tetrahedron Lett., 2000, 41, 3705; and S. Ghosh, W. A. Kinney, D. A. Gauthier, E. C. Lawson, T. Hudlicky, B. E. Maryanoff., Can. J.Chem. 2006, 84, 555-560).
  • Conversion of Compound E2 to the structures of Formula (l)-4 is accomplished by the methods described in general Scheme D for the conversion of Compound D1 to final product Formula (l)-3.
  • the double bond of Ring A in Compound E3 can be retained (by skipping the reduction step as described for converting Compound D3 to Compound D4 in Scheme D) and the sequence continues analogously to deliver products of Formula (l)-4 in which Ring A contains a double bond.
  • Compound E3 can be hydrogenated to give Compound E4 using the procedure described in Scheme D and taken through the remaining steps to deliver products of Formula (l)-4 in which Ring A is saturated, representative of a compound of Formula (I).
  • the acid portion of Compound E4 may be functionalized using the procedures shown in Scheme C and Scheme F, as well as by using standard techniques known to those skilled in the art.
  • Scheme F describes the preparation of certain compounds of the present invention wherein reductive amination is performed on a ketone.
  • the Boc-protected carboxylic acid ester Compound E4 can be converted to the corresponding carboxyl acid Compound F1 by the action of a base such as sodium hydroxide. Coupling of Compound F1 to Compound C3 is accomplished using the procedure for coupling Compound B1 and Compound B2 in Scheme B. Compound F2 is then deprotected as described in Scheme B to give a Compound F3.
  • a solution of potassium carbonate (4.40 g, 32 mmol), K 3 Fe(CN) 6 (10.5 g, 32 mmol), and K 2 OsO 4 H 2 O (195 mg, 0.53 mmol) in f-BuOH/H 2 O (12 mL of 1/1) was prepared in a 200 mL round bottom flask. The mixture was chilled in an ice bath, then a solution of Compound 1-2 (2.0 g, 11 mmol) in f-BuOH/H 2 O (12 mL of 1/1) was added at 4 0 C and the reaction mixture was allowed to stir for 24 hrs while warming to rt.
  • Compound 1-5 was prepared by the same method as Compound 1-2 with the exception that 3-chloro-2-methylpropene was utilized instead of allyl bromide.
  • Ozone was bubbled through a cold (-70 0 C) solution of Compound 1-5 (30.0 g, 147 mmol) and Sudan III (trace) in dichloromethane (450 mL) for 1.5 hrs.
  • Triphenylphosphine (46.3 g, 177 mmo!) was added at a rate that the internal temperature was maintained at -70 0 C.
  • the resulting solution was stirred at -70 0 C for 30 min, warmed to rt, and stirred for 1 hr.
  • Step 5 Synthesis of (2-oxo-3,4-dihydro-2H-quinolin-1-yl)-acetaldehyde (Compound 1-8).
  • Compound 1-7 was prepared by the same method as Compound 1-2 with the exception that dihydroquinolinone was utilized instead of Compound 1-1.
  • Ozone (8 psi) was bubbled slowly into a cold (-78 0 C) solution of Compound 1-7 (10 g, 54 mmol) in methanol (535 ml_) for 90 min, while the solution turned from yellow to blue-green.
  • Step 7 Synthesis of 2- ⁇ 1 -[2-(3-oxo-2,3-dihydro-benzol[1 ,4]oxain-4-yl-ethyl]- piperidine-4-yl-benzoic acid methyl ester (Compound 93).
  • Compound Compound 93 was synthesized in the same manner as Compound 86 with the exception that 2-(piperidin-4-yl)benzoic acid methyl ester was used instead of Compound 1 -9 as starting material.
  • Compound 93 was purified on silica gel (elution with 50% EtOAc in hexane) to afford a glass-like oil (25%).
  • Step 1 Synthesis of 4-(4-chloropheny1)-4-dimethylcarbamoyl-piperidine-1 - carboxylic acid tert-butyl ester (Compound 2-2).
  • N-Boc-4-(4-chlorophenyl)-4-piperidine carboxylic acid Compound 2-1 (5.96 g, 18 mmol, Arch Chemical) was dissolved in DMF (175 ml_) and chilled in an ice bath temp. To the solution was added N-methylmorpholine (5.76 ml_, 53 mmol). HOBt (1.18 g, 8.8 mmol), dimethylamine hydrochloride (1.41 g, 18 mmol), and HBTU (10.0 g, 26 mmol). The solution was allowed to warm overnight to rt, poured into 1N sodium hydroxide solution (100 ml_), and extracted with EtOAc (3 x 75 ml_).
  • Compound 115 was prepared by the same method as Compound 86 with the exception that Compound 2-3 was used instead of Compound 1-9 and that Compound 1-8 was used instead of Compound 1-4.
  • Compound 115 was isolated as a white solid (53%, mp 243-245 0 C).
  • 1 H 300 MHz, CDCI 3 .) ⁇ 7.44-7.01 (m, 8H), 4.55 (m, 2H), 3.62 (m, 2H) 1 3.31-2.40 (m, 18H); MS (ES + ) m/z 440.0 (M +1).
  • Arylethylamines that were not commercially available were made by the following procedure. 2-Naphthylacetonitrile Compound 3-2 (16.7 g, 0.10 mol) in anhydrous tetrahydrofuran (50 mL) was added to 1M solution of BH 3 -THF (250 mL, 0.25 mol) over 10 min at room temperature. The reaction proceeds with an induction period of 2-4 min. Following the addition, the mixture was heated under reflux and under argon for one hour (TLC of a quenched aliquot showed no starting material). The reaction was cooled in an ice bath and 10% aqueous HCI (150 ml_) was added with caution over a 30 min period (vigorous reaction with the first few drops).
  • Step 1 Synthesis of 4-(4-chloro-2-methoxycarbonyl-phenyl)-3,6-dihydro-2H- pyridine-1-carboxylic acid te/f-butyl ester (Compound 4-3).
  • Step 4 Synthesis of 5-Chloro-2- ⁇ 1 - ⁇ 2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl>- ethyl]-piperidin-4-yl ⁇ -benzoic acid methyl ester (Compound 4-6).
  • Tetramethylammonium triacetoxyborohydride was added and the reaction mixture was stirred for 2 hrs, quenched with NH4OH/H2O (1:1, 5 mL), washed with NH 4 OH:H 2 O (1:1, 2 x 10 mL), dried over anhydrous Na 2 SO 4 , filtered, concentrated and purified by flash chromatography (gradient elution with 25-100% EtOAc in heptane with 0.1 % TEA). The product Compound 4-6 was isolated as white solid (0.86 g, 74%).
  • Step 6 Synthesis of 4-[2-(5-chloro-2- ⁇ 1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin- 4-yl)-ethyl]-piperidin-4-yI ⁇ -benzoylamino)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (Compound 66).
  • Step 1 Synthesis of [5-(5-chloro-2- ⁇ 8-[2-(3-oxo-2 > 3-clihydrobenzo[1 ,4]oxazin-4- yl)-ethy1]-8-aza-bicyclo[3.2.1]oct-3-y1 ⁇ -benzoylamino)-pentyl]-cart>amic acid tert-butyl ester (Compound 100).
  • Compound 100 was made using the methods described for Compound 66
  • Example 4 with the exception that Compound 5-1 was used instead of Compound 4-4 and Compound 5-2 was used instead of Compound 4-8.
  • Compound 5-1 was prepared as described and is shown as compound 10-f in "Convenient Preparation of Aryl-Substituted Nortropanes by Suzuki-Miyaura Methodology" SGhosh, WA Kinney, DA Gauthier, EC Lawson, T Hudlicky, BE
  • Step 2a Into a mixture of diethyl acetonedicarboxylate (103.6 g, 0.512 mol) and acetaldehyde (45.3 g, 1.33 mol) was bubbled ammonia gas until that liquid was saturated at -30 0 C. The solution was stored in freezer overnight. The yellow sludge was dissolved in dichloromethane (15 mL), filtered though silica gel and washed with EtOAc.
  • Step 2b A solution of the diester (90 g, 0.332 mol) in 10% aqueous hydrochloric acid solution (400 mL) was refluxed for overnight. Water was evaporated to yield 2,6-Dimethyl-4- piperidone/HCI, which was used for the next step without further purification.
  • Step 2c 2,6-Dimethyl-4-piperidone HCI salt (25.0 g, 0.153 mol) was partitioned into dioxane (250 mL) and H2O (250 mL), and sodium bicarbonate (50 g, 0.59 mol) was added in several portions. Boc anhydride (80 g, 0.37mol) was added and the resulting reaction mixture was stirred at rt overnight. The reaction mixture was evaporated to remove dioxane. The residue was extracted with Et2 ⁇ and the organic layer was washed with brine and dried over sodium sulfate.
  • Compound 5-4 was prepared from Compound 5-3 (7.5 g, 33 mmol) by methods described in Canadian Journal of Chemistry 2006. Compound 5-4 was obtained in two batches: pure trans-Compound 5-4 as a solid (0.97 g, 9%, mp 84- 85 0 C) and a mixture of trans- and cis-isomers of Compound 5-4 as an oil (4.25 g, 2.25:1 of trans:cis, 38%).
  • Step 4 Synthesis of [5-(5-chloro-2- ⁇ 2,6-dimethyl-1 -[2-(3-oxo-2,3-dihydro- benzo[1 ,4]oxazin-4-yl)-ethyl]-1 ,2,3,6-tetrahydro-pyridin-4-yl ⁇ - benzoylamino)pentyl]-carbamic acid tert-butyl ester (Compound 102).
  • Compound 5-4 as a mixture of cis- and trans-isomers, was converted to Compound 5-6 by the methods described for the conversion of Compound 4-1 to Compound 4-3, with the exception that the triflate Compound 5-5 was utilized instead of the arylbromide Compound 4-2.
  • Compound 5-6 was converted to Compound 102 in several steps by the methods described for the conversion of Compound 4-4 to Compound 66 (Example 4), utilizing amine Compound 5-2 in the final step instead of Compound 4-8.
  • Compound 102 was isolated as a gummy solid (trifluoroacetate salt).
  • Step 3 Synthesis of 4- ⁇ 4-chlono-2-[(1 -phenylmethanesulfonyl-piperidin-4- ylmethyl)-carbamoyl]-phenyl ⁇ -piperidine-1-carboxylic acid tert-buty ⁇ ester (Compound 7-6).
  • Compound 7-4 (311 mg, 0.881 mmol) was dissolved in methanol (8 mL) and 1 N sodium hydroxide solution (14 mL) was added. This solution was heated to reflux for 18 hrs, cooled to rt and concentrated to give Compound 7-5 (200 mg, 63%) as the sodium salt.
  • reaction mixture was cooled to rt and a slurry of sodium borohydride (171 mg, 4.62 mmol) in absolute ethanol (1 mL) was added. After 15 min additional absolute ethanol (10 mL) was added. After 20 hrs, the reaction mixture was poured into 1 N sodium hydroxide solution (20 mL) and the solids were filtered off. The basic filtrate was diluted with 50 mL of EtOAc and separated. The EtOAc layer was washed with 1 N NaOH (2 x 20 mL), dried over sodium sulfate and concentrated to a glass like oil.
  • rat U-Il Genebank Accession No. U32673
  • PCR was carried out by using the DNA polymerase PFU (Stratagene) following conditions suggested by the manufacturer.
  • the PCR products were cloned into pcDNA3 (Invitrogen) digested with EcoR I and Xba i.
  • Clones containing rat U-Il receptor were verified by complete sequencing of the U- Il receptor insert to ensure a lack of PCR-introduced errors.
  • the constructed vector was transfected into CHO cells by using lipofectamine (GIBCO BRL).
  • CHO cells with high expression of rat U-Il receptor were selected and established as stable cell lines by using G418. CHO cells were seeded at 25,000 cells per well into 96-well, black-wall, clear-bottom microtiter plates 24 hrs before assay.
  • Cells in culture media (DMEM/F12 containing 15 mM HEPES, L-glutamine, pyridoxine hydrochloride; 10% fetal bovine serum; 1 mg/mL G418 sulfate; antibiotic- antimycotic; pH 7.4) were loaded with proprietary dye, from the FLIPR Calcium Assay Kit (Molecular Devices), prepared in assay buffer (Hanks Balanced Salts Solution, 20 mM HEPES 1 0.1% BSA, 2.5 mM probenecid, pH 7.4), and incubated for 1 hr at 37 0 C. Calcium mobilization determinations were performed at room temperature (23 0 C).
  • rat GPR14 was considered acceptable, because human U-Il has similar affinity for human or rat GPR14 in the transfected cells (S. A. Douglas, E. H. Ohlstein, Trends Cardiovasc. Med. 2000, 10, 229-237). The resulting data is shown in Table 3.
  • Human Skeletal Muscle Myoblasts were obtained from Cambrex, and were cultured according to manufacturer's instruction. Cell viability was examined by trypan blue exclusion. Cells at less than 4 passages were used in all studies.
  • ( 125 I)-U-II binding experiments Described in: "Characterization of Functional Urotensin Il Receptors in Human Skeletal Muscle Myoblasts: Comparison with Angiotensin Il Receptors" J. Qi, L. K. Minor, C. Smith, B, Hu, J. Yang, P. Adrade-Gordon, B.
  • HSMM Damiano, Peptides 2005, 26, 683-690
  • HSMM were plated in 12-well Costar plates in complete medium for 48 hrs to reach 70% confluence.
  • the binding medium used was Dulbecco's modified Eagle's medium (DMEM) containing 2 mg/ml BSA and 25 mM HEPES (pH 7.4).
  • DMEM Dulbecco's modified Eagle's medium
  • the cells were washed at room temperature 2x with the binding medium, and were incubated with 0.2 ml per well of prepared binding medium containing 0.150 nM ( 125 I)-U-II and compounds for 3 hrs.
  • the cells were washed 4x with the binding medium and solubilized in 1% SDS and 0.5 N NaOH. Radioactivity was quantified by gamma counting.
  • the binding assays were performed at 25 'C to lower nonspecific uptake of ( 125 I)-U-II by the cells that is seen at 37 °C. Using this method, the nonspecific binding was below 10% of total binding.
  • Analysis of the saturation data using the non-linear curve-fitting technique of GraphPad Prism Version 3.0 revealed that the best fit observed was for a one-site model.

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Abstract

The invention is directed to Urotensin II receptor antagonists. More specifically, the present invention relates to certain novel compounds and methods for preparing compounds, compositions, intermediates and derivatives thereof. Pharmaceutical compositions and methods for treating or ameliorating a Urotensin-II mediated disorder using compounds of the invention are also described.

Description

UROTENSIN Il RECEPTOR ANTAGONISTS
CROSS REFERENCE TO RELATED APPLICATIONS
This present application claims benefit of U.S. Provisional Patent Application Serial No. 60/834,720 filed July 31, 2006, which is incorporated herein by reference in its entirety and for all purposes.
FIELD OF THE INVENTION
The present invention relates to certain novel compounds, methods for preparing compounds, compositions, intermediates and derivatives thereof and methods for treating or ameliorating a Urotensin-ll mediated disorder. More particularly, the compounds of the present invention are Urotensin-ll receptor antagonists useful for treating or ameliorating Urotensin-ll mediated disorders.
BACKGROUND OF THE INVENTION
Urotensin-ll (U-Il) is a cysteine-linked cyclic peptide, which exerts potent effects on the cardiovascular, renal, pancreatic, and central nervous systems. Originally, this substance was isolated from the urophysis (a caudal neurosecretory organ) of the goby fish (GiHichthys mirabilis) as a 12-mer, AGTAD- cyclo(CFWKYC)-V (D. Pearson. J. E. Shively, B. R. Clark, 1. 1. Geschwind, M. Barkley, R. S. Nishioka, H. A. Bern, Proc. Natl. Acad. Sci. USA 1980, 77, 5021- 5024), but it has now been identified in all classes of vertebrates. The composition of U-Il ranges from 11 amino acids in humans to 14 amino acids in mice, always with a conserved cysteine-linked macrocycle, CFWKYC. Recently, the U-Il receptor was identified (R. S. Ames, H. M. Sarau, J. K. Chambers, R. N. Willette, N. V. Aiyar, A. M. Romanic, C. S. Louden, J. J. Foley, C. F. Sauermelch, R. W. Coatney, Z. Ao, J. Disa, S. D. Holmes, J. M. Stadel, J. D. Martin, W.-S. Liu, G. I. Glover, S. Wilson, D. E. McNulty, C. E. Ellis, N. A. Elshourbagy, U. Shabon, J. J. Trill, D. W. P. Hay, E. H. Ohlstein, D. J. Bergsma, S. A. Douglas, Nature (London) 1999, 401, 282-286) as a G-protein-coupled receptor (GPCR) previously known as the GPR14 orphan receptor, (M. TaI, D. A. Ammar, M. Karpuj, V. Krizhanovsky, M. Nairn, D. A. Thompson, Biochem. Biophys. Res. Commun. 1995, 209, 752-759; and A. Marchese, M. Heiber, T. Nguyen, H. H. Q. Heng, V. R. Saldivia, R. Cheng, P. M. Murphy, L.-C. Tsui, X. Shi, P. Gregor, S. R. George, B. F. O'Dowd, J. M. Docherty, Genomics 1995, 29, 335-344) which is expressed predominantly in cardiovascular tissues.
Goby U-Il possesses powerful vasoconstrictor activity in fish, mammals, and humans (J. M. Conlon, K. Yano, D. Waugh, N. Hazon, J. Exp. Zool. 1996, 275, 226-238; F. Bόhm, J. Pemow, Br. J. Pharmacol. 2002, 135, 25-27). Moreover, it appears to be the most potent vasoconstrictor known, (S. A. Douglas, E. H. Ohlstein, Trends Cardiovasc. Med. 2000, 10, 229-237) causing concentration-dependent contraction of isolated arterial rings of rats and humans with an EC50 value of less than 1 nM, which is ca. ten times more potent than endothelin-1. Recently, Kikkawa, H. and Kushida, H. in International Publication WO 2005/072226 disclosed the use of Urotensin-ll antagonists for the prevention and/or treatment of inflammatory bowel diseases including, but not limited to, Crohn's disease, ulcerative colitis, and inflammatory colitis caused by bacteria, ischemia, radiation, drugs, or chemical substances.
Relative to the role of U-Il in chronic vascular disease, this peptide was reported to induce hypertrophy in cardiomyocytes (Y. Zou, R. Nagai, T. Yamazaki, FEBS Letters 2001 , 508, 57-60) and the proliferation of smooth muscle cells (T. Watanabe, R. Pakala, T. Katagiri, C. R. Benedict, Circulation 2001 , 104, 16-18), which suggests an involvement in heart failure and atherosclerosis. In addition, U- Il has been shown to increase peripheral vascular tone, a characteristic of chronic heart failure (M. Lim, S. Honisett, C. D. Sparkes, P. Komesaroff, A. Kompa, H. Krum, Circulation 2004, 109, 1212-1214). Recent results have shown increased U-Il receptor levels observed in the atherosclerotic lesions of the human aorta (N. Bousette, L. Patel, S. A. Douglas, E. H. Ohlstein, A. Giaid, Atherosclerosis 2004, 176, 117-123). Relative to healthy individuals, the expression of U-ll-like immunoreactivity was 2-fold higher in the plasma of patients with renal dysfunction who were not on dialysis, and 3-fold higher in those on haemodialysis (K. Totsune, K. Takahashi, Z. Arihara, M. Sone, F. Satoh, S. Ito, Y. Kimura, H. Sasano, O. Murakami, Lancet 2001, 358, 810-811). Recently, Kinoshita, M. and Kushida, H. in International Publication WO 2005/034873 disclosed the use of Urotensin-ll antagonists for reducing nephrotoxicity and diarrhea caused by anti-neoplastic agents.
U-Il has been described as a potential mediator in diabetes. For instance, U-Il was shown to inhibit the release of insulin in the perfused rat pancreas in response to increasing glucose levels (R. A. Silvestre, J. Rodπguez-Gallardo, E. M. Egido, J. Marco, Horm. Metab. Res. 2001, 33, 379-381). Elevated U-H levels were seen in patients with diabetis mellitus (K. Totsune, K. Takahashi, Z. Arihara, M. Sone,.S. Ito, O. Murakami, Clin. Sci. 2003, 104, 1-5) even without renal failure. Haplotypes in the urotensin Il gene and urotensin Il receptor gene are reported to be associated with insulin resistance and impaired glucose tolerance (K. Ong, L. Wong, Y. Man, R. Leung, Y. Song, K. Lam, B. Cheung, Peptides, 2006, 27(7), 1659-1667).
A U-Il antagonist may be useful for the treatment of pain, neurological and psychiatric conditions, migraine, neuromuscular deficit, anxiety disorders and cardiovascular disorders. ICV (intracerebroventricular) administration of U-Il increases rearing, grooming, and motor activity suggesting a CNS stimulatory activity (J. Gartlon, F. Parker, D. C. Harrison, S. A. Douglas, T. E. Ashmeade, G. J. Riley, Z. A. Hughes, S. G. Taylor, R. P. Munton, J. J. Hagan, J. A. Hunter, D. N. C. Jones, Psychopharmacology 2001 , 155, 426-433). U-M increases Fos expression in the cingulate cortex and periaqueductal grey brain regions important in cognitive, emotional, and motor responses; the perceptions of pain; and panic responses (J. E. Gartlon, T. Ashmeade, M. Duxon, J. J. Hagan, D. N. C. Jones, Eur. J. of Pharmacol. 2004, 493, 95-98). U-Il induces anxiogenic-like responses in rodents in the elevated plus maze and hole-board tests (Y. Matsumoto, M. Abe, T. Watanabe, Y. Adachi, T. Yano, H. Takahashi, T. Sugo, M. Mori, C. Kitada, T. Kurokawa, M. Fujino, Neuroscience Letters 2004, 358, 99-102). Application JP 07242662 (also referred to as JP1995242662) describes substituted 4H-benzo[1 ,4]oxazin-3-ones as phospholipase A2 and interleukin 1 inhibitors.
PCT Application WO 03/091248 describes 7-fluoro-6-{1-[2-(7-fluoro-2- methyl-quinolin-5-yloxy)-ethyl]-piperidin-4-ylmethyl}-4H-benzo[1 ,4]oxazin-3-one as a 5-HTIA receptor inhibitor.
PCT Application WO 05/061457 describes substituted benzo[1 ,4]oxazines as renin inhibitors.
Accordingly, it is an object of the present invention to provide compounds that are Urotensin-ll antagonists useful for treating Urotensin-li mediated disorders.
It is another object of the invention to provide a process for preparing compounds, compositions, intermediates and derivatives thereof.
It is a further object of the invention to provide methods for treating Urotensin-ll mediated cardiovascular, renal, pancreatic and central nervous system disorders including, but not limited to, chronic vascular disease, vascular hypertension, heart failure, atherosclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, inflammatory colitis (caused by bacteria, ischemia, radiation, drugs or chemical substances), renal dysfunction, renal failure, renal failure caused by drug induced toxicity, nephrotoxicity and diarrhea caused by anti-neoplastic agents, nephrotoxicity caused by radiocontrast agents and aminoglycosides, post-myocardial infarction, pulmonary hypertension, pulmonary fibrosis, insulin resistance and impaired glucose tolerance, diabetes, diabetic complications, diabetic nephropathy, pain, Alzheimer's disease, convulsions, depression, migraine, psychosis, anxiety, neuromuscular deficit and stroke. SUMMARY OF THE INVENTION
The present invention is directed to a compound of Formula (I):
Figure imgf000006_0001
and forms thereof, wherein Ring A, Y, L1, L2, L3. R2. R3 and R4 are as defined herein. Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I). Illustrative of the invention is a process for making a pharmaceutical composition comprising mixing a compound of Formula (I) and a pharmaceutically acceptable carrier.
The present invention is further directed to methods for treating or ameliorating a Urotensin ll-mediated disorder. In particular, the method of the present invention is directed to treating or ameliorating a Urotensin ll-mediated disorder including, but not limited to, chronic vascular disease, vascular hypertension, heart failure, atherosclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, inflammatory colitis, renal dysfunction, renal failure, renal failure caused by drug induced toxicity, nephrotoxicity and diarrhea caused by anti-neoplastic agents, nephrotoxicity caused by radiocontrast agents and aminoglycosides, post-myocardial infarction, pulmonary hypertension, pulmonary fibrosis, insulin resistance and impaired glucose tolerance, diabetes, diabetic complications, diabetic nephropathy, pain, Alzheimer's disease, convulsions, depression, migraine, psychosis, anxiety, neuromuscular deficit and stroke. The present invention is also directed to methods for producing the instant compounds and pharmaceutical compositions and medicaments thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed a compound of Formula (I):
Figure imgf000007_0001
and forms thereof, wherein
Ring A is selected from the group consisting of piperidinyl, 8-aza-bicyclo[3.2.1]oct-2- enyl, 8-aza-bicyclo[3.2.1]octyl and 1,2,3,6-tetrahyclro-pyridinyl;
Y is selected from the group consisting of CH2, O and S; Li is absent or is selected from the group consisting of -C(O)O-Ri , -C(O)N(Rs)-Ri and -NHC(O)-Ri; l_2 is d-βalkyl;
L3 is absent or is -C(O)N(Rs)-R7;
Ri is selected from the group consisting of Ci^alkyl, Ci^alkoxy, aryl, aryl-Ci^alkyl, C3-i4cycloalkyl,
Figure imgf000007_0002
heterocyclyl, heterocyclyl-Ci-βalkyi, heteroaryl and heteroaryl-Ci-βalkyl, wherein Chalky! is optionally substituted with one, two or three substituents each selected from the group consisting of Ci-8alkoxy, halogen, hydroxy and -NHR6, wherein Ci^alkoxy is optionally substituted with one, two or three substituents each selected from the group consisting of Ci-βalkoxy, halogen, hydroxy and -NHR6, wherein each instance of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of Ci-βalkyI, Ci.8alkoxy, halogen and halo-d-βalkyl, and wherein each instance of heterocyclyl is optionally substituted with oxo, Ci-βalkyl-carbonyl, Ci-βalkoxy-carbonyl, Ci-βalkyl-N(R5)-carbonyl, aryl-carbonyl, aryl-Ci-βalkyl-carbonyl, aryl-Ci-βalkoxy-carbonyl, aryl-N(R5)-carbonyl, aryl-Ci-8alkyl-N(R5)-carbonyl or
Figure imgf000008_0001
R2 is one, two or three substituents each selected from the group consisting of hydrogen, C1-8alkyl, Ci-βalkoxy and halogen;
R3 is one, two or three substituents each selected from the group consisting of hydrogen and C^alkyl;
R4 is one, two or three substituents each selected from the group consisting of hydrogen, Chalky!, Ci-βalkoxy, hydroxy and halogen;
R5 is selected from the group consisting of hydrogen and Ci-4alkyl;
Re is selected from the group consisting of Ci-βalkyl-carbonyl, C-i-βalkoxy-carbonyl, CM-βalkyl-NfRsJ-carbonyl, aryl-carbonyl, aryl-Ci-βalkyl-carbonyl, aryl-Ci-βalkoxy-carbonyl, aryl-N(Rs)-carbonyl, aryl-Ci-βalkyl-NfRsVcarbonyl and aryl-Ci-βalkyl-sulfonyl; and,
R7 is selected from the group consisting of Chalky!, aryl, aryl-Ci-βalkyl,
C3-i4cydoalkyl, Cs-ucycloalkyl-d-ealkyl, heterocyclyl, heterocyclyl-d-βa'kyl, heteroaryl and heteroaryl-Ci-βalkyl.
An example of the present invention includes a compound of Formula (I) and forms thereof, wherein Ring A is piperidinyl. An example of the present invention includes a compound of Formula (I) and forms thereof, wherein Ring A is 8-aza-bicyclo[3.2.1]oct-2-enyl.
An example of the present invention includes a compound of Formula (I) and forms thereof, wherein Ring A is 8-aza-bicyclo[3.2.1]octyl. An example of the present invention includes a compound of Formula (I) and forms thereof, wherein Ring A is 1,2,3,6-tetrahydro-pyridinyl.
An example of the present invention includes a compound of Formula (I) and forms thereof, wherein Ring A is substituted with one or two d^alkyl.
An example of the present invention includes a compound of Formula (I) and forms thereof, wherein Y is CH2.
An example of the present invention includes a compound of Formula (I) and forms thereof, wherein Y is O.
An example of the present invention includes a compound of Formula (I) and forms thereof, wherein Y is S. An example of the present invention includes a compound of Formula (I) and forms thereof, wherein
Ri is selected from the group consisting of Chalky!, Ci^alkoxy, aryl-Ci-βalkyl,
C3-i4cycloalkyl, C3-i4cycloalkyl-Ci^alkyl, heterocyclyl, heterocyclyl-Ci-βalkyl and heteroaryl-Ci-8alkyl, wherein Chalky! is optionally substituted with a substituent selected from the group consisting of Ci-βalkoxy, hydroxy and -NHRe, wherein Ci-βalkoxy is optionally substituted with -NHR6, wherein each instance of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of C1-8alkoxy, halogen
Figure imgf000009_0001
wherein each instance of heterocyclyl is optionally substituted with oxo, Ci-βalkyl-carbonyl, Ci-βalkoxy-carbonyl, aryl-carbonyl, aryl-Ci-βalkoxy-carbonyl, aryl-Ci^alkyl-N(R5)-carbonyl or aryl-Ci-βalkyl-sulfonyl.
