BRPI0714804A2 - urotensin receptor antagonists ii - Google Patents

Abstract

UROTENSIN RECEPTOR ANTAGONISTS II. 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

Report of the Invention Patent for "UROTENSIN II RECEPTOR ANTAGENISTS".

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims benefit of United States 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 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 II-mediated disorder. More particularly, the compounds of the present invention are Urotensin II receptor antagonists useful for treating or ameliorating Urotensin II mediated disorders. BACKGROUND OF THE INVENTION

Urotensin II (U II) is a cysteine-linked cyclic peptide that 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 goby fish (Gillichthys mirabilis) as a 12-mer, AGTAD-cycle (CFWKYC) -V (D. Pearson. JE Shively, BR Clark, II Geschwind , M. Barkley, RS Nishioka, HA Well, Proc. NatL Acad. Sci. USA 1980, 77, 5021-5024), but it has already been identified in all classes of vertebrates. The composition of U II 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 has been identified (RS Ames, M. M. Sarau, JK Chambers, RN Willette, V. V. Aiyar, AM Romanic, CS Louden, JJ Foley, CF Sauermelch, RW Coatney, Z. Ao, J. Disa, SD Holmes, JM Stadel, JD Martin, W.-S. Liu, GI Glover, S. Wilson, DE McNuIty, CE Ellis, NA Elshourbagy, U. Shabon, JJ Trill, DWP Hay, H. Ohlstein, DJ Bergsma, SA Dougas, Nature (London) 1999, 401, 282-286) as a G-protein coupled receptor (GPCR) previously known as the orphan GPR14 receptor, (Tal Tal, DA Ammar1 Kar Karpuj Krizhanovsky, J. Naim, DA Thompson, Biochem, Biophys, Res Commun., 1995, 209, 752-759, and A. Marchese, M. Heiber, T. Nguyen, H. HQ Heng, VR Saldivia R. Cheng, Ρ M. Murphy, L.- C. Tsui, X. Shi, P. Gregor, SR George, BF O'Dowd, JM Dobryty, Genomics 1995, 29, 335-344) which is expressed predominantly in cardiovascular tissues.

Goby's IL has powerful vasoconstrictive activity in fish, mammals, and humans (JM Conlon1 K. Yano, D. Waugh, N. Hazon, J. Exp. ZooL 1996, 275, 226-238; F. Bóhm, J Pernow, Br. J. Pharmaco (2002, 135, 25-27). Moreover, it appears to be the most potent vasoconstrictor known, (SA Douglas, H. H. Ohlstein, Trends Cardiovasc. Med. 2000, 10, 229-237) causing concentration-dependent contraction of isolated arterial rings. rats and humans with an EC50 value of less than 1 nM, which is about ten times more potent than endothelin-1. Recently, Kikkawa, H. and Kushida, H. in International Publication WO 2005/072226 have described the use of Urotensin II antagonists for the prevention and / or treatment of inflammatory bowel disease including, but not limited to, Crohn's disease. , ulcerative colitis, and inflammatory colitis caused by bacteria, ischemia, radiation, drugs, or chemicals.

Regarding the role of U Il in chronic vascular disease, this peptide has been reported to induce hypertrophy in cardiomyocytes (Y. Zou, R. Nagai, T. Yamazaki, FEBS Letters 2001, 508, 57-60) and the proliferation of smooth muscle (T. Watanabe, R. Pakala, T. Katagiri, CR Benedict, Circulation 2001, 104, 16-18), which suggests involvement in heart failure and atherosclerosis. In addition, U Il has been shown to increase peripheral vascular tone, a feature of chronic heart failure (M. Lim, S. Honisett, CD Sparkes, P. Komesaroff, A. Kompa, H. Krum, Circulation 2004, 109, 1212-1214). . Recent results have shown increased U II receptor levels observed in atherosclerotic lesions of the human aorta (N. Bousette, L. Patel, SA Douglas, H. H. Ohlstein, A. Giaid, Atherosclerosis 2004, 176, 117-123). . For healthy subjects, the expression of U Il-type immunoreactivity was 2-fold higher in plasma of renal dysfunction patients not on dialysis, and 3-fold higher in those on hemodialysis (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 have described the use of Urotensin II antagonists to reduce nephrotoxicity and diarrhea caused by antineoplastic agents.

U Il has been described as a potential mediator in diabetes. For example, UI1 has been shown to inhibit insulin release in the rat pancreas in response to increased glucose levels (RA Silvestre, J. Rodríguez-GalIardo, M. M. Egido1 J. Marco, Horm. Metab Res. 2001, 33, 379-381). Elevated U Il levels were seen in patients with diabetes mellitus (K. Totsune, K. Takahashi, Z. Arihara, M. Sone, S. Ito, O. Murakami, Clin. Sci. 2003, 104, 1-5). without kidney failure. Haplotypes in the uro-tensin 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).

An U II antagonist may be useful for the treatment of

pain, neurological and psychiatric disorders, migraine, neuromuscular deficit, anxiety disorders and cardiovascular disorders. IC Il (intracerebroventricular) administration of U Il increases upbringing, tidiness, and motor activity suggesting a CNS-stimulating activity (J. Gartlon1 F. Parker, DC Harrison, SA Douglas, E. Ashmeade, GJ Riley, ZA Hughes, SG Taylor , RP Munton, JJ Hagan, JA Hunter, DNC Jones, Psycho-pharmacology 2001, 155, 426-433). U Il increases Fos expression in the cingulate cortex and periaqueductal gray brain regions important in cognitive, emotional, and motor responses; pain perceptions; 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 rodent anxiogenic responses in the higher hole and maze board tests (Y. Matsumoto, M. Abe, T. Watanabe, Y. Adachi, T. Yano, H. Takahashi, T. Sugo, M. Moril C. Kitada, T. Kurokawa, M. Fujino, Neuroscence Letters 2004, 358, 99-102).

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-HT 1A receptor inhibitor. PCT Application WO 05/061457 describes benzo [1,4] oxazines

replaced as renin inhibitors.

Accordingly, it is an object of the present invention to provide compounds which are Urotensin II antagonists useful for treating Urotensin II mediated disorders. It is another object of the invention to provide a process for preparing

of compounds, compositions, intermediates and derivatives thereof.

It is a further object of the invention to provide methods for treating Urotensin II-mediated cardiovascular, renal, pancreatic, and central nervous system disorders including, but not limited to, chronic vascular disease, vascular hypertension, heart failure, atherosclerosis, disease. 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 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, seizures, depression, migraine , psychosis, anxiety, neuromuscular deficit and stroke. SUMMARY OF THE INVENTION

The present invention is directed to a compound of Formula (I):

L2

'FU

XX5

and forms thereof, wherein Ring A, Y1 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 producing a pharmaceutical composition comprising admixing a compound of Formula (I) and a pharmaceutically acceptable carrier.

The present invention is further directed to methods for treating or ameliorating a urotensin II mediated disorder. In particular, the method of the present invention is directed to treating or ameliorating a Urotensin II 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 insufficiency, renal insufficiency caused by drug-induced toxicity, nephrotoxicity and diarrhea caused by antineoplastic agents, nephrotoxicity caused by radiocontrast agents and aminoglycosides, after -myocardial infarction, pulmonary hypertension, pulmonary fibrosis, insulin resistance and impaired glucose tolerance, diabetes, diabetic complications, diabetic nephropathy, pain, Alzheimer's disease, seizures, depression, migraine, psychosis, anxiety, neuromuscular deficit and stroke.

The present invention is also directed to methods for producing the present pharmaceutical compounds and compositions and medicaments thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a compound of Formula

(I):

Y '

and forms of this in which

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-tetrahydropyridinyl;

Y is selected from the group consisting of CH2, O and S;

Li is absent or selected from the group consisting of -C (O) O-R 1, -C (O) N (R 5) -R 1 and -NHC (O) -R 1; L2 is C1-6 alkyl;

L3 is absent or is -C (O) N (R5) -R ?;

Ri is selected from the group consisting of C1-Salquila, C1-Salcoxy,

aryl, aryl-C 1-8 alkyl, C 3-14 Cycloalkyl, C 3 -cycloalkyl-Cl-Silyl, heterocyclyl, heterocyclyl-C 1-1 -alkyl, heteroaryl and heteroaryl-C 1-8 alkyl,

wherein C1-Salquila is optionally substituted with one, two or three substituents each selected from the group consisting of C1-Salcoxy,

halogen, hydroxy and -NHR6,

wherein C1-Salcoxy is optionally substituted with one, two or three substituents each selected from the group consisting of C1-Salcoxy, halogen, hydroxy and -NHR6, wherein each example of aryl is optionally substituted with one, two or three substituents each. one selected from the group consisting of C1-6 alkyl, C1-8 alkoxy, halogen and halo-C1-8 alkyl, and

wherein each example of heterocyclyl is optionally substituted by oxo, C1-8 alkylcarbonyl, C1-8 alkoxycarbonyl, C1-6 alkyl-NKRs) carbonyl, arylcarbonyl, aryl-C1-8 alkylcarbonyl, aryl-C1-4. -8 alkoxycarbonyl, aryl- N (R5) -Carbonyl aryl-C1-8 alkyl-N (R5) -carbonyl or aryl-C1-8 alkylsulfonyl;

R2 is one, two or three substituents each selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 alkoxy and halogen; R3 is one, two or three substituents each selected from the group

po consisting of hydrogen and C1-4 alkyl;

R4 is one, two or three substituents each selected from the group consisting of hydrogen, C1-8 alkyl, C1-6 alkoxy, hydroxy and halogen;

Rs is selected from the group consisting of hydrogen and C-i-

4alkyl;

Re is selected from the group consisting of C1-8 alkylcarbonyl, C1-8 alkoxycarbonyl, C1.8 alkyl-N (R5) -carbonyl, arylcarbonyl, aryl-C1-8alkylcarbonyl, aryl-C1-8 alkoxycarbonyl, aryl-N (R5) -carbonyl, aryl-C1-8 alkyl-N (R5) -carbonyl and aryl-C1-8-alkylsulfonyl; and, R7 is selected from the group consisting of C1-8 alkyl, aryl, aryl-

C 1-8 alkyl, C 3-14 Cycloalkyl, C 3-14 CycloC 1-8 alkylalkyl, heterocyclyl, heterocyclylC 1-8 alkyl, heteroaryl and heteroarylC 1-8 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-tetrahydropyridinyl.