An example of the present invention includes a compound of Formula (I) and forms thereof, wherein Ri is selected from the group consisting of Ci-8alkyl, C1-βalkoxy, phenyl-d-βalkyl, naphthyl-d-βalkyl, indanyl, cyclopropyl-d-βalkyl, cyclohexyl-Ci-βalkyl, 1 ,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-d-βalkyi, piperidinyl-d-βalkyl, piperazinyl-Ci-8alkyl, furanyl-d-βalkyl, thienyl-Ci-8alkyl, imidazolyl-d-βalkyl, pyridinyl-C1-8alkyl and indolyl-d-βalkyl, wherein d-βalkyl is optionally substituted with a substituent selected from the group consisting of d-βalkoxy, hydroxy and -NHRe. wherein d-βalkoxy is optionally substituted with -NHR6, wherein each instance of phenyl is optionally substituted with one, two or three substituents each selected from the group consisting of d-βalkoxy, chloro, fluoro, bromo and halo-d-βalkyl, and wherein each instance of 1 ,2.3,4-tetrahydro-isoquinolinyl, pyrrol idinyl-Ci-8alkyl, piperidinyl-d-βalkyl, piperazinyl-d-βalkyl is optionally substituted with oxo, Ci-βalkyl-carbonyl, d-βalkoxy-carbonyl, aryl-carbonyl, aryl-Ci-βalkoxy-carbonyl, aryl-d-8alkyl-N(R5)-carbonyl or aryl-C1-8alkyl-sulfonyl.
An example of the present invention includes a compound of Formula (I) and forms thereof, wherein R2 is one substituent selected from the group consisting of hydrogen, d-βalkyl, Ci-βalkoxy and halogen.
An example of the present invention includes a compound of Formula (I) and forms thereof, wherein R3 is one or two substituents each selected from the group consisting of hydrogen and d-4alkyl.
An example of the present invention includes a compound of Formula (I) and forms thereof, wherein R4 is one substituent selected from the group consisting of hydrogen, Ci-8alkyl and halogen.
An example of the present invention includes a compound of Formula (I) and forms thereof, wherein R5 is hydrogen.
An example of the present invention includes a compound of Formula (I) and forms thereof, wherein R5 is C^alkyl.
An example of the present invention includes a compound of Formula (I) and forms thereof, wherein R6 is selected from the group consisting of Ci-βalkyl-carbonyl, Ci-βalkoxy-carbonyl, Ci-βalkyl-N(Rs)-carbonyl, aryl-Ci-βalkoxy-carbonyl, aryl-N(R5)-carbonyl, aryl-Ci-8alkyl-N(R5)-carbonyl and aryl-Ci-βalkyl-sulfonyl.
An example of the present invention includes a compound of Formula (I) and forms thereof, wherein R6 is selected from the group consisting of Ci-βalkyl-carbonyl. Ci.8alkoxy-carbonyl, Ci-8alkyl-N(R5)-carbonyl, phenyl-Ci-βaikoxy-carbonyl, phenyl-N(R5)-carbonyl, phenyl-Ci-8alkyl-N(R5)-carbonyl and phenyl-Ci-βalkyl-sulfonyl.
An example of the present invention includes a compound of Formula (I) and forms thereof, wherein R7 is selected from the group consisting of Ci-βalkyI and aryl-Ci-βalkyl.
An example of the present invention includes a compound of Formula (I) and forms thereof, wherein R7 is selected from the group consisting of Ci-βalkyl and phenyl-Ci-βalkyl.
An example of the present invention includes a compound of Formula (I) and forms thereof, wherein
Ring A is selected from the group consisting of piperidinyl, 8-aza-bicyclo[3.2.1]oct-2- enyl, 8-aza-bicyclo[3.2.1]octyl and 1,2,3,6-tetrahydro-pyridinyl;
Y is selected from the group consisting of CH2, O and S;
Li is absent or is selected from the group consisting of -C(O)ORi, -C(O)N(R5)-Ri and -NHC(O)-Ri; l_2 is Ci-βalkyl; L3 is absent or is -C(O)N(R5)-R7;
Ri is selected from the group consisting of Ci^alkyi, Ci-βalkoxy, aryl-Ci-ealkyl, Ca-ucycloalkyl,
Figure imgf000012_0001
and heteroaryl-Ci-βalkyl, wherein C1-8alky1 is optionally substituted with a substituent selected from the group consisting of Ci-βalkoxy, hydroxy and -NR6, wherein Ci-βalkoxy is optionally substituted with -NHR6, wherein each instance of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of Ci-βalkoxy, halogen and halo-Ci-8alkyl, and wherein each instance of heterocyclyl is optionally substituted with oxo,
Ci-8alkyl-carbonyl, Ci-βalkoxy-carbonyl, aryl-carbonyl, aryl-Ci-βalkoxy-carbonyl, aryl-Ci-βalkyl-N(R5)-carbonyl or aryl-d-βalkyl-sulfonyl ;
R2 is one substituent selected from the group consisting of hydrogen, Ci-βalkyI, Ci-βalkoxy and halogen;
R3 is one or two substituents each selected from the group consisting of hydrogen and d^alkyl;
R4 is one substituent selected from the group consisting of hydrogen, Chalky! and halogen;
Rs is selected from the group consisting of hydrogen and Chalky!;
Re is selected from the group consisting of Ci-βalkyt-carbonyl,
Figure imgf000012_0002
Ci-8alkyl-N(R5)-carbonyl, aryl-Ci-βalkoxy-carbonyl, aryl-NfRsJ-carbonyl, aryl-Ci-8alkyl-N(R5)-carbonyl and
Figure imgf000012_0003
and F?7 is selected from the group consisting of Ci-βalkyI and
Figure imgf000013_0001
An example of the present invention includes a compound of Formula (I) and forms thereof, wherein
Ring A is selected from the group consisting of piperidinyl, 8-aza-bicyclo[3.2.1]oct-2- enyl, 8-aza-bicyclo[3.2.1]octyl and 1,2,3,6-tetrahydro-pyridinyl;
Y is selected from the group consisting of CH2, O and S;
Li is absent or is selected from the group consisting of -C(O)O-Ri, -C(O)N(Rs)-Ri and -NHC(O)-Ri;
L2 is C1-8alkyl; L3 is absent or is -C(O)N(R5J-R?;
Ri is selected from the group consisting of Ci-βalkyI, Ci-βalkoxy, phenyl-Ci-βalkyl, naphthyl-Ci-βalkyl, indanyl, cyclopropyl-Ci-βalkyl, cyclohexyl-Ci-ealkyl, 1 ,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-Ci-ealkyl, piperidinyl-Ci-βalkyl, piperazinyl-Ci-βalkyl, furanyl-Ci-ealkyl, thienyl-d-aalkyl, imidazolyl-Ci-ealkyl, pyridinyl-Ci-βalkyI and indolyl-Ci-βalkyl, wherein Ci-βalkyI is optionally substituted with a substituent selected from the group consisting of Ci-aalkoxy, hydroxy and -NR6, wherein d-βalkoxy is optionally substituted with -NHR6, wherein each instance of phenyl is optionally substituted with one, two or three substituents each selected from the group consisting of Ci-βalkoxy, chloro, fluoro, bromo and halo-Ci^alkyl, and wherein each instance of 1,2,3,4-tetrahydro-isoquinolinyl,
Figure imgf000013_0002
piperidinyl-Ci-βalkyl, piperazinyl-d-βalkyl is optionally substituted with oxo, Ci-βalkyl-carbonyl, Ci-βalkoxy-carbonyl, aryl-carbonyl, aryl-Ci-βalkoxy-carbonyl,
Figure imgf000013_0003
or aryl-Ci-βalkyl-sulfonyl; F?2 is one substituent selected from the group consisting of hydrogen, d-βalkyl, Ci-βalkoxy and halogen;
R3 is one or two substituents each selected from the group consisting of hydrogen
Figure imgf000014_0001
R4 is one substituent selected from the group consisting of hydrogen, Chalky! and halogen;
R5 is selected from the group consisting of hydrogen and C^alkyl;
Re is selected from the group consisting of Ci-βalkyl-carbonyl, Ci-βalkoxy-carbonyl,
Ci-8alkyl-N(R5)-carbonyl, phenyl-Ci-βalkoxy-carbonyl, phenyl-N(Rs)-carbonyl, phenyl-Ci^alkyl-N(R5)-carbonyl and phenyl-d-βalkyl-sulfonyl; and
R7 is selected from the group consisting of Chalky! and phenyl-Ci-βalkyl. The present invention is directed a compound of Formula (Ia):
Figure imgf000014_0002
and forms thereof, wherein Y is selected from the group consisting of CH2, 0 and S;
Li is absent or is selected from the group consisting of -C(O)O-Ri, -C(O)N(Rs)-R1 and -NHC(O)-Ri;
L2 is Ci-βalkyl; L3 is absent or is -C(O)N(R5J-Rr;
Ri is selected from the group consisting of Ci-βalkyI, Ci-βalkoxy, aryl, aryl-d-βalkyl, C3-i4cycloalkyl, CVi-tcycloalkyl-Ci-βalkyl, heterocyclyl, heterocyclyl-Ci-ealkyl, heteroaryl and
Figure imgf000015_0001
wherein Chalky! is optionally substituted with one, two or three substituents each selected from the group consisting of Ci-βalkoxy, halogen, hydroxy and -NHR6, wherein C-i-βalkoxy is optionally substituted with one, two or three substituents each selected from the group consisting of Ci-8alkoxy, halogen, hydroxy and -NHR6, wherein each instance of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of Ci-βalkyl, d-βalkoxy, halogen and halo-Ci-ealkyl, and wherein each instance of heterocyclyl is optionally substituted with oxo, Ci-8alkyl-carbonyl, d-βalkoxy-carbonyl, Ci.8alkyl-N(R5)-carbonyl, aryl-carbonyl, aryl-d-βalkyl-carbonyl, aryl-d-βalkoxy-carbonyl, aryl-N(R5)-carbonyl, aryl-Ci-ealkyl-N(R5)-carbonyl or aryl-Ci-βalkyl-sulfonyl;
R2 is one, two or three substituents each selected from the group consisting of hydrogen, Ci.8alkyl, d-βalkoxy and halogen; R3 is one, two or three substituents each selected from the group consisting of hydrogen and d-*alkyl;
R4 is one, two or three substituents each selected from the group consisting of hydrogen, d-βalkyl, Ci-aalkoxy, hydroxy and halogen;
R5 is selected from the group consisting of hydrogen and C^alkyl; Re is selected from the group consisting of d-βalkyl-carbonyl, Ci-βalkoxy-carbonyl, Ci-βalkyl-N(R5)-carbonyl, aryl-carbonyl, aryl-d-βalkyl-carbonyl, aryl-d-βalkoxy-carbonyl, aryl-N(R5)-carbonyl, aryl-C1-8alkyl-N(R5)-carbonyl and aryl-Ci-βalkyl-sulfonyl; and,
R7 is selected from the group consisting of Ci-8alkyl, aryl,
Figure imgf000016_0001
C3-i4cycloalkyl, Ca-^cycloalkyl-Ci-ealkyl, heterocyclyl, heterocyclyl-Ci-βalkyl, heteroaryl and heteroaryl-Ci-βalkyl. An example of the present invention includes a compound of Formula (Ia) and forms thereof, wherein
Y is selected from the group consisting of CH2, O and S;
Li is absent or is selected from the group consisting of -C(O)O-Ri, -C(O)N(R5)-Ri
Figure imgf000016_0002
L2 is Ci-8alkyl;
L3 is absent or is -C(O)N(R5)-R7;
Ri is selected from the group consisting of Ci-βalkyl, Ci-βalkoxy, phenyl-Ci-βalkyl, naphthyl-Ci-βalkyl, indanyl,
Figure imgf000016_0003
cyclohexyl-Ci-βalkyl, 1 ,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-Ci-βalkyl, piperidinyl-Ci-βalkyl, piperazinyl-Ci-ealkyl, imidazolyl-Cvβalkyl. pyridinyl-Ci-βalkyl an
Figure imgf000016_0004
wherein is optionally substituted with a substituent selected from the group consisting of
Figure imgf000016_0005
hydroxy and -NRe, wherein
Figure imgf000016_0006
is optionally substituted with -NHRe, wherein each instance of phenyl is optionally substituted with one, two or three substituents each selected from the group consisting of
Figure imgf000016_0007
chloro, fluoro, bromo and halo-Chalky!, and wherein each instance of 1,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-Ci.8alkyl, piperidinyl-Ci-βalkyl, piperazinyl-d-βalkyl is optionally substituted with oxo, Ci-βalkyl-carbonyl,
Figure imgf000016_0008
aryl-carbonyl,
Figure imgf000016_0009
aryl-Ci-8alkyl-N(R5)-carbonyl or aryl-Ci-βalkyl-sulfonyl;
R2 is one substituent selected from the group consisting of hydrogen, C1-8alkyl, d-βalkoxy and halogen;
R3 is one or two substituents each selected from the group consisting of hydrogen and d^alkyl;
R4 is one substituent selected from the group consisting of hydrogen, Ci-βalkyI and halogen;
R5 is selected from the group consisting of hydrogen and C1-4alkyl;
R6 is selected from the group consisting of C1-8alkyl-carbonyl, Ci-βalkoxy-carbonyl, Ci-8alkyl-N(R5)-carbonyl, phenyl-Ci-βalkoxy-carbonyl, phenyl-N(Rs)-carbonyl, phenyl-Ci-8alkyl-N(R5)-carbonyl and phenyl-Ci-βalkyl-sulfonyl; and
R7 is selected from the group consisting of Chalky! and phenyl-Ci-βalkyl. The present invention is directed a compound of Formula (Ib):
Figure imgf000017_0001
and forms thereof, wherein
Y is selected from the group consisting of CH2, O and S;
Li is absent or is selected from the group consisting of -C(O)O-Ri, -C(O)N(R5)-Ri and -NHC(O)-R1; L2 is Ci-βalkyl;
L3 is absent or is -C(O)N(R5J-R7;
Ri is selected from the group consisting of Ci-βalkyI, Ci-βalkoxy, aryl, aryi-Ci-ealkyl, C3-i4cycloalkyl, C3-i4cycloalkyl-Ci-ealkyl, heterocyclyl, heterocyclyl-Ci-βalkyl, heteroaryl and heteroaryl-d-βalkyl, wherein Ci-βalkyl is optionally substituted with one, two or three substituents each selected from the group consisting of Ci-βalkoxy, halogen, hydroxy and -NHR6, wherein Ci-βalkoxy is optionally substituted with one, two or three substituents each selected from the group consisting of Ci-βalkoxy, halogen, hydroxy and
-NHR6, wherein each instance of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of Chalky!, Ci-βalkoxy, halogen and halo-Chalky!, and wherein each instance of heterocyclyl is optionally substituted with oxo, C1-8alkyl-carbonyl, d-βalkoxy-carbonyl, Ci-8alkyl-N(R5)-carbonyl, aryl-carbonyl, aryl-Ci-βalkyl-carbonyl, aryl-Ci-βalkoxy-carbonyl, aryl-N(R5)-carbonyl, aryl-Ci-8alkyl-N(R5)-carbonyl or aryl-Ci-βalkyl-sulfonyl;
R2 is one, two or three substituents each selected from the group consisting of hydrogen, Ci-βalkyI, d-βalkoxy and halogen;
R3 is one, two or three substituents each selected from the group consisting of hydrogen and d^alkyl;
R4 is one, two or three substituents each selected from the group consisting of hydrogen, Ci-βalkyI, d-βalkoxy, hydroxy and halogen; R5 is selected from the group consisting of hydrogen and d^alkyl;
Re is selected from the group consisting of d-βalkyl-carbonyl, Ci-βalkoxy-carbonyl, Ci-βalkyl-N(R5)-carbonyl, aryl-carbonyl, aryl-Ci-βalkyl-carbonyl, aryl-Ci-βalkoxy-carbonyl, aryl-N(R5)-carbonyl, aryl-Ci-8alkyl-N(R5)-carbonyl and aryl-Ci-8alkyl-sulfonyl; and,
R7 is selected from the group consisting of Chalky!, aryl, aryl-Ci-βalkyl, C3-i4cycloalkyl, C3-i4Cycloalkyl-Ci-8alkyl, heterocyclyl, heterocyclyl-Ci-βalkyl, heteroaryl and heteroaryl-Ci-βalkyl.
An example of the present invention includes a compound of Formula (Ib) and forms thereof, wherein
Y is selected from the group consisting of CH2, O and S; Li is absent or is selected from the group consisting of -C(O)O-Ri, -C(O)N(Rs)-Ri and -NHC(O)-Ri; l_2 is Ci-βalkyl;
L3 is absent or is -C(O)N(Rs)-Rz;
R1 is selected from the group consisting of Chalky!, Ci-βalkoxy, phenyl-Ci-βalkyl, naphthyl-Ci-βalkyl, indanyl, cyclopropyl-d-βalkyl, cyclohexyl-Ci-βalkyl,
1 ,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-Ci-ealkyl, piperidinyl-Ci-βalkyi, piperazinyl-Ci-8alkyl, furanyl-Ci-βalkyl, thienyl-Ci-βalkyl,
Figure imgf000019_0001
pyridinyl-Ci-βalkyl and indolyl-Ci-galkyl, wherein Chalky! is optionally substituted with a substituent selected from the group consisting of Ci-βalkoxy, hydroxy and -NR6, wherein Ci-βalkoxy is optionally substituted with -NHRβ, wherein each instance of phenyl is optionally substituted with one, two or three substituents each selected from the group consisting of
Figure imgf000019_0002
chloro, fluoro, bromo and halo-Chalky!, and wherein each instance of 1 ,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-C^alkyl, piperidinyl-d-βalkyl,
Figure imgf000019_0003
is optionally substituted with oxo, Ci-βalkyl-carbonyl, Ci-βalkoxy-carbonyl, aryl-carbonyl, aryl-Ci-βalkoxy-carbonyl, aryl-Ci^alkyl-N(Rs)-carbony1 or aryl-Ci-βalkyl-sulfonyl;
R2 is one substituent selected from the group consisting of hydrogen, Chalky), C-i-βalkoxy and halogen;
R3 is one or two substituents each selected from the group consisting of hydrogen and Ci-4alkyl;
R4 is one substituent selected from the group consisting of hydrogen, Chalky! and halogen; R5 is selected from the group consisting of hydrogen and Chalky);
Re is selected from the group consisting of Ci-βalkyl-carbonyl, Ci-βalkoxy-carbonyl, Ci-βalkyl-N(R5)-carbonyl, phenyl-Ci-βalkoxy-carbonyl, phenyl-N(R5)-carbonyl, phenyl-Ci^alkyl-N(R5)-carbonyl and phenyl-Ci^alkyl-sulfonyl; and
R7 is selected from the group consisting of Ci-βalkyI and phenyl-Ci-βalkyl. The present invention is directed a compound of Formula (Ic):
Figure imgf000020_0001
and forms thereof, wherein
Y is selected from the group consisting of CH2, O and S; Li is absent or is selected from the group consisting of -C(O)O-Ri, -C(O)N(R5)-Ri and -NHC(O)-Ri;
L2 is Ci-βalkyl;
L3 is absent or is -C(O)N(R5J-R7; Ri is selected from the group consisting of d-βalkyl, d-βalkoxy, aryl, aryl-Ci-ealkyl, C3-i4cycloalkyl,
Figure imgf000021_0001
heteroaryl and heteroaryl-d-βalkyl, wherein Ci-βalkyI is optionally substituted with one, two or three substituents each selected from the group consisting of Ci-βalkoxy, halogen, hydroxy and -NHR6, wherein Ci-βalkoxy is optionally substituted with one, two or three substituents each selected from the group consisting of Ci-βalkoxy, halogen, hydroxy and -NHR6, wherein each instance of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of d-βalkyl, Ci-βalkoxy. halogen and halo-d-βalkyl, and wherein each instance of heterocyclyl is optionally substituted with oxo, Ci-8alkyl-carbonyl, Ci-βalkoxy-carbonyl, Ci-βalkyl-N(R5)-carbonyl, aryl-carbonyl, aryl-Ci-βalkyl-carbonyl, aryl-Ci^alkoxy-carbonyl, aryl-N(R5)-carbonyl, aryl-Ci-βalkyl-N(R5)-carbonyl or aryl-Ci-βalkyl-sulfonyl;
R2 is one, two or three substituents each selected from the group consisting of hydrogen, Ci-βalkyI, Ci-βalkoxy and halogen;
R3 is one, two or three substituents each selected from the group consisting of hydrogen and d^alkyl; R4 is one, two or three substituents each selected from the group consisting of hydrogen, Ci-βalkyl, Ci-βalkoxy, hydroxy and halogen; Rs is selected from the group consisting of hydrogen and C^alkyl;
R6 is selected from the group consisting of Ci-βalkyl-carbonyl, C^alkoxy-carbonyl, Ci-βalkyl-N(R5)-carbonyl, aryl-carbonyl, aryl-Ci-aalkyl-carbbnyl, aryl-Ci-βalkoxy-carbonyl, aryl-N(R5)-carbonyl,
Figure imgf000022_0001
and aryl-d-βalkyl-sulfonyl; and,
R7 is selected from the group consisting of Chalky!, aryl, aryl-Ci-ealkyl,
C3-i4cycloalkyl, C3-i4cycloalkyl-Ci-8alkyl, heterocyclyl, heterocyclyl-Ci-ealkyl, heteroaryl and heteroaryl-Ci-βalkyl.
An example of the present invention includes a compound of Formula (Ic) and forms thereof, wherein
Y is selected from the group consisting of CH2, O and S;
Li is absent or is selected from the group consisting of -C(O)O-Ri, -C(O)N(Rs)-Ri and -NHC(O)-Ri;
L_2 is Ci-βalkyl; L3 is absent or is -C(O)N(R5J-R7;
RI is selected from the group consisting of Ci-βalkyI, C1^aIkOXy, phenyl-Ci-ealkyl, naphthyl-Ci-βalkyI, indanyl, cyclopropyl-Ci-ealkyl, cyclohexyl-d-βalkyl, 1 ,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-Ci-ealkyl,
Figure imgf000022_0002
Figure imgf000022_0003
furanyl-Ci-ealkyl,
Figure imgf000022_0004
imidazolyl-Ci-ealkyl, pyridinyl-Ci-ealkyl and indolyl-Ci^alkyl, wherein is optionally substituted with a substituent selected from the group consisting of Ci-8alkoxy, hydroxy and -NR6, wherein d-βalkoxy is optionally substituted with -NHRe, wherein each instance of phenyl is optionally substituted with one, two or three substituents each selected from the group consisting of d-βalkoxy, chloro, fluoro, bromo and halo-d-βalkyl, and wherein each instance of 1,2,3,4-tetrahydro-isoquinolinyi, pyrrolidinyl-Ci-βalkyl, piperidinyl-Ci-βalkyl, piperazinyl-Ci-ealkyl is optionally substituted with oxo, Ci-βalkyl-carbonyl, Ci-βalkoxy-carbonyl, aryl-carbonyl, aryl-Ci-βalkoxy-carbonyl, aryl-Ci_βalkyl-N(R5)-carbonyl or aryl-Ci-βalkyl-sulfonyl;
R2 is one substituent selected from the group consisting of hydrogen, d-aalkyt, Ci-salkoxy and halogen;
R3 is one or two substituents each selected from the group consisting of hydrogen and Ci-4alkyl; R4 is one substituent selected from the group consisting of hydrogen, Chalky! and halogen;
R5 is selected from the group consisting of hydrogen and Chalky!;
Re is selected from the group consisting of Ci-βalkyl-carbonyl, Ci-βalkoxy-carbonyl,
Ci-8a!kyl-N(R5)-carbonyl, phenyl-Ci-βalkoxy-carbonyl, phenyl-N(R5)-carbonyl, phenyl-Ci-8alkyl-N(R5)-carbonyl and phenyl-Ci-βalkyi-sulfonyl; and
R7 is selected from the group consisting of Chalky! and phenyl-Ci-βalkyl. The present invention is directed a compound of Formula (Id):
Figure imgf000023_0001
and forms thereof, wherein Y is selected from the group consisting of CH2, O and S;
L1 is absent or is selected from the group consisting of -C(O)O-R1, -C(O)N(Rs)-R1 and -NHC(O)-R1;
L2 is Ci-βalkyl; L3 is absent or is -C(O)N(Rs)-R7;
R1 is selected from the group consisting of d-βalkyl, d-βalkoxy, aryl, aryl-Ci-ealkyl, C3-14cycloalkyl, Cj-ucycloalkyl-d-βalkyl, heterocyclyl, heterocyclyl-d-βalkyl, heteroaryl and heteroaryl-d-βalkyl, wherein Chalky! is optionally substituted with one, two or three substituents each selected from the group consisting of d-βalkoxy, halogen, hydroxy and
-NHR6, wherein d-βalkoxy is optionally substituted with one, two or three substituents each selected from the group consisting of d-βalkoxy, halogen, hydroxy and -NHR6, wherein each instance of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of C1-8alkyl, d-βalkoxy, halogen and halo-d-aalkyl, and wherein each instance of heterocyclyl is optionally substituted with oxo, Ci-βalkyl-carbonyl, d-βalkoxy-carbonyl, d-8alkyl-N(Rs)-carbonyl, aryl-carbonyl, aryl-d-βalkyl-carbonyl, aryl-d-βalkoxy-carbonyl, aryl-N(R5)-carbonyl, aryl-d-8alkyl-N(R5)-carbonyl oraryl-d-βalkyl-sulfonyl;
R2 is one, two or three substituents each selected from the group consisting of hydrogen, d-βalkyl, d-βalkoxy and halogen;
R3 is one, two or three substituents each selected from the group consisting of hydrogen and d^alkyl;
R4 is one, two or three substituents each selected from the group consisting of hydrogen, Ci-βalkyI, Ci-βalkoxy, hydroxy and halogen; R5 is selected from the group consisting of hydrogen and C1-4alkyl;
Re is selected from the group consisting of Ci-βalkyl-carbonyl, Ci-βalkoxy-carbonyl,
Ci-8alkyl-N(R5)-carbonyl, aryl-carbonyl, aryl-Ci-βalkyl-carbonyi, aryl-Ci-βalkoxy-carbonyl, aryl-N(R5)-carbonyl, aryl-Ci-8alkyl-N(R5)-carbonyl and aryl-Ci-βalkyl-sulfonyl; and,
R7 is selected from the group consisting of Ci-8alkyl, aryl, aryl-C1-8alkyl,
C3-i4cycloalkyl, Ca-^cycloalkyl-Ci-ealkyl, heterocyclyl, heterocydyl-Ci-βalkyl, heteroaryl and heteroaryl-Ci-βalkyl. An example of the present invention includes a compound of Formula (Id) and forms thereof, wherein
Y is selected from the group consisting of CH2, O and S;
Li is absent or is selected from the group consisting of -C(O)O-Ri, -C(O)N(Rs)-Ri
Figure imgf000025_0001
L2 is Ci-8alkyl;
L3 is absent or is -C(O)N(Rs)-R7;
Ri is selected from the group consisting of Ci-βalkyl, Ci-βalkoxy,
Figure imgf000025_0002
naphthyl-Ci-βalkyl, indanyl, cyclopropyl-Ci-βalkyl, cyclohexyl-Ci-ealkyl, 1 ,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-Ci-βalkyl, piperidinyl-Ci-βalkyl, piperazinyl-Ci-βalkyl, furanyl-Ci.βalkyl, thienyl-d-βalkyl, imidazolyl-Ci-8alkyl, pyridinyl-Ci-ealkyl and indolyl-Ci-βalkyl, wherein d-βalkyl is optionally substituted with a substituent selected from the group consisting of Ci-βalkoxy, hydroxy and -NR6, wherein Ci-βalkoxy is optionally substituted with -NHRe, wherein each instance of phenyl is optionally substituted with one, two or three substituents each selected from the group consisting of Ci-βalkoxy, chloro, fluoro, bromo and halo-d-βalkyt, and wherein each instance of 1 ,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-Ci-βalkyl, piperidinyl-Ci-8alky is optionally substituted with oxo,
Figure imgf000026_0002
Figure imgf000026_0001
ryl-carbonyl, aryl-Ci-βalkoxy-carbonyl, aryl-Ci-8alkyl-N(R5)-carbonyl or aryl-Ci-βalkyl-sulfonyl;
R2 is one substituent selected from the group consisting of hydrogen, Ci-aalkyl, Ci-βalkoxy and halogen;
R3 is one or two substituents each selected from the group consisting of hydrogen and Oi^alkyl;
R4 is one substituent selected from the group consisting of hydrogen, Ci-βalkyI and halogen;
R5 is selected from the group consisting of hydrogen and d^alkyl;
Re is selected from the group consisting of Ci-βalkyl-carbonyl, Ci-βalkoxy-carbonyl, Ci-8alkyl-N(R5)-carbonyl, phenyl-Ci-βalkoxy-carbonyl, phenyl-N(R5)-carbonyl, phenyl-Ci-8alkyl-N(R5)-carbonyl and phenyl-C1-8alkyl-sulfonyl; and
R7 is selected from the group consisting of d-βalkyl and phenyl-Ci-βalkyl.
An example of the present invention includes a compound of Formula (I) and forms thereof selected from the group consisting of:
Figure imgf000026_0003
Figure imgf000026_0004
Cpd 1 Cpd 4
Figure imgf000026_0005
Figure imgf000027_0001
Cpd13 Cpd14 Cpd15 Cpd16
Figure imgf000028_0001
Cpd25 Cpd26 Cpd27 Cpd28
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Cpd69 Cpd70 Cpd71 Cpd72
Figure imgf000033_0001
Cpd77 Cpd78 Cpd79 Cpd80
Figure imgf000034_0001
33
Figure imgf000035_0001
Cpd 97 Cpd 98 Cpd 99 Cpd 100
Figure imgf000036_0001
Cpd 101 Cpd 102 Cpd 103 Cpd 104
Figure imgf000036_0002
Cpd 105
Figure imgf000036_0004
Figure imgf000036_0003
Figure imgf000036_0005
Cpd 109 Cpd 110 Cpd 111 Cpd 112
Figure imgf000037_0001
Cpd 113 114 115 116
Definitions
Bond lines drawn into a ring system from a substituent variable indicate that the substituent may be attached to any of the substitutable ring atoms.
As used herein, the following terms are intended to have the following definitions. The definitions herein may specify that a chemical term has an indicated formula. The particular formula provided is not intended to limit the scope of the invention, but is provided as an illustration of the term. The scope of the per se definition of the term is intended to include the plurality of variations expected to be included by one of ordinary skill in the art. The term "Chalky!" refers to straight and branched carbon chains having 1 to 8 carbon atoms or any number within this range. Therefore, designated numbers of carbon atoms (e.g. Ci-β) shall refer independently to the number of carbon atoms in the chain. A d-βalkyl chain may be attached to a core molecule and further substituted on any atom when allowed by available valences. The term "d-βalkoxy" refers to a -O-d-βa'kyl substituent group, wherein d-βalkyl is as defined supra. An Ci-βalkoxy chain may be attached to a core molecule and further substituted on any atom when allowed by available valences.
The term "Ca-ucycloalkyl" refers to saturated or partially unsaturated, monocyclic or polycyclic hydrocarbon rings of from 3 to 14 carbon atom ring members which may be optionally fused to a benzene ring. The term uC3-i4cycloalkyr also includes a C3-8cycloalkyl, Ca-iocycloalkyl, Cs-βcycloalkyl, Cδ-βcycloalkyl, Cs-^cycloalkyl, C9-i3cycloalkyl or benzofused-Ca-iacycloalkyl ring system radical and the like, including, but not limited to, cyclopropyl. cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1/-/-indenyl, indanyl, 9H-fluorenyl, 1 ,2,3,4-tetrahydro-naphthalenyl, adamantyl and the like. Cycloalkyl may be attached to a core molecule and further substituted on any atom when allowed by available valences.
The term "heterocyclyl" refers to a saturated or partially unsaturated, monocyclic or polycyclic ring of 5 to 9 members in which up to 4 members are nitrogen, or in which one or two members are nitrogen and one other member is O or S, or in which one member is O, S, S(O) or S(O)2 and which may be optionally fused to a benzene ring.
Examples of heterocyclyl groups include, and are not limited to, azetidinyl, 2H-pyrrole, 2-pyrrolinyl, 3-pyrrolinyl, pyrrol idinyl, 1 ,3-dioxolanyl, 2-imidazolinyl (also referred to as 4,5-dihydro-1H-imidazolyl), imidazolidinyl, 2-pyrazolinyl, pyrazol idinyl, tetrazolyl, tetrazolidinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1 ,4- dithianyl, thiomorpholinyl, piperazinyl, azepanyl, hexahydro-1,4-diazepinyl, hexahydro-1,4-oxazepanyl, tetrahydro-furanyl, tetrahydro-thienyl, tetrahydro- pyranyl, tetrahydro-pyridazinyl, 8-aza-bicyclo[3.2.1]oct-2-enyl, 8-aza- bicyclo[3.2.1]octyl, 1 ,2,3,6-tetrahydro-pyridinyl and the like.
The term "heterocyclyl" also includes a benzofused-heterocyclyl ring system radical and the like, such as indolinyl (also referred to as 2,3-dihydro- indolyl), benzo[1 ,3]dioxolyl, 2,3-dihydro-1 ,4-benzodioxinyl, 2,3-dihydro- benzofuranyl, 1,2-dihydro-phthalazinyl and the like. A heterocyclyl radical may be attached to a core molecule and further substituted on any atom when allowed by available valences. The term "benzofused-heterocyclyl" means a heterocyclyl ring system radical having a benzene ring fused on the ring system on adjacent carbons. A benzofused-heterocyclyl radical may be attached to a core molecule and further substituted on any atom when allowed by available valences.
The term "aryt" refers to an unsaturated, aromatic monocyclic ring of 6 carbon members or to an unsaturated, aromatic polycyclic ring of from 10 to 14 carbon members. Examples of such aryl rings include, and are not limited to, phenyl, naphthalenyl or anthracenyl.
The term "heteroaryl" refers to an aromatic ring of 5 or 6 members wherein the ring consists of carbon atoms and has at least one heteroatom member. Suitable heteroatoms include nitrogen, oxygen or sulfur. In the case of 5 membered rings, the heteroaryl ring contains one member of nitrogen, oxygen or sulfur and, in addition, may contain up to three additional nitrogens. In the case of 6 membered rings, the heteroaryl ring may contain from one to three nitrogen atoms. For the case wherein the 6 membered ring has three nitrogens, at most two nitrogen atoms are adjacent. Optionally, the heteroaryl ring is fused to a benzene ring (benzo fused heteroaryl), a 5 or 6 membered heteroaryl ring (containing one of O, S or N and, optionally, one additional nitrogen), a 5 to 7 membered cycloalkyl ring or a 5 to 7 membered heterocyclo ring (as defined supra but absent the option of a further fused ring).
Examples of heteroaryl groups include, and are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyi, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and the like. The term "heteroaryl" also includes a benzofused-heteroaryl ring system radical and the like, such as indolizinyl, indolyl, azaindolyl, isoindolyl, benzofuranyl, benzothienyl, indazolyl, azaindazolyl, benzoimidazolyl, benzothiazolyl, benzoxazolyl, benzoisoxazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl and the like. A heteroaryl radical may be attached to a core molecule and further substituted on any atom when allowed by available valences.
The term "benzofused-heteroaryl" means a heteroaryl ring system radical having a benzene ring fused on the ring system on adjacent carbons. A benzofused-heteroaryl radical may be attached to a core molecule and further substituted on any atom when allowed by available valences.
The term "aryl-Ci-βalkyr means a radical of the formula: -Ci-βalkyl-aryl (e.g., benzyl, phenethyl). Similarly, the term "aryl-C-i-βalkoxy" means a radical of the formula: -Ci-βalkoxy-aryl (e.g., benzyloxy).
The term "Cs-ucycloalkyl-Ci-ealkyl" means a radical of the formula: -Ci-βalkyl-Cs-ucycloalkyl.
The term "heterocyclyl-Ci-ealkyl" means a radical of the formula: -Ci-βalkyl-heterocyclyl. The term "heteroaryl-Ci-ealkyl" means a radical of the formula:
-C 1 -βal kyl-heteroa ryl .
The term "Cvβalkyl-carbonyl" means a radical of the formula:
Figure imgf000040_0001
The term "d-βalkoxy-carbonyl" means a radical of the formula: -C(O)-C1-8alkoxy.
The term "aryl-carbonyl" means a radical of the formula: -C(O)-aryl.
The term "aryl-Ci-ealkyl-carbonyl" means a radical of the formula: -C(O)-Ci-8alkyl-aryl.
The term "aryl-Ci-βalkoxy-carbonyl" means a radical of the formula: -C(O)-C1-8alkoxy-aryl.
The term "aryl-Ci-8alkyl-N(R5)-carbonyr means a radical of the formula: -C(O)-N(R5)-Ci.8alkyl-aryl.
The term "aryl-C-i-ealkyl-sulfonyl" means a radical of the formula: -SOa-Ci-βalkyl-aryl. The term "Ci-8alkyl-N(R5)-carbonyl" means a radical of the formula:
-C(O)-N(R5)-Ci^alkyl.
The term "aryl-N(R5)-carbonyl" means a radical of the formula: -C(O)-N(R5)-aryl.
The term "halogen" or "halo" means the group chloro, bromo, fluoro or iodo.
The term "halo-Chalky!" means a radical of the formula: -Ci-8alkyl-(halo)n, wherein one or more halogen atoms may be substituted on d-βalkyl when allowed by available valences (wherein n represents that amount of available valences based on the number of carbon atoms in the chain), and includes monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl and the like.
It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.
The term "substituted" means the independent replacement of one or more hydrogen atoms within a radical with that amount of substitutents allowed by available valences.
The term "dependency selected" means that the structure variables are specified in an indicated combination.
In general, IUPAC nomenclature rules are used herein.
Compound Forms
The term "form" means, in reference to compounds of the present invention, such may exist as, without limitation, a salt, stereoisomer, tautomer, crystalline, polymorph, amorphous, solvate, hydrate, ester, prodrug or metabolite form. The present invention encompasses all such compound forms and mixtures thereof.
The term "isolated form" means, in reference to compounds of the present invention, such may exist in an essentially pure state such as, without limitation, an enantiomer, a racemic mixture, a geometric isomer (such as a cis or trans stereoisomer), a mixture of geometric isomers, and the like. The present invention encompasses all such compound forms and mixtures thereof.
The compounds of the invention may be present in the form of pharmaceutically acceptable salts. For use in medicines, the "pharmaceutically acceptable salts" of the compounds of this invention refer to non-toxic acidic/anionic or basic/cationic salt forms.
Suitable salt forms include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of an acid such as acetic acid, adipic acid, benzoic acid, carbonic acid, citric acid, fumaric acid, glycolic acid, hydrochloric acid, maleic acid, malonic acid, phosphoric acid, saccharinic acid, succinic acid, sulphuric acid, tartaric acid, trifluoroacetic acid and the like.
Furthermore when the compounds of the present invention carry an acidic moiety, suitable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
Thus, representative salts include the following: acetate, adipate, ammonium, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, camsylate (or camphosulphonate), carbonate, chloride, clavulanate, citrate, di hydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluconate, gluceptate, glutamate, glyconate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, saccharinate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, trichloroacetate, triethiodide, trifluoroacetate, valerate and the like. Representative acids and bases which may be used in the preparation of pharmaceutically acceptable salts include the following: acids including acetic acid, 2,2-dichloroactic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, A- acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)- camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1 ,5-disulfonic acid, 1-hydroxy-2- naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino- salicylic acid, sebaic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)- L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid; and bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)- ethanol, ethanolamine, ethyleπediamine, N-methyl-glucamine, hydrabamine, 1H- imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.
The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, compounds of the present invention may have one or more crystalline polymorph or amorphous forms and, as such, are intended to be included in the scope of the invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents (e.g., organic esters such as ethanolate and the like) and, as such, are also intended to be encompassed within the scope of this invention..
Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated using various well known chromatographic methods such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. Even though the compounds of the present invention (including their pharmaceutically, acceptable salts and pharmaceutically acceptable solvates) can be administered alone, they will generally be administered in admixture with a pharmaceutical carrier, excipient or diluent selected with regard to the intended route of administration and standard pharmaceutical or veterinary practice. Thus, the present invention is directed to pharmaceutical and veterinary compositions comprising compounds of Formula (I) and one or more pharmaceutically acceptable carriers, excipients or diluents.
By way of example, in the pharmaceutical and veterinary compositions of the present invention, the compounds of the present invention may be admixed with any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), and/or solubilising agent(s).
Tablets or capsules of the compounds may be administered singly or two or more at a time, as appropriate. It is also possible to administer the compounds in sustained release formulations. Alternatively, the compounds of the general Formula (I) can be administered by inhalation or in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. An alternative means of transdermal administration is by use of a skin patch. For example, they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. They can also be incoφorated, at a concentration of between 1 and 10% by weight, into an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and preservatives as may be required.
For some applications, preferably the compositions are administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavoring or coloring agents.
The compositions (as well as the compounds alone) can also be injected parenterally, for example intracavernosally, intravenously, intramuscularly or subcutaneously. In this case, the compositions will comprise a suitable earner or diluent.
For parenteral administration, the compositions are best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or monosaccharides to make the solution isotonic with blood.
For buccal or sublingual administration the compositions may be administered in the form of tablets or lozenges which can be formulated in a conventional manner.
By way of further example, pharmaceutical and veterinary compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral). Thus for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations, such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate the major site of absorption. For parenteral administration, the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.
Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those skilled in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. It is also apparent to one skilled in the art that the therapeutically effective dose for active compounds of the invention or a pharmaceutical composition thereof will vary according to the desired effect. Therefore, optimal dosages to be administered may be readily determined and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease condition. In addition, factors associated with the particular subject being treated, including subject age, weight, diet and time of administration, will result in the need to adjust the dose to an appropriate therapeutic level. The above dosages are thus exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
Compounds of this invention may be administered in any of the foregoing compositions and dosage regimens or by means of those compositions and dosage regimens established in the art whenever use of the compounds of the invention as analgesics is required for a subject in need thereof. The invention also provides a pharmaceutical or veterinary pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical and veterinary compositions of the invention. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
The present invention is also directed to a method for treating or ameliorating a Urotensin-ll mediated disorder.
An example of the method of the present invention is a method for treating or ameliorating a disease or condition in a mammal which disease or condition is affected by antagonism of a Urotensin Il receptor, which method comprises administering to the mammal in need of such treatment or prevention an effective amount of a compound of Formula (I):
Figure imgf000048_0001
and forms thereof, wherein
Ring A is selected from the group consisting of piperidinyl, 8-aza-bicyclo[3.2.1]oct-2- enyl, 8-aza-bicyclo[3.2.1]octyl and 1.2,3,6-tetrahydro-pyridinyl;
Y is selected from the group consisting of CH2, O and S; Li is absent or is selected from the group consisting of -C(O)O-Ri, -C(O)N(Rs)-Ri and -NHC(O)-Ri;
L2 is Ci-βalkyI;
L3 is absent or is -C(O)N(R5J-R?;
Ri is selected from the group consisting of Ci.8alkyl, d-βalkoxy, aryl, aryl-Ci-ealkyl, C3-i4cycloalkyl, Ca-^cycloalkyl-d-ealkyl, heterocyclyl, heterocyclyl-d-βalkyl, heteroaryl and heteroaryl-Ci-βalkyl, wherein d-βalkyl is optionally substituted with one, two or three substituents each selected from the group consisting of d-βalkoxy, halogen, hydroxy and -NHR6, wherein d-βalkoxy is optionally substituted with one, two or three substituents each selected from the group consisting of d-βalkoxy, halogen, hydroxy and -NHR6, wherein each instance of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of Chalky!, d-βalkoxy, halogen and halo-d-βalkyl, and wherein each instance of heterocyclyl is optionally substituted with oxo, d-βalkyl-carbonyl, d-βalkoxy-carbonyl, Ci-8alkyl-N(R5)-carbonyl, aryl-carbonyl, aryl-Ci-βalkyl-carbonyl, aryl-d-aalkoxy-carbonyl, aryl-N(R5)-carbonyl, aryl-d-8alkyl-N(Rs)-carbonyl or aryl-d-βalkyl-sulfonyl;
R2 is one, two or three substituents each selected from the group consisting of hydrogen, d-βalkyl, d-βalkoxy and halogen;
R3 is one, two or three substituents each selected from the group consisting of hydrogen and d-^alkyl; R4 is one, two or three substituents each selected from the group consisting of hydrogen, d-8alkyl, d^alkoxy, hydroxy and halogen;
R5 is selected from the group consisting of hydrogen and d^alkyl;
R6 is selected from the group consisting of d-βalkyl-carbonyl, d-βalkoxy-carbonyl,
Ci-8alkyl-N(R5)-carbonyl, aryl-carbonyl, aryl-d-βalkyl-carbonyl, aryl-d-βalkoxy-carbonyl, aryl-N(R5)-carbony1,
Figure imgf000049_0001
and aryl-d-βalkyl-sulfonyl; and,
R7 is selected from the group consisting of d-βalkyl, aryl, aryl-d-βalkyl, Ca-Mcycloalkyl, C3.14cycloalkyl-C1.ea I kyl, heterocyclyl, heterocyclyl-d-βalkyl, heteroaryl and heteroaryl-Ci-βalkyl.
Another example of the method of the present invention is a method for treating or ameliorating a Urotensin-ll mediated disorder in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I) or a form thereof.
In particular, a Urotensin ll-mediated disorder includes, and is not limited to, chronic vascular disease, vascular hypertension, heart failure, atherosclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, inflammatory colitis (caused by bacteria, ischemia, radiation, drugs or chemical substances), renal dysfunction, renal failure, renal failure caused by drug induced toxicity, nephrotoxicity and diarrhea caused by anti-neoplastic agents, nephrotoxicity caused by radiocontrast agents and aminoglycosides, post-myocardial infarction, pulmonary hypertension, pulmonary fibrosis, insulin resistance and impaired glucose tolerance, diabetes, diabetic complications, diabetic nephropathy, pain, Alzheimer's disease, convulsions, depression, migraine, psychosis, anxiety, neuromuscular deficit and stroke.
The present invention also includes the use of the compound of formula (I) or a form thereof for the manufacture of a medicament for treating or ameliorating a Urotensin-ll mediated disorder in a subject in need thereof.
An example of the present invention includes a method for treating or ameliorating a Urotensin-ll mediated disorder, wherein the disorder is heart failure.
The term "medicament" refers to a product for use in treating or ameliorating a Urotensin-ll mediated disorder. The term "subject" as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been a patient or the object of treatment, observation or experiment.
The term "effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
The effective amount of said compound or form thereof is from about 0.001 mg/kg/day to about 300 mg/kg/day.
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 combinations of the specified ingredients in the specified amounts. As used herein, the term "neoplasm" refers to an abnormal growth of cells or tissue and is understood to include benign, i.e., non-cancerous growths, and malignant, i.e., cancerous growths. The term "neoplastic" means of or related to neoplasm.
As used herein, the term "agent" is understood to mean a substance that produces a desired effect in a tissue, system, animal, mammal (in particular human), or other subject. Accordingly, the term "antineoplastic agent" is understood to mean a substance producing an anti-neoplastic effect in a tissue, system, animal, mammal (in particular human), or other subject. It is understood that an "agent" may be a single compound or a combination or composition of two or more compounds.
Some of the typical anti-neoplastic agents include alkylating agents such as melphalan, chlorambucil, cyclophosphamide, mechlorethamine, hexamethylmelamine, busulfan, carmustine, lomustine, and dacarbazine; antimetabolites such as 5-fluorouracil, methotrexate, cytarabine, mecaptopurine, and thioguanine; antimitotic agents such as paclitaxel, docetaxel, vinblastine, vincristine; topoisomerase I inhibitors such as irinotecan, campthothecin and camptothecin derivatives, for example topotecan; topoisomerase Il inhibitors such as doxorubicin; and platinum coordination complexes such as cisplatin and carboplatin. An embodiment of the present invention is a method for treating a U-Il mediated disorder including, but not limited to, vascular hypertension, heart failure, atherosclerosis, renal failure, renal failure caused by drug induced toxicity, nephrotoxicity and diarrhea caused by anti-neoplastic agents, nephrotoxicity caused by radiocontrast agents and aminoglycosides, post-myocardial infarction, pulmonary hypertension, pulmonary fibrosis, insulin resistance and impaired glucose tolerance, diabetes, diabetic complications, diabetic nephropathy, depression, psychosis, anxiety and stroke.
The present method of using Urotensin Il receptor antagonists to reduce anti-neoplastic agent induced diarrhea and nephrotoxicity is applicable in any situation when anti-neoplastic agents (such as cisplatin, cis- diaminedichloroplatinum) are being administered to treat cancers or tumors. However, most often UII antagonists are used when tumors or cancers being treated are those of solid malignancies, notably those of the bladder, cervix, lung, ovary, and testis such as testicular tumor, bladder cancer, ureterpyelonephritic tumor, prostatic cancer, ovarian cancer, head and neck cancer, non-small-cell lung cancer, esophageal cancer, cervical cancer, neuroblastoma, gastric cancer, small cell lung cancer, bone cancer, non-Hodgkin's lymphomas, tumors of brain, endometrium, upper gastrointestinal tract, head and neck and thymus, neuroblastoma and sarcoma of bone and soft tissue.
Recent data has demonstrated that Urotensin Il receptor antagonists may be useful for improving cardiac function and for cardiac remodeling associated with chronic heart failure (CHF) (N. Bousette, F. Hu1 E. H. Ohlstein, D. Dhanak, S. A. Douglas, A. Giaid, Journal of Molecular and Cellular Cardiology 2006, In Press). Long-term treatment of streptozotocin-induced diabetic rats with palosuran improved survival, increased insulin, and slowed the increase in glycemia, glycosylated hemoglobin, and serum lipids. Furthermore, palosuran increased renal blood flow and delayed the development of proteinuria and renal damage (M. Clozel, P. Hess, C. Qiu, S. S. Ding, M. Rey, J. Pharmacol. Exp. Ther. 2006, 316 (3), 1115-1121). A therapeutically effective amount for use of the instant compounds or a pharmaceutical composition thereof comprises a dose range from about 0.1 mg to about 3000 mg, in particular from about 1 mg to about 1000 mg or, more particularly from about 10 mg to about 500 mg of active ingredient in a regimen of about 1 to 4 times per day for an average (70 kg) human; although, it is apparent to one skilled in the art that the therapeutically effective amount for active compounds of the invention will vary as will the conditions being treated.