An example of the present invention includes a compound of Formula (I) and forms thereof, wherein Ring A is substituted with one or two C1-4 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 R 1 is selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy,

C 1-8 alkyl aryl, C 3- Mc cycloalkyl, C 3-14 cycloC 1-8 alkyl alkyl, heterocyclyl, heterocyclyl C 1-8 alkyl and heteroaryl C 1-8 alkyl,

wherein C1-8 alkyl is optionally substituted with a substituent selected from the group consisting of C1-8 alkoxy, hydroxy and -NHR6, where C1-8 alkoxy is optionally substituted with -NHR6,

wherein each example of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of C1-8 alkoxy, halogen and halo-C1-8 alkyl, and

wherein each example of heterocyclyl is optionally substituted by oxo, C1-8 alkylcarbonyl, C1-8 alkoxycarbonyl, arylcarbonyl, aryl-C1-8 alkoxycarbonyl, aryl-C1-8alkyl-N (R5) -carbonyl or arylC 1-8 alkylsulfonyl.

An example of the present invention includes a compound of Formula (I) and forms thereof, wherein

R 1 is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, phenylC 1-8 alkyl, naphthyl-C 1-8 alkyl, indanyl, cyclopropyl-C 1-8 alkyl, cyclohexyl-C 1-8 alkyl, 1,2,3,4-tetrahydro -isoquinolinyl, pyrrolidinyl-C 1-8 alkyl, piperidinyl-C 1-8 alkyl, piperazinyl-C 1-8 alkyl, furanyl-C 1-8 alkyl, thienyl-C 1-8 alkyl, imidazolyl-C 1-8 alkyl, pyridinyl-C 1-8 alkyl and indolyl-C 1-8 alkyl ,

wherein C1-8 alkyl is optionally substituted with a substituent selected from the group consisting of C1-8 alkoxy, hydroxy and -NHR6, wherein C1-8 alkoxy is optionally substituted with -NHR6, where each example of phenyl is optionally substituted with one. , two or three substituents each selected from the group consisting of C1-alkoxy, chloro, fluoro, bromo and halo-C1-6 alkyl, and

wherein each example of 1,2,3,4-tetrahydro-isoquinolinyl, pyrrolidin-C 1-8 alkyl, piperidinyl-C 1-8 alkyl, piperazinyl-C 1-8 alkyl is optionally substituted with oxo, C 1-8 alkylcarbonyl, C 1-8 alkoxycarbonyl, arylcarbonyl, arylC 1-8 alkoxycarbonyl, arylC 1-8 alkyl-N (R 5) -carbonyl or arylC 1-8 alkylsulfonyl.

An example of the present invention includes a compound of Formula (I) and forms thereof, wherein R2 is a substituent selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 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 C 1-4 alkyl.

An example of the present invention includes a compound of Formula (I) and forms thereof, wherein R 4 is a substituent selected from the group consisting of hydrogen, C 1-8 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 1-4 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 C 1-8 alkylcarbonyl, C 1-8 alkoxycarbonyl, C 1-8 alkyl-N (R 5) -carbonyl aryl-C1-8 alkoxycarbonyl, aryl-N (R5) -carbonyl, aryl-C1-8-alkyl-N (R5) -carbonyl and aryl-C1-8-alkylsulfonyl.

An example of the present invention includes a compound of Formula (I) and forms thereof, wherein R 8 is selected from the group consisting of C 1-8 alkylcarbonyl, C 1-8 alkoxycarbonyl, C 1-8 alkyl-N (R 5) -carbonyl phenyl-C1-8 alkoxycarbonyl, phenyl-N (R5) -carbonyl, phenyl-C1-8-alkyl-N (R5) -carbonyl and phenyl-C1-8-alkylsulfonyl.

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 C 1-8 alkyl and aryl-C 1-8 alkyl.

An example of the present invention includes a compound of Formula (I) and forms thereof, wherein R7 is selected from the group consisting of C1-Salkyl and phenyl-C1-8 alkyl.

An example of the present invention includes a compound of

formula (I) and forms thereof, in which

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-tetrahydropyridinyl;

Y is selected from the group consisting of CH2, O and S;

Li is absent or selected from the group consisting of -C (O) O-R 1, -C (O) N (R 5) -R 1 and -NHC (O) -R 1; L2 is C1-Salquila;

L3 is absent or is -C (O) N (R5) -R7; R2 is selected from the group consisting of C1-Salkyl C1-Salkoxy,

C 1-8 alkyl, C 3 -cycloalkyl, C 3 -cycloalkyl-C 1 -alkyl, heterocyclyl, heerocyclyl-C 1 -alkyl and heteroaryl-C 4 -alkyl,

wherein C1-Salkyl is optionally substituted with a substituent selected from the group consisting of C1-Salcoxy, hydroxy and -NR6, wherein C1-Salcoxy is optionally substituted with -NHR6,

wherein each example of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of C1-8 alkoxy, halogen and halo-CT-ealkyl, and

wherein each example of heterocyclyl is optionally substituted by oxo, C1-alkylcarbonyl, C1-6 alkoxycarbonyl, arylcarbonyl, aryl-C1-8 alkoxycarbonyl, aryl-C1-8 alkyl-N (R5) -carbonyl or aryl-C4-alkylsulfonyl;

R2 is a substituent selected from the group consisting of hydrogen, C1-Salquila, C1-Salcoxy and halogen;

R3 is one or two substituents each selected from the group consisting of hydrogen and C1-4 alkyl;

R4 is a substituent selected from the group consisting of hydrogen, C1-Salquila and halogen; R5 is selected from the group consisting of hydrogen and C1.

4alkyl;

R6 is selected from the group consisting of C1-Alkyl-Carbonyl C1-8-alkoxycarbonyl, C1-Saki-N-R (R5) -Carbonyl, aryl-Ct-alkoxycarbonyl, aryl-N (R5) -Carbonyl-aryl-C1-8alkyl -N (R 5) -carbonyl and aryl-C 1-4 alkylsulfonyl; and

R 7 is selected from the group consisting of C 1-8 alkyl and aryl-C 1-

8alkyl.

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.

aza-bicyclo [3.2.1] oct-2-enyl, 8-aza-bicyclo [3.2.1] octyl and 1,2,3,6-tetrahydropyridinyl;

Y is selected from the group consisting of CH2l O and S; L 1 is absent or selected from the group consisting of -C (O) O-R 1, -C (O) N (R 5) -R 1 and -NHC (O) -R 1; L 2 is C 1-8 alkyl;

L3 is absent or is -C (O) N (R5) -R7;

R 1 is selected from the group consisting of C 1-8 C 1-8 alkoxyalkyl, phenylC 1-6 alkyl, naphthyl-C 1-6 alkyl, indanyl, eiclopropyl-C 1-6 alkyl, C 1-6 -alkyl, 1,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl and C 1-6 alkyl, piperidinyl-C 1-8 alkyl, Piperazinyl-C 1-4 alkyl, furanyl-C 1-4 alkyl, thienyl-C 1-8 alkyl, imidazolyl-C 1-8 alkyl, Pyridinyl-C 1-4 alkyl and IndoI-C 1-1 -alkyl,

wherein C1-Salkyl is optionally substituted with a substituent selected from the group consisting of C1-Salcoxy, hydroxy and -NR6l wherein C1-Salcoxy is optionally substituted with -NHR6,

wherein each example of phenyl is optionally substituted with one, two or three substituents each selected from the group consisting of C1-Salcoxy, chloro, fluoro, bromo and Iialo-Cl-Salquila, and

wherein each example of 1,2,3,4-tetrahydro-isoquinolinyl, pyrrolidin-C 1 -alkyl, Piperidinyl-C 1 -alkyl, Piperazinyl-C-Salquyl is optionally substituted with oxo, C 1 -Salkylcarbonyl, C 1-6 alkoxycarbonyl, arylcarbonyl, aryl-C 1-4 -alkoxycarbonyl, BnI-Cl-Saalkyl-N (R 5) -Carbonyl or aryl-C 1-8 alkylsulfonyl;

R2 is a substituent selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 alkoxy and halogen;

R3 is one or two substituents each selected from the group consisting of hydrogen and C1-4 alkyl;

R4 is a substituent selected from the group consisting of hydrogen, C1-8 alkyl and halogen;

R5 is selected from the group consisting of hydrogen and C1.

4alkyl;

R6 is selected from the group consisting of C1-8 alkylcarbonyl,

C1-8 alkoxycarbonyl, C1-6 alkyl-N (R5) -Carbonyl, phenyl-C1-8 alkoxycarbonyl, phenyl-N (R5) -carbonyl, phenyl-C1-8 alkyl-N (R5) -carbonyl and phenyl -C 1-8 alkylsulfonyl; and

R7 is selected from the group consisting of C1-8 alkyl and phenyl-C-1-

8alkyl,

The present invention is directed to a compound of Formula

(Ia):

and forms of this in which

Y is selected from the group consisting of CH2, O and S; Li is missing or is selected from the group consisting of -

C (O) O-R 1, -C (O) N (R 5) -R 1 and -NHC (O) -R 1; L2 is C1-Salquila;

L3 is absent or is -C (O) N (R5) -R7;

R 1 is selected from the group consisting of C 1-4 alkyl, C 1-6 alkoxy, aryl, C 1-8 alkyl, C 3-14 Cycloalkyl, C 3-14CycloC 1-8 alkyl, heterocyclyl, heterocyclyl C 1-8 alkyl, heteroaryl and heteroaryl C 1-8 alkyl ,

wherein C1-8 alkyl is optionally substituted with one, two or three substituents each selected from the group consisting of C1-8 alkoxy, halogen, hydroxy and -NHR6,

wherein C1-6 alkoxy is optionally substituted with one, two or three substituents each selected from the group consisting of C1-8 alkoxy, halogen, hydroxy and -NHR6,

wherein each example of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of C1-8 alkyl, C1-8 alkoxy, halogen and halo-C1-8 alkyl, and

wherein each example of heterocyclyl is optionally substituted by oxo, C1-8 alkylcarbonyl, C1-8 alkoxycarbonyl, C1-8alkyl-N (R5) -carbonyl, arylcarbonyl, aryl-C1-8alkylcarbonyl, aryl -C 1-8 alkoxycarbonyl, aryl-N (R 5) -Carbonyl, aryl-C 1-8 alkyl-N (R 5) -carbonyl or aryl-C 7 -alkyl sulfonyl;

R2 is one, two or three substituents each selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 alkoxy and halogen;

R3 is one, two or three substituents each selected from the group consisting of hydrogen and C1-4 alkyl; R4 is one, two or three substituents each selected from the group

po consisting of hydrogen, C 1-8 alkyl, C 1-8 alkoxy, hydroxy and halogen;

R5 is selected from the group consisting of hydrogen and

4alkyl;