Optimal dosages of the compounds of Formula (I) to be administered for the treatment of or prevention of Urotensin Il mediated disorders may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages. For oral administration, a pharmaceutical composition is preferably provided in the form of tablets containing 0.01 , 10.0, 50.0, 100, 150, 200, 250, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
A representative compound of Formula (I) or a form thereof includes a compound selected from the group consisting of:
Cpd Name
1 2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-N- phenethyl-benzamide,
2 N-benzyl-2-(1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}- benzamide,
3 2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl-piperidin-4-yl}-Λ/-(3- phenyl-propyl )-benzamidβ,
4 2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-N-(4- phenyl-butyl >-benzamide,
5 N-benzyl-N-methyl-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyi]- piperidin-4-yl}-benzamide, Cpd Name
6 N-[2-(3-methoxy-phenyl)-ethyl]-2-{1-[2-{3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)- ethyl]-piperidin-4-yl}-benzamide,
7 N-[2-(2,4-dichloro-phenyl)-ethyl]-2-{1 -[2-(3-oxo-2,3-dihydro-ben2θ[1 ,4]oxazin-4- yl)-ethyl]-piperidin-4-yI}-benzamidθ,
8 N-[2-(2-chloro-phenyl)-ethyl]-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)- ethyI]-piperidin-4-yi}-benzamide,
9 N-[2-(4-chloro-phenyl)-ethyl]-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)- ethyl]-piperidin-4-yl}-benzamide,
10 N-[2-(3,4-dimethoxy-phenyl)-ethyl]-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4- yl)-ethyl]-piperidin-4-yl}-benzamide,
11 N-[2-(3,4-dichlorophenyl)-ethyl]-2-{1 -[2-(3-oxo-2,3-dihydrobenzo[1 ,4]oxazin-4- yl )-ethyl]-piperidin-4-yl}-benzamide,
12 N-[2-{4-chloro-phenyl)-1-methyl-ethyl]-2-{1-[2-(3-oxo-2f3-dihydro- benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide,
13 N-[2-(2,5-dimethoxy-phenyl)-ethyl]-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4- yl)-ethyl]-piperidin-4-yl}-benzamide,
14 N-[2-(4-methoxy-phenyl)-ethyl]-2-{1-[2-{3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)- ethyl]-piperidin-4-yl}-benzamide,
15 N-[2-(2-methoxy-phenyl)-ethyl]-2-{1-[2-{3-oxo-2,3-dihydrc)-benzo[1 ,4]oxazin-4-yl)- ethyl]-piperidin-4-yl}-benzamide,
16 N-[2-(4-fluoro-phenyl)-ethyl]-2-{1-[2-{3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)- ethyl]-piperidin-4-yl}-benzamide,
17 N-[2-(3,5-dimethoxy-phenyl)-ethyl]-2-{1 -[2-(3-oxo2,3-dihydro-benzo[1 ,4]oxazin-4- yl)-ethyl]-piperidin-4-yl}-benzamide,
18 N-methyl-2-{1 -[2-(3-oxo-2,3-dihydro-bβnzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}- N-phenethyl-benzamide,
19 N-[2-(3t4-difluoro-phenyl>-ethyl]-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4- yl)-ethyI]-piperidin-4-yl}-benzamide,
20 N-(2-naphthalen-2-yl-ethyl)-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)- ethyl]-piperidin-4-yl}-benzamide,
21 N-[2-(3,5-dif!uoro-phenyl)-ethyl]-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4- yl)-ethyl]-piperidin-4-yl}-benzamide,
22 N-[2-(2,5-difiuoro-phenyl)-ethyl]-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4- yl)-ethyl]-piperidin-4-yl}-benzamide,
23 N-[2-(2,3-difluorophenyl)-ethylI-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4- yl)-ethyl]-piperidin-4-yl}-benzamide,
24 N-cyclopropylmethyl-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzamide, Cpd ' Name
25 N-(1 -methyl-3-phenyl-propyt}-2-{1 -[2-(3-oxo-2,3-dihydro-beπzo[1 ,4]oxazin-4-yl>- ethyl]-piperidin-4-yl}-benzamide,
26 N-[2-(1 H-indol-3-yl)-ethyl]-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)- ethyl]-piperidin-4-yl}-benzamide,
27 N-indan-1 -yl-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4- yl}-benzamide,
28 2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-N-(2- phenyl-propyl)-benzamide,
29 2-{1 -[2-{3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl )-ethyl]-piperidin-4-yl}-N-propyl- benzamide,
31 2-{1-[2-(3-oxo2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-N-(2- pyιτolidin-1 -yl-ethyl)-benzamide,
32 N-cyclohexylmethyl-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzamide,
33 N-furan-2-yjmethyl-N-methyl-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)- ethyl]-piperidin-4-yl}-benzamide,
34 N-(2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yI)-ethyl]-piperidin-4-yl}-phenyl)- 3-phenyl-propionamide,
35 [4-(2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}- benzoylamino)-butyl]-carbamic acid tert-butyl ester,
36 N-(2-methoxy-ethyl)-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzamide,
37 N-(3-methoxy-propyl)-2-{1-[2-(3-oxo-2l3-dihydro-benzo[1 ,4]oxazirv4-yl>-ethyl]- piperidin-4-yl}-benzamide,
38 N-{3-ethoxy-propyl>-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyll- pipβridin-4-yl}-benzamidef
39 N-(3-hydroxy-propyl)-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl>-ethyl]- piperidin-4-yl}-benzamide,
40 2-{1 -[2-{3-oxo-2,3-dihydrc>-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-N-[2-(4- trifluoromethyl-phenyl)-ethyl]-benzamide,
41 2-{1 -[2-(3-oxo-2,3-dihydrobenzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-N-pyridin- 2-ylmethyl-benzamide,
42 2-{1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-N-(2- pyridin-2-yl-ethyl)-benzamide,
43 2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-N-pyridin- 3-ylmethyl-benzamide,
44 2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl)-N-pyridin- 4-ylmethyl-benzamide, Cpd Name
45 2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethy1]-ptperidin-4-yl}-N-{2- pyridin-4-yl-ethyl)-benzamide,
46 2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-N- thiophen-2-ylmethyl-benzamidθ,
47 2-{1 -[2-{3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-N-(2- thiophen-2-yl-ethyl)-benzamide,
48 N-(3-imidazol-1-yl-propyl>-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl>- ethyl]-piperidin-4-yl}-benzamide,
49 N-(2-acetylamino-ethyl)-2-{1 -[2-(3-oxo-2l3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyi]- piperidin-4-yl}-benzamide,
50 4-[(2-{1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}- benzoylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester,
51 2-{1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-N-[3-(2- oxo-pyrrolidin-1 -y))-pιx>pyl]-benzamide,
52 2-{1-[2-{3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl>^ethyl]-piperidin-4-yl}-N-{2- piperidin-1-yl-ethyl)-benzamide,
53 4-(2-{4-[2-(3,4-dihydro-1 H-isoquinoline-2-carbonyl)-phenyl]-piperidin-1 -yl>-ethyl>- 4H-benzo[1 ,4]oxazin-3-one,
54 N-[2-(3-naphthalen-2-y1-ureido)-ethyl]-2-{1 -[2-{3-oxo-2,3-dihydro- benzo[1,4]oxazJπ-4-yl)-ethyll-piperidin-4-yl}-benzamide,
55 N-[2-(3-naphthalen-1 -yl-ureido)-ethyl]-2-{1 -[2-(3-oxo-2,3-dihydro- benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide,
56 5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4- yl}-benzoic acid methyl ester,
57 5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4- yl}-N-phenethyl-benzamide,
58 4-[(5-chloro-2-{1 -[2-(3-oxo-2,3-dihydrobenzo[1 ,4]oxazin-4-yl)-θthyl]-piperidin- 4-yl}-benzoylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester,
59 5-chloro-N,N-dimethyl-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzamide,
60 [4-(5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidm- 4-yl}-benzoylamino)-butyl]-carbamic acid tert-butyl ester,
61 5-chloro-N-(2-naphthalen-2-yl-ethyl)-2-{1 -[2-(3-oxo-2,3-dihydro- benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide,
62 5-chloro-N-[2-(1 H-indol-3-yl)-ethyl]-2-{1-[2-(3-oxo-2,3-dihydro- benzoli^loxazin^yl^ethyll-piperidin^-y^-benzamide,
63 4-[(5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin- 4-yl}-benzoylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester, Cpd Name
64 N-(1 -benzoyl-piperidin-4-yImethyl)-5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro- benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide,
65 S-chloro-N-ti-tS.S-dimethyl-butyrylJ-piperidin^-ylmethyll-a-fi-^-CS-oxo-a.a- dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide,
66 4-[2-(5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-bβnzoylamino)-ethyl]-piperazine-1 -carboxylic acid tert-butyl ester,
67 4-[(5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin- 4-yl}-benzoylamino)-methyl]-piperidine-1 -carboxylic acid benzylamide,
68 4-[2-(5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzoylamino)-βthyl]-piperidine-1 -carboxylic acid tert-butyl ester,
69 [4-(5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin- 4-yl}-benzoylamino)-butyl]-carbamic acid benzyl ester,
70 [5-(5-chloro-2-{1 -[2-<3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin- 4-yI}-benzoylamino)-pentyl]-carbamic acid tert-butyl ester,
71 5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4- yl}-N-(2-piperidin-1-yl-ethyl)-benzamide,
72 5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4- yl}-N-(1-phenylmethanesulfonyl-piperidin-4-yl methyl )-benzamide,
73 5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4- yl}-N-(2-piperazin-1-yl-ethyl)-benzamide,
74 [6-(5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin- 4-yl}-benzoylamino)-hexyl]-carbamic acid tert-butyl ester,
75 [5-(5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin- 4-yl}-benzoylamino)-pentyl]-carbamic acid benzyl ester,
76 5-chloro-N-[5-(3,3-dimethyl-butyrylamino)-pentyl]-2-{1-[2-(3-oxo-2,3-dihydro- benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide,
77 N-[5-(3-benzyl-ureido)-pentyl]-5-chloro-2-{1-[2-(3-oxo-2,3-dihydro- benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide,
78 5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4- yl}-N-(5-phenylmethanesulfonylamino-pentyl)-benzamide,
79 {2-[2-(5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzoylamino)-ethoxy]-ethyl}-carbamic acid tert-butyl ester,
80 5-chloro-N-[5-(3-isopropyl-ureido)-pentyl]-2-{1-[2-(3-oxo-2.3-dihydro- benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide,
81 5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4- yl}-N-[5-(3-phenyl-ureido)-pentyl]-benzamide, Cpd Name
82 5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4- yl}-N-[5-(3-phenethyl-ureido)-pentyl]-benzamide,
83 [5-(5-chloro-2-{1 -[2-(2-oxo-3,4-dihydro-2H-quinolin-1 -yt)-ethyl]-piperidin-4-yl}- benzoylamino)-pentyl]-carbamic acid tert-butyl ester,
84 5-chloro-2-{1 -[1 -methy1-2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-N-(1-phenylmethanesulfonyl-piperidin-4-ylmethyl)-beπzamide,
85 4-{2-[4-(4-chloro-phenyl)-piperidin-1 -yl]-ethyl}-4H-benzo[1 ,4]oxazin-3-one,
86 4-[2-(4-phenyl-piperidin-1 -yl)-ethyl]-4H-benzo[1 ,4]oxazin-3-one,
87 4-{2-[4-(4-methoxy-phenyl)-piperidin-1-yl]-ethyl}-4H-benzo[1,4]oxazin-3-one,
88 4-{2-[4-(3-fluorophenyl)-piperidin-1-yl]-ethyl}-4H-benzo[1 ,4]oxazin-3-one,
89 4-{2-[4-(2-fluorophenyl>-piperidin-1 -yl]-ethyl}-4H-benzo[1 ,4]oxazin-3-one,
90 4-[2-(4-p-tolyl-piperidin-1-yl)-ethyl]-4H-benzo[1 ,4]oxazin-3-one,
91 4-[2-(4-o-tolyl-piperidin-1-yl)-ethyl]-4H-benzo[1,4]oxazin-3-one,
92 4-{2-[4-(3-chlorophenyl)-piperidin-1 -yl]-ethyl}-4H-benzo[1 ,4]oxazin-3-one,
93 2-{1 -[2-(3-oxo-2,3-dihydro-benzol[1 ,4]oxain-4-yl-ethyl]-piperidine-4-yl-benzoic acid methyl ester,
94 4-[2-(5-chloro-2-{8-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-8-aza- bicyclo[3.2.1]oct-2-en-3-yl}-benzoylamino)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester,
95 [5-(5-chloro-2-{8-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-8-aza- bicyclo[3.2.1]oct-2-en-3-yl}-benzoylamino)-pentyl]-carbamic acid tert-butyl ester,
96 4-[2-(2-{8-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-8-aza- bicyclo[3.2.1]oct-3-yl}-benzoylamino)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester,
97 [5-(2-{8-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-8-aza- bicyclo[3.2.1]oct-3-yl}-benzoylamiπo)-pentyl]-carbamic acid tert-butyl ester,
98 [5-(2-{8-[2-(3-oxo-2,3-dihyd robenzo[1 ,4]oxazin-4-yl )-ethyl]-8-aza- bicyclo[3.2.1]oct-3-yl}-benzoylamino)-pentyl]-carbamic acid tert-butyl ester,
99 4-[2-{2-{8-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-8-aza- bicyclo[3.2.1]oct-3-yl}-benzoylamino)-ethyl]-piperazine-1-carboxytic acid tert-butyl ester,
100 [5-(5-chloro-2-{8-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-8-aza- bicyclo[3.2.1]oct-3-yl}-benzoylamino)-pentyl]-carbamic acid tert-butyl ester,
101 4-[2-(3-phenyl-8-aza-bicyclo[3.2.1 ]oct-8-yl)-ethyl]-4H-benzo[1 ,4]oxazin-3-one,
102 [5-(5-chloro-2-{2,6-dimethyl-1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl>- ethyl]-1 ,2.3,6-tetrahydro-pyridin-4-yl}-benzoylamino)pentyl]-carbamic acid tert- butyl ester, Cpd Name
103 1 -[2-(3-oxo-2,3-dihydrobenzo[1 ,4]oxazin-4-yl)-ethyl]-4-phenyl-piperidine-4- carboxylic acid dimethyl amide,
104 1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-4-phenyl-piperidine-4- carboxylic acid benzyiamide,
105 1 -f2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-4-phenyl-piperidine-4- carboxylic acid phenethyl-amide,
106 1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-4-phenyl-piperidine-4- carboxylic acid methyl-phenethyl-amide,
107 1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-4-phenyl-piperidine-4- carboxylic acid (3-phenyl-propyl)-amide,
108 1 -[2-{3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-4-phenyl-piperidine-4- carboxytic acid (4-phenyl-buty1)-amide,
109 4-{4-chloro-phenyl>-1 -[2-(3-oxo-2,3-dihydro-beήzo[1 ,4]oxazin-4-yl)-ethyl]- piperidine-4-carboxyfic acid phenethyl-amide,
110 1 -[2-(6-chloro-3-oxo-2,3-dihydro-beπzo[1 ,4]oxazin^-yl)-ethyl]-4-(4-chloro- phenyl)-piperidine-4-carboxylic acid dimethylamide,
111 4-(4-chloro-phenyl)-1 -[2-(6-methyl-3-oxo-2,3-dihydrobenzo[1 ,4]oxazin-4-yl)- ethyl]-piperidine-4-carboxylic acid dimethylamide,
112 4-(4-chloro-phenyI)-1-[2-(6-fluoro-3-oxo2t3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- piperidine-4-carboxylic acid dimethylamide,
113 4-{4-chloro-phenyl)-1 -[2-(3-oxo-2, 3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- piperidine-4-carboxylic acid dimethylamide,
114 4-{4-ch!oro-phenyl)-1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]thiazin-4-yl)-ethyl]- piperidine-4-carboxylic add dimethylamide,
115 4-(4-chloro-phenyl)-1-[2-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)-ethyl]-piperidine- 4-carboxylic acid dimethylamide, and
116 4-[2-(4-phenyl-piperidin-1 -yl)-propyl]-4H-benzo[1 ,4]oxazin-3-one.
A compound of Formula (I) or a form thereof further includes a compound selected from the group consisting of:
Cpd Name
3 2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl-piperidin-4-yl}-Λ/-(3- phenyl-propyl)-benzamide,
20 N-(2-naphthalen-2-yl-ethyl)-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)- ethyl]-piperidin-4-yl}-benzamide,
26 N-[2-(1 H-indol-3-yl)-ethyl]-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl>- ethyl]-piperidin-4-yl}-benzamide,
34 N-[2-(4-bromo-phenyl)-ethyl]-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)- ethyl]-piperidin-4-yl}-benzamide, [4-(2-{1-[2-(3-oxo-2,3-dihydro-beπzo[1,4]oxazin-4-yl)-θthyl]-piperidiπ-4-yl}- benzoylamino)-butyl]-carbamic acid tert-bυtyl ester, 4-[(2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}- benzoylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester, N-[2-(3-naphthalen-1 -y!-ureido)-ethyl]-2-{1 -[2-(3-oxo-2,3-dihydro benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzarnide, 5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyI]-piperidin-4- yl}-N-phenethyl-benzamide, 4-[(5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin- 4-yl}-benzoylamino)-methyl]-piperidine-1-carboxy1ic acid tert-butyl ester, [4-(5-chloro-2-{1 -[2-(3-oxo-2,3-dihydrc-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin- 4-yl}-benzoylamino)-butyl]-carbamic add tert-butyl ester, 5-chloro-N-(2-naphthalen-2-yl-ethyl)-2-{1-[2-(3-oxo-2.3-dihydro- benzo[1 ,4]oxazin-4-yI)-ethyl]-piperidin-4-yl}-benzamide, ; 5-chloro-N-[2-(1H-indol-3-yl)-ethyll-2-{1-[2-(3-oxo-2,3-dihydro- benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide, 4-[(5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin- 4-yl}-benzoylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester, N-(1-benzoyl-piperidin-4-ylmethyl)-5-chloro-2-{1-[2-(3-oxo-2,3-dihydro- benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide, 5-chloro-N-[1-(3,3-dimethyl-butyryl)-piperidin-4-yImethyl]-2-{1-[2-{3-oxo-2,3- dihydro-benzofi ^loxazin^-yO-ethylj-piperidin^-y^-benzamide, 4-[2-(5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzoylamino)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester, 4-[(5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin- 4-yl}-benzoylamino)-methyl]-piperidine-1 -carboxylic acid benzylamide, 4-[2-(5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzoylamino)-ethyl]-piperidine-1 -carboxylic acid tert-butyl ester, [4-(5-chlorc-2-{1 -[2-(3-oxc-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin- 4-yl}-benzoylamino)-butyl]-carbamic acid benzyl ester, [5-(5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin- 4-yl}-benzoylamino)-pentyl]-carbamic acid tert-butyl ester, 5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4- yl}-N-(2-piperidin-1-yl-ethyl)-benzamide> 5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4- yl}-N-(1-phenylmethanesulfonyl-piperidin-4-ylmethyl)-benzamide, [6-(5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin- 4-yl}-benzoylamino)-hexyl]-carbamic acid tert-butyl ester. 75 [5-(5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin- 4-yl}-benzoylamino)-pentyl]-carbamic acid benzyl ester,
76 5-chloro-N-[5-(3,3-dimethyl-butyrylamino)-pentyl]-2-{1-[2-(3-oxo-2,3-dihydro- benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide,
77 N-[5-(3-benzyl-ureido)-pentyl]-5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro- benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide,
78 5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyI]-piperidin-4- yl}-N-(5-phenylmethanesulfonylamino-pentyl)-benzamide,
79 {2-[2-(5-chloro-2-{1 -[2-(3-oxo-2.3-dihydro-benzo[1 ,4}oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzoylamino)-ethoxy]-ethyl}-carbamic acid tert-butyl ester,
80 5-chloro-N-[5-(3-isopropyl-ureido)-pentyl]-2-{1-[2-<3-oxo-2,3-dihydro- benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide,
81 5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4- yl}-N-[5-(3-phenyl-ureido)-pentyl]-benzamide,
82 5-ch!oro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin~4-yl)-ethyl]-piperidin-4- yl}-N-[5-(3-phenethyl-ureido)-pentyl]-benzamide,
83 [5-(5-ch!oro-2-{1 -[2-(2-oxo-3,4-dihydro-2H-quinolin-1 -yl>ethyl]-piperidin-4-yl}- benzoylamino)-pentyl]-carbamic acid tert-butyl ester,
84 5-chloro-2-{1-[1 -methyl-2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-N-{1-phenylmethanesulfonyl-piperidin-4-ylmethyl)-benzamide,
94 4-[2-(5-chloro-2-{8-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-8-aza- bicyclo[3.2.1 ]oct-2-en-3-yl}-benzoylamino)-ethyl]-piperazine-1 -carboxylic acid tert-butyl ester, and
95 [5-(5-chloro-2-{8-[2-(3-oxo-2,3-dihydro-benzo[1 )4]oxazin-4-yl)-ethyl]-8-aza- bicyclo[3.2.1]oct-2-en-3-yl}-benzoylamino)-pentyl]-carbamic acid tert-butyl ester.
SYNTHETIC METHODS
Representative compounds of the present invention can be synthesized in accordance with the general synthetic schemes described below and are illustrated more particularly in the specific synthetic examples that follow. The general schemes and specific examples are offered by way of illustration; the invention should not be construed as being limited by the chemical reactions and conditions expressed. The methods for preparing the various starting materials used in the schemes and examples are well within the skill of persons versed in the art. No attempt has been made to optimize the yields obtained in any of the example reactions. One skilled in the art would know how to increase such yields through routine variations in reaction times, temperatures, solvents and/or reagents.
General: 1H and 13C NMR spectra were measured on a Bruker AC-300 (300
MHz) spectrometer using tetramethylsilane and the deuterated solvent respectively as internal standards. Elemental analyses were obtained by
Quantitative Technologies Inc. (Whitehouse, New Jersey) and the results were within 0.4% of the calculated values unless otherwise mentioned. Melting points were determined in open capillary tubes with a Mel-Temp Il apparatus (Laboratory
Devices Inc.) and were uncorrected. Electrospray mass spectra (MS-ES) were recorded on a Hewlett Packard 59987A spectrometer. High resolution mass spectra (HRMS) were obtained on a Micromass Autospec. E spectrometer by fast atom bombardment (FAB) technique.
The terms used in describing the invention are commonly used and known to those skilled in the art. Abbreviations used in the instant specification, particularly the Schemes and Examples, are as follows:
BAP borane-pyπdine complex
Boc te/t-butoxycarbonyl
BSA bovine serum albumin
DCM dichloromethane
DMF N.N-dimethylformamide
DMSO dimethylsulfoxide
DIPEA diisopropylethylamine
Et2O diethyl ether
EtOAc ethyl acetate
EtOH ethanol hr(s) hour(s)
HBTU O-benzotriazol-i-yl-N.N.N'.N'-tetramethyluiOnium hexafluorophosphate
HOBt hydroxybenzotriazole hydrate
HPLC High Performance Liquid Chromatography
HEPES 4-(2-hydroxyethyl)-1- piperazine-ethanesulfonic acid
MeOH methanol min minutes MTBE methyl f-butyl ether
PdCI2dppf-CH2Cl2 [i.i'-bisCdiphenylphosphinoJferrocenel-dichloropalladiumtll) dichloromethane complex psi pounds per square inch rt room temperature
SDS sodium dodecasulfate
TEA or Et3N triethylamine
THF tetrahydrofuran
TFA trifluoroacetic acid
Scheme A
Scheme A describes the synthesis of compounds of the present invention wherein A; is a piperidinyl ring of Formula (I).
Figure imgf000063_0001
Formula (l)-1 A commercially available heterocycle of Compound A1 may be reacted with a strong base such as sodium hydride and a commercially available or readily accessible electropile Compound A2 in which an appropriate leaving group (LG) is displaced. Examples of appropriate leaving groups include fluoride, bromide, iodide, triflate, mesylate, and the like.
The leaving group of Compound A2 may be displaced to give a Compound A3. The terminal olefin in Compound A3 can be converted to a carbonyl of Compound A5 directly or through the intermediate Compound A4.
For example oxidation of Compound A3 with potassium osmate (Vl) can deliver diol Compound A4, which may be decomposed to Compound A5 with sodium metaperiodate.
Alternatively ozone will convert Compound A3 to Compound A5 directly after a reductive workup with a reductant such as dimethylsulfide or triphenylphosphine. The carbonyl of Compound A5 may be coupled to Compound A6 under reductive amination conditions to afford compounds of Formula (l)-1 , representative of a compound of Formula (I).
Reductive amination conditions would include a reducing agent such as borane-pyridine, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like. Use of Brόnsted or Lewis acids and a dehrydating agent may also be beneficial.
Scheme B
Scheme B describes the synthesis of compounds of the present invention wherein Ring A is piperidinyl and L3 is -C(O)N (Rs)-Rz.
Figure imgf000064_0001
Figure imgf000065_0001
Formula (l)-2
A commercially available or readily prepared carboxylic acid Compound B1 may be converted to a corresponding carboxamide Compound B3 by coupling to an amine Compound B2 by standard amide coupling methods. For example, the coupling conditions of N-methylmorpholine, HOBt and
HBTU may be utilized. The Boc-group of Compound B3 can be removed with an acid such as hydrogen chloride or trifluoroacetic acid to afford the free amine of Compound B4.
Reductive coupling of Compound B4 and Compound A5 by the methods described in general Scheme A for coupling of A6 and A5 may afford compounds of Formula (l)-2, representative of a compound of Formula (I).
Scheme C
Scheme C describes the synthesis of certain compounds of the present invention in which Lt is a carboxamide substituent.
Figure imgf000066_0001
Formula (l)-3
An ester Compound C1 is prepared by the methods described in general Scheme A. Compound C1 can be hydrolyzed to the carboxylic acid Compound C2 with a base such as lithium hydroxide. Coupling of Compound C2 to the amine Compound C3 by methods described in general Scheme B for the coupling of Compound B1 and Compound B2 provides compounds of Formula (l)-3, representative of a compound of Formula (I).
Figure imgf000066_0002
A subset of amine Compound C3 are the primary amines of Compound C5. Compound C5 can be prepared by reduction of the corresponding nitrile Compound C4 by a reagent such as a borane-tetrahydrofuran complex.
Scheme D
Scheme D describes the synthesis of compounds of the present invention wherein the phenylpiperidine group is not commercially available.
Figure imgf000066_0003
Figure imgf000067_0001
Commercially available boronate Compound D1 can be coupled with a Compound D2, in which LG may be a leaving group as previously defined or, for the reaction illustrated in this Scheme, when LG is bromide or triflate. The Suzuki Miyaura coupling (P. R. Eastwood, Tetrahedron Lett., 2000, 41, 3705) is facilitated by a palladium catalyst such as PdCl2dppf-CH2Cl2.
Reduction of the double bond in Compound D3 may be accomplished with hydrogen and a catalyst such as platinum (IV) oxide. Deprotection of the Boc- group on Compound D4 can be done as described in general Scheme B for Compound B3. Reductive coupling of Compound D5 and Compound A5 is achieved by the methods described in general Scheme A for Compound A6 and Compound A5. Conversion of Compound C1 to the structures of Formula (l)-3 is accomplished by the sequence described in general Scheme C.
Scheme E Scheme E describes the synthesis of compounds in which the vinyl boronate within Ring A needs to be prepared.
Figure imgf000067_0002
Figure imgf000068_0001
Formula (l)-4
A Boc-protected Compound E1 may be converted to the vinyl boronate Compound E2 (as described in P. R. Eastwood, Tetrahedron Lett., 2000, 41, 3705; and S. Ghosh, W. A. Kinney, D. A. Gauthier, E. C. Lawson, T. Hudlicky, B. E. Maryanoff., Can. J.Chem. 2006, 84, 555-560).
Conversion of Compound E2 to the structures of Formula (l)-4 is accomplished by the methods described in general Scheme D for the conversion of Compound D1 to final product Formula (l)-3. The double bond of Ring A in Compound E3 can be retained (by skipping the reduction step as described for converting Compound D3 to Compound D4 in Scheme D) and the sequence continues analogously to deliver products of Formula (l)-4 in which Ring A contains a double bond.
Alternatively, Compound E3 can be hydrogenated to give Compound E4 using the procedure described in Scheme D and taken through the remaining steps to deliver products of Formula (l)-4 in which Ring A is saturated, representative of a compound of Formula (I). The acid portion of Compound E4 may be functionalized using the procedures shown in Scheme C and Scheme F, as well as by using standard techniques known to those skilled in the art.
Scheme F Scheme F describes the preparation of certain compounds of the present invention wherein reductive amination is performed on a ketone.
Figure imgf000069_0001
Formula (l)-5
The Boc-protected carboxylic acid ester Compound E4 can be converted to the corresponding carboxyl acid Compound F1 by the action of a base such as sodium hydroxide. Coupling of Compound F1 to Compound C3 is accomplished using the procedure for coupling Compound B1 and Compound B2 in Scheme B. Compound F2 is then deprotected as described in Scheme B to give a Compound F3.
The reductive amination of ketone Compound F4 with Compound F3 is achieved by using a neat Lewis acid such as titanium (IV) isopropoxide with heat. The reaction mixture is then treated a hydride source such as sodium borohydride in an alcoholic solvent to afford a compound of Formula (l)-5, representative of a compound of Formula (I). Example 1
4-[2-(4-phenyl-piperidin-1 -yl)-ethyl]-4H-benzo[1 ,4]oxazin-3- one (Compound 86)
2-{1-[2-(3-oxo-2,3-dihydro-benzol[1,4]oxain-4-yl-ethyl]- piperidine-4-yl-benzoic acid methyl ester (Compound 93)
H2O,
Figure imgf000070_0001
Step 1. Synthesis of 4-allyl-4H-benzo[1 ,4]oxazin-3-one (Compound 1 -2).
Compound 1-1 (5.06 g, 34 mmol) was dissolved in DMF (200 ml_) and chilled to 4°C in an ice bath. To this solution was added 95% sodium hydride (946 mg, 39 mmol) in three equal parts keeping the temperature at 4 °C. Stirring was continued in the ice bath for 30 min before adding the allyl bromide (3.23 mL, 37 mmol) dropwise through an addition funnel. The reaction mixture was stirred (20 hrs), allowing the mixture to come to room temperature. The reaction mixture was then poured slowly into cold 1N hydrochloric acid solution (100 mL) and diluted with EtOAc (150 mL). The organic layer was washed with 1N sodium hydroxide solution (2 x 50 mL), water (2x 50 mL) and brine (1x 100 mL), then dried over Na2SO4; and concentrated to give a glass-like oil. The compound was purified on silica gel (elution with 25% EtOAc in hexane) to give Compound 1-2 (5.2 g, 28 mmol, 82%). 1H NMR (300 MHz, CDCI3) δ 6.95 (s, 4H), 5.89-5.78 (m, 1H), 5.21- 5.17 (m, 2H)1 4.57 (s, 2H), 4.51- 4.45 (m. 2H); MS (ES+) m/z 190.1 (M+1). Step 2. Synthesis of 4-(2,3-dihydroxy-propyl)-4W-benzo[1 ,4]oxazin-3-one (Compound 1-3).
A solution of potassium carbonate (4.40 g, 32 mmol), K3Fe(CN)6 (10.5 g, 32 mmol), and K2OsO4 H2O (195 mg, 0.53 mmol) in f-BuOH/H2O (12 mL of 1/1) was prepared in a 200 mL round bottom flask. The mixture was chilled in an ice bath, then a solution of Compound 1-2 (2.0 g, 11 mmol) in f-BuOH/H2O (12 mL of 1/1) was added at 40C and the reaction mixture was allowed to stir for 24 hrs while warming to rt. The reaction mixture was poured into EtOAc (100 mL) and washed with 2 N hydrochloric acid solution (5x 75 mL). The organic layer was dried over Na2SO4, concentrated, and purified on silica gel (elution with 90:9:1 dichloromethane/rnethanol/amrnonium hydroxide) to give Compound 1-3 (2.2 g, 96%) as a glass-like oil. H1 NMR (300 MHz, CDCI3) δ 7.20-7.16 (m, 1H), 7.07- 6.98 (m, 3H), 4.60 (s, 2H), 4.20-3.92 (m, 3H), 3.72-3.56 (m. 2H); MS (ES+) m/z 224.1 (M+1). Step 3. Synthesis of (3-oxo-2,3dihydro-benzo[1 ,4]oxazin-4-yl)-acetaldehyde (Compound 1-4).
Compound 1-3 (1.69 g, 7.58 mmol) was dissolved in MeOH (126 mL) and H2O (25 mL) in a 300 mL round bottom flask at rt, and treated with NaIO4 (4.86 g, 23.0 mmol). After 2 hrs the solid was filtered, washing with methanol. The filtrate was concentrated to a white solid, taken up in dichloromethane (50 mL), washed with water (3x) and brine, then dried over sodium sulfate, and concentrated to give Compound 1-4 as a white solid (1.23 g, 83%, mp = 97.1-98.00C). 1H NMR (500 MHz, CDCI3) δ 9.68 (s, 1H), 7.04-7.00 (m, 3H), 6.68-6.65 (m, 1H), 4.73 (s, 2H), 4.70 (S, 2H); 13C NMR (125 MHz, CDCI3) 195, 165.2, 145.3, 128.7, 124.7, 123.2. 117.6, 114.7, 67.6, 51.2; Anal Calcd. for Ci0H9NO3: C, 62.82; H, 4.74; N, 7.33. Found: C, 62.85; H, 4.46; N, 7.22.
Figure imgf000072_0001
1-5 1-6
Step 4. Synthesis of 4-(2-oxo-propyl)-4H-benzo[1 ,4]oxazin-3-one (Compound 1 - 6).
Compound 1-5 was prepared by the same method as Compound 1-2 with the exception that 3-chloro-2-methylpropene was utilized instead of allyl bromide. Ozone was bubbled through a cold (-700C) solution of Compound 1-5 (30.0 g, 147 mmol) and Sudan III (trace) in dichloromethane (450 mL) for 1.5 hrs. Triphenylphosphine (46.3 g, 177 mmo!) was added at a rate that the internal temperature was maintained at -70 0C. The resulting solution was stirred at -70 0C for 30 min, warmed to rt, and stirred for 1 hr. The volatile materials were removed by evaporation to give a crude residue, which was dissolved in dichloromethane and applied to a flash column for purification (1.36 kg of 230-400 mesh silica gel, gradient elution with 0-30% EtOAc in hexane). Evaporation of the appropriate fractions gave Compound 1-6 as a white solid (13.0 g, 43%, mp 74-76 0C). 1H NMR (300 MHz1 CDCI3) δ 7.04-6.95 (m, 3H), 6.64-6.59 (m, 1H), 4.69 (s, 4H), 2.26 (s, 3H); 13C NMR (75 Hz. CDCI3) δ 201.8, 164.9, 145.2, 128.8, 124.4, 123.1, 117.4, 114.6, 67.6, 51.2, 27.1; MS (ES+) m/z 206.1 (M+1); Anal Calcd. for C11H11NO3: C, 64.38; H, 5.40; N, 6.83. Found: C, 64.23; H, 5.12; N, 6.75.
Figure imgf000072_0002
Step 5. Synthesis of (2-oxo-3,4-dihydro-2H-quinolin-1-yl)-acetaldehyde (Compound 1-8). Compound 1-7 was prepared by the same method as Compound 1-2 with the exception that dihydroquinolinone was utilized instead of Compound 1-1. Ozone (8 psi) was bubbled slowly into a cold (-780C) solution of Compound 1-7 (10 g, 54 mmol) in methanol (535 ml_) for 90 min, while the solution turned from yellow to blue-green. Oxygen was bubbled through the solution until the solution turned yellow, and then dimethylsulfide (5.3 mL, 73 mmol) was added dropwise at such a rate that the internal temperature was maintained at —780C. The resulting solution was kept at 30C for 18 hrs, then warmed to rt. The solvent was evaporated to give a crude product, which was purified by column chromatography on silica gel (gradient elution with 10-50% EtOAc in hexane). Evaporation of the appropriate fractions gave 9 g of an oil that was treated with tetrahydrofuran (150 mL), water (50 mL), and 4 M HCI (20 mL). The resulting mixture was stirred for 1 hr at rt and treated with MTBE. The organic layer was washed with water, dried over sodium sulfate, filtered, and evaporated to give a clear oil which was treated a second time with THF1 water and 4 M HCI, and stirred for 2 hrs. Extraction again with MTBE1 washing, drying, and evaporation afforded Compound 1-8 as an oil (6.1 g, 60%). 1H NMR (300 MHz, CDCI3) δ 9.65 (s, 1H), 7.24-7.16 (m, 2H), 7.06-7.00 (m, 1H), 6.67 (d, J = 9.3 Hz, 1H), 4.71 (s, 2H), 3.01-2.95 (m, 2H), 2.77- 2.71 (m, 2H); 13C NMR (75Hz, CDCI3) δ 197.40, 171.05, 139.65, 128.44, 127.90, 126.51, 123.71, 114.66. 52.78, 31.55. 25.58; MS (ES+) m/z 190.11 (M+1).