Rq is selected from the group consisting of C1-6 alkylcarbonyl, C1-8 alkoxycarbonyl, C1-8 alkyl-N (R5) -carbonyl, arylcarbonyl, aryl-C1-8 alkylcarbonyl, aryl-C1-8 alkoxycarbonyl, aryl- N (R 5) -carbonyl, aryl-C 1-8 alkyl-N (R 5) -carbonyl and aryl-C 1-8 alkylsulfonyl; and,

R 7 is selected from the group consisting of C 1-8 alkyl, aryl, aryl C 1-8 alkyl, C 3-14 cycloalkyl, C 3-14 CycloC 1-8 alkylalkyl, heterocyclyl, heterocyclylC 1-8 alkyl, heteroaryl and heteroarylC 1-8 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; Li is absent or selected from the group consisting of -C (O) O-R 1, -C (O) N (R 5) -R 1 and -NHC (O) -R 1; L2 is C1-Salquila;

L3 is absent or is -C (O) N (R5) -R7;

R 1 is selected from the group consisting of C 1 -alkyl, C 1 -alkoxy, phenyl-C 1-8 alkyl, naphthyl-C 1-6 alkyl, indanyl, Cyclopropyl-C 1-6 alkyl, C 1 -C 8 -alkyl, 1,2,3,4-tetrahydro -isoquinolinyl, pyrrolidinyl-C 1-8 alkyl, piperidinyl-C 1-8 alkyl, piperazinyl-C 1-8 alkyl, furanyl-C 1-8 alkyl, Iienyl-C 1- Salkylal imidazolyl-C 1- Salkylal pyridinyl-C 1-8 alkyl, and indolyl-C 1-8 alkyl,

wherein C1-Salkyl is optionally substituted with a substituent selected from the group consisting of C1-Salcoxyl hydroxy and -NR6,

wherein C 1-8 alkoxy is optionally substituted by -NHR 6, wherein each example of phenyl is optionally substituted with one, two or three substituents each selected from the group consisting of C 1 -Salcoxy, chloro, fluoro, bromo and halo-C ^ alkyl, and

wherein each example of 1,2,3,4-tetrahydro-isoquinolinyl, pyrrolidin-C 1 -alkyl, piperidinyl-C 1-8 alkyl, Piperazinyl-C-Salquila is optionally substituted with oxo, C 4 -alkylcarbonyl, C 1-6 alkoxycarbonyl, arylcarbonyl, arylC 1-8 alkoxycarbonyl, arylC 1-6 alkylcarbonyl or arylC 1-8 alkylsulfonyl;

R2 is a substituent selected from the group consisting of hydrogen, C1-Salkyl C1-Salkoxy and halogen;

R3 is one or two substituents each selected from the group consisting of hydrogen and C1-4 alkyl;

R4 is a substituent selected from the group consisting of hydrogen, C1-Salquila and halogen;

R5 is selected from the group consisting of hydrogen and C1-

4alkyl;

R6 is selected from the group consisting of C1 -C4 alkylcarbonyl,

C1-Alkoxycarbonyl, C1-Alkyl-N (R5) -Carbonyl, Phenyl-C 1-8 alkoxycarbonyl, Phenyl-N (R5) -carbonyl, Phenyl-Cl-Alkyl-N (R5) -Carbonyl and phenyl -C 1-8 alkylsulfonyl; Θ

R 7 is selected from the group consisting of C 1-8 alkyl and phenylC 1-

8alkyl.

The present invention is directed to a compound of Formula

(Ib):

r2KXl '

and forms of this in which

Y is selected from the group consisting of CH2, O and S; L-i is absent or selected from the group consisting of -C (O) O-R 1, -C (O) N (R 5) -R 1 and -NHC (O) -R 1; L 2 is C 1 -alkyl;

L3 is absent or is -C (O) N (R5) -R7;

R1 is selected from the group consisting of C1-8 alkyl, C1-8 alkoxy, aryl, aryl-C1-8 alkyl, C3-cycloalkyl, C3-cycloalkyl-C1-alkyl, heterocyclyl, heterocyclyl-C1-8 alkyl, heteroaryl and heteroaryl-C1-8 alkyl wherein C1-8 alkyl is optionally substituted with one, two or

three substituents each selected from the group consisting of C 1-6 alkoxy, halogen, hydroxy and -NHR 6,

wherein C1-8 alkoxy is optionally substituted with one, two or three substituents each selected from the group consisting of C1-Salcoxy, halogen, hydroxy and -NHR6,

wherein each example of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of C1-Salquyl, C1-Salcoxy, halogen and halo-Cvsalkyl, and

wherein each example of heterocyclyl is optionally substituted by oxo, C 1-8 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-8 alkyl-N (R 5) carbonyl, arylcarbonyl, arylC 1-8 alkylcarbonyl, aryl -C 1-8 alkoxycarbonyl, aryl-N (R 5) -Carbonyl, aryl-C 1-8 alkyl-N (R 5) -carbonyl or aryl-C 1-8 alkylsulfonyl;

R2 is one, two or three substituents each selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 alkoxy and halogen;

R3 is one, two or three substituents each selected from the group consisting of hydrogen and C1-4 alkyl;

R4 is one, two or three substituents each selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 alkoxy, hydroxy and halogen; R5 is selected from the group consisting of hydrogen and

4alkyl;

R6 is selected from the group consisting of C1-8 alkylcarbonyl, C1-8 alkoxycarbonyl, C1-8 alkyl-N (R5) -carbonyl, arylcarbonyl, aryl-C1-8alkylcarbonyl, aryl-C1-8alkoxycarbonyl, aryl-N (R5) -carbonyl, aryl-C1-8 alkyl-N (R5) -carbonyl and aryl-C1-8 alkylsulfonyl; and,

R 7 is selected from the group consisting of C 1-8 alkyl, aryl, C 1-8 arylalkyl, C 3-14 cycloalkyl, C 3-14 cycloC 1-8 alkylalkyl, heterocyclyl, heterocyclylC 1-8 alkyl, heteroaryl and heteroarylC 1-8 alkyl.

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 selected from the group consisting of -C (O) O-R 1, -C (O) N (R 5) -R 1 and -NHC (O) -R 1; L 2 is C 1-8 alkyl; L3 is absent or is -C (O) N (R5) -R7;

R1 is selected from the group consisting of C1-8 alkyl, C1-8 alkoxy, phenyl-C1-8 alkyl, naphthyl-C1-8 alkyl, indanyl, cyclopropyl-C1-8 alkyl, cyclohexyl-C1-8 alkyl, 1,2,3,4-tetrahydro -isoquinolinyl, pyrrolidinyl-C 1-8 alkyl, piperidinyl-C 1-8 alkyl, piperazinyl-C 1-8 alkyl, furanyl-C 1-8 alkyl, thienyl-C 1-8 alkyl, imidazolyl-C 1-8 alkyl, pyridinyl-C 1-8 alkyl and indolyl-C 1-8 alkyl ,

wherein C1-8 alkyl is optionally substituted with a substituent selected from the group consisting of C1-8 alkoxy, hydroxy and -NR6, wherein C1-8 alkoxy is optionally substituted with -NHR6, where each example of phenyl is optionally substituted with one. two or three substituents each selected from the group consisting of C1-8 alkoxy, chloro, fluoro, bromo and halo-C1-8 alkyl, and wherein each example of 1,2,3,4-tetrahydro-isoquinolinyl, pyrrolidin

C 1-6C-Alkyl, piperidinyl-C 1-8 alkyl, piperazinyl-C 1-8 alkyl is optionally substituted by oxo, C 1-8 alkylcarbonyl, C 1-8 alkoxycarbonyl, arylcarbonyl, arylC 1-8 alkoxycarbonyl, aryl -C 1-8 alkyl-N (R 5) -carbonyl or aryl-C 1-8 alkyl sulfonyl;

R2 is a substituent selected from the group consisting of hydroxy-

genius, C 1-8 alkyl, C 1-8 alkoxy and halogen;

R3 is one or two substituents each selected from the group consisting of hydrogen and C1-4 alkyl;

R4 is a substituent selected from the group consisting of hydrogen, C1-8 alkyl and halogen;

R5 is selected from the group consisting of hydrogen and

4alkyl;

R 6 is selected from the group consisting of C 1-8 alkylcarbonyl, C 1-8 alkoxycarbonyl, C 1-8 alkyl-N (R 5) -carbonyl, phenyl-C 1-8 alkoxycarbonyl, phenyl-N (R 5) -carbonyl, phenyl -C 1-8 alkyl-N (R 5) -carbonyl and phenylC 1-8 alkylsulfonyl; and

R7 is selected from the group consisting of C1-8 alkyl and phenylC1-

8alkyl.

The present invention is directed to a compound of Formula

(Ic): and forms thereof, in which

Y is selected from the group consisting of CH2, O and S; L 1 is absent or selected from the group consisting of -C (O) O-R 1 -C (O) N (R 5) -R 1 and -NHC (O) -R 1;

L2 is C1-Salquila;

L3 is absent or is -C (O) N (R5) -R7;

R 1 is selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, aryl, arylC 1-4 alkyl, C 3-4 Cycloalkyl, C 3-4Cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclylC 1-6 alkyl, heteroaryl and heteroaryl C 1-6 alkyl; wherein C1-Salquila is optionally substituted with one, two or

three substituents each selected from the group consisting of C1-Salcoxy, halogen, hydroxy and -NHR6,

wherein C1-Salcoxy is optionally substituted with one, two or three substituents each selected from the group consisting of C1-Salcoxy, halogen, hydroxy and -NHR6,

wherein each example of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of C-i-alkyl, C1-Salcoxy, halogen and halo-C1.8 alkyl, and

wherein each example of heterocyclyl is optionally substituted by oxo, C1-Salkyl-Carbonyl, C1-Salkoxy-Carbonyl, C1-Alkyl-N (R5) -carbonyl, arylcarbonyl, aryl-C1-8 alkylcarbonyl, aryl C 1-6 alkoxycarbonyl, aryl-N (R 5) -Carbonyl aryl-C 1-8 alkyl-N (R 5) -carbonyl or aryl C 1-6 alkylsulfonyl;

R2 is one, two or three substituents each selected from the group consisting of hydrogen, C1-Salquila, C1-Salcoxy and halogen; R3 is one, two or three substituents each selected from the group consisting of hydrogen and C1-4 alkyl;

R4 is one, two or three substituents each selected from the group consisting of hydrogen, C1-4 alkyl, C1-4 alkoxy, hydroxy and halogen;

R5 is selected from the group consisting of hydrogen and C1.