Figure imgf000073_0001
Step 6. Synthesis of 4-[2-(4-phenyl-piperidine-1-yl)-ethyl]-4H-benzo[1 ,4]oxazin-3- one (Compound 86). Following the procedure of Synthetic Comm. 23 (6), 789-795, 1993, to a solution of 4-phenylpiperidine hydrochloride Compound 1-9 (290 mg, 1.5 mmol) and Compound 1-4 (300 mg, 1.5 mmol) in 10 ml_ of absolute ethanol was added BAP (154 μL, 1.5 mmol). After stirring for 2 hrs, an additional equivalent of aldehyde Compound 1-4 and BAP was added. The reaction mixture was stirred overnight and concentrated to give an oily residue. The residue was taken up in DCM, washed with saturated sodium bicarbonate solution NaHCθ3 and brine, dried over Na∑SCM, and concentrated. The residue was purified on silica gel (elution with 30% EtOAc in hexane) to yield Compound 86 as a glass-like oil (287 mg, 57%) of a glass-like oil. 1H NMR (300 MHz, CDCI3) δ 7.25-7.11 (m, 5H), 7.04- 6.91 (m, 4H), 4.53 (s, 2H), 4.04 (m, 2H), 3.04 (m, 2H), 2.58 (m, 2H), 2.45-2.40 (m, 1H), 2.15, (t of d, J = 11 and 3 Hz, 2H), 1.83-1.64 (m, 4H); MS (ES+) m/z 337.2 (M+1); Anal Calcd. for C2IH24N2O2 O-SIH2O: C, 73.02; H. 7.29; N, 8.11. Found: C, 72.98; H, 7.11; N, 8.00.
Figure imgf000074_0001
Step 7. Synthesis of 2-{1 -[2-(3-oxo-2,3-dihydro-benzol[1 ,4]oxain-4-yl-ethyl]- piperidine-4-yl-benzoic acid methyl ester (Compound 93).
Compound Compound 93 was synthesized in the same manner as Compound 86 with the exception that 2-(piperidin-4-yl)benzoic acid methyl ester was used instead of Compound 1 -9 as starting material. Compound 93 was purified on silica gel (elution with 50% EtOAc in hexane) to afford a glass-like oil (25%). 1H NMR (300 MHz, CDCI3) δ 7.77 (d, J = 7 Hz, 1H), 7.46-7.40 (m, 2H), 7.08 (m, 1H), 7.05-7.00 (m, 4H), 4.60 (s, 2H)1 4.12 (m, 2H), 3.89 (s, 3H), 3.42-3.31 (m, 1H), 3.12 (m, 2H), 2.69 (m, 2H), 2.27 (t of d, J = 11 and 3 Hz, 2H)1 1.85-1.73 (m, 4H); MS (ES+) m/z 395.2 (M+1 ).
Using the procedure of Example 1 , other compounds representative of the present invention may be prepared:
Cpd Name MS
85 4-{2-[4-(4-chloro-phenyl)-piperidin-1-yl]-ethyl>4H- 371.2 benzo[1 ,4]oxazin-3-one
87 4-{2-[4-(4-methoxy-phenyl)-piperidin-1-yl]-ethyJ}-4H- 367.2 benzo[1 ,4]oxazin-3-one
88 4-{2-[4-(3-fluoro-phenyl)-piperidin-1-yl]-ethyl}-4H- 355.2 benzo[1 ,4]oxazin-3-one
89 4-{2-[4-(2-fluoro-phenyl)-piperidin-1-y1]-ethyl}-4H- 355.2 benzo[1 ,4]oxazin-3-one
90 4-[2-(4-p-tolyl-piperidin-1-yl)-ethyIJ-4H-benzo[1,4]oxazin-3-one 351.3
91 4-[2-(4-o-tolyl-piperidin-1-yl)-ethyl]-4H-benzo[1,4]oxazin-3-one 351.1
92 4-{2-[4-(3-chloro-phenyl)-piperidin-1-yl]-ethyl}-4H- 371.2 benzo[1 ,4]oxazin-3-one
Example 2
4-(4-chloro-phenyl)-1-[2-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)- ethyl]-piperidine-4-carboxylic acid dimethylamide
(Compound 115)
Figure imgf000075_0001
Figure imgf000076_0001
Cpd 115
Step 1. Synthesis of 4-(4-chloropheny1)-4-dimethylcarbamoyl-piperidine-1 - carboxylic acid tert-butyl ester (Compound 2-2).
N-Boc-4-(4-chlorophenyl)-4-piperidine carboxylic acid Compound 2-1 (5.96 g, 18 mmol, Arch Chemical) was dissolved in DMF (175 ml_) and chilled in an ice bath temp. To the solution was added N-methylmorpholine (5.76 ml_, 53 mmol). HOBt (1.18 g, 8.8 mmol), dimethylamine hydrochloride (1.41 g, 18 mmol), and HBTU (10.0 g, 26 mmol). The solution was allowed to warm overnight to rt, poured into 1N sodium hydroxide solution (100 ml_), and extracted with EtOAc (3 x 75 ml_). The combined organic layers were washed with 1N NaOH (2x), 1N hydrochloric acid solution (2x), and brine (3x); and dried over Na2SO4 and concentrated to give Compound 2-2 (6.1 g, 17 mmol, 94%) as a white solid. 1H NMR (300 MHz, CDCI3.) δ 7.32 (d, J = 9 Hz, 2H), 7.17 (d, J = 9 Hz, 2H), 4.2-3.8 (br m, 2H), 3.0-2.6 (br m, 2H), 2.96 (s, 3H), 2.80 (s, 3H), 2.25 (m, 2H), 2.1-1.7 (br m, 2H), 1.45 (s, 9 H).
Step 2. Synthesis of 4-(4-chloro-phenyl)-piperidine-4-carboxylic acid dimethylamide hydrochloride (Compound 2-3).
Compound 2-2 (6.1 g 17 mmol) was dissolved in 4 M hydrogen chloride in dioxane (5 ml_) and stirred at rt for 1 hr. Concentration in vacuo gave Compound 2-3-HCI (4.2 g, 14 mmol, 82%) as a white solid, which is carried forward without purification. MS (ES+) m/z 267.1 (M+1); Anal Calcd. for CI4HI9CIN2O-HCI-H2O; C, 52.34 H, 6.90; N, 8.72. Found: C, 52.28; H 6.71; N, 8.71. Step 3. Synthesis of 4-(4-chloro-phenyl)-1-[2-(2-oxo-3,4-dihydro-2H-quinolin-1 - y!)-ethyl]-piperidine-4-carboxylic acid diethylamide (Compound 115).
Compound 115 was prepared by the same method as Compound 86 with the exception that Compound 2-3 was used instead of Compound 1-9 and that Compound 1-8 was used instead of Compound 1-4. Compound 115 was isolated as a white solid (53%, mp 243-2450C). 1H (300 MHz, CDCI3.) δ 7.44-7.01 (m, 8H), 4.55 (m, 2H), 3.62 (m, 2H)1 3.31-2.40 (m, 18H); MS (ES+) m/z 440.0 (M +1).
Using the procedure of Example 2, other compounds representative of the present invention may be prepared:
Cpd Name MS
103 1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-4-phenyl- 408.1 piperidine-4-carboxylic acid dimethyl amide
104 1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-4-phenyl- 470.2 piperidine-4-carboxylic acid benzylamide
105 1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-4-phenyl- 484.3 piperidine-4-carboxylic acid phenethyl-amide
106 1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-4-phenyl- 498.1 piperidine-4-carboxylic acid methyl-phenethyl-amide
107 1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-4-phenyl- 498.1 piperidine-4-carboxylic acid (3-phenyl-propyl)-amide
108 1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-4-phenyl- 512.3 piperidine-4-carboxylic acid (4-phenyl-butyl)-amide
109 4-(4-chloro-phenyl)-1-[2-(3-oxo-2,3-dihydro-benzo[1 l4]oxazin-4- 518.2 yl)-ethyl]-piperidine-4-carboxylic acid phenethyl-amide
110 1-[2-(6-chloro-3-oxo-2>3-dihydrc~benzo[1,4]oxazin-4-yl)-ethyl]-4- 476.2 (4-chloro-phenyl)-piperidine-4-carboxylic acid diethylamide
111 4-(4-chloro-phenyl)-1-[2-(6-methyl-3-oxo-2,3-dihydro- 456.1 benzo[1 ,4]oxazin-4-yl>-etiiyl]-piperidine-4-carboxylic acid diethylamide
112 4-(4-chloro-phenyl)-1-[2-(6-fluoro-3-oxo-2l3-dihydro- 460.0 benzo[1 ,4]oxazin-4-yl]hethyl]-piperidine-4-carboxylic acid diethylamide
113 4-(4-chloro-phenyl)-1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4- 442.2 yl)-ethyI]-piperidine-4-carboxylic acid diethylamide
114 4-(4-chloro-phenyl)-1-[2-(3-oxo-2,3-dihydro-benzo[1l4]thiazin-4- 458.0 yl)-ethyl]-piperidine-4-carboxylic acid dimethylamide Example 3
2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl- piperidin-4-yl}-Λ/-(3-phenyl-propyl)-benzamide (Compound 3)
N-(2-naphthalen-2-yl-ethyl)-2-{1-[2-(3-oxo-2,3-dihydro- benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide
(Compound 20)
Figure imgf000078_0001
Step 1. Synthesis of 2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,41oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzoic acid (Compound 3-1).
2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}- benzoic acid methyl ester Compound 93 (1.2 g, 3.0 mmol) was dissolved in THF (10 ml_) and treated with lithium hydroxide monohydrate (864 mg, 21 mmol). The reaction mixture was heated to 400C for 24 hrs, cooled to rt, adjusted to pH 3 with 1N HCI, and concentrated in vacuo. Purification by Gilson HPLC (elution with 10 to 90 gradient of H2O 0.2% TFA buffer /acetonitrile with 0.1 % TFA buffer) afforded Compound 3-1 as a white solid (1.45 g, 2.93 mmol, 98%). 1H NMR (300 MHz, CDCI3) δ 8.71 (d, J = 5 Hz, 1H), 7.92 (m, 1H), 7.59-7.43 (m, 2H), 7.32-7.22 (m, 1H), 7.14-6.89 (m, 3H), 4.62 (s, 2H), 3.97-3.68 (m, 2H), 3.45-2.94 (m, 4H), 2.71- 2.33 (m, 3H), 2.13-1.96 (m, 2H), 1.80-1.65 (m, 2H); MS (ES+) m/z 381.1 (M+1).
Step 2. Synthesis of 2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl- piperidin-4-yl}-/V-(3-phenyl-propyl)-benzamide (Compound 3).
Compound 3-1 (150 mg, 0.39 mmol) was dissolved in dry DMF (10 ml_), and treated with N-methylmorpholine (162 μl_, 1.5 mmol), 1-hydroxybenzotriazole (6.3 mg, 0.047 mmol), and phenylpropylamine (70 μl_, 0.49 mmol). The reaction mixture was chilled to 4 0C in an ice bath, treated with HBTU (280 mg, 0.74 mmol), and stirred overnight, allowing it to warm to rt. The reaction mixture was poured into EtOAc (50 ml_) and washed with 1 N sodium hydroxide solution (3 x), 1 N hydrochloric acid solution (3x), and brine. The organic layer was dried over Na2SC»4 and concentrated to give a crude product, which was purified on silica gel (elution with 90% EtOAc in hexane) to give Compound 3 (125 mg, 0.25 mmol, 64%) as a yellow oil. 1H NMR (300 MHz, CDCI3) δ 7.37-6.98 (m, 13H), 5.97 (t, J = 6 Hz, 1H), 4.56 (s, 2H), 4.09 (t, J = 7 Hz, 2H), 3.45 (t, J = 7 Hz, 2H), 3.10-2.93 (m, 3H), 2.74-2.61 (m, 4H), 2.27, (t of d, J = 8 and 3 Hz, 2H), 2.02-1.83 (m, 6H); MS (ES+) m/z 498.3 (M+1); Anal Calcd. for C3i H35N3O3-0.18 H2O-0.62 HCI: C, 71.13; H, 6.93; N, 8.03; H2O, 0.62; found C, 71.13; H, 6.90; N, 7.91; KF = 0.60.
Figure imgf000079_0001
Step 3. Synthesis of 2-naphthalen-2-yl-ethylamine (Compound 3-3).
Arylethylamines that were not commercially available were made by the following procedure. 2-Naphthylacetonitrile Compound 3-2 (16.7 g, 0.10 mol) in anhydrous tetrahydrofuran (50 mL) was added to 1M solution of BH3-THF (250 mL, 0.25 mol) over 10 min at room temperature. The reaction proceeds with an induction period of 2-4 min. Following the addition, the mixture was heated under reflux and under argon for one hour (TLC of a quenched aliquot showed no starting material). The reaction was cooled in an ice bath and 10% aqueous HCI (150 ml_) was added with caution over a 30 min period (vigorous reaction with the first few drops). Following the addition concentrated hydrochloric acid (100 ml_) was added and the mixture brought up to reflux for 30 min. The reaction was cooled in an ice bath and extracted once with ethyl ether. The aqueous layer was carefully brought to pH 12 with 40% sodium hydroxide solution (use of concentrated base allows for smaller volumes of the aqueous layer and simplifies the extraction of the amine) and extracted with diethyl ether (4 x 250 ml_). The organic layer was washed with brine (50 ml_), dried over sodium sulfate, and evaporated at reduced pressure below 400C. The solvent was not completely removed to avoid loss of product. TLC (85:15 CHCI3ZMeOH, Rf = 0.1) shows that the amine is essentially pure. Oxalic acid (9.0 g, 0.10 mole) was dissolved in methanol (10 ml_) and added to the crude amine diluted with diethyl ether to a 300 ml_ volume. The white precipitate was collected by filtration, washed with ether, and dried in vacuo to provide Compound 3-3 (22.3 g, 85%) as the oxalate salt (mp = 191-1930C). Anal Calcd. for C12Hi3N-0.85 C2O4H2: C, 66.42; H, 5.98. Found: C, 66.67; H, 6.05. Compound 3-3 freebase: 1H NMR (300 MHz, CDCI3) δ 7.83- 7.77 (m, 3H), 7.65 (s, 1H), 7.49-7.40 (m, 2H), 7.34 (d of d, J = 8.5 and 1.6 Hz, 1 H), 3.06 (t, J = 7 Hz, 2H). 2.92 (t, J = 7 Hz, 2H). Step 4. Synthesis of N-(2-naphthalen-2-yl-ethyl)-2-{1-[2-(3-oxo-2,3-dihydro- benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide (Compound 20).
Compound 20 was prepared by the method of step 2 above with the exception that Cpmpound 3-3 was used instead of phenylpropylamine. MS (ES+) m/z 534.4 (M+1). Using the procedure of Example 3, other compounds representative of the present invention may be prepared:
Cpd Name MS
1 2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]- 484.4 piperidin-4-yl}-N-phenethy!-benzamide Cpd Name MS
2 N-benzyl-2-{1-[2-(3-oxo-2,3-clihydro-benzo[1,4]oxazin-4-yl)- 470.2 ethyl]-piperidin-4-yl}-benzamide
4 2-{1-[2-(3-oxo-2,3-dihydrD-benzo[1,4]oxazin-4-yl)-ethyl]- 512.4 piperidin-4-yl}-N-(4-phenyl-butyl)-benzamide
5 N-benzyi-N-methyl-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin- 484.4 4-yl)-ethyl]-piperidin-4-yl}-benzamide
6 N-[2-(3-nnethoxy-phenyl)-ethyl]-2-{1-[2-(3-oxo-2,3-dihydro- 514.3 benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide
7 N-[2-(2,4-dichloro-phenyl)-ethyl]-2-{1-[2-(3-oxo-2,3-dihydro- 552.3 benzo[1,4]oxazin-4-yf)-ethyl]-piperidin-4-yl}-benzamide
8 N-[2-(2-chloro-phenyl)-ethyl]-2-{1-[2-(3-oxo-2,3-dihydro- 518.2 benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide
9 N-[2-(4-chloro-phenyl)-ethyi]-2-{1-[2-(3-oxo-2,3-dihydro- 518.0 benzo[1,4]oxazin-4-yl)-ethyi]-piperidin-4-yl}-benzamide
10 N-[2-(3,4-dimethoxy-phenyl)rethyl]-2-{1-[2-(3-oxα-2,3-dihydro- 544.2 benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide
11 N-[2-(3,4-dichloro-phenyl)-ethyl]-2-{1-[2-(3-oxo-2,3-dihydro- 552.2 benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide
12 N-[2-(4-chloro-phenyl)-1-methyl-ethyl]-2-{1-[2-(3-oxo-2,3- 532.0 dihydro-benzo[1 ,4Joxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide
13 N-[2-(2,5-dimethoxy-phenyl)-ethyl]-2-{1-[2-(3-oxo-2,3-dihydro- 544.4 benzo[1,4]oxazin-4-yl>-ethyl]-piperidin-4-yl}-benzamide
14 N-[2-(4-methoxy-phenyl)-ethyl]-2-{1-[2-(3-oxo-2,3-dihydro- 514.2 benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide
15 N-[2-(2-methoxy-phenyl)-ethyl]-2-{1-[2-(3-oxo-2,3-dihydro- 514.1 benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide
16 N-[2-(4-fluoro-phenyl)-ethyl]-2-{1-[2-(3-oxo-2,3-dihydro- 502.0 benzo[1 ,4]oxazin-4-yl )-ethyl]-piperidin-4-yl}-benzamide
17 N-[2-(3,5-dimethoxy-phenyl)-ethyl]-2-{1-[2-(3-oxo-2,3-dihydro- 544.1 benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide
18 N-methyI-2-{1-I2-(3-oxo-2,3-dihydro-benzo[1(4]oxazin-4-yl)- 498.3 ethyl]-piperidin-4-yl}-N-phenethyl-benzamide
19 N-[2-(3,4-difluoro-phenyl)-ethyl]-2-{1-[2-(3-oxc>-2l3-dihydro- 520.2 benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide
21 N-[2-(3,5-difluoro-phenyl)-ethyl]-2-{1-[2-(3-oxo-2,3-dihydro- 520.4 benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide
22 N-[2-(2,5-difluoro-phenyl)-ethyl]-2-{1-[2-(3-oxo-2,3-dihydro- 520.1 benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide Cpd Name MS
23 N-[2-(2,3-difluorc)-pheny1)-ethyl]-2-{1-[2-(3-oxo-2,3-dihydro- 520.1 benzo[1,4]oxazin-4-yl}-ethylϊ-piperidin-4-yl}-benzamide
24 N-cyclopropylmethyl-2-{1-[2-(3-oxo-2>3-dihydro- 434.1 benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide
25 N-(1-methyl-3-phenyl-propyl)-2-{1-[2-(3-oxo-2,3-dihydro- 512.1 benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide
26 N-[2-(1H-indol-3-yl)-ethyl]-2-{1-[2-(3-oxo-2,3-dihydro- 523.1 benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide
27 N-indan-i-yl^i-P-p-oxo^.S-dihydro-benzoti ,4]oxazin-4-yl>- 496.2 ethyl]-piperidin-4-yl}-benzamide
28 2-{1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin^-yl)-ethyl]- 497.9 piperidin-4-yl}-N-(2-phenyl-propyl)-benzamide
29 2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]- 422.2 piperidin-4-yl}-N-propyl-benzamide
30 2-{1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- 477.2 piperidin-4-yl}-N-(2-pyιτolidin- 1 -yl-ethyl )-benzamide
31 N-cyclohexylmethyl-2-{1-[2-(3-oxo-2,3-dihydro- 476.3 benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide
32 N-furan-2-ylmethyl-N-methyl-2^1-[2-(3-oxo-2,3-dihydro- 474.2 benzo[1,4]oxazin-4-yl}-ethyl]-piperidin-4-yl}-benzamide
33 N-(2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-€thyl]- 483.8 piperidin-4-yl}-phenyl)-3-phenyl-propionamide
34 N-[2-(4-bromo-phenyl)-ethyl]-2-{1-[2-(3→Dxo-2,3-dihydro- 563.6 benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide
35 [4-(2-{1-[2-(3-oxo-2,3-dihydro-benzo[1>4]oxazin-Φ-yl)-ethyl]- 551.7 piperidin-4-yl}-benzoylamino)-butyl]-carbamic acid tert-butyl ester
36 N-(2-methoxy-ethyl>-2-{1-[2-(3-oxo-2l3-dihydro- 438.3 benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide
37 N-(3-methoxy-propyl)-2-{1-[2-(3-oxo-2,3-dihydro- 452.1 benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide
38 N-(3-ethoxy-propyl)-2-{1-[2-(3-oxo-2,3-dihydro- 466.3 benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide
39 N-(3-hydroxy-propyl)-2-{1-[2-(3-oxo-2,3-dihydro- 438.3 benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide
40 2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]- 552.4 piperidin-4-yl}-N-[2-(4-trifluoromethyl-phenyl)-ethyl]-benzamide
41 2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- 471.2 piperidin-4-yl}-N-pyridin-2-ylmethyl-benzamide Cpd Name MS
~42 2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin^-yl)-ethyl]- 485.6 pipericlin-4-yl}-N-(2-pyridin-2-yl-ethyl>-benzamide
43 2-{1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- 471.2 piperidin-4-yl}-N-pyridin-3-ylmethyl-benzamide
44 2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]- 470.8 piperidiπ-4-yl}-N-pyridin-4-ylmethyl-benzamide
45 2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]- 485.1 piperidin-4-yl}-N-(2-pyridin-4-yl-ethyl^-benzamide
46 2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]- 476.0 piperidin-4-yl}-N-thiophen-2-ylmethyl-benzamide
47 2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]- 490.2 piperidin-4-yl}-N-(2-th»ophen-2-yl-ethyl)-benzamide
48 N-(3-imidazol-1-yl-propyl>-2-{1-[2-(3-oxo-2(3-dihydro- 488.2 benzo[1,4]oxazin-4-yl)-ethyll-piperidin-4-yl}-benzamide
49 N-(2-acetylamino-ethyl)-2-{1-[2-(3-oxo-2>3-dihydr(>- 465.0 benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide
50 4-[(2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-*-yl)-ethy1]- 577.4 piperidin-4-yl}-benzoylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester
51 2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin^-yl)-ethyl]- 505.5 piperidin-4-yl}-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-benzamide
52 2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin^-yl)-ethyl]- 491.5 piperidin-4-yl}-N-(2-piperidin-1-yl-ethyl)-benzamide
53 4-(2-{4-[2-(3,4-dihydro-1H-isoquinoline-2-carbonyl)-phenyl]- 496.2 piperidin-1 -yl}-ethyl)-4H-benzo[1 ,4]oxazin-3-one
54 N-[2-(3-naphthalen-2-yl-ureido)-ethyl]-2-{1-[2-(3-oxo-2,3- 592.2 dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide
55 N-[2-(3-naphthalen-1-yl-ureido)-ethyl]-2-{1-[2-(3-oxo-2,3- 592.2 dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide
Example 4
4-[2-(5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4- yl)-ethyl]-piperidin-4-yl}-benzoylamino)-ethyl]-piperazine-1- carboxylic acid tert-butyl ester (Compound 66)
Figure imgf000084_0001
Step 1. Synthesis of 4-(4-chloro-2-methoxycarbonyl-phenyl)-3,6-dihydro-2H- pyridine-1-carboxylic acid te/f-butyl ester (Compound 4-3).
A solution of 2-bromo-5-chloro-benzoic acid methyl ester Compound 4-2 (5.08 g, 20.4 mmol), the boronate Compound 4-1 (6.00 g, 19.4 mmol), PdCI2dppf- CH2CI2 (1.06 g, 1.30 mmol) and K2CO3 (8.9 g, 58.21 mmol) in DMF and EtOH (4:1, 90 ml_) was prepared in a thick walled tube. The mixture was stirred under argon at rt for 5-10 min and the tube was closed and heated at 90 °C for 5 hrs (4- 16 hrs for other examples). The mixture was cooled to rt then filtered thru a pad of Celite®, washing with EtOAc. The solvent was evaporated and purified by flash chromatography (gradient elution with 5-50% EtOAc in heptane with 0.1% TEA). The desired product Compound 4-3 was isolated as yellow liquid (4.05 g, 60%). 1H NMR (300 MHz, CDCI3) δ 7.82 (d, J = 2.2 Hz, 1H), 7.43 (d of d, J = 8.2 and 2.2 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H). 5.51 (br s, 1H), 4.02 (br s, 2H), 3.85 (s, 3H), 3.63 (t, J = 5.6 Hz, 2H), 2.30 (br s, 2H), 1.50 (s, 9H); MS (ES+) m/z 374.0 (M+Na).
Step 2. Synthesis of 4-(4-chloro-2-methoxycarbonyl-phenyl)-piperidine-1- carboxylic acid terf-butyl ester (Compound 4-4).
Compound 4-3 (2.73 g, 7.76 mmol), EtOH/AcOH (1 :1 , 60 ml_) and RO2 (0.895 g) were shaken in a Parr apparatus (15 psig of hydrogen) for 10 hrs. The reaction mixture was filtered thru Celite®, washing with ethanol. The solution was concentrated, and the residue was diluted with dichloromethane and washed with saturated NaHCO3. The aqueous layer was again extracted with dichloromethane, and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The product was purified by flash chromatography (gradient elution with 15-50 % ethylacetate (0.1 % TEA) in heptane. The desired product Compound 4-4 was isolated as thick colorless oil (2.55 g, 93%). 1H NMR (300 MHz, CDCI3) δ 7.79 (d, J = 2.3 Hz, 1H), 7.43 (d of d, J = 8.5 and 2.3 Hz, 1H), 7.28 (d, J = 8.5 Hz, 1H), 4.22 (m, 2H), 3.91 (s, 3H), 3.52 (m, 1H), 2.82 (m, 2H), 2.8-1.5 (m, 4H), 1.48 (s, 9H); MS (ES+) m/z 253.8 (M- Boc+1); HRMS (FAB+) Calcd for C18H23CINO4: 352.1316. Found: 352.1329.
Step 3. Synthesis of 5-chloro-2-piperidin-4-yl-benzoic acid methyl ester (Compound 4-5).
Compound 4-4 (40 mg, 0.11 mmol), dioxane (3 mL), 4N HCI in dioxane (3 ml_) and a drop of anisole were added and stirred at rt for 2 hrs. The reaction mixture was concentrated, triturated with ether and dried in vacuo. Compound 4-5 was isolated as a white solid (33 mg, 100 %). MS (ES+) m/z 253.7 (M+1).
Step 4. Synthesis of 5-Chloro-2-{1 -{2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl>- ethyl]-piperidin-4-yl}-benzoic acid methyl ester (Compound 4-6).
Intermediate Compound 4-5 (0.80 g, 2.8 mmol) was dissolved in dichloroethane (20 ml_) and triethylamine (0.42 mL, 3.0 mmol) was added to neutralize the HCI salt of Compound 4-5 to give the free amine. Benzoxazinone aldehyde Compound 1-4 (0.52 g, 2.8 mmol) was added at rt and stirring was continued for 45 min. Tetramethylammonium triacetoxyborohydride was added and the reaction mixture was stirred for 2 hrs, quenched with NH4OH/H2O (1:1, 5 mL), washed with NH4OH:H2O (1:1, 2 x 10 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by flash chromatography (gradient elution with 25-100% EtOAc in heptane with 0.1 % TEA). The product Compound 4-6 was isolated as white solid (0.86 g, 74%). 1H NMR (300 MHz, CDCI3) δ 7.77 (m, 1 H), 7.45-7.30 (m, 2H), 7.07-7.01 (m, 4H), 4.61 (s, 2H), 4.13 (m, 2H), 3.90 (s, 3H), 3.34 (m, 1H), 3.12 (m, 2H), 2.67 (m, 2H), 2.26 (m, 2H), 1.8-1.6 (m, 4H); MS (ES+) m/z 429.0 (M+1).
Step 5. Synthesis of 5-chloro-2-[1 -[2(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)- ethyl]-piperidin-4-yf}-benzoic acid (Compound 4-7).
Compound 4-6 (1.00 g, 2.33 mmol) was dissolved in methanol (3 mL), treated with 3N sodium hydroxide solution (3.1 mL, 9.33 mmol) at rt, and stirred for 24 hrs. The reaction was neutralized with 2N hydrochloric acid solution (7 mL, 14 mmol) and purified by RP HPLC (gradient elution with 15-90% acetonitrile in water, each containing 0.1 % TFA). Lyophilization afforded product Compound 4- 7 as a white solid (trifluoroacetate salt, 0.62 g, 64%). 1H NMR (300 MHz, DMSO) δ 7.76 (br s, 1H), 7.64 (br d. J = 8 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 6.9 Hz, 1H), 7.11-7.06 (m, 3H), 4.70 (s, 2H), 4.33 (m, 2H), 3.86-3.20 (m, 7H), 2.04-1.86 (m, 4H); MS (ES+) m/z 414.9 (M+1); Anal Calcd. for C22H23CIN2O4- 1.75CF3CO2H: C, 50.05; H, 4.08, N, 4.60. Found: C, 50.11 ; H, 4.23; N, 4.56.
Step 6. Synthesis of 4-[2-(5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin- 4-yl)-ethyl]-piperidin-4-yI}-benzoylamino)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (Compound 66). A solution of Compound 4-7 (0.24 g, 0.58 mmol) in dimethylformamide (3 ml_) was combined with N-methylmopholine (0.19 ml_, 1.74 mmol), 1- hydroxybenzotriazole (0.04 g, 0.29 mmol), O-benzotriazol-1-yl-Λ/,Λ/,/v\Λ/'- tetramethyluronium hexafluorophosphate (HBTU, 0.26 g, 0.70 mmol) and Compound 4-8 (0.16 g, 0.70 mmol). The reaction mixture was stirred overnight at rt, quenched with saturated ammonium chloride, and extracted with ethylacetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by RP HPLC (gradient elution with 10-60% acetonitrile in water, each with 0.1% TFA) and lyophilized to yield Compound 66 as white solid (trifluroacetate salt, 0.26 g, 72%). 1H NMR (300 MHz, DMSO) δ 7.58-7.53 (m, 2H), 7.37(d, J = 8.5 Hz, 1H), 7.30 (m, 1 H), 7.12-7.05 (m, 3H), 4.70 (s, 2H), 4.3-3.1 (m, 21H), 2.0-1.8 (m, 4H), 1.42 (s, 9H); MS (ES+) m/z 626.1 (M+1); Anal Calcd. for C33H44CIN5O5-3.6CF3CO2H: C, 46.58; H, 4.63; N, 6.76. Found: C, 46.25, H, 4.48; N, 6.73.
Using the procedure of Example 4, other compounds representative of the present invention may be prepared:
Cpd Name MS
56 5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)- 429.0 ethyl]-piperidin-4-yl}-benzoic acid methyl ester
57 5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)- 518.2 ethyl]-piperidin-4-yl}-N-phenethyl-benzamide
58 4-[(5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin^-yl>- 611.3 ethyl]-piperidin-4-yl}-benzoylamino)-methyl]-piperidine-1- carboxylic acid tert-butyl ester
59 5-chloro-N,N-dimethyl-2-{1-[2-(3-oxo-2,3-dihydro- 442.2 benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide [4-(5-chloro-2-{1-[2-(3-oxo-2,3-clihydro-benzo[1,4]oxazin^-yl)- 585.3 ethyl]-piperidin-4-yl}-benzoylamino)-butyl]-carbamic acid tert- butyl ester 5-chloro-N-(2-naphthalen-2-yl-ethyl)-2-{1-l2-(3-oxo-2,3-dihydro- 568.0 benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide 5-chloro-N-[2-(1H-indo!-3-yl)-ethyl]-2-{1-[2-(3-oxo-2I3-dihydro- 557.0 benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide 4-[(5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)- 645.3 ethyl]-piperidin-4-yl}-benzoylamino)-methyl]-piperidine-1- carboxylic acid benzyl ester N-(1-benzoyl-piperidin-4-ylmethyl)-5-chloro-2-{1-[2-(3-oxo-2,3- 615.3 dihydro-benzo[1,4]oxazin-4-yl)-etnyl]-piperidin-4-yl}-benzamide 5-chloro-N-[1-(3,3-dimethyl-butyryl)-piperidin-4-ylmethyl]-2-{1-[2- 609.2 (3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyI]-piperidin-4-yl]h benzamide 4-[(5-chloro-2-{1-[2-(3-oxo-2>3-dihydro-benzo[1 ,4]oxazin-4-yl)- 644.2 ethyl]-piperidin-4-yl}-benzoylamino>-methyt]-piperidine-1- carboxylic acid benzylamide 4-[2-(5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl>- 625.2 ethyl]-piperidin-4-yl}-benzoylamino)-ethyl]-piperidine-1- carboxylic acid tert-butyl ester [4-(5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)- 619.2 ethyl]-piperidin-4-yl}-benzoylamino)-butyl]-carbamic acid benzyl ester [5-(5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)- 599.2 ethyl]-piperidin-4-yl}-benzoylamino)-pentyl]-carbamic acid tert- butyl ester 5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)- 525.1 ethyl]-piperidin-4-yl}-N-(2-piperidin-1-yl-ethyl)-benzamide 5-chloro-2-{1-[2-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)- 665.2 ethyl]-piperidin-4-yl}-N-(1-phenylmethanesulfonyl-piperidin-4- ylmethyl )-benzamide 5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)- 526.0 ethyl]-piperidin-4-yl}-N-(2-piperazin-1-y|-etnyl)-benzamide [6-(5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)- 613.2 ethyl]-piperidin-4-yl}-benzoylamino)-hexyl]-carbamic acid tert- butyl ester [5-(5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin^-yl)- 633.0 ethyll-piperidin-Φyl^benzoylaminoJ-pentyll-carbamic acid benzyl ester 76 5-chloro-N-[5-(3,3-dimethyl-butyrylamino)-pentyl]-2-{1-[2-(3-oxo- 597.2 2,3-clihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}- benzamide
77 N-[5-(3-benzyl-ureido>-pentyl]-5-chlorO-2-{1-[2-(3-oxo-2,3- 632.1 d ihyd ro-benzo[1 ,4]oxazin-4-y1 )-ethyl]-piperid in-4-yl}-benzamide
78 5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)- 653.3 ethyl]-piperidiπ-4-yl}-N-(5-phenylmethanesulfonylamino-pentyl)- benzamide
79 {2-[2-(5-chloro-2-{1-[2-(3-oxo2,3-dihydro-benzo[1,4]oxazin-4- 601.2 y1)-«thyl]-piperidin-4-yl}-benzoylamino)-ethoxy]-ethyl}-carbamic acid tert-butyl ester
80 5-chloro-N-[5-(3-isopropyl-ureido)-pentyl]-2-{1-[2-(3-oxo-2,3- 584.1 dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamidθ
81 5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)- 618.2 ethyl]-piperidin-4-yl}-N-[5-(3-phenyl-ureido)-pentyl]-benzamide
82 5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1I4]oxazin-4-yl)- 645.9 ethyl]-piperidin-4-yl}-N-[5-(3-phenethyl-ureido}-pentyl]- benzamide
83 [5-(5-chloro-2-{1-[2-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)-ethyl]- 597.3 piperidin-4-yl}-benzoylamino)-pentyl]-carbamic acid tert-butyl ester
Example 5
[5-(5-chloro-2-{8-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4- yl)-ethyl]-8-aza-bicydo[3.2.1]oct-3-yl}-benzoylamino)-pentyl]- carbamic acid tert-butyl ester (Compound 100)
[5-(5-chloro-2-{2,6-dimethyl-1-[2-(3-oxo-2J3-dihydro- benzo[1 ,4]oxazin-4-yl)-ethyl]-1 ,2,3,6-tetrahydro-pyridin-4-yl}- benzoylamino)penty1]-carbamic acid tert-butyl ester
(Compound 102)
Figure imgf000090_0001
Figure imgf000091_0001
Step 1. Synthesis of [5-(5-chloro-2-{8-[2-(3-oxo-2>3-clihydrobenzo[1 ,4]oxazin-4- yl)-ethy1]-8-aza-bicyclo[3.2.1]oct-3-y1}-benzoylamino)-pentyl]-cart>amic acid tert-butyl ester (Compound 100). Compound 100 was made using the methods described for Compound 66
(Example 4) with the exception that Compound 5-1 was used instead of Compound 4-4 and Compound 5-2 was used instead of Compound 4-8. Compound 5-1 was prepared as described and is shown as compound 10-f in "Convenient Preparation of Aryl-Substituted Nortropanes by Suzuki-Miyaura Methodology" SGhosh, WA Kinney, DA Gauthier, EC Lawson, T Hudlicky, BE
Maryanoff, Can. J.Chem. 2006, 84, 555-560. 1H NMR (300 MHz, CDCI3) δ 7.6-7.0 (m, 7H), 4.61 (s, 2H), 4.7-4.3 (m, 2H), 4.16 (m, 2H), 3.7-2.8 (m, 7H), 2.5-1.3 (m, 14H), 1.88 (s, 9H); MS (ES+) m/z 625.3 (M+1); HRMS (FAB+) Calcd. for C34H45CIN4O5+H: 625.3157. Found: 625.3170. Step 2. Synthesis of 2,6-dimethyl-4-oxo-piperidine-1 -carboxylic acid tert-butyl ester (Compound 5-3).
Compound 5-3 was made in a manner similar to Hall, H. K. Jr.; J. Am. Chem. Soc, 1957, 79, 5444-5447. Step 2a: Into a mixture of diethyl acetonedicarboxylate (103.6 g, 0.512 mol) and acetaldehyde (45.3 g, 1.33 mol) was bubbled ammonia gas until that liquid was saturated at -300C. The solution was stored in freezer overnight. The yellow sludge was dissolved in dichloromethane (15 mL), filtered though silica gel and washed with EtOAc. The organic layer was concentrated to give diethyl 2,6-dimethyl-4-oxopiperidine-3,5- dicarboxylate as a thick yellow oil (92 g, 54%). Step 2b: A solution of the diester (90 g, 0.332 mol) in 10% aqueous hydrochloric acid solution (400 mL) was refluxed for overnight. Water was evaporated to yield 2,6-Dimethyl-4- piperidone/HCI, which was used for the next step without further purification. Step 2c: 2,6-Dimethyl-4-piperidone HCI salt (25.0 g, 0.153 mol) was partitioned into dioxane (250 mL) and H2O (250 mL), and sodium bicarbonate (50 g, 0.59 mol) was added in several portions. Boc anhydride (80 g, 0.37mol) was added and the resulting reaction mixture was stirred at rt overnight. The reaction mixture was evaporated to remove dioxane. The residue was extracted with Et2θ and the organic layer was washed with brine and dried over sodium sulfate. After evaporation, the crude product was purified by chromatography (gradient elution of 9-14% EtOAc in hexane) to give Compound 5-3 as a white solid (18.0 g, 52%, mixture of 70:30 trans:cis) (based on comparison to NMR spectra of trans
Compound 5-3 reported by Beak, P.; Lee, W. K.; J. Org. Chem. 1993, 58, 1109- 1117). MS (ES+) m/z 128 (M-Boc+ 1 ).
Trans Compound 5-3: 1H NMR (300 MHz, CDCI3) δ 4.39 (t, J = 6.4 Hz, 2H, C-2,6), 2.85 (dd, J = 18 and 6.4, Hz, 2Hax, C-3,5), 2.38 (dd, J = 18 and 1.8 Hz, 2Heq, C-3,5), 1.50 (s, 9H, BOC), 1.26 (d, J = 6.8 Hz, 6H, 2CH3). 13C NMR (75 MHz, CDCI3) δ 208.11, 154.59, 80.06, 46.70, 44.37, 28.66, 22.90.
Cis Compound 5-3: 1H NMR (300 MHz, CDCI3) δ 4.73 (t of d, J = 7.2 and 2.4 Hz, 2H, C-2,6), 2.73 (dd, J = 14.8 and 8.0 Hz, 2H3x, C-3,5), 2.28 (dd, J = 14.8 and 2.4 Hz, 2Heq, C-3,5), 1.49 (s, 9H, BOC). 1.28 (d, J = 7.2 Hz, 6H, 2CH3).13C NMR (75 Hz, CDCI3) δ 208.93, 154.69, 80.34, 48.63, 45.57, 28.60, 23.05. Step 3. Synthesis of 2,6-dimethyl-4-(4,4)5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)- 3,6-dihydro2H-pyridine-1-carboxylic acid tert-butyl ester (Compound 5- 4).
Compound 5-4 was prepared from Compound 5-3 (7.5 g, 33 mmol) by methods described in Canadian Journal of Chemistry 2006. Compound 5-4 was obtained in two batches: pure trans-Compound 5-4 as a solid (0.97 g, 9%, mp 84- 850C) and a mixture of trans- and cis-isomers of Compound 5-4 as an oil (4.25 g, 2.25:1 of trans:cis, 38%).
Compound 5-4 (trans): 1H NMR (300 MHz, CDCI3) δ 6.58 (m, 1H), 4.23- 4.14 (m, 2H), 2.41-2.36 (m, 1H), 2.17 (d, J = 18 Hz, 1H), 1.48 (s, 9H), 1.27 (br S, 15 H), 1.05 (d, J = 7 Hz, 3H); 13C NMR (75 Hz, CDCI3) δ 155.70, 145.66, 83.81 , 79.54, 48.59, 47.26, 31.20 , 28.90. 25.19, 25.14, 21.11 , 19.59; MS (El+) m/z 337 (M+); HRMS (El+) Calcd. for Ci8H32NO4B:; 337.2424. Found: 337.2433 ; Rf: 0.52 (pentane/EtOAc, 9:1); Anal Calcd. for Ci8H32NO4B: C, 64.10; H, 9.56. Found: C, 64.15; H, 9.80.
Compound 5-4 (trans and cis in a ratio of 2.25:1): 1H NMR (300 MHz, CDCI3) δ 6.58 (m, 0.7H), 6.39 (m, 0.3H), 4.56-4.31 (m, 0.6H), 4.23-4.14 (m, 1.4H), 2.41-2.04 (m, 2H), 1.47 (m, 9H), 1.27 (m, 15 H), 1.09 (d, J = 7 Hz, 0.9H), 1.05 (d, J = 7 Hz, 2.1H); 13C NMR (75 Hz, CDCI3) δ 155.65, 154.74, 145.60, 143.14, 83.76, 83.72, 79.47, 48.57, 48.42, 47.24, 43.43, 31.20 , 28.89, 28.87, 25.36,
25.15, 25.10, 21.08, 20.91, 19.55; MS (El+) m/z 337 (M+); HRMS (El+) Calcd. for Ci8H32NO4B:; 337.2424. Found: 337.2424 ; Rf: 0.52 and 0.46 (pentane/EtOAc, 9:1); Anal Calcd. for C18H32NO4B: C, 64.10; H, 9.56. Found: C, 63.97; H1 9.75.
Step 4. Synthesis of [5-(5-chloro-2-{2,6-dimethyl-1 -[2-(3-oxo-2,3-dihydro- benzo[1 ,4]oxazin-4-yl)-ethyl]-1 ,2,3,6-tetrahydro-pyridin-4-yl}- benzoylamino)pentyl]-carbamic acid tert-butyl ester (Compound 102).
Compound 5-4, as a mixture of cis- and trans-isomers, was converted to Compound 5-6 by the methods described for the conversion of Compound 4-1 to Compound 4-3, with the exception that the triflate Compound 5-5 was utilized instead of the arylbromide Compound 4-2. Compound 5-6 was converted to Compound 102 in several steps by the methods described for the conversion of Compound 4-4 to Compound 66 (Example 4), utilizing amine Compound 5-2 in the final step instead of Compound 4-8. Compound 102 was isolated as a gummy solid (trifluoroacetate salt). 1H NMR (300 MHz, CDCI3) δ 7.55 (d, J = 2.2 Hz, 1H), 7.31 (d of d, J = 8.2 and 2.2 Hz, 1H), 7.10-6.91 (m, 5H), 6.06, 5.67 (m, 1H), 4.60 (s, 2H), 4.01 (m, 2H), 3.4-2.0 (m, 10H), 1.56 (s, 9H), 1.6-1.3 (m, 6H), 1.19 (d, J = 6.7Hz, 3H), 1.05 (d, J = 6.6Hz, 3H); MS (ES+) m/z 624.9 (M+1).
Using the procedure of Example 5, other compounds representative of the present invention may be prepared:
Cpd Name MS
~94 4-[2-(5-chloro-2-{8-[2-(3-oxo-2I3-dihydro-benzo[1,4]oxazin-4-yl)- 649.8 ethylj-δ-aza-bicyclop^.iloct^-en-S-yl^benzoylaminoJ-ethyl]- piperazine-1-carboxylic acid tert-butyl ester
95 [5-(5-chloro-2-{8-[2-(3-oxo-2,3-dihydro-benzo[1t4]oxazin-4-yl)- 622.8 ethyl]-8-aza-bicyclo[3.2.1 ]oct-2-en-3-yl}-benzoylamino)-pentyl]- carbamic acid tert-butyl ester
96 4-[2-(2-{8-[2-(3-oxc-2.3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-8- 618.5 aza-bicyclo[3.2.1 ]oct-3-yl}-benzoylamino)-ethyl]-piperazine-1 - carboxylic acid tert-butyl ester
97 [5-(2-{8-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin^-yl)-ethyl]-8- 591.5 aza-bicyclo[3.2.1]oct-3-yl}-benzoylamino)-pentyl]-carbamic acid tert-butyl ester
98 [5-(2-{8-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-8- 581.5 aza-bicyclo[3.2.1 ]oct-3-yl}-benzoylamino)-pentyl]-carbamic acid tert-butyl ester
99 4-[2-(2-{8-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-8- 618.5 aza-bicyclo[3.2.1 ]oct-3-yl}-benzoylamino)-ethyl]-piperazine-1 - carboxylic acid tert-butyl ester
101 4-[2-(3-phenyl-8-aza-bicyclo[3.2.1]oct-8-yl)-ethyl]-4H- 363.3 benzo[1 ,4]oxazin-3-one Example 6
4-[2-(4-phenyl-piperidin-1-yl)-propyl]-4H-benzo[1,4]oxazJn-3- one (Compound 116)
Figure imgf000095_0001
Synthesis of 4-[2-(4-phenyl-piperidin-1-yl)-propyl]-4H-benzo[1 ,4]oxazin-3- one (Compound 116). A 100 mL flask was equipped with a magnetic stirring bar. The flask was purged with N2 and charged with ketone Compound 1-6 (0.45 g, 2.2 mmol), 4-phenylpiperidine Compound 1-9 (0.39 g, 2.4 mmol) and titanium (IV) isopropoxide (2.83 g, 10 mmol). The mixture was heated in an oil bath at 500C for 1.5 hrs, when the reaction was judged complete by TLC. The reaction mixture was cooled to rt and a suspension of sodium borohydride (0.52 g, 14 mmol) in absolute ethanol (10 mL) was carefully added to the reaction mixture, which was diluted with absolute ethanol (18 mL). After stirring for 15 hrs, 1N sodium hydroxide solution (28 mL) was added and a large amount of white solid was formed. It was diluted with H2O (10 mL) and stirred vigorously with CH2CI2 (50 mL). The suspension was filtered through a Celite® pad (15 g), which was washed with dichloromethane (3 x 20 mL). The filtrate was transferred to a separatory funnel. The organic phase was separated and the aqueous phase was extracted with methylene chloride (2 x 40 mL). The organic extracts were combined, dried (Na2SO-O, concentrated, and purified by chromatographed on flash silica gel (50 g, elution with 20% EtOAc in hexanes, 1000 mL). The eluent was collected in 50 mL fractions. Fractions 7-11 were combined and concentrated to give Compound 116 as a colorless oil (0.30 g, 39%). R,= 0.49 (30% EtOAc/Hexanes); 1H NMR (300 MHz, CDCI3) δ 7.32-7.25 (m, 2H), 7.21-7.16 (m, 3H), 7.11-6.99 (m, 4H), 4.66-4.55 (m, 2H), 4.11-3.94 (m, 2H), 3.10-2.97 (m, 2H), 2.78-2.74 (m, 1H), 2.57-2.32 (m, 3H), 1.86-1.59 (m, 4H), 1.02 (d, J = 9.2 Hz, 3H); 13C NMR (75 MHz, CDCI3): 164.8, 146.7, 145.9, 128.9, 128.5, 127.0, 126.2, 123.9, 122.8, 117.3, 115.7, 67.9, 56.7, 52.1, 47.4, 43.8, 43.2, 34.4, 33.8, 11.7.
Example 7
5-chloro-2-{1 -[1 -methyl-2-(3-oxo-2,3-dihydro- benzo[1 ,4]oxazin-4-y1)-ethy1]-piperidin-4-yl}-N-(1 - phenylmethanesulfonyl-piperidin-4-ylmethy1)-benzamide
(Compound 84)
Figure imgf000096_0001
7-4 7-5
Figure imgf000097_0001
Step 1. Synthesis of (1-phenylmethanesulfonyl-piperidine-4ylmethyl)-carbamic acid terf-butyl ester (Compound 7-2).
Compound 7-1 (1.00 g, 4.67 mmol) was dissolved in dichloromethane (50 mL) and treated with DIPEA (2.44 ml_, 14.0 mmol). The reaction mixture was placed in an ice bath before adding the alpha-toluenesulfonyl chloride (890 mg, 4.67 mmol). The reaction mixture was allowed to warm to rt over a 48 hr period. The reaction was poured into 50 ml of dichloromethane and washed with 1 N hydrochloric acid solution (2 x 30 mL), 1 N sodium hydroxide solution (2 x 30 mL), and brine (50 mL). The organic layer was dried over sodium sulfate and concentrated to give Compound 7-2 (1.1 g, 64%) as a white solid. 1H NMR (300 MHz, CDCI3) δ 7.38 (m, 5H), 4.60 (bs, NH), 4.20 (s, 2H), 3.65 (d. J = 12 Hz, 2H), 2.97 (t, J = 6 Hz, 2H), 2.53 (m, 2H), 1.63 (d, J = 12 Hz, 2H), 1.43 (m & s, 10H), 1.12 (m, 2H); MS (ES+) m/z 269.1 (M-Boc+1). Step 2. Synthesis of (1-phenylmethanesulfonyl-piperidin-4-yl)-methylamine hydrochloride (Compound 7-3).
A suspension of Compound 7-2 (142 mg, 0.386 mmol) was stirred in dioxane (2 mL). A solution of 4 M hydrogen chloride in dioxane (1 mL, 4 mmol) was added and stirring continued for 2 hrs before concentrating to a yield Compound 7-3-HCI as a white solid. 1H NMR (300 MHz1 DMSO d6) δ 7.38 (m, 5H), 4.39 (s, 2H), 3.57 (d, J =12 Hz, 2H), 2.70-2.63 (m, 4H), 1.77- 1.60 (m, 3H)1 1.12 (m, 2H); MS (ES+) m/z 269.1 (M+1).
Step 3. Synthesis of 4-{4-chlono-2-[(1 -phenylmethanesulfonyl-piperidin-4- ylmethyl)-carbamoyl]-phenyl}-piperidine-1-carboxylic acid tert-buty\ ester (Compound 7-6). Compound 7-4 (311 mg, 0.881 mmol) was dissolved in methanol (8 mL) and 1 N sodium hydroxide solution (14 mL) was added. This solution was heated to reflux for 18 hrs, cooled to rt and concentrated to give Compound 7-5 (200 mg, 63%) as the sodium salt. MS (m/z, ES+) 240 (M-Boc+1). Compound 7-5 (200 mg, 0.55 mmol) was dissolved in dimethylformamide (5 mL) and treated with N- methylmorpholine (194 μL, 1.77 mmol) and HOBt (7 mg, 0.05 mmol). This mixture was chilled to ice bath temperature before adding a mixture of Compound 7-3 (206 mg, 0.77 mmol) and N-methylmorpholine (194 μL, 1.77 mmol) in 5 mL of DMF. Once the solution has equilibrated to ice bath temperature, HBTU (263 mg, 0.696 mmol) was added and stirring was continued in an ice bath for 4 hrs. The reaction mixture was diluted with 50 mL of EtOAc and washed with 1 N sodium hydroxide solution (2 x 30 mL), 1 N hydrochloric acid solution (2 x 30 mL), and brine (30 mL). The organic layer was dried over sodium sulfate and concentrated to give Compound 7-6 (0.26 g, 75% crude yield) and was used as is in the next reaction. MS (ES+) m/z 489.9 (M-Boc+1). Step 4. Synthesis of 5-chloro-2-{1-[1-methyl-2-(3-oxo-2,3-dihydro- benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-N-(1 -phenylmethanesulfonyl- piperidin-4-ylmethyl)-benzamide (Compound 84).
Compound 7-6 (0.26 g, 0.44 mmol) was disssolved in dioxane (2 mL) and treated with a solution of 4 M hydrogen chloride in dioxane (1 mL, 4 mmol). This solution was stirred at rt for 2 hrs, concentrated, and dissolved in EtOAc (20 mL). The organic layer was washed with 1 N sodium hydroxide (2 x 10 mL), dried over sodium sulfate, and concentrated to give the piperidine intermediate as a clear oil. Compound 1-6 (182 mg, 0.883 mmol) was combined with the piperidine intermediate and titanium (IV) isopropoxide (1.0 mL, 3.3 mmol) and heated to 50 0C for 1.5 hrs. The reaction mixture was cooled to rt and a slurry of sodium borohydride (171 mg, 4.62 mmol) in absolute ethanol (1 mL) was added. After 15 min additional absolute ethanol (10 mL) was added. After 20 hrs, the reaction mixture was poured into 1 N sodium hydroxide solution (20 mL) and the solids were filtered off. The basic filtrate was diluted with 50 mL of EtOAc and separated. The EtOAc layer was washed with 1 N NaOH (2 x 20 mL), dried over sodium sulfate and concentrated to a glass like oil. The oil was purified on by reversed phase HPLC (gradient 35-90% acetonitrile in water, both with 0.2 % TFA) to give Compound 84 (17.7 mg, 5% over 3 steps). 1H NMR (300 MHz, CDCI3) δ 7.46-7.39 (m, 7H), 7.25-7.00 (m, 5H), 6.01 (t, J = 7 Hz, NH), 4.62 (m, 2H), 4.6-4.3 (m, 2H), 4.22 (s, 2H), 3.8-2.7 (m, 12H), 2.6-1.2 (m, 8H), 1.34 (d, J = 6.7 Hz, 3H); MS (ES+) m/z 679.2 (M+1).
Biological Examples
Example 1 Calcium Flux Assay
A calcium mobilization assay based on a Fluorescence Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale, CA) was used to determine antagonist activity, after a 5 min incubation, in response to the agonist cyclic peptide (Ac)-CFWK(2-Nal)C-NH2 (FLIPR EC50 = 0.54 ± 0.2 nM. rU-ll Ki = 0.12 ± 0.05 nM) at 1 nM (W. A. Kinney, H. R. Almond, Jr., J. Qi, C. E. Smith, R. J. Santulli, L. de Garavilla, P. Andrade-Gordon, D. S. Cho, A. M. Everson, M. A. Feinstein, P. A. Leung, B. E. Maryanoff, Angew. Chem., Intl. Ed. 2002, 41, 2940- 2944), in CHO cells transfected with rat GPR14 (U-Il receptor) (M. TaI, D. A. Ammar, M. Karpuj, V. Krizhanovsky, M. Nairn, D. A. Thompson, Biochem. Biophys. Res. Commun. 1995, 209, 752-759. A. Marchese, M. Heiber, T. Nguyen, H. H. Heng, V. R. Saldivia, R. Cheng, P. M. Murphy, L. C. Tsui, X. Shi, P. Gregor, Genomics 1995, 29, 335-344).
To derive these cells, the complete coding sequence of rat U-Il (Genbank Accession No. U32673) was amplified by nested PCR from rat heart marathon- Ready cDNA. PCR was carried out by using the DNA polymerase PFU (Stratagene) following conditions suggested by the manufacturer. The PCR products were cloned into pcDNA3 (Invitrogen) digested with EcoR I and Xba i. Clones containing rat U-Il receptor were verified by complete sequencing of the U- Il receptor insert to ensure a lack of PCR-introduced errors. The constructed vector was transfected into CHO cells by using lipofectamine (GIBCO BRL). CHO cells with high expression of rat U-Il receptor were selected and established as stable cell lines by using G418. CHO cells were seeded at 25,000 cells per well into 96-well, black-wall, clear-bottom microtiter plates 24 hrs before assay. Cells in culture media (DMEM/F12 containing 15 mM HEPES, L-glutamine, pyridoxine hydrochloride; 10% fetal bovine serum; 1 mg/mL G418 sulfate; antibiotic- antimycotic; pH 7.4) were loaded with proprietary dye, from the FLIPR Calcium Assay Kit (Molecular Devices), prepared in assay buffer (Hanks Balanced Salts Solution, 20 mM HEPES1 0.1% BSA, 2.5 mM probenecid, pH 7.4), and incubated for 1 hr at 37 0C. Calcium mobilization determinations were performed at room temperature (23 0C). The use of rat GPR14 was considered acceptable, because human U-Il has similar affinity for human or rat GPR14 in the transfected cells (S. A. Douglas, E. H. Ohlstein, Trends Cardiovasc. Med. 2000, 10, 229-237). The resulting data is shown in Table 3.
Example 2 Human Radioligand Binding Assay
Human Skeletal Muscle Myoblasts (HSMM) were obtained from Cambrex, and were cultured according to manufacturer's instruction. Cell viability was examined by trypan blue exclusion. Cells at less than 4 passages were used in all studies. For the (125I)-U-II binding experiments (Described in: "Characterization of Functional Urotensin Il Receptors in Human Skeletal Muscle Myoblasts: Comparison with Angiotensin Il Receptors" J. Qi, L. K. Minor, C. Smith, B, Hu, J. Yang, P. Adrade-Gordon, B. Damiano, Peptides 2005, 26, 683-690), HSMM were plated in 12-well Costar plates in complete medium for 48 hrs to reach 70% confluence. The binding medium used was Dulbecco's modified Eagle's medium (DMEM) containing 2 mg/ml BSA and 25 mM HEPES (pH 7.4). The cells were washed at room temperature 2x with the binding medium, and were incubated with 0.2 ml per well of prepared binding medium containing 0.150 nM (125I)-U-II and compounds for 3 hrs. The cells were washed 4x with the binding medium and solubilized in 1% SDS and 0.5 N NaOH. Radioactivity was quantified by gamma counting.