4alkyl;

R 6 is selected from the group consisting of C 1-8 alkylcarbonyl, C 1-8 alkoxycarbonyl, C 1-6 Alkyl-N (R 5) -Carbonyl, arylcarbonyl, arylC 1-8 alkylcarbonyl, arylC 1-8 alkoxycarbonyl, aryl-N (R5) -carbonyl, aryl-C1-8 alkyl-N (R5) -carbonyl and aryl-C1-8-alkylsulfonyl; and,

R7 is selected from the group consisting of C1-8 alkyl, aryl, aryl-C1-8 alkyl, C3-4 cycloalkyl, C3-4 cycloC1-8 alkyl, heterocyclyl, heterocyclyl-C1-8 alkyl, heteroaryl and heteroaryl-C1-4 alkyl.

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; L1 is absent or selected from the group consisting of -C (O) O-R1, -C (O) N (R5) -R1 and -NHC (O) -R1; L2 is C1-Salquila; L3 is absent or is -C (O) N (R5) -R ?;

R1 is selected from the group consisting of C1-Salquyl, C1-Salcoxy, Tenyl-C1-Salquila, Naphthyl-C1-8alkyl, Indanyl, Cyclopropyl-C1-salquila, CiCloexi-C1-Salquila, 1,2,3,4-Tetrahydro -isoquinolinyl, pyrrolidinyl-C1-8 alkyl, piperidinyl-C1-alkyl, Piperazinyl-C1-alkyl, furanyl-C1-alkyl, thienyl-C1-alkyl, imidazolyl-C1-alkyl, pyridinyl-C1-alkyl and indolyl-C1-6 alkyl,

wherein C1-Salkyl is optionally substituted with a substituent selected from the group consisting of C1-Salcoxy, hydroxy and -NR6,

wherein C1-Salcoxy is optionally substituted with -NHR6, where each example of phenyl is optionally substituted with one, two or three substituents each selected from the group consisting of C1-Salcoxy, chloro, fluoro, bromo and halo-C1 .8 alkyl, and

wherein each example of 1,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-C 1-6 alkyl, piperidinyl-C 1-8 alkyl, piperazinyl-C 1-8 alkyl is optionally substituted with oxo, C 1-8 alkylcarbonyl, C 1-8 alkoxycarbonyl, arylcarbonyl, arylC 1-8 alkoxycarbonyl, arylC 1-8 alkyl-N (R 5) -carbonyl or arylC 1-8 alkylsulfonyl;

R2 is a substituent selected from the group consisting of hydroxy-

genius, C1-8 alkyl, C1-8 alkoxy and halogen;

R3 is one or two substituents each selected from the group consisting of hydrogen and C1-4 alkyl;

R4 is a substituent selected from the group consisting of hydrogen, C1-8 alkyl and halogen;

Rs is selected from the group consisting of hydrogen and C1-

4alkyl;

R 6 is selected from the group consisting of C 1-8 alkylcarbonyl, C 1-8 alkoxycarbonyl, C 1-8 alkyl-N (R 5) -carbonyl, phenyl-C 1-8 alkoxycarbonyl, phenyl-N (R 5) -carbonyl, Ienyl -C1 -alkyl-N (R5) -Carbonyl and phenyl-C1-8 alkylsulfonyl; and

R7 is selected from the group consisting of C1-8 alkyl and phenylC1-

8alkyl. (Id):

The present invention is directed to a compound of Formula

Y - M

and forms of this in which

Y is selected from the group consisting of CH2, O and S; L 1 is absent or selected from the group consisting of C (O) O-R 1, -C (O) N (R 5) -R 1 and -NHC (O) -R 1; L 2 is C 1-8 alkyl;

L3 is absent or is -C (O) N (R5) -R7;

R1 is selected from the group consisting of C1-8 alkyl, C1-8 alkoxy, aryl, aryl-C1-8 alkyl, C3-4 cycloalkyl, C3-4Cycloalkyl-C1-8 alkyl, heterocyclyl, heterocyclyl-C1-8 alkyl, heteroaryl and heteroaryl-C1-8 alkyl ,

wherein C 1-8 alkyl is optionally substituted with one, two or three substituents each selected from the group consisting of C 1-8 alkoxy, halogen, hydroxy and -NHR 6,

wherein C 1-8 alkoxy is optionally substituted with one, two or three substituents each selected from the group consisting of C 1-8 alkoxy, halogen, hydroxy and -NHR 6,

wherein each example of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of C1-8 alkyl, C1-8 alkoxy, halogen and halo-C1-8 alkyl, and wherein each example of heterocyclyl is optionally substituted.

oxo, C 1-8 alkylcarbonyl, C 1-8 alkoxycarbonyl, C 1-8 alkyl-N (R 5) carbonyl, arylcarbonyl, arylC 1-8 alkylcarbonyl, arylC 1-8 alkoxycarbonyl, aryl-N (R5) -Carbonyl, aryl-C1-8 alkyl-N (R5) -carbonyl or aryl-C1-8 alkylsulfonyl;

R2 is one, two or three substituents each selected from the group consisting of hydrogen, C1-8 alkyl, C1-6 alkoxy and halogen;

R3 is one, two or three substituents each selected from the group consisting of hydrogen and C1-4 alkyl;

R4 is one, two or three substituents each selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 alkoxy, hydroxy and halogen; R5 is selected from the group consisting of hydrogen and C-i-

4alkyl;

R6 is selected from the group consisting of C1-8 alkylcarbonyl, C1-8 alkoxycarbonyl, C1-8 alkyl-N (R5) -carbonyl, arylcarbonyl, aryl-C1-8alkylcarbonyl, aryl-C1-8alkoxycarbonyl, aryl-N (R 5) -carbonyl, aryl-C 1-8 alkyl-N (R 5) -carbonyl and aryl-C 1-8 alkylsulfonyl; and,

R7 is selected from the group consisting of C1-8 alkyl, aryl, C1-8 alkyl aryl, C3-4 cycloalkyl, C3-4 cycloalkyl-C1-alkyl, heterocyclyl, heterocyclyl-C1-8 alkyl, heteroaryl and heteroaryl-C1-8 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;

L1 is missing or is selected from the group consisting of -

C (O) O-R 1, -C (O) N (R 5) -R 1 and -NHC (O) -R 1; L2 is C1-Balkyl;

L3 is absent or is -C (O) N (R5) -R7;

R1 is selected from the group consisting of C1-Salquyl, C1-4 alkoxy, phenyl-C1-6 alkyl, naphthyl-C1-8 alkyl, indanyl, cyclopropyl-C5-6 alkyl, cyclohexyl-C1-alkyl, 1,2,3,4-tetrahydro-isoquinolinyl , Pyrrolidinyl-Cl-Salyl, Piperidinyl-C 1-4 alkyl, piperazinyl-C 1-8 alkyl, furanyl-C 4 -alkyl, thienyl-C 4 -alkyl, imidazolyl-C 1 -alkyl, Pyridinyl-C-Salquila and indolyl-C 1-8 alkyl,

wherein C1-Salkyl is optionally substituted with a substituent selected from the group consisting of C1-Salcoxy, hydroxy and -NR6,

wherein C1-Salcoxy is optionally substituted with -NHR6, where each example of phenyl is optionally substituted with one, two or three substituents each selected from the group consisting of C1-Salcoxy, chloro, fluoro, bromo and Iialo-Cl -Alkyl, and wherein each example of 1,2,3,4-tetrahydro-isoquinolinyl, pyrrolidin

C 1 -C 4 -alkyl, piperidinyl-C 1-8 alkyl, Piperazinyl-C 1-4 -alkyl is optionally substituted by oxo, C 4 -alkylcarbonyl, C 1 -alkoxycarbonyl, arylcarbonyl, aryl-C 4 -alkoxycarbonyl, aryl -CT-alkyl-N 1 -R-carbonyl or aryl-C 1-4 alkylsulfonyl;

R2 is a substituent selected from the group consisting of hydroxy-

genius, C1-Salquila, C1-Salcoxy and halogen;

R3 is one or two substituents each selected from the group consisting of hydrogen and C1-4 alkyl;

R4 is a substituent selected from the group consisting of hydrogen, C1-Salquila and halogen;

R5 is selected from the group consisting of hydrogen and C1-

4alkyl; R6 is selected from the group consisting of C1-6 alkylcarbonyl, C1-8 alkoxycarbonyl, C1-8 alkyl-N (R5) carbonyl, phenyl-C1-8 alkoxycarbonyl, phenyl-N (R5) carbonyl, phenyl -C 1-8 alkyl-N (R 5) -carbonyl and phenylC 1-8 alkylsulfonyl; and

R7 is selected from the group consisting of C1-8 alkyl and phenylC1-

8alkyl.

An example of the present invention includes a compound of Formula (I) and forms thereof selected from the group consisting of:

Cpt 1

The

Cpt 2

Cl

Cpt 5

Cpt 6

Cpt 7 Cpt 9

Cpt 13

Cpt 10

Cpt 14

Cpt 17 Cpt 18

Cpt 11

Cpt 15

Cpt 12

Cpt 19

Cpt 20 Cpt 22

Hn

CK-

Cpt 26

Q

= \ MH

Cpt 29

Cpt 23

Cpt 27

The

Cpt 28

Cpt 31

Cpt 32 H

THE

Cpt 33 Cpt 34

Cpt 41

Hh

= \ NH

Cpt 35

OH

== \ NH

Cpt 39

Cpt 36

■ = \ NH

Cpt 40

Cpt 43 Cpt 44 Cpt 45

Grandfather

Hn

= \ NH

THE

Cpt 49

W /

Cpt 47

Cpt 51

Cpt 48

Cpt 52

Cpt 53

Cpt 54

Cpt 55

Cpt 56

Cpt 61

Cl,

Cpt 58

Cpt 62

The

^ / NH

^ / O ^ N,

= X V

Cpt 59

\)

H>

Cl,

= \ NH

Cpt 63

THE

Hn

Cl

= V NH

Cpt 65

Cpt 66

= \ NH

Cpt 64

CkJ \ l.

Cpt 68 Cpt 74

.ο

\ lH Cl.

= ν NH Cl.

Q

= V NH

JP

Cpt 71

0 Cl.

Cpt 76

Jjh

NH

Cl,

H

The Cpt 81

Cpt 85

Cpt 78

Cpt 79

Cpt 80

Cl,

Cpt 82

Cpt 83

Cpt 86

Cpt 87

Cl

Cpt 84

Cpt 88

Cpt 89

Cpt 90

Cpt 91

Cpt 92

Cpt 93

0 =, Vjh

Cl,

Cpt 94

^ Inh

the Cl.

Cpt 95

THE

= V H

THE

Cpt 96

o =

NH

^ = V KlH / = \ NH

Cpt 97

Cpt 98

CL

% /

Cpt 99

= \ NH

W f

Cpt 100

L

Cpt 101 Cpt 102 Cpt 103 Cpt 104 Cpt 105

CkNN.

Cpt 109

Cpt 106

Cpt 110

Cpt 107

Cpt 111

115

Cpt 108

Cpt 112

N '

116

Cpt 113 Definitions

Binding lines drawn on a variable substituent ring system indicate that the substituent may be attached to any of the replaceable 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 a given 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 that of ordinary versatility in the art.

The term "C 1-1 -alkyl" refers to straight and branched carbon chains having 1 to 8 carbon atoms or any number within this range. For this reason, designated numbers of carbon atoms (for example, Ci-β) will refer independently to the number of carbon atoms in the chain. A C1-8 alkyl chain may be attached to a core molecule and further substituted at any atom when allowed at available valencies. The term "C-i-alkoxy" refers to a substituent group of -O-C 1-

and alkyl, wherein C 1-8 alkyl is as defined above. A C1-4 alkoxy chain may be attached to a core molecule and further substituted at any atom when permitted at available valencies.

The term "C3-14cick) alkyl" refers to saturated or partially unsaturated monocyclic or polycyclic hydrocarbon rings of 3 to 14 carbon atom ring members that may be optionally fused to a benzene ring. The term "C3-4cycloalkyl" also includes a C3-8cycloalkyl, C3-10cycloalkyl, C5-6cycloalkyl, C5-8cycloalkyl, C5-6cycloalkyl or C3-6cycloalkyl, and similar cycloalkyl ring system radicals. but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloeptyl, cyclooctyl, 1H-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 at any atom when permitted at available valencies. The term "heterocyclyl" refers to a monocyclic or poly-ring

saturated or partially unsaturated cyclic of 5 to 9 members wherein up to 4 members are nitrogen, or where one or two members are nitrogen and another member is O or S1 or where one member is O, S, S (O) or S (0) 2 and which may optionally be fused to a benzene ring. Examples of heterocyclyl groups include, and are not limited to

a, azetidinyl, 2H-pyrrol, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, 2-imidazolinyl (also referred to as 4,5-dihydro-1H-imidazolyl), imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl , tetrazolyl, tetrazolidinyl, piperidinyl, 1,4-dioxanyl, morpholinia, 1,4-dithianyl, thiomorpholinyl, piperazinyl, olive-panyl, 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-dihydroindolyl), 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 at any atom when permitted at available valencies.

By "benzofused heterocyclyl" is meant a heterocyclyl ring system radical having a benzene ring fused to the ring system on adjacent carbons. A benzofused heterocyclyl radical may be attached to a core molecule and further substituted at any atom when permitted at available valencies.

The term "aryl" refers to an unsaturated 6-membered carbon aromatic monocyclic ring or an unsaturated 10- to 14-membered aromatic polycyclic ring. Examples of such aryl rings include, and are not limited to, phenyl, naphthalenyl or anthracenyl.

The term "heteroaryl" refers to a 5- or 6-membered aromatic ring 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 may contain up to three additional nitrogen. In the case of 6-membered rings, the heteroaryl ring may contain from one to three nitrogen atoms. For the case where the 6-membered ring has three nitrogen, a maximum of two nitrogen atoms are adjacent. Optionally, the heteroaryl ring is fused to a benzene ring (fused benzo heteroaryl), a 5- or 6-membered heteroaryl ring (containing one of the S, N, and optionally an additional nitrogen), a cycloalkyl ring of 5 to 7 members or a 5 to 7 membered heterocycle ring (as defined above but lacking the option of an additional fused ring).

Examples of heteroaryl groups include, and are not limited to

a, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, 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, benzoyloxyzolazole benzoylazolez , purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl and the like. A heteroaryl radical may be attached to a core molecule and further substituted at any atom when permitted at available frequencies.

By "benzofused heteroaryl" is meant a heteroaryl ring system radical having a benzene ring fused to the ring system on adjacent carbons. A benzofused heteroaryl radical may be attached to a core molecule and further substituted at any atom when permitted at available valencies.

By "arylC 1-8 alkyl" is meant a radical of the formula: -C 1-8 alkyl aryl (e.g. benzyl, phenethyl). Similarly, the term "aryl-C 8 -alkyl> xi" means a radical of the formula: -Cvealcoxy-aryl (e.g. benzyloxy).

The term "C 3-14 Cyclo-C 1-8 alkylalkyl" means a radical of the formula: -C 1-8Cylo-C 3-14Cycloalkyl.

By "heterocyclylC 1-8 alkyl" is meant a radical of the formula: -C 1-8 alkylheterocyclyl.

By "heteroarylC 1-8 alkyl" is meant a radical of the formula: -C 1-8 alkylheteroaryl. By "C 1-8 alkylcarbonyl" is meant a radical of the formula: -C (O) -C 1-8 alkyl.

The term "C 1-6 alkoxycarbonyl" means a radical of the formula: -C (O) -C 1-8 alkoxy.

The term "arylcarbonyl" means a radical of the formula: -C (O) -

arila.

The term "aryl-C 1-8 alkylcarbonyl" means a radical of the formula: -C (O) -C 1-8 alkylaryl.

The term "arylC 1-8 alkoxycarbonyl" means a radical of the formula: -C (O) -C 1-8 alkoxy aryl.

The term 'R1-Cl-Saalkyl-N (R5) -Carbonyl' means a radical of the formula: -C (O) -N (R5) -C1-8 alkylaryl.

By "aryl-C 1-8 alkylsulfonyl" is meant a radical of the formula: -SC> 2-C 1-8 alkyl-aryl. The term "C1-8 alkyl-N (R5) -carbonyl" means a radical of the

formula: -C (O) -N (R 5) -C 1 -Salkyl.

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 chlorine, bromine, fluoro or iodine.

The term "halo C1-8 alkyl" means a radical of the formula: -C1-8 alkyl- (halo) n, wherein one or more halogen atoms may be substituted with C1-8 alkyl when permitted at available valencies (in (η represents this amount of available valencies based on the number of carbon atoms in the chain), and includes monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl and the like.

The definition of any substituent or variable at a particular location in a molecule is intended to be independent of its definitions elsewhere in that molecule. It is intended that substituents and substitution patterns on the compounds of this invention may be selected from that of ordinary skill in the art to provide compounds that are chemically stable and which can be easily synthesized by techniques known in the art as well as those. methods presented here.

By "substituted" is meant the independent substitution of one or more hydrogen atoms within a radical with this amount of substituents allowed on available valencies.

The term "dependently selected" means that structure variables are specified in a given combination.

In general, IUPAC naming rules are used here. Compound Forms The term "form" means, in reference to compounds of the present

invention so that it can 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

so that it can exist in an essentially pure state such as, without limitation, an enantiomer, a racemic mixture, a geometric isomer (such as a sis 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 as pharmaceutically acceptable salts. For use in medicaments, 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, saccharin acid, succinic acid, sulfuric acid, tartaric acid, trifluoroacetic acid and the like.

In addition, when the compounds of the present invention carry an acidic moiety, suitable salts thereof may include alkali metal salts, for example sodium or potassium salts; alkaline earth metal salts, for example, calcium or magnesium salts; and salts formed with suitable organic ligands, for example, quaternary ammonium salts.

Thus representative salts include the following: acetate,

adipate, ammonium, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, cansilate (or camphosulfonate), carbonate, chloride, clavulanate, citrate, dihydrochloride, edetylate, estolate, esylate, fumarate, glycolate, gluceptate, glutamate, glyconate, glycolylarylsanilate, hexyl resorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, malonate, mandate, mesylate, methylbromide, methylnate, methylnitrate, napsylate, nitrate, N-methylglycamine, oleate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, saccharate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, theoclate, tosylate, trichloroacetate thiodide, 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-dichloromatic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, acid benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+) - camphoric acid, camphorsulfonic acid, (+) - (1S) -canfor-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-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactic acid, gentisic acid, glycoeptonic acid, D-gluconic acid , D-glucuronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hypuric 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, acid 1 -hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, parmitic acid, pamic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino salicylic acid, sebacic 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, benetamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2- (diethylamino) ethanol, ethanolamine, ethylenediamine, N-methylglycine, 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.

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 which are readily convertible in vivo to the required compound. Thus, in the treatment methods of the present invention, the term "administration" will encompass the treatment of the various disorders described with the specifically described compound or with a compound that may not be specifically described but which converts to the compound. specified 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 thus exist as enantiomers. Where the compounds have two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are within the scope of the present invention. In addition, compounds of the present invention may have one or more crystalline polymorph or amorphous forms and, as such, are intended to be included within the scope of the invention. In addition, some of the compounds may form solvates with water (i.e. hydrates) or common organic solvents (for example, organic esters such as ethanolate and the like) and as such are also intended to be encompassed within the scope. scope of this invention.

Where processes for the preparation of the compounds according to the invention give rise to a 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 formation of diastereomeric pairs by salt formation with an optically active acid such as (-) - di-p acid. -toluoyl-d-tartaric and / or (+) - di-p-toluoyl-1-tartaric acid followed by fractional crystallization and free base regeneration. 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 preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved. This can be achieved by conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. verdee & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Protective groups may be removed at a convenient subsequent stage using methods known in the art.

Even though the compounds of the present invention (including pharmaceutically acceptable salts thereof and pharmaceutically acceptable solvates) may be administered alone, they will generally be administered in admixture with a carrier, excipient or pharmaceutical diluent selected for the intended routine of administration and pharmaceutical practice. or veterinary standard. Accordingly, 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 mixed with any binder, lubricant, suspending agent (s), suitable coating, and / or solubilizing agent (s).

Tablets or capsules of the compounds may be administered separately 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 general Formula (I) may 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 may be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. They may also be incorporated, at a concentration of from 1 to 10% by weight, in an ointment consisting of a white wax base or white soft paraffin together with such stabilizers and preservatives as may be required.

For some applications, preferably the compositions are orally administered as tablets containing excipients such as starch or lactose, or in capsules or ova or alone or in admixture with excipients, or as elixirs, solutions or suspensions containing flavoring or coloring agents.

The compositions (as well as the compounds alone) may also be injected parenterally, for example, intracavernously, intravenously, intramuscularly or subcutaneously. In this case, the compositions will comprise a suitable carrier 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 produce the isotonic solution with blood.

For buccal or sublingual administration, the compositions may be administered in the form of tablets or ozozanes which may 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 may be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to pharmaceutical composition techniques. conventional. The carrier may take a wide variety of forms depending on the desired administration routine (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 enteric coated to modulate the main absorption site. For parenteral administration, the carrier usually consists of sterile water and other ingredients may be added to increase solubility or preservation. Injectable suspensions or solutions may also be prepared using 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. In addition, compounds for the present invention may be administered intranasally by topical use of suitable intranasal vehicles, or by transdermal skin patches well known to those skilled in the art. To be administered in the form of a transdermal delivery system, dosage administration will, of course, be continuous rather than intermittent throughout the dosing 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. For this reason, optimal dosages to be administered may be readily determined and will vary with the particular compound used, the mode of administration, the intensity of the preparation, and the progression 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 the dose to an appropriate therapeutic level. The above dosages are thus exemplary of the average case. In that regard they may, of course, be examples of individuals where higher or lower dosage ranges are deserved, 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 patient in need thereof.

The invention also provides a pharmaceutical or veterinary package or kit comprising one or more containers loaded with one or more of the ingredients of the pharmaceutical and veterinary compositions of the invention. Optionally associated with such container (s) may be a notice in the form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceutical or biological products, the notice of which reflects approval by the manufacturing, use, or sale agency. human administration.

The present invention is also directed to a method for treating or ameliorating a urotensin II 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 whose disease or condition is affected by antagonism of a Urotensin II receptor whose method comprises administering to the mammal in need. of such treatment or prevention of an effective amount of a compound of Formula (I):

and forms of this in which

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-tetrahydropyridinyl;

Y is selected from the group consisting of CH2, O and S; Li is missing or is selected from the group consisting of -

C (O) O-R 1, -C (O) N (R 5) -R 1 and -NHC (O) -R 1; L 2 is C 1-8 alkyl;

L3 is absent or is -C (O) N (R5) -R7;

R 1 is selected from the group consisting of C 1-6 alkyl, C 1-8 alkoxy, aryl, aryl C 1-8 alkyl, C 3-14 Cycloalkyl, C 3-14 CycloC 1-8 alkylalkyl, heterocyclyl, heterocyclyl-C 1-8 alkyl, heteroaryl and heteroaryl C 1-8 alkyl ,

wherein C1-8 alkyl is optionally substituted with one, two or three substituents each selected from the group consisting of C1-8 alkoxy, halogen, hydroxy and -NHR6, wherein C1-8 alkoxy is optionally substituted with one, two or three.

three substituents each selected from the group consisting of C1-8 alkoxy, halogen, hydroxy and -NHR6,

wherein each example of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of C1-8 alkyl, C1-8 alkoxy, halogen and halo-C1-8 alkyl, and

wherein each example of heterocyclyl is optionally substituted by oxo, C1-8 alkylcarbonyl, C1-8 alkoxycarbonyl, C1-8 alkyl-N (R5) carbonyl, arylcarbonyl, aryl-C1-4 alkylcarbonyl, aryl -C 1-8 alkoxycarbonyl, aryl- N (R 5) -Carbonyl aryl-C 1-8 alkyl-N (R 5) -carbonyl or aryl-C 1-8 alkylsulfonyl;

R2 is one, two or three substituents each selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 alkoxy and halogen;

R3 is one, two or three substituents each selected from the group consisting of hydrogen and C-Malkyl;

R4 is one, two or three substituents each selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 alkoxy, hydroxy and halogen;

R5 is selected from the group consisting of hydrogen and C-i-

4alkyl;

R6 is selected from the group consisting of C1-8 alkylcarbonyl,

C 1-8 alkoxycarbonyl, C 1-8 alkyl-N (R 5) -carbonyl, arylcarbonyl, aryl-C 1-6 alkylcarbonyl, aryl-C 1-8 alkoxycarbonyl, aryl-N (R 5) -carbonyl, arylC- 8-N-alkyl (R5) -carbonyl and aryl-C1-8 alkylsulfonyl; and,

R7 is selected from the group consisting of C1-8 alkyl, aryl, aryl-C1-8 alkyl, C3-4 cycloalkyl, C6-cycloalkyl-C1-6 alkyl, heterocyclyl, heterocyclyl-C1-8 alkyl, heteroaryl and heteroaryl-C1-6 alkyl.

Another example of the method of the present invention is a method for treating or ameliorating an Urotensin II-mediated disorder in a patient in need thereof comprising administering to the patient an effective amount of a compound of Formula (I) or a form. of this one.

In particular, a Urotensin II-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 chemicals), renal dysfunction, renal failure, renal failure caused by drug-induced toxicity, nephrotoxicity and diarrhea caused by antineoplastic agents, nephrotoxicity caused by radiocontrast and aminoglycoside agents, post-infarction myocardium, pulmonary hypertension, pulmonary fibrosis, insulin resistance, and impaired glucose tolerance, diabetes, diabetic complications, diabetic nephropathy, pain, Alzheimer's disease, seizures, 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 II mediated disorder in a patient in need thereof.

An example of the present invention includes a method for treating or ameliorating a urotensin II-mediated disorder, wherein the disorder is heart failure.

The term "medicament" refers to a product for use in treating or ameliorating a urotensin II-mediated disorder.

The term "patient" as used herein refers to an animal, preferably a mammal, more 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 produces the biological or medical response in a tissue, animal or human system that is being targeted by a researcher, veterinarian, physician or another clinic, which includes relief from the symptoms of the disease or disorder being treated.

The effective amount of said compound or form thereof is

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 that 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 intended to include benign, i.e. noncancerous, and malignant, i.e. cancerous, growths. The term "neoplastic" is intended to or related to neoplasm.

As used herein, the term "agent" is intended to mean a substance that produces a desired effect on a tissue, system, animal, mammal (particularly human), or other patient. Thus, the term "anti-neoplastic agent" is intended to mean a substance production of an anti-neoplastic effect on a tissue, system, animal, mammal (in particular human), or another patient. It is intended that an "agent" may be a single compound or a combination or composition of two or more compounds.

Some of the typical antineoplastic agents include alkylating agents such as melphalan, chlorambucil, cyclophosphamide, mechlorethamine, hexamethylmelamine, busulfan, carmustine, lomustine, and dacarbazine; anticababolites such as 5-fluorouracil, methotrexate, cytarabine, mecaptopurine, and thioguanine; anti-mitotic agents such as paclitaxel, docetaxel, vinblastine, vincristine; topoisomerase I inhibitors such as irinotecan, camptothecin and camptothecin derivatives, for example topotecan; topoisomerase II inhibitors such as doxorubicin; and platinum coordination complexes such as cisplatin and carboplatin.

One embodiment of the present invention is a method for treating a UII-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 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. The present method of using Uro-receptor antagonists

Tensin II for reducing antineoplastic agent-induced diarrhea and nephrotoxicity is applicable in any situation when antineoplastic agents (such as cisplatin, cis-diaminadichloroplatin) are being administered to treat cancers or tumors. More often, however, Ull 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, tumors. ureterpielonephritic, prostate 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 the brain, endometrium, upper gastrointestinal tract, head and neck and thymus, neuro-blastoma and bone and soft tissue sarcoma.

Recent data have shown that urotensin II receptor antagonists may be useful for improving cardiac function and for cardiac modeling associated with chronic heart failure (CHF) (N. Bousette, F. Hu, H. H. Ohlstein, D. Dhanak Douglas SA, A. Giaid, Journal of Molecular and Cellular Cardiology 2006, Press). Long-term treatment of streptozotocin-induced diabetic rats with palosuran improved survival, increased insulin, and reduced increase in glycemia, glycosylated hemoglobin, and serum lipids. In addition, palosuran increased renal blood flow and delayed the development of proteinuria and renal injury (M. Clozel, P. Hess, C. Qiu, SS Ding, M. Rey, J. Pharmacol. Exp. Ther. 2006, 316 (3), 1115-1121).

A therapeutically effective amount for use of the present compounds or a pharmaceutical composition thereof comprises a dose range of from about 0.1 mg to about 3000 mg, in particular from about 1 mg to about 1000 mg or, e.g. more particularly from about 10 mg to about 500 mg of active ingredient on a regimen of about 1 to 4 times per day for an average human (70 kg); although it is apparent to one skilled in the art that the therapeutically effective amount for active compounds of the invention will vary as desired under the conditions being treated.

Optimal dosages of the compounds of Formula (I) to be administered for the treatment or prevention of Urethesterine II-mediated disorders can be readily determined by those skilled in the art, and will vary with the particular compound employed, the mode of administration of the invention. administration, the intensity of the preparation, and the progress 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 symptomatic dosage adjustment. to the patient to be treated.

A representative compound of Formula (I) or a form thereof

includes a compound selected from the group consisting of: Level 1 Cpt Name

1 2- {1 - [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) ethyl] -benzamide

piperidin-4-yl} -N-phenethyl benzamide,

2 N-benzyl-2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-one

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} - [N- (3-phenylpropyl) benzamide,

2- {1 - [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -benzamide

piperidin-4-yl} -N- (4-phenylbutyl) benzamide,

N-benzyl-N-methyl-2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-yl} -benzamide benzamide,

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-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-yl} -benzamide,

8 N- [2- (2-chloro-phenyl) -ethyl] -2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl ] -piperidin-4-yl} -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,

N- [2- (3,4-dimethoxy-phenyl) -ethyl] -2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -benzamide ethyl] piperidin-4-yl} benzamide,

11 N- [2- (3,4-dichloro-phenyl) -ethyl] -2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-yl} -benzamide, Level 1 Cpt Name

12 N- [2- (4-chloro-phenyl) -1-methyl-ethyl] -2- {1- [2- (3-oxo-2,3-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,

N- [2- (2-methoxy-phenyl) -ethyl] -2- {1- [2- (3-oxo-2,3-dihydro-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-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-yl} -benzamide,

18 N-methyl-2- {1 - [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -

ethyl] -piperidin-4-yl} -N-phenethyl-benzamide,

19 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,

21 N- [2- (3,5-difluoro-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-difluoro-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-difluoro-phenyl) ethyl] -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,

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,

26 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,

27 N-indan-1-yl-2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-2-one

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-phenyl-propyl) benzamide,

29 2- {1 - [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) ethyl] -benzamide

piperidin-4-yl} -N-propyl benzamide, Cpt Name

31 2- {1 - [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) ethyl] -benzamide

piperidin-4-yl} -N- (2-pyrrolidin-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-ylmethyl-N-methyl-2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-2-one 4-yl} benzamide,

34 N- (2- {1 - [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) ethyl] -benzamide

piperidin-4-yl} phenyl) -3-phenylpropionamide,

[4- (2- {1- [2- (3-oxo-2,3-acid) tert-butyl ester

dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) butyl] carbamic,

36 N- (2-Methoxy-ethyl) -2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-one il} benzamide,

37 N- (3-Methoxy-propyl) -2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-one il} benzamide,

38 N- (3-ethoxy-propyl) -2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-one il} benzamide,

39 N- (3-hydroxy-propyl) -2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-one il} benzamide,

40 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,

41 2- {1 - [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -

piperidin-4-yl} -N-pyridin-2-ylmethylbenzamide,

42 2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) ethyl] -benzamide

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,

2- {1 - [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -benzamide

piperidin-4-yl} -N-pyridin-4-ylmethylbenzamide,

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,

46 2- {1 - [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) ethyl] -benzamide

piperidin-4-yl} -N-thiophen-2-ylmethylbenzamide,

2- {1 - [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) ethyl] -benzamide

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] -benzamide piperidin-4-yl} benzamide, Cpt_Name_

N- (2-acetylamino-ethyl) -2- {1- [2- (3-oxo-2,3-dihydro-benzothl-1-oxazin-4-yl-ethyl-piperidin-1-yl-benzamide),

4 - [(2- {1 - [2- (3-oxo-2,3-acid) tert-butyl ester

dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) methyl] piperidine-1-carboxylic,

2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -acetamide

piperidin-4-yl} -N- [3- (2-oxo-pyrrolidin-1-yl) -propyl] -benzamide,

2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -benzamide

piperidin-4-yl} -N- (2-piperidin-1-yl-ethyl) benzamide,

4- (2- {4- [2- (3,4-dihydro-1H-isoquinoline-2-carbonyl) -phenyl] -acetamide

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-yl)

dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzamide,

N- [2- (3-naphthalen-1-yl-ureido) ethyl] -2- {1- [2- (3-oxo-2,3-yl)

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-acid) tert-butyl ester

2,3-dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) methyl] piperidine-1-carboxylic,

59 5-chloro-N, N-dimethyl-2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-one il} benzamide,

60 [4- (5-Chloro-2- {1- [2- (3-oxo-acid) tert-butyl ester

2,3-dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) butyl] carbamic,

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- (1H-indol-3-yl) ethyl] -2- {1- [2- (3-oxo-2,3-yl)

dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzamide,

63 - 4 - [(5-chloro-2- {1 - [2- (3-oxo-2,3-acid) benzyl ester

dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) methyl] piperidine-1-carboxylic, Level 1 Cpt Name

64 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,

65 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-2-one

4-yl} benzamide,

66 4- [2- (5-Chloro-2- {1 - [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -acetate tert-butyl ester ethyl] -piperidin-4-yl} -

benzoylamino) ethyl] piperazine-1-carboxylic,

67 - 4 - [(5-chloro-2- {1 - [2- (3-oxo-2,3-acid) benzylamide

dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) methyl] piperidine-1-carboxylic,

68 4- [2- (5-Chloro-2- {1 - [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -acetate-tert-butyl ester ethyl] -piperidin-4-yl} -

benzoylamino) ethyl] piperidine-1-carboxylic,

69 [4- (5-chloro-2- {1 - [2- (3-oxo-2,3-acid) benzyl ester

dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) butyl] carbamic,

70 [5- (5-chloro-2- {1- [2- (3-oxo-acid) tert-butyl ester

2,3-dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) pentyl] carbamic,

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-

ylmethyl) 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-acid) tert-butyl ester

2,3-dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) hexyl] carbamic,

75 [5- (5-chloro-2- {1 - [2- (3-oxo-2,3-acid) benzyl ester

dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) pentyl] carbamic,

76 5-chloro-N- [5- (3,3-dimethyl-butyrylamino) -pentyl] -2- {1 - [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-2-one 4-yl) ethyl] piperidin-4-yl} -

benzamide, Level 1 Cpt Name

77 N- [5- (3-benzyl ureido) pentyl] -5-chloro-2- {1- [2- (3-oxo-2,3-yl)

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,

{2- [2- (5-Chloro-2- {1 - [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) tert-butyl ester -ethyl] -piperidin-4-yl} -

benzoylamino) ethoxy] ethyl} carbamic,

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-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-2-oxo-tert-butyl) ester

3,4-dihydro-2H-quinolin-1-yl) ethyl] -piperidin-4-yl} -benzoylamino) -pentii] -carbamic,

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,

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-benzo [1,4] oxazin-3-

ona,

4- {2- [4- (4-Methoxy-phenyl) -piperidin-1-yl] -ethyl} -4H-

benzo [1,4] oxazin-3-one,

88 4- {2- [4- (3-fluoro-phenyl) -piperidin-1-yl] -ethyl} -4H-

benzo [1,4] oxazin-3-one,

89 4- {2- [4- (2-fluoro-phenyl) -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-

ona,

4- [2- (4-o-tolyl-piperidin-1-yl) ethyl] -4H-benzo [1,4] oxazin-3

ona, Level 1 Cpt Name__

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] -piperidin-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,

95 [5- (5-Chloro-2- {8- [2- (3-oxo-acid) tert-butyl ester

2,3-dihydro-benzo [1,4] oxazin-4-yl) ethyl] -8-aza-bicyclo [3.2.1] oct-2-en-3-yl} -benzoylamino) -pentyl] -carbamic ,

96 4- [2- (2- {8- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -8 acid tert-butyl ester -aza-bicyclo [3.2.1] octane

3-yl} -benzoylamino) -ethyl] -piperazine-1-carboxylic,

97 [5- (2- {8- [2- (3-Oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -8-aza acid tert-butyl ester bike [3.2.1] octane

3-yl} -benzoylamino) -pentyl] -carbamic,

98 [5- (2- {8- [2- (3-Oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -8-aza acid tert-butyl ester bike [3.2.1] octane

3-yl} -benzoylamino) -pentyl] -carbamic,

99 4- [2- (2- {2- [2- (3-Oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -8 acid tert-butyl ester -aza-bicyclo [3.2.1] octane

3-yl} -benzoylamino) -ethyl] -piperazine-1-carboxylic,

100 [5- (5-chloro-2- {8- [2- (3-oxo-oxo]

2,3-dihydro-benzo [1,4] oxazin-4-yl) ethyl] -8-aza-bicyclo [3.2.1] oct-3-yl} -benzoylamino) -pentyl] -carbamic,

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) acid tert-butyl ester -yl) -ethyl] -1,2,3,6-

tetrahydro-pyridin-4-yl} -benzoylamino) pentyl] -carbamic,

103 1- [2- (3-oxo-2,3-dihydroxy acid) dimethyl amide

benzo [1,4] oxazin-4-yl) ethyl] -4-phenylpiperidine-4-carboxylic,

104 1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -4-phenyl-piperidine-4-acid benzylamide

Carboxylic, Level 1 Cpt Name

105 1- [2- (3-Oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -4-phenyl-piperidine-4-acid phenethyl amide

carboxylic,

106 1- [2- (3-Oxo-2,3-dihydroxy acid) methyl-phenethyl amide

benzo [1,4] oxazin-4-yl) ethyl] -4-phenylpiperidine-4-carboxylic,

107 1- [2- (3-Oxo-2,3-dihydroxy) acid (3-phenylpropyl) -amide

benzo [1,4] oxazin-4-yl) ethyl] -4-phenylpiperidine-4-carboxylic,

108 1- [2- (3-Oxo-2,3-dihydroxy) acid (4-phenyl-butyl) -amide

benzo [1,4] oxazin-4-yl) ethyl] -4-phenylpiperidine-4-carboxylic,

109 4- (4-chloro-phenyl) -1 - [2- (3-oxo-2,3-acid) phenethyl amide

dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidine-4-carboxylic,

110 1- [2- (6-Chloro-3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -4- (4-chloro-phenyl) -acetamide piperidine-4-

carboxylic,

111 4- (4-Chloro-phenyl) -1 - [2- (6-methyl-3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -acetamide dimethylamide piperidine-4-

carboxylic,

112 4- (4-Chloro-phenyl) -1 - [2- (6-fluoro-3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -acetamide dimethylamide piperidine-4-

carboxylic,

113 4- (4-chloro-phenyl) -1 - [2- (3-oxo-2,3-acid) dimethylamide

dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidine-4-carboxylic,

114 4- (4-Chloro-phenyl) -1- [2- (3-oxo-2,3-dihydro-benzo [1,4] thiazin-4-yl) -ethyl] -piperidine-4-acid dimethylamide carboxylic,

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-1-one

3-one.

A compound of Formula (I) or a form thereof further includes a compound selected from the group consisting of: Level 2 Cpt Name

3- 2- {1 - [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl

piperidin-4-yl} -A / - (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, 26 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,

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-acid) tert-butyl ester

dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-yl} -benzoylamino) -butyl] -carbamic acid 50 - [(2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-yl} -benzoylamino) -methyl] -piperidine-1-carboxylic acid 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,

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-acid) tert-butyl ester

2,3-dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) methyl] piperidine-1-carboxylic,

60 [4- (5-Chloro-2- {1 - [2- (3-oxo-oxo-tert-butyl) ester

2,3-dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) butyl] carbamic,

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- (1H-indol-3-yl) ethyl] -2- {1- [2- (3-oxo-2,3-yl)

dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzamide,

63 - 4 - [(5-chloro-2- {1 - [2- (3-oxo-2,3-acid) benzyl ester

dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) methyl] piperidine-1-carboxylic,

64 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, Level 2 Cpt Name

65 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-2-one

4-yl} benzamide,

66 4- [2- (5-Chloro-2- {1 - [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -acetate tert-butyl ester ethyl] -piperidin-4-yl} -

benzoylamino) ethyl] piperazine-1-carboxylic,

67 - 4 - [(5-chloro-2- {1 - [2- (3-oxo-2,3-acid) benzylamide

dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) methyl] piperidine-1-carboxylic,

68 4- [2- (5-Chloro-2- {1 - [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -acetate-tert-butyl ester ethyl] -piperidin-4-yl} -

benzoylamino) ethyl] piperidine-1-carboxylic,

69 [4- (5-chloro-2- {1 - [2- (3-oxo-2,3-acid) benzyl ester

dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) butyl] carbamic,

70 [5- (5-chloro-2- {1 - [2- (3-oxo-acid) tert-butyl ester

2,3-dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) pentyl] carbamic,

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-

ylmethyl) benzamide,

74 [6- (5-Chloro-2- {1 - [2- (3-oxo-acid) tert-butyl ester

2,3-dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) hexyl] carbamic,

75 [5- (5-chloro-2- {1 - [2- (3-oxo-2,3-acid) benzyl ester

dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) pentyl] carbamic,

76 5-chloro-N- [5- (3,3-dimethyl-butyrylamino) -pentyl] -2- {1 - [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-2-one 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,

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, Level 2 Cpt Name

{2- [2- (5-Chloro-2- {1 - [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) tert-butyl ester -ethyl] -piperidin-4-yl} -

benzoylamino) ethoxy] ethyl} carbamic,

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-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-acid) tert-butyl ester

3,4-dihydro-2H-quinolin-1-yl) ethyl] piperidin-4-yl} benzoylamino) pentyl] carbamic,

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] - piperazyria-1-carboxylic, and

95 [5- (5-Chloro-2- {8- [2- (3-oxo-acid) tert-butyl ester

2,3-dihydro-benzo [1,4] oxazin-4-yl) ethyl] -8-aza-bicyclo [3.2.1] oct-2-en-3-yl} -benzoylamino) -pentyl] -carbamic .

SYNTHETIC METHODS

Representative compounds of the present invention may be synthesized according to the general synthetic Schemes described below and are more particularly illustrated in the following specific synthetic examples. 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 versatility of those skilled in the art. No attempt has been made to optimize the yields obtained in any of the example reactions. One of ordinary skill in the art would know how to increase such yields through variations of routin in reaction times, temperatures, solvents and / or reagents.

General: 1 H and 13 C NMR spectra were measured on a Bruker AC-300 (300 MHz) spectrometer using tetramethylsilane and the deuterated solvent respectively as internal standards. Elemental analyzes were obtained using Quantitative Technologies Inc. (Whitehouse, New Jersey) and the results were within 0.4% of the calculated values unless otherwise stated. Melting points were determined in open capillary tubes with a Mel-Temp II 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 spectrometer. And by fast atom bombardment (FAB) technique.

Terms used in describing the invention are commonly used and known to those skilled in the art. Abbreviations used in the present specification, particularly the Schemes and Examples, are co-

as follows: BAP borane-pyridine complex Boc tert-butoxycarbonyl BSA bovine serum albumin DCM dichloromethane DMF N, N-dimethylformamide DMSO dimethylsulfoxide DIPEA diisopropylethylamine Et2O diethyl ether EtOAc ethyl acetate EtOH ethanol hour (s) hexofluoride hexosulfate O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium HOBt hydroxybenzotriazole hydrate

HPLC High Performance Liquid Chromatography

HEPES 4- (2-hydroxyethyl) -1-piperazine-ethanesulfonic acid

Methanol MeOH

min minutes

MTBE methyl t-butyl ether

PdC4 dppf-CH2 Cl2 dichloromethane complex of [1,1'-

bis (diphenylphosphino) ferrocene] -dichloropalladium (ll) psi pounds per square inch

rt room temperature

SDS Sodium DodecassuIfate

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).

η H

H o ΗΛ L-Th

L! r4 lT2 I

Vn ^ X A2! no R

0T ^

A31 A3

'H0> V2

HO ^ 1 / V2

2

Hi, N ..,., VN

A4

l

γ

A5

THE

^ 2

O ^ N

A5 A commercially available heterocycle of Compound A1 may be reacted with a strong base such as sodium hydride and a readily available commercially available electrophile or Compound A2 wherein an appropriate leaving group (LG) is removed. Examples of suitable leaving groups include fluoride, bromide, iodide, triflate, mesylate, and the like.

The starting group of Compound A2 may be removed to produce Compound A3. The terminal olefin in Compound A3 may be converted to a carbonyl of Compound A5 either directly or via intermediate Compound A4.

For example, oxidation of Compound A3 with potassium (VI) osmate may release 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 preparation with a reductant such as dimethylsulfide or triphenylphosphine. The carbonyl of Compound A5 may be coupled to Compound A6 under reductive amination conditions to provide compounds of Formula (1> -1, representative of a compound of Formula (I).

Reductive amination conditions would include a reduction of reagents such as borane pyridine, sodium cyanoboroidide, sodium triacetoxyborohydride, and the like. Use of Brönsted or Lewis acids and a dehydrating 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 (R5) -R '.

B1 Boc B3 Boc Formula (1) -2

A commercially available or readily prepared carboxylic acid Compound B1 can be converted to a corresponding carboxamide Compound B3 by coupling to an Amine Compound B2 by standard amide coupling methods.

For example, coupling conditions of N-methylmorpholine, HOBt and HBTU may be used. The Boc group of Compound B3 may be removed with an acid such as hydrogen chloride or trifluoroacetic acid to provide Compound B4 free amine.

Reductive coupling of Compound B4 and Compound A5 by the methods described in General Scheme A for coupling of A6 and A5 may provide compounds of Formula (1) -2, representative of a compound of Formula (I). Scheme C

Scheme C describes the synthesis of certain compounds of the present invention wherein Li is a carboxamide substituent.

Q

The

H

C3 in General Scheme A. Compound C1 may be hydrolyzed to carboxylic acid Compound C2 with a base such as lithium hydroxide. Coupling of compound C2 to amine Compound C3 by methods described in General Scheme B for coupling Compound B1 and Compound B2 provides compounds of Formula (1) -3, representative of a compound of Formula (I).

Laughs

_ ^ NH2

C4 C5

A subgroup of amine Compound C3 are the primary amines of Compound C5. Compound C5 may be prepared by reducing 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.

Commercially available boronate compound D1 may be

coupled with a Compound D2, wherein LG may be a leaving group as previously defined or, for the reaction illustrated in this Scheme, 10.

15

when LG is bromide or triflate. 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 performed with hydrogen and a catalyst such as platinum (IV) oxide. Deprotection of the Boc group in Compound D4 may 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 Formula (l) -3 structures is performed by the sequence described in Scheme C.

Scheme E

Scheme E describes the synthesis of compounds wherein vinyl boronate within Ring A needs to be prepared.

XO

20

Formula (l) -4

A Boc-protected Compound E1 can be converted to vinyl boronate Compound E2 (as described in PR Eastwood, Tetrahedron Lett., 2000, 41, 3705; and S. Ghosh, WA Kinney, DA Gauthier, EC Lawson, T. Hudlicky, E. E. Maryanoff., Can. J. Chem. 2006, 84, 555-560).

Conversion of Compound E2 to structures of Formula (1) -4 is performed by the methods described in General Scheme D for the conversion of compound D1 to Formula (1) -3 of final product. The double bond of Ring A in Compound E3 may be retained (by skipping the reduction step as described for conversion of Compound D3 to Compound D4 in Scheme D) and the sequence continues analogously to release products of Formula (1) -4 in Ring A contains a double bond.

Compound E4 using the procedure described in Scheme D and taken through the remaining steps to release products of Formula (1) -4 wherein Ring A is saturated, representative of a compound of Formula (I). The acid moiety of Compound E4 may be functionalized using the procedures shown in Scheme C and Scheme F, as well as 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 in a ketone.

Alternatively, Compound E3 may be hydrogenated to produce

F2 Boc

E4 Boc

F1 Boc

Formula (l) -5

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 performed using the procedure for coupling Compound B1 and Compound B2 to Scheme B. Compound F2 is then deprotected as described in Scheme B to produce Compound F3.

Reductive amination of ketone Compound F4 with Compound F3 is achieved by use of a pure Lewis acid such as heating titanium (IV) isopropoxide. The reaction mixture is then treated by a hydride source such as sodium borohydride in an alcoholic solvent to provide a compound of Formula (1) -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-Acid methyl ester - (3-oxo-2,3-dihydro-benzol [1,4] oxain-4-yl-ethyl] -piperidin-4-yl-benzoic (Compound 93)

H NaH, DMF1

O ^ N ^^ aiiyi bromide, K3 Fe (CN) 61K2OsO4 - H2O1

the ^ 1

1-1

ovemight K2C03 · '-Bu0H / H20

(96%)

1-2

HO ^

HO ^

, No.

NaIO4, Me0H / H2O

^ CHO N ^ O

O '1-4

Ό

1-3

Caption: allyl bromide / overnight

Step 1. Synthesis of 4-Allyl-4β-benzon.41oxazin-3-one (Compound 1-2).

Compound 1-1 (5.06 g, 34 mmol) was dissolved in DMF (200 mL) and cooled to 4 ° C in an ice bath. To this solution was added 95% sodium hydride (946 mg, 39 mmol) in three equal parts maintaining the temperature at 40 ° C. Stirring was continued on the ice bath for 30 min before the dropwise addition of allyl bromide (3.23 ml, 37 mmol) via an addition funnel. The reaction mixture was stirred (20h), allowing the mixture to reach room temperature. The reaction mixture was then slowly poured into ice-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 (2 x 50 mL) and brine (1 x 100 mL), then dried over Na 2 SO 4; and concentrated to produce a glassy oil. The compound was purified on silica gel (elution with 25% EtOAc in hexane) to yield compound 1-2 (5.2 g, 28 mmol, 82%). 1H NMR (300 MHz, CDCl3) δ 6.95 (s, 4H), 5.89 to 5.78 (m, 1H), 5.21 to 5.17 (m, 2H), 4.57 (s, 2H), 4.51 to 4.45 (m, 2H); MS (ES +) mlz 190.1 (M + 1). Step 2. Synthesis of 4- (2,3-dihydroxypropyl) -4H-benzo [1,41oxazin-3-one (Compound 1-3).

A solution of potassium carbonate (4.40 g, 32 mmol), K3 Fe (CN) 6 (10.5 g, 32 mmol), and K2OsO4H2O (195 mg, 0.53 mmol) in t-Bu0H / H2 O (12 1/1 mL) was prepared in a 200 mL round bottom flask. The mixture was cooled in an ice bath, then a solution of compound 1-2 (2.0 g, 11 mmol) in f-BuOH / H2 O (12 mL of 1/1) was added in 40 ° C and The reaction mixture was allowed to stir for 24 h while warming to room temperature. The reaction mixture was poured into EtOAc (100 mL) and washed with 2 N hydrochloric acid solution (5 x 75 mL). The organic layer was dried over Na 2 SO 4, concentrated, and purified on silica gel (elution with 90: 9: 1 dichloromethane / methanol / ammonium hydroxide) to yield compound 1-3 (2.2 g, 96%) as a solid. glassy type oil. 1 H NMR (300 MHz 1 CDCl 3) δ 7.20 to 7.16 (m, 1H), 7.07 to 6.98 (m, 3H), 4.60 (s, 2H), 4.20 to 3 ,. 92 (m, 3H), 3.72 to 3.56 (m, 2H); MS (ES +) mlz 224.1 (M + 1).

Step 3. Synthesis of (3-oxo-2,3-dihydro-benzof1,41oxoxin-4-oxo-acetaldehyde (Compound 1-4).

Compound 1-3 (1.69 g, 7.58 mmol) was dissolved in MeOH (126 ° C).

mL) and H 2 O (25 mL) in a 300 mL round bottom flask at room temperature and treated with NaIO 4 (4.86 g, 23.0 mmol). After 2h, 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 afford Compound 1-4 as a white solid (1 23 g, 83%, melting point = 97.1 to 98.0 ° C). 