Radiolabeled (125I)-U-II bound specifically and saturably to intact adherent HSMM. The binding assays were performed at 25 'C to lower nonspecific uptake of (125I)-U-II by the cells that is seen at 37 °C. Using this method, the nonspecific binding was below 10% of total binding. Analysis of the saturation data using the non-linear curve-fitting technique of GraphPad Prism Version 3.0 revealed that the best fit observed was for a one-site model. The derived Kd value was 0.309 ± 0.022 nM (N=3 experiments) with the Hill slope close to unity. Based on the number of cells in a well and Bmax value, the number of UT receptors in HSMM was 2311 ± 236 per cell (N=3 experiments). A time course experiment demonstrated that (125I)-U-II binding to HSMM reached steady state at 3 hrs, and remained constant up to 5 hr, the longest time point measured. Human U-Il, when add at time 0, efficiently displaced specific binding of (125I)-U-II with a Ki of 0.425 ± 0.096 nM (N=3 experiments). The resulting data is shown in Table 4.
Table 3
In Vitro Evaluation Rat UII receptors using FLIPR*
Cpd IC50 (μM) Cpd IC50 (μM)
1 7.5 59 10
2 7.9 60 0.50
3 4.2 61 2.0
4 3.1 62 0.90
5 11 63 0.40
6 10 64 0.52 Cpd IC50 (μM) Cpd IC50 (μM)
7 19 65 0.33
8 14 66 0.015
9 3.2 67 0.21
10 13 68 0.10
11 5.4 69 0.15
12 10 70 0.032
13 8.0 71 0.27
14 4.0 72 0.053
15 8.0 73 1.9
16 8.0 74 0.045
17 7.0 75 0.040
18 15 76 0.15
19 6.0 77 0.027
20 2.0 78 0.10
21 9.0 79 0.037
22 13 80 0.21
23 7.0 81 0.53
24 12 82 0.17
25 4.0 83 0.36
26 2.0 84 2.0
27 43 85 18
28 9.0 86 24
29 20 87 47
30 32 88 28
31 13 89 23
32 14 90 15
33 4.0 91 21
34 3.0 92 20
35 3.0 93 32
36 25 94 0.29
37 30 95 0.64
38 23 96 3.5
39 32 97 5.4
40 4.0 98 1.6 Cpd IC50 (μM) Cpd IC50 (μM)
41 21 99 1.1
42 20 100 0.45
43 18 101 19
44 21 102 7.6
45 16 103 24
46 6.0 104 26
47 7.0 105 7.0
48 43 106 14
49 38 107 9.1
50 2.5 108 8.8
51 22 109 5.0
52 16 110 11
53 18 111 8.0
54 7.0 112 5.0
55 2.0 113 4.4
56 8.0 7.0
57 1.3 21
58 0.60 70 inhibition of acetyl-cyclic[Cys-Phe-Trp-Lys-(2-Nal)-Cys]-NH2 induced Ca2+ mobilization (FLIPR) in CHO cells transfected with rat UII receptor referenced in: "Structure-Function Analysis of Urotensin Il and Its Use in the Construction of a Ligand-Receptor Working Model" W. A. Kinney, H. R. Almond, Jr., J. Qi1 C. E. Smith, R. J. Santulli, L. de Garavilla, P. Andrade-Gordon, D. S. Cho, A. M. Everson, M. A. Feinstein, P. A. Leung, B. E. Maryanoff, Angewandte Chemie, Int. Ed. 2002, 41, 2940-2944.
Table 4
In Vitro Evaluation Human UII receptors Binding*
Cpd Ki (μM) Cpd Ki (μM)
1 2.9 70 0.025
3 0.33 72 0.030
20 0.72 74 0.10
26 0.75 75 0.034 Cpd Ki (μM) Cpd Ki (μM)
34 0.62 76 0.043
35 0.59 77 0.037
50 0.43 78 0.040
55 0.84 79 0.053
57 0.19 82 0.12
58 0.14 83 0.22
60 0.15 84 0.21
61 0.26 94 1.9
63 0.054 95 1.3
65 0.032 98 1.4
66 0.057 99 1.4
67 0.030 100 1.2
68 0.047 113 1.7
69 0.062
•The (125I)-U-II binding experiments are described in: "Characterization of Functional Urotensin Il Receptors in Human Skeletal Muscle Myoblasts: Comparison with Angiotensin Il Receptors" J. Qi, L K. Minor, C. Smith, B, Hu, J. Yang, P. Adrade-Gordon, B. Damiano, Peptides 2005, 26, 683-690. While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents. All publications disclosed in the above specification are hereby incorporated by reference in full.

Claims

What is claimed is:
1. A compound of Formula (I):
Figure imgf000105_0001
and forms thereof, wherein Ring A is selected from the group consisting of piperidinyl, 8-aza- bicyclo[3.2.1]oct-2-enyl, 8-aza-bicyclo[3.2.1]octyl and 1,2,3,6- tetrahydro-pyridinyl;
Y is selected from the group consisting of CH2, O and S;
L1 is absent or is selected from the group consisting of -C(O)O-Ri, -C(O)N(Rs)-R1 and -NHC(O)-R1;
L2 is d-βalkyl;
L3 is absent or is -C(O)N(R5J-R7;
R1 is selected from the group consisting of d-βalkyl, d-βalkoxy, aryl, aryl-d-βalkyl, C^ucycloalkyl, C3.14cycloalkyl-C1-βalkyl, heterocyclyl, heterocyclyl-C^alkyl, heteroaryl and heteroaryl-Ci.8alkyl, wherein
Figure imgf000105_0002
is optionally substituted with one, two or three substituents each selected from the group consisting of
Figure imgf000105_0003
halogen, hydroxy and -NHR6, wherein d-βalkoxy is optionally substituted with one, two or three substituents each selected from the group consisting of Ci-8alkoxy, halogen, hydroxy and -NHRe, wherein each instance of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of d-βalkyi, d-βalkoxy, halogen and halo-d-βalkyl, and wherein each instance of heterocyciyl is optionally substituted with oxo, Ci-βalkyl-carbonyl, d-βalkoxy-carbonyl, Ci-8alkyl-N(R5>-carbonyl, aryl-carbonyl, aryl-Ci-βalkyl-carbonyl, aryl-d-βalkoxy-carbonyl, aryl-N(R5)-carbonyl, aryI-d-8alkyl-N(R5)-carbonyl or aryl-Ci-βalkyl-sulfonyl;
R2 is one, two or three substituents each selected from the group consisting of hydrogen, Ci-8alkyl, d-βalkoxy and halogen;
R3 is one, two or three substituents each selected from the group consisting of hydrogen and
Figure imgf000106_0001
R4 is one, two or three substituents each selected from the group consisting of hydrogen, d-βalkyl, d-βalkoxy, hydroxy and halogen;
R5 is selected from the group consisting of hydrogen and d^alkyl;
Re is selected from the group consisting of d-ealkyl-carbonyl, d-βalkoxy-carbonyl, d-βalkyl-N(R5>-carbonyl, aryl-carbonyl, aryl-d-βalkyl-carbonyl, aryl-d-βalkoxy-carbonyl, aryl-N(R5)-carbonyl, aryl-Ci-βalkyl-NCRsJ-carbonyl and aryl-d-βalkyl-sulfonyl; and,
R7 is selected from the group consisting of d-βalkyl, aryl, aryl-d-βalkyl,
C3-i4cycloalkyl, Cjj-ucycloalkyl-d-βalkyl, heterocyciyl, heterocyclyl-d-βalkyl, heteroaryl and heteroaryl-Ci-8alkyl.
2. The compound of claim 1 , wherein Ring A is piperidinyl.
3. The compound of claim 1 , wherein Ring A is 8-aza-bicyclo[3.2.1]oct-2-enyl.
4. The compound of claim 1 , wherein Ring A is 8-aza-bicyclo[3.2.1]octyl.
5. The compound of claim 1 , wherein Ring A is 1 ,2,3,6-tetrahydro-pyridinyl.
6. The compound of claim 1 , wherein Y is CH2.
7. The compound of claim 1 , wherein Y is O.
8. The compound of claim 1 , wherein Y is S.
9. The compound of claim 1 , wherein Ri is selected from the group consisting of Ci-βalkyl, Ci-βalkoxy, aryl-C1-8alkyl, C3-14cycloalkyl, Cs-^cycloalkyl-d-ealkyl, heterocyclyl, heterocyclyl-d-βalkyl and heteroaryl-Ci-βalkyl, wherein Ci-βalkyI is optionally substituted with a substituent selected from the group consisting of Ci-βalkoxy, hydroxy and -NHRβ, wherein C1-8alkoxy is optionally substituted with -NHRβ, wherein each instance of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of Ci-βalkoxy, halogen and halo-Ci-βalkyl, and wherein each instance of heterocyclyl is optionally substituted with oxo,
Ci-8alkyl-carbonyl, Ci-βalkoxy-carbonyl, aryl-carbonyl, aryl-Ci-βalkoxy-carbonyl,
Figure imgf000107_0001
or aryl-Ci-βalkyl-sulfonyl.
10. The compound of claim 9, wherein Ri is selected from the group consisting of Ci-8alky1, Ci-βalkoxy, phenyl-d -βalkyl, naphthyl-C-i-βalkyl, indanyl, cyclopropyl-d-βalkyl, cyclohexyl-d-βalkyl, 1 ,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-d-βalkyl, piperidinyl-Ci-βalkyl, piperazinyl-d-βalkyl, furanyl-d-βalkyl, thienyl-C1-8alkyl, imidazolyl-Ci-βalkyl, pyridinyl-Ci-βalkyl and indolyl-d-βalkyl, wherein each instance of phenyl is optionally substituted with one, two or three substituents each selected from the group consisting of
Figure imgf000108_0001
chloro, fluoro, bromo and halo-d-βalkyl, and wherein each instance of 1,2,3,4-tetrahydro-isoquinolinyt, pyrrolidinyl-d-ealkyl, piperidinyl-d-βalkyl, and piperazinyl-d-βalkyl is optionally substituted with oxo, Ci-βalkyl-carbonyl, d-βalkoxy-carbonyl, aryl-carbonyl, aryl-d-βalkoxy-carbonyl, aryl-Ci-8alky1-N(R5)-carbonyl or aryl-Ci-βalkyl-sulfonyl.
11. The compound of claim 1 , wherein R2 is one substituent selected from the group consisting of hydrogen, Ci-βalkyl, d-aalkoxy and halogen.
12. The compound of claim 1 , wherein R3 is one or two substituents each selected from the group consisting of hydrogen and C^alkyl.
13. The compound of claim 1 , wherein R4 is one substituent selected from the group consisting of hydrogen, d-βalkyl and halogen.
14. The compound of claim 1 , wherein R5 is hydrogen.
15. The compound of claim 1 , wherein R5 is Ci-4alkyl.
16. The compound of claim 1 , wherein R6 is selected from the group consisting of d-βalkyl-carbonyl, d-βalkoxy-carbonyl, Ci-βalkyl-N(R5)-carbonyl, aryl-Ci-βalkoxy-carbonyl, aryl-N(Rs)-carbonyl, aryl-Ci-βalkyl-N(R5)-carbonyl and aryl-d-βalkyl-sulfonyl.
17. The compound of claim 1 , wherein Re is selected from the group consisting of Ci-8alkyl-carbonyl, Ci-βalkoxy-carbonyl, Ci-8alkyl-N(R5)-carbony1, phenyl-Ci-8alkoxy-carbonyl, phenyl-N(R5)-carbony1, phenyl-d-ealkyl-N(R5)-carbonyl and phenyl-d-βalkyl-sulfonyl.
18. The compound of claim 1 , wherein R7 is selected from the group consisting of d-ealkyl and aryl-d-βalkyl.
19. The compound of claim 1 , wherein R7 is selected from the group consisting of d-βalkyl and phenyl-d-βalkyl.
20. The compound of claim 1 , wherein
Ring A is selected from the group consisting of piperidinyl, 8-aza- bicyclo[3.2.1]oct-2-enyl, 8-aza-bicyclo[3.2.1]octyl and 1,2,3,6- tetrahydro-pyridinyl; Ri is selected from the group consisting of d-βalkyl, d-βalkoxy, aryl-d-βalkyl,
Ca-ucycloalkyl, Ca-ucycloalkyl-d-βalkyl, heterocyclyl, heterocyclyl-d-βalkyl and heteroaryl-Ci-βalkyl, wherein d-βalkyl is optionally substituted with a substituent selected from the group consisting of d-βalkoxy, hydroxy and -NR6, wherein d-βalkoxy is optionally substituted with -NHR6, wherein each instance of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of d-βalkoxy, halogen and halo-d-βalkyl, and wherein each instance of heterocyclyl is optionally substituted with oxo, Ci-βalkyl-carbonyl, d-βalkoxy-carbonyl, aryl-carboπyl, aryl-d-βalkoxy-carbonyl, aryl-Ci-8alkyl-N(R5)-carbonyl or aryl-Ci-βalkyl-sulfonyl;
R2 is one substituent selected from the group consisting of hydrogen, d-βalkyl, d-βalkoxy and halogen; R3 is one or two substituents each selected from the group consisting of hydrogen and d^al kyl;
R4 is one substituent selected from the group consisting of hydrogen, Chalky! and halogen;
Re is selected from the group consisting of d-βalkyl-carbonyl, Ci-8alkoxy-carbonyl, d-βalkyl-N(R5)-carbonyl, aryl-Ci-βalkoxy-carbonyl, aryl-N(R5)-carbonyl, aryl-Ci-8alkyl-N(R5)-carbonyl and aryl-Ci-8alkyl-sulfonyl; and R7 is selected from the group consisting of d-βalkyl and aryl-Ci-βalkyl.
21. The compound of claim 20, wherein
Ri is selected from the group consisting of Ci-βalkyI, Ci-βalkoxy, phenyl-Ci-8alkyl,
Figure imgf000110_0001
indanyl, cyclopropyl-Ci-ealkyl, cyclohexyl-Ci-βalkyl, 1,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-Ci-βalkyl, piperidinyl-Ci-salkyl, piperazinyl-C-i-βalkyl, furanyl-Ci-8alkyl, thienyl-Ci-βalkyl, imidazolyl-Ci-8alkyl, pyridinyl-Ci-βalkyl and indolyl-Ci-βalkyl, wherein each instance of phenyl is optionally substituted with one, two or three substituents each selected from the group consisting of
Ci-salkoxy, chloro, fluoro, bromo and halo-d-βalkyl, and wherein each instance of 1,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-Ci-βalkyI, piperidinyl-Ci-βalkyl, piperazinyl-Ci-βalkyl is optionally substituted with oxo, Ci-aalkyl-carbonyl, Ci-βalkoxy-carbonyl, aryl-carbonyl, aryl-Ci-βalkoxy-carbonyl, aryl-Ci-8alkyl-N(R5)-carbonyl or aryl-Ci^alkyl-sulfonyl;
R6 is selected from the group consisting of Ci-βalkyl-carbonyl, Ci-βalkoxy-carbonyl, Ci-8alkyl-N(R5)-carbonyl, phenyl-Ci-βalkoxy-carbonyl, phenyl-N(R5)-carbonyl, phenyl-Ci^alkyl-N(R5)-carbonyl and phenyl-Ci-βalkyl-sulfonyl; and
R7 is selected from the group consisting of Ci-8alkyl and
Figure imgf000110_0002
22. A compound of Formula (Ia):
Figure imgf000111_0001
and forms thereof, wherein
Y is selected from the group consisting of CH2, O and S; Li is absent or is selected from the group consisting of -C(O)O-Ri ,
-C(O)N(R5)-Ri and -NHC(O)-R1;
L2 is Ci-βalkyl;
L3 is absent or is -C(O)N(Rs)-R7;
Ri is selected from the group consisting of Ci-βalkyI, Ci-βalkoxy, aryl, aryl-Ci-βalkyl, Ca-ucydoalkyl, C3-i4cycloalkyl-Ci-aalkyl, heterocyclyl, heterocyclyl-Ci-βalkyl, heteroaryl and heteroaryl-Ci-ealkyl, wherein
Figure imgf000111_0002
is optionally substituted with one, two or three substituents each selected from the group consisting of C^alkoxy, halogen, hydroxy and -NHR6, wherein Ci-8alkoxy is optionally substituted with one, two or three substituents each selected from the group consisting of Ci-βalkoxy, halogen, hydroxy and -NHRβ, wherein each instance of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of Chalky!, Ci-8alkoxy, halogen and
Figure imgf000112_0001
and wherein each instance of heterocyclyl is optionally substituted with oxo, Ci-βalkyl-carbonyl, Ci-βalkoxy-carbonyl, Ci-βalkyl-N(R5)-carbonyl, aryl-carbonyl, aryl-Ci-βalkyl-carbonyl, aryl-Ci-βalkoxy-carbonyl, aryl-N(R5)-carbonyl, aryl-Ci.8alkyl-N(R5)-carbonyl or aryl-Ci-8alkyl-sulfonyl;
R2 is one, two or three substituents each selected from the group consisting of hydrogen, C1-8alkyl, C1-8alkoxy and halogen;
R3 is one, two or three substituents each selected from the group consisting of hydrogen and C1^aI kyl;
R4 is one, two or three substituents each selected from the group consisting of hydrogen, d-βalkyf, Ci^alkoxy, hydroxy and halogen;
R5 is selected from the group consisting of hydrogen and Chalky!;
R6 is selected from the group consisting of Ci-βalkyl-carbonyl, Ci-βalkoxy-carbonyl, Ci-8alkyl-N(Rs)-carbonyl, aryl-carbonyl, aryl-Ci-βalkyl-carbonyl, aryl-Ci-aalkoxy-carbonyl, aryl-N(R5)-carbonyI, aryl-Ci-8alkyl-N(R5)-carbonyl and aryl-Ci-βalkyl-sulfonyl; and,
R7 is selected from the group consisting of Ci-βalkyl, aryl, aryl-Ci-ealkyl,
Ca-^cycloalkyl, Cs-ucycloalkyl-Ci-βalkyl, heterocyclyl, heterocyclyl-Ci-ealkyl, heteroaryl and heteroaryl-Ci-βalkyl.
23. The compound of claim 22, wherein
Ri is selected from the group consisting of Chalky!, d-βalkoxy, phenyl-Ci-βalkyl, naphthyl-Ci-ealkyl, indanyl, cyclopropyl-Ci-βalkyl, cyclohexyl-Ci-βalkyl, 1 ,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-Cvβalkyl, piperidinyl-d-βalkyl, piperazinyl-Ci-ealkyl, furanyl-C1-8alkyl, thienyl-Ci-βalkyl, imidazolyl-Ci-8alkyl, pyridinyl-Ci-8alkyl and indolyl-Ci-ealkyl, wherein d-βalkyl is optionally substituted with a substituent selected from the group consisting of d-βalkoxy, hydroxy and -NRβ, wherein d-βalkoxy is optionally substituted with -NHR6, wherein each instance of phenyl is optionally substituted with one, two or three substituents each selected from the group consisting of
Ci-βalkoxy, chloro, fluoro, bromo and halo-d-βalkyl, and wherein each instance of 1 ,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-Ci-8alkyl, piperidinyl-d-βalkyl, piperazinyl-d-βalkyl is optionally substituted with oxo, d-βalkyl-carbonyl, d-βalkoxy-carbonyl, aryl-carbonyl, aryl-Ci-βalkoxy-carbonyl, aryl-Ci-8alkyl-N(R5)-carbonyl or aryl-Ci-8alkyl-sulfonyl;
R2 is one substituent selected from the group consisting of hydrogen, d-βalkyl, d-βalkoxy and halogen;
R3 is one or two substituents each selected from the group consisting of hydrogen and Ci^aI kyl;
R4 is one substituent selected from the group consisting of hydrogen, d-βalkyl and halogen;
R5 is selected from the group consisting of hydrogen and d^alkyl;
Re is selected from the group consisting of d-βalkyl-carbonyl, d-βalkoxy-carbonyl, d-βalkyl-N(R5)-carbonyl, phenyl-d-βalkoxy-carbonyl , phenyt-N (R5)-carbonyl , phenyl-Ci-8alkyl-N(R5>-carbonyl and phenyl-d-βalkyl-sulfonyl; and
R7 is selected from the group consisting of d-βalkyl and phenyl-d-βalkyl.
24. A compound of Formula (Ib):
Figure imgf000114_0001
and forms thereof, wherein
Y is selected from the group consisting of CH2, O and S; Li is absent or is selected from the group consisting of -C(O)ORi,
-C(O)N(R5VRi and -NHC(O)-Ri;
L2 is Ci-8alkyl;
L3 is absent or is -C(O)N(Rs)-R?;
Ri is selected from the group consisting of Chalky!, Ci-βalkoxy, aryl, aryl-Ci-8alkyl, C^i-icycloalkyl, Ca-ucycloalkyl-Ci-βalkyl, heterocyclyl, heterocyclyl-Ci-aalkyl, heteroaryl and heteroaryl-Ci.8alkyl, wherein d^alkyl is optionally substituted with one, two or three substituents each selected from the group consisting of Ci-βalkoxy, halogen, hydroxy and -NHR6, wherein Ci-8alkoxy is optionally substituted with one, two or three substituents each selected from the group consisting of
Figure imgf000114_0002
halogen, hydroxy and -NHR6, wherein each instance of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of d-βalkyl, d-βalkoxy, halogen and halo-d-βalkyl, and wherein each instance of heterocyclyl is optionally substituted with oxo, Ci-βalkyl-carbonyl, d-βalkoxy-carbonyl, Ci-βalkyl-N(R5)-carbonyl, aryl-carbonyl, aryl-C1-8alkyl-carbonyl, aryl-d-βalkoxy-carbonyl, aryl-N(Rs)-carbonyl, aryl-Ci-8alkyl-N(R5)-carbonyl or a ryl-Ci -βal kyl-sulfonyl ;
R2 is one, two or three substituents each selected from the group consisting of hydrogen, d-βalkyl, d-βalkoxy and halogen;
R3 is one, two or three substituents each selected from the group consisting of hydrogen and C^alkyl;
R4 is one, two or three substituents each selected from the group consisting of hydrogen, Chalky), d-βalkoxy, hydroxy and halogen;
R5 is selected from the group consisting of hydrogen and d^alkyl;
Re is selected from the group consisting of C-i-aalkyi-carbonyl, d-βalkoxy-carbonyl, Ci-βalkyl-N(R5)-carbonyl, aryl-carbonyl, aryl-Ci-βalkyl-carbonyl, aryl-Ci-aalkoxy-carbonyl, aryl-N(R5>-carbonyl, aryl-Ci-8alkyl-N(R5)-carbonyl and aryl-Ci-βalkyl-sulfonyl; and,
R7 is selected from the group consisting of d-βalkyl, aryl, aryl-d-βalkyl,
C3-i4cycloalkyl, Ca-ucydoalkyl-d-βalkyl, heterocyclyl, heterocyclyl-d-βalkyl, heteroaryl and heteroaryl-d-βalkyl.
25. The compound of claim 24, wherein
Ri is selected from the group consisting of d-βalkyl, d-βalkoxy, phenyl-d-βalkyl, naphthyl-d-βalkyl, indanyl, cyclopropyl-d-βalkyl, cyclohexyl-d-βalkyl, 1 ,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-d-βalkyl, piperidinyl-d-βalkyl, piperazinyl-d-βalkyl,
Figure imgf000115_0001
thienyl-d-βalkyl, imidazolyl-Ci-ealkyl, pyridinyl-d-8alkyl and indolyl-Ci-ealkyl, wherein d-βalkyl is optionally substituted with a substituent selected from the group consisting of d-βalkoxy, hydroxy and -NRβ, wherein d-βalkoxy is optionally substituted with -NHRe, wherein each instance of phenyl is optionally substituted with one, two or three substituents each selected from the group consisting of d-βalkoxy, chloro, fluoro, bromo and halo-d-βalkyl, and wherein each instance of 1,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-Ci-βalkyl, piperidinyl-d-βalkyl, piperazinyl-C1-8alkyl is optionally substituted with oxo, C1-8alkyl-carbonyl, d-βalkoxy-carbonyl, aryl-carbonyl, aryl-d-βalkoxy-carbonyl, aryl-d-8alky1-N(R5)-carbonyl or aryl-Ci-8alkyl-sulfonyl;
R2 is one substituent selected from the group consisting of hydrogen, d-βalkyl, d-βalkoxy and halogen;
R3 is one or two substituents each selected from the group consisting of hydrogen and C^alkyl;
R4 is one substituent selected from the group consisting of hydrogen, d-βalkyl and halogen;
R5 is selected from the group consisting of hydrogen and d^alkyl;
Re is selected from the group consisting of d-βalkyl-carbonyl, d-βalkoxy-carbonyl, C1-8alkyl-N(R5)-carbonyl, phenyl-d-βalkoxy-carbonyl, phenyt-N(R5>-carbonyl, phenyl-d-8alkyl-N(R5)-carbonyl and phenyl-d-βalkyl-sulfonyl; and
R7 is selected from the group consisting of d-βalkyl and phenyl-d-βalkyl.
26. A compound of Formula (Ic):
Figure imgf000117_0001
and forms thereof, wherein
Y is selected from the group consisting of CH2, O and S;
Li is absent or is selected from the group consisting of -C(O)O-Ri , -C(O)N(R5)-Ri and -NHC(O)-Ri;
Figure imgf000117_0002
L3 is absent or is -C(O)N(Rs)-R7;
Ri is selected from the group consisting of C1-8alkyl, d-βalkoxy, aryl, aryl-Ci-8alkyl, Cs-ucycloalkyl,
Figure imgf000117_0003
heterocyclyl, heterocyclyl-Ci-βalkyl, heteroaryl and heteroaryl-Ci^alkyl, wherein d-βalkyl is optionally substituted with one, two or three substituents each selected from the group consisting of
Figure imgf000117_0004
halogen, hydroxy and -NHRβ, wherein Ci-βalkoxy is optionally substituted with one, two or three substituents each selected from the group consisting of Ci-βalkoxy, halogen, hydroxy and -NHR6, wherein each instance of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of Ci-βalkyI, Ci-βalkoxy, halogen and
Figure imgf000117_0005
and wherein each instance of heterocyclyl is optionally substituted with oxo, Ci-βalkyl-carbonyl, Ci^alkoxy-carbonyl, Cvβalkyl-NfRsJ-carbonyl, aryl-carbonyl, aryl-Ci-βalkyl-carbonyl, aryl-Ci-βalkoxy-carbonyl, aryl-N(R5)-carbonyl, aryl-Ci-βalkyl-N(R5)-carbonyl or aryl-Ci-8alkyl-sulfonyl;
R2 is one, two or three substituents each selected from the group consisting of hydrogen, Ci-8alkyl, Ci-βalkoxy and halogen;
R3 is one, two or three substituents each selected from the group consisting of hydrogen and Ci-4alkyl; R4 is one, two or three substituents each selected from the group consisting of hydrogen, d-βalkyl, Ci-βalkoxy, hydroxy and halogen;
R5 is selected from the group consisting of hydrogen and d^alkyl;
R6 is selected from the group consisting of Ci-βalkyl-carbonyl,
Ci-8alkoxy-carbonyl, Ci^alkyl-N(Rs)-carbonyl, aryl-carbonyl, aryl-Ci-βalkyl-carbonyl, aryl-Ci-βalkoxy-carbonyl, aryl-N(Rs)-carbonyl, aryl-Ci-βalkyl-N(R5)-carbonyl and aryl-Ci-βalkyl-sulfonyl; and,
R7 is selected from the group consisting of Ci-8alkyl, aryi, aryl-d-βalkyl, C3-i4cycloalkyl,
Figure imgf000118_0001
heterocyclyl, heterocyclyl-Ci-ealkyl, heteroaryl and heteroaryl-C1-ealkyl.
27. The compound of claim 26, wherein
Ri is selected from the group consisting of Chalky!, Ci-βalkoxy, phenyl-Ci-βalkyl, naphthyl-Ci-βalkyl, indanyl, cyclopropyl-Ci-βalkyl, cyclohexyl-Ci-βalkyl, 1 ,2,3,4-tetrahydro-isoquinolinyl,
Figure imgf000118_0002
piperidinyl-Ci-ealkyl, piperazinyl-Ci-βalkyl, furanyl-Ci-βalkyl,
Figure imgf000118_0003
imidazolyl-Ci-βalkyl, pyridinyl-Ci-βalkyl and
Figure imgf000118_0004
wherein Ci-βalkyI is optionally substituted with a substituent selected from the group consisting of Ci-βalkoxy, hydroxy and -NR6, wherein Ci-βalkoxy is optionally substituted with -NHRe. wherein each instance of phenyl is optionally substituted with one, two or three substituents each selected from the group consisting of Ci-βalkoxy, chloro, fluoro, bromo and halo-Ci-ealkyl, and wherein each instance of 1,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-Ci-βalkyl, piperidinyl-Ci-aalkyl, piperazinyl-Ci-βalkyl is optionally substituted with oxo, Ci-βalkyl-carbonyl, d-βalkoxy-carbonyl, aryl-carbonyl, aryl-Ci-βalkoxy-carbonyl, aryl-Ci-8alkyl-N(R5)-carbonyl or aryl-Ci-8alkyl-sulfonyl;
R2 is one substituent selected from the group consisting of hydrogen, Ci-βalkyI, Ci-βalkoxy and halogen;
R3 is one or two substituents each selected from the group consisting of hydrogen and d^alkyl; R4 is one substituent selected from the group consisting of hydrogen, d-βalkyl and halogen;
R5 is selected from the group consisting of hydrogen and Chalky!;
R6 is selected from the group consisting of C1-8alkyl-carbonyl,
Ci-βalkoxy-carbonyl, Ci-βalkyl-N(R5)-carbonyl1 phenyl-Ci-βalkoxy-carbonyl, phenyl-N(Rs)-carbonyl, phenyl-Ci-8alkyl-N(R5)-carbonyl and phenyl-d-βalkyl-sulfonyl; and
R7 is selected from the group consisting of d-βalkyl and phenyl-d-βalkyl.
28. A compound of Formula (Id):
Figure imgf000120_0001
and forms thereof, wherein
Y is selected from the group consisting of CH2, O and S;
Li is absent or is selected from the group consisting of -C(O)O-Ri , -C(O)N(Rs)-Ri and -NHC(O)-Ri;
L2 is Ci-βalkyl;
L3 is absent or is -C(O)N(Rs)-R7;
Ri is selected from the group consisting of C1-8alkyl, Ci-βalkoxy, aryl, aryl-Ci-8alkyl, C3-i4cycloalkyl,
Figure imgf000120_0002
heterocyclyl, heterocyclyl-Ci-βalkyl, heteroaryl and
Figure imgf000120_0003
wherein d-ealkyl is optionally substituted with one, two or three substituents each selected from the group consisting of Ci.8alkoxy, halogen, hydroxy and -NHRe, wherein Ci-aalkoxy is optionally substituted with one, two or three substituents each selected from the group consisting of Ci-βalkoxy, halogen, hydroxy and -NHR6, wherein each instance of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of Ci^alkyl, Ci-aalkoxy, halogen and halo-Ci-ealkyl, and wherein each instance of heterocyclyl is optionally substituted with oxo, Ci-βalkyl-carbonyl, d-βalkoxy-carbonyl, Ci-8alkyl-N(R5)-carbonyl, aryl-carbonyl, aryl-d-βalkyl-carbonyl, aryl-Ci-βalkoxy-carbonyl, aryl-N(R5)-carbonyl, aryl-Ci-8alkyl-N(R5)-carbonyl or aryl-d-βalkyl-sulfonyl;
R2 is one, two or three substituents each selected from the group consisting of hydrogen, d-βalkyl, d-βalkoxy and halogen;
R3 is one, two or three substituents each selected from the group consisting of hydrogen and C^alkyl; R4 is one, two or three substituents each selected from the group consisting of hydrogen, d-βalkyl, d-βalkoxy, hydroxy and halogen;
R5 is selected from the group consisting of hydrogen and d^alkyl;
R6 is selected from the group consisting of d-βalkyl-carbonyl,
Ci-8alkoxy-carbonyl, Ci-8alkyl-N(R5)-carbonyl, aryl-carbonyl, aryl-Ci-βalkyl-carbonyl, aryl-d-βalkoxy-carbonyl, aryl-N(R5)-carbonyl, aryl-Ci^alkyl-N(R5)-carbonyl and aryl-Ci-βalkyl-sulfonyl; and,
R7 is selected from the group consisting of Ci-8alkyl, aryl, aryl-d-βalkyl, C3-i4cycloalkyl, Q^cycloalkyl-d-ealkyl, heterocyclyl, heterocyclyl-Ci-βalkyl, heteroaryl and heteroaryl-Ci-βalkyl.
29. The compound of claim 28, wherein
Ri is selected from the group consisting of Ci-8alkyl, d-βalkoxy, phenyl-C1-8alkyl, naphthyl-Ci-8alkyl, indanyl, cyclopropyl-C-i-βalkyl, cyclohexyl-Ci-βalkyl, 1 ,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-Ci-8alkyl, piperidinyl-d-βalkyl, piperazinyl-Ci-ealkyl, furanyl-Ci-ealkyl, thienyl-d-βalkyl, imidazolyl-Ci-8alkyl, pyridinyl-Ci-βalkyI and indolyl-Ci-ealkyl, wherein C1-8alkyl is optionally substituted with a substituent selected from the group consisting of Ci-8alkoxy, hydroxy and -NR6, wherein C1-BaIkOXy is optionally substituted with -NHR6, wherein each instance of phenyl is optionally substituted with one, two or three substituents each selected from the group consisting of d-βalkoxy, chloro, fluoro, bromo and halo-d-ealkyl, and wherein each instance of 1 ,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-Ci-βalkyl, piperidinyl-Ci-βalkyl, piperazinyl-Ci-βalkyl is optionally substituted with oxo, C-i-βalkyl-carbonyl, Ci-βalkoxy-carbonyl, aryl-carbonyl, aryl-Ci-βalkoxy-carbonyl, aryl-Ci-8alkyl-N(R5)-carbonyl or aryl-Ci-8alkyl-sulfonyl;
R2 is one substituent selected from the group consisting of hydrogen, Ci-βalkyl,
Figure imgf000122_0001
and halogen;
R3 is one or two substituents each selected from the group consisting of hydrogen and C1-4alkyl; R4 is one substituent selected from the group consisting of hydrogen, Chalky! and halogen;
Rs is selected from the group consisting of hydrogen and
Figure imgf000122_0002
R6 is selected from the group consisting of Ci-βalkyl-carbonyl,
Ci-βalkoxy-carbonyl, Ci-8alkyl-N(Rs)-carbonyl, phenyl-Ci-βalkoxy-carbonyl, phenyl-N(R5)-carbonyl, phenyl-Ci-8alkyl-N(R5)-carbonyl and phenyl-Ci-βalkyl-sulfonyl; and
R7 is selected from the group consisting of Chalky! and phenyl-Ci-βalkyl.
30. A compound selected from the group consisting of:
2-{1 -[2-{3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-N- phenethyl-benzamide,
N-benzyl-2-{1-[2-(3-oxo-2,3-dihydrc>-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}- benzamide, 2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl-piperidin-4-yl}-Λ/-(3- phenyl-propyl)-benzamide,
2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-N-(4- phenyl-butyl)-benzamide,
N-benzyl-N-methy1-2-{1 -[2-<3-oxo-2l3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzamidθ,
N-[2-(3-methoxy-phenyl)-ethyl]-2-{1-[2-(3-oxo-2,3-dihydro-bθnzo[1,4]oxazin-4-yl)- ethyl]-piperidin-4-yl}-benzamide,
N-[2-(2,4-dichloro-phenyl)-ethy1]-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4- yl)-ethyl]-piperidin-4-yl}-benzamide,
N-[2-(2-chloro-phenyl)-ethyl]-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)- ethy1]-piperidin-4-yl}-benzamide,
N-[2-(4-chloro-phenyl)-ethyl]-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)- ethyl]-piperidin-4-yl}-benzamide,
N-[2-(3,4-dimethoxy-phenyl)-ethyl]-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4- yl)-ethyl]-piperidin-4-yl}-benzamide;
N-[2-(3,4-dichloro-phenyl)-ethyf]-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4- yl)-ethyl]-piperidin-4-yl}-benzamide,
N-[2-(4-chloro-pheny!)-1 -methyl-ethyl]-2-{1 -[2-(3-oxo-2,3-dihydro- benzo{1 ,4]oxazin-4-y1)-ethyl]-piperidin-4-yl}-benzamide,
N-[2-(2,5-dimethoxy-phenyl)-ethyl]-2-{1 -[2-{3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4- yl)-ethyl]-piperidin-4-yl}-benzamide,
N-[2-(4-methoxy-phenyl>^thyl]-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yf)- ethyl]-piperidin-4-yl}-benzamide,
N-[2-(2-methoxy-pheny!)-βthyl]-2-{1-[2-(3-oxo-2.3-dihydro-benzo[1,4]oxazin-4-y1)- ethyl]-piperidin-4-yl}-benzamide,
N-[2-(4-fluoro-phenyl)-ethy1]-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)- ethyl]-piperidin-4-yl}-benzamide,
N-[2-(3,5-dimethoxy-phenyl)-ethyl]-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4- yl)-ethyl]-piperidin-4-yl}-benzamide,
N-methyl-2-{1-[2-(3-oxo-2>3-dihydrc>-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}- N-phenethyl-benzamide,
N-[2-(3,4-difluoro-phenyl)-ethyl]-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4- yl)-ethyl]-piperidin-4-yl}-benzamide,
N-(2-naphthalen-2-yl-ethyl)-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1.4]oxazin-4-yl)- ethyl]-piperidin-4-yl}-benzamide,
N-[2-{3,5-difluoro-phenyl)-ethyl]-2-{1 -[2-(3-oxo-2,3-dihydrc>-benzo[1 ,4]oxazin-4- yl)-ethyl]-piperidin-4-yl}-benzamide,
N-[2-(2,5-difluoro-phenyf )-ethyl]-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4- yl)-ethyl]-piperidin-4-yl}-benzamide,
N-[2-(2,3-difluoro-pheπyl)-ethyl]-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4- yl)-ethyl]-piperidin-4-yl}-benzamide, N-cyclopropylmethyl-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzamide,
N-(1 -methyl-3-phenyl-propyl>-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)- ethyl]-piperidin-4-yl}-benzamide,
N-[2-(1 H-indol-3-yl)-ethyl]-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)- ethyl]-piperidin-4-yl}-benzamide,
N-indan-1-yl-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4- yl}-benzamide,
2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin^-yl}-N-{2- phenyl-propylj-benzamide,
2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-N-propyl- benzamide,
2-{1 -[2-(3-oxo-2,3-dihydro-bβnzo[1 ,4]oxaziπ-4-yl)-ethyl]-piperidin-4-yl}-N-(2- pyrrolidin-1-yl-ethyl)-benzamide,
N-cyclohexylmethyl-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzamide,
N-furan-2-ylmethyl-N-methyl-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)- ethyl]-piperidin-4-yl}-benzamidet
N-(2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl>-ethyl]-piperidin-4-yl}-phenyl)- 3-phenyl-propionamide,
[4-(2-{1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}- benzoylamino)-butyl]-carbamic acid tert-butyl ester,
N-(2-methoxy-ethyl)-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-€thyl]- piperidin-4-yl}-benzamide,
N-(3-methoxy-propyl)-2-{1-{2-(3-oxo-2l3-dihydro-benzo[1.4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzamide,
N-(3-ethoxy-propyl)-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzamide,
N-(3-hydroxy-propyl)-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzamide,
2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-N-[2-(4- trifluoromethyl-phenyl)-ethyl]-benzamide,
2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-N-pyridin- 2-ylmethyl-benzamide,
2-{1 -[2-{3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyll-piperidin-4-yl}-N-(2- pyridin-2-yl-ethyl)-benzamide,
2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-N-pyridin- 3-ylmethyl-benzamide,
2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-N-pyridin- 4-yl methyl-benzamide,
2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl)-N-(2- pyridin-4-yl-ethyl)-benzamide, 2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-N- thiophen-2-ylmethyl-benzamide,
2-{1 -[2-<3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-N-(2- thiophen-2-yl-ethyl)-benzamide,
N-(3-imidazol-1-yl-propyl)-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)- ethyl]-piperidin-4-yi}-benzamide,
N-(2-acetylamino-ethyl)-2-{1 -{2-(3-oxo-2l3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzamide,
4-[(2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}- benzoylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester,
2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-N-[3-(2- oxo-pyrrolidin-1-yl)-piOpyl]-benzamide,
2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-N-{2- piperidin-1 -yl-ethyl)-benzamide,
4-{2-{4-[2-(3,4-dihydro-1H-isoquinoline-2-carbonyl)-phenyl]-piperidin-1-yl}-ethyl)- 4H-beπzo[1 ,4]oxazin-3-one,
N-[2-(3-naphthalen-2-yl-ureido)-ethyi]-2-{1-[2-{3-oxo-2,3-dihydro- benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide,
N-[2-(3-naphthalen-1 -yl-ureido)-ethy1]-2-{1 -[2-(3-oxo-2,3-dihydro- benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide,
5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4- yl}-benzoic acid methyl ester,
5-chloro-2-{1-[2-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4- yl}-N-phenethyl-benzamide,
4-[(5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethy1]-piperidin- 4-yl}-benzoylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester,
5-chloro-N,N-dimethyl-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzamide,
[4-(5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzot1 ,4]oxazin-4-yI)-ethyl]-piperidin- 4-yl}-benzoylamino)-butyl]-carbamic acid tert-butyl ester,
5-chloro-N-(2-naphthalen-2-yl-ethyl)-2-{1-[2-(3-oxo-2,3-dihydro- benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide,
5-chloro-N-[2-(1 H-indol-3-yl)-ethyl]-2-{1 -[2-(3-oxo-2,3-dihydro- benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide,
4-[(5-chloro-2-{1-[2-(3-oxo-2l3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin- 4-yl}-benzoylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester,
N-(1-benzoyl-piperidin-4-ylmethyl)-5-chloro-2-{1-[2-(3-oxo-2,3-dihydro- benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide,
5-chloro-N-[1-(3,3-dimethyl-butyryl)-piperidin-4-ylmethyl]-2-{1-[2-(3-oxo-2,3- dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide, 4-[2-(5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzoylamino)-ethyl]-piperazine-1 -carboxylic acid tert-butyl ester,
4-[(5-chloro-2-{1-[2-{3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin- 4-yl}-benzoylamino)-methyl]-piperidine-1 -carboxylic acid benzylamide,
4-[2-(5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzoylamino)-ethyl]-piperidine-1 -carboxylic acid tert-butyl ester,
[4-(5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin- 4-yl}-benzoylamino)-butyl]-carbamic acid benzyl ester,
; [5-(5-chloro-2-{1 -[2-{3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin- 4-yl}-benzoylamino)-pentyl]-carbamic acid tert-butyl ester,
' 5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4- yl}-N-(2-piperidin-1 -yl-ethyl)-benzamide,
5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4- yl}-N-(1-phenylmethanesulfonyl-piperidin-4-ylrinethyl)-benzamide,
5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethylJ-piperidin-4- yl}-N-(2-piperazin-1-yl-ethyl)-benzamide,
[6-(5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin- 4-yl}-benzoylamino)-hexyl]-carbamic acid tert-butyl ester,
[5-(5-chloro-2-{1-[2-{3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin- 4-yl}-benzoylamino)-pentyl]-carbamic acid benzyl ester,
5-chjoro-N-[5-(3,3-dimethyl-butyrylamino)-pentyl]-2-{1-[2-(3-oxo-2,3-dihydro- benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide,
N-[5-(3-benzyl-ureido)-pentyl]-5-chloro-2-{1-[2-(3-oxo-2,3-dihydrc~ benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzarnide,
5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4- yl}-N-(5-phenyImethanesulfonylamino-pentyl)-benzamide,
{2-[2-(5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1)4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzoylamino)-ethoxy]-ethyl}-carbamic acid tert-butyl ester,
5-chloro-N-[5-(3-isopropyl-ureido)-pentyl]-2-{1-[2-(3-oxo-2,3-dihydro- benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide,
5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl )-ethyl]-piperidin-4- yl}-N-[5-(3-phenyl-ureido)-pentyl]-benzamide,
5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-beπzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4- yl}-N-[5-(3-phenethyl-ureido)-pentyl]-benzamide,
[5-(5-chloro-2-{1-[2-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)-ethyl]-piperidin-4-yl}- benzoylamino)-pentyl]-carbamic acid tert-butyl ester,
5-chloro-2-{1-[1-methyl-2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-N-(1-phenylmethanesulfonyl-piperidin-4-ylmethyl)-benzamide, 4-{2-[4-(4-chloro-phenyl )-piperidin-1 -yl]-ethyl}-4H-benzo[1 ,4]oxazin-3-one, 4-[2-(4-phenyl-piperidin-1 -yl)-ethyl]-4H-berizo[1 ,4]oxazin-3-one, 4-{2-[4-(4-methoxy-phenyl)-piperidin-1-yl]-ethyl}-4H-benzo[1,4]oxazin-3-one, 4-{2-[4-(3-fluoro-phenyl)-piperidin-1 -yl]-ethyl}-4H-benzo[1 ,4]oxazin-3-oπe, 4-{2-[4-(2-fluoro-phenyl)-piperidin-1 -yl]-ethyl}-4H-benzo[1 ,4]oxazin-3-one, 4-[2-(4-p-tolyl-piperidin-1 -yl)-ethyl]-4H-benzo[1 ,4]oxazin-3-one, 4-[2-(4-o-tolyl-piperidin-1 -yl)-ethyl]-4H-benzo[1 ,4]oxazin-3-one, 4-{2-[4-(3-chloro-phenyl)-piperidin-1 -yl]-ethyl}-4H-benzo[1 ,4]oxazin-3-one,
2-{1-[2-(3-oxo-2,3-dihydro-benzol[1,4]oxain-4-yl-ethyl]-piperidine-4-yl-benzoic acid methyl ester,
4-[2-(5-chloro-2-{8-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-8-aza- bicyclo[3.2.1]oct-2-en-3-yl}-benzoylamino)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester.
[5-(5-chloro-2-{8-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin^4-yl)-ethyl]-8-aza- bicyclo[3.2.1 ]oct-2-en-3-yl}-benzoylamino)-pentyl]-carbamic acid tert-butyl ester,
4-[2-(2-{8-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-8-aza- bi(^do[3.2.1]ocΛ-3-yl}-benzoylamino)-ethyl]-piperazine-1 -carboxylic acid tert-butyl ester,
[5-(2-{8-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethylJ-8-aza- bicyclo[3.2.1]oct-3-yl}-benzoylamino)-pentyl]-carbamic acid tert-butyl ester,
[5-(2-{8-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-8-aza- bicyclo[3.2.1]oct-3-yl}-benzoylamino)-pentyl]-carbamic acid tert-butyl ester,
4-[2-(2-{8-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-8-aza- bicyclo[3.2.1]oct-3-yl}-benzoylamiπo)-ethyl]-piperazine-1-carboxyHc acid tert-butyl ester,
[5-(5-chloro-2-{8-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-8-aza- bicyclo[3.2.1]oct-3-yl}-benzoylamino)-pentyl]-carbamic acid tert-butyl ester,
4-[2-(3-phenyl-8-aza-bicyclo[3.2.1 ]oct-8-yl)-ethyl]-4H-benzo[1 ,4]oxazin-3-one,
[5-(5-chlorα-2-{2,6-dimethyl-1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl>- ethyl]-1 ,2,3,6-tetrahydro-pyridin-4-yl}-benzoylamino)pentyl]-carbamic acid tert- butyl ester,
1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl>-ethyl]-4-phenyl-piperidine-4- carboxylic acid dimethyl amide,
1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-4-phenyl-piperidine-4- carboxylic acid benzylamide,
1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl >-ethyl]-4-phenyl-piperidine-4- carboxylic acid phenethyl-amide,
1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazJn-4-yl>-ethyl]-4-phenyl-piperidine-4- carboxylic acid methyl-phenethyl-amide, 1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-4-phenyl-piperidine-4- carboxylic acid (3-phenyl-propyl)-amide,
1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-4-phenyl-piperidine-4- carboxylic acid (4-phenyl-butyl)-amide,
4-(4-chloro-phenyl)-1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]- piperidine-4-carboxylic acid phenethyl-amide,
1 -[2-(6-chloro-3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-4-(4-chloro phenyl)-piperidine-4-carboxylic acid dimethylamide,
4-(4-chloro-phenyl)-1-[2-(6-methyl-3-oxo-2,3-dihydro-bβπzo[1,4]oxazin-4-yl)- ethyl]-piperidine-4-carboxylic acid dimethylamide,
4-(4-chloro-phenyl)-1-[2-(6-fluoro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]- piperidine-4-carboxylic add dimethylamide,
4-(4-chloro-phenyl>-1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]- piperidine-4-carboxylic acid dimethylamide,
4-(4-chloro-phenyl)-1-t2-(3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl)-ethyl]- piperidine-4-carboxylic acid dimethylamide,
4-(4-chlorc-phenyl)-1-[2-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)-ethyl]-piperidine- 4-carboxylic acid dimethylamide, and
4-[2-(4-phenyl-piperidin-1-yl)-propyl]-4H-benzo[1 ,4]oxazin-3-one.
31. The compound of claim 30, wherein the compound is selected from the group consisting of:
2-{1-[2-(3-oxo-2,3-dihydro-benzo[1.4]oxazin-4-yl)-ethyl-piperidin-4-yl}-Λ/-(3- phenyl-propyl)-benzamide,
N-(2-naphthalen-2-yl -ethyl )-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4- yl)-ethyl]-piperidin-4-yl}-benzamide,
N-[2-(1 H-indol-3-yl)-ethyl]-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)- ethyl]-piperidin-4-yl}-benzamide,
N-[2-(4-bromo-phenyl)-ethyl]-2-{1-[2-(3-oxo-2l3-dihydro-benzo[1,4]oxazin-4- yl)-ethyl]-piperidin-4-yl}-benzamide,
[4-(2-{1-[2-(3-oxo-2,3-dihydro-benzot1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}- benzoylamino)-butyl]-carbamic acid tert-butyl ester,
4-[(2-{1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl>- benzoylamino^methylj-piperidine-i-carboxylic acid tert-butyl ester,
N-[2-(3-naphthalen-1 -yl-ureido)-ethyl]-2-{1 -[2-(3-oxo-2.3-dihydro- benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide,
5-chloro-2-{1-[2-(3-oxo-2.3-dihydro-benzo[1 ,4]oxazin-4-yl>-ethyl]-piperidin-4- yl}-N-phenethyl-benzamide, 4-[(5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzoylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester,
[4-(5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzoylamino>-butyl]-carbamic add tert-butyl ester,
5-chloro-N-(2-naphthalen-2-yl-ethyl)-2-{1-[2-(3-oxo-2,3-dihydro- benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide,
5-chloro-N-[2-(1H-indol-3-yl)-ethyl]-2-{1-[2-(3-oxo-2,3-dihydro- benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide,
4-[(5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzoylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester,
N-(1-benzoyl-piperidin-4-ylmethyl)-5-chloro-2-{1-[2-(3-oxo-2,3-dihydro- benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide,
5-chloro-N-[1-(3,3-dimethyl-butyryI)-piperidin-4-ylmethyl]-2-{1-[2-(3-oxo-2,3- dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yI}-benzamide,
4-[2-(5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]- piperidin^-yl^benzoylaminoj-ethyll-piperazine-i-carboxylic acid tert-butyl ester,
4-[(5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- piperidin^-yl^benzoylaminoj-methylj-piperidine-i-carboxylic acid benzylamide,
4-[2-(5-chloro-2-{1-[2-(3-oxo-2l3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzoylamino)-ethyl]-piperidine-1 -carboxylic acid tert-butyl ester,
[4-(5-chloro-2-{1 -t2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzoylamino)-butyl]-carbamic acid benzyl ester,
[5-(5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzoylamino)-pentyl]-carbamic acid tert-butyl ester,
5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4- y^-N^-piperidin-i-yl-ethylJ-benzamide,
5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4- yl}-N-(1-phenylmethanesulfonyl-piperidin-4-ylmethyl)-benzamide,
[6-(5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl>-ethyl]- piperidin-4-yl}-benzoylamino)-hexyl]-carbamic acid tert-butyl ester,
[5-(5-chloro-2-{1 -[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzoylamino)-pentyl]-carbamic acid benzyl ester,
5-chloro-N-[5-(3,3-dimethyl-butyrylamino)-pentyl]-2-{1-[2-(3-oxo-2,3-dihydro- benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide,
N-[5-(3-benzyl-ureido)-pentyl]-5-chloro-2-{1-[2-(3-oxo-2,3-dihydro- benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide, 5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4- yl}-N-(5-p he nylmethanesulf onylamino-pentyl )- benzam ide,
{2-[2-(5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1 l4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-benzoylamino)-ethoxy]-ethyl}-carbamic acid tert-butyl ester,
5-chloro-N-[5-(3-isopropyl-ureido)-peπtyl]-2-{1-[2-(3-oxo-2,3-dihydro- benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzamide,
5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1 ,43oxazin-4-yl)-ethyl]-piperidin-4- yl}-N-[5-(3-phenyl-ureido)-pentyl]-benzamide,
5-chloro-2-{1-[2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]-piperidin-4- yty-NKS-fS-phenethyl-ureido^pentyll-benzamide,
[5-(5-chloro-2-{1-[2-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)-ethyl]-piperidin-4- yl}-benzoylamino)-pentyl]-carbamic acid tert-butyl ester,
5-chloro-2-{1-[1-methyl-2-(3-oxo-2,3-dihydro-benzo[1 ,4]oxazin-4-yl)-ethyl]- piperidin-4-yl}-N-(1-phenylmethanesulfonyl-piperidin-4-ylrnethyl)-benzamidθ,
4-[2-(5-chloro-2-{8-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-8-aza- bicycloIS^.Iloct^-en-S-yll-benzoylaminόJTethyll-piperazine-i-carboxylic acid tert-butyl ester, and
[5-(5-chloro-2-{8-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-8-aza- bicyclo[3.2.1]oct-2-en-3-yl}-benzoylamino)-pentyli-carbamic acid tert-butyl ester.
32. A pharmaceutical composition comprising the compound of claim 1 or a form thereof and a pharmaceutically acceptable earner, excipient or diluent.
33. A method of treating or preventing a disease or condition in a subject which disease or condition is affected by antagonism of a Urotensin Il receptor, which method comprises administering to the subject in need of such treatment or prevention an effective amount of the compound of claim 1 or a form thereof.
34. A method for treating or ameliorating a Urotensin-ll mediated disorder in a subject in need thereof comprising administering to the subject an effective amount of the compound of claim 1 or a form thereof.
35. The method of claim 34, wherein the Urotensin ll-mediated disorder is selected from chronic vascular disease, vascular hypertension, heart failure, atherosclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, inflammatory colitis, renal dysfunction, renal failure, renal failure caused by drug induced toxicity, nephrotoxicity and diarrhea caused by antineoplastic agents, nephrotoxicity caused by radiocontrast agents and aminoglycosides, post-myocardial infarction, pulmonary hypertension, pulmonary fibrosis, insulin resistance and impaired glucose tolerance, diabetes, diabetic complications, diabetic nephropathy, pain, Alzheimer's disease, convulsions, depression, migraine, psychosis, anxiety, neuromuscular deficit and stroke.
36. The method of claim 34, wherein the Urotensin ll-mediated disorder is selected from vascular hypertension, heart failure, atherosclerosis, renal failure, renal failure caused by drug induced toxicity, nephrotoxicity and diarrhea caused by antineoplastic agents, nephrotoxicity caused by radiocontrast agents and aminoglycosides, post-myocardial infarction, pulmonary hypertension, pulmonary fibrosis, insulin resistance and impaired glucose tolerance, diabetes, diabetic complications, diabetic nephropathy, depression, psychosis, anxiety and stroke.
37. The method of claim 34, wherein said effective amount is from about 0.001 mg/kg/day to about 300 mg/kg/day.
38. The method of claim 36, wherein the Urotensin ll-mediated disorder is heart failure.
39. A use of the compound of claim 1 for the manufacture of a medicament for treating or ameliorating a Urotensin-ll mediated disorder in a subject in need thereof.
40. The use of daim 39, wherein the Urotensin ll-mediated disorder is selected from chronic vascular disease, vascular hypertension, heart failure, atherosclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, inflammatory colitis, renal dysfunction, renal failure, renal failure caused by drug induced toxicity, nephrotoxicity and diarrhea caused by antineoplastic agents, nephrotoxicity caused by radiocontrast agents and aminoglycosides, post-myocardial infarction, pulmonary hypertension, pulmonary fibrosis, insulin resistance and impaired glucose tolerance, diabetes, diabetic complications, diabetic nephropathy, pain, Alzheimer's disease, convulsions, depression, migraine, psychosis, anxiety, neuromuscular deficit and stroke.
41. The use of claim 40, wherein the Urotensin ll-mediated disorder is selected from vascular hypertension, heart failure, atherosclerosis, renal failure, renal failure caused by drug induced toxicity, nephrotoxicity and diarrhea caused by anti-neoplastic agents, nephrotoxicity caused by radiocontrast agents and aminoglycosides, post-myocardial infarction, pulmonary hypertension, pulmonary fibrosis, insulin resistance and impaired glucose tolerance, diabetes, diabetic complications, diabetic nephropathy, depression, psychosis, anxiety and stroke.
42. The use of claim 41 , wherein the Urotensin ll-mediated disorder is heart failure.
PCT/US2007/016806 2006-07-31 2007-07-26 Urotensin ii receptor antagonists WO2008016534A1 (en)

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IL196758A IL196758A0 (en) 2006-07-31 2009-01-27 Urotensin ii receptor antagonists
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US8759342B2 (en) 2014-06-24
CA2659412A1 (en) 2008-02-07
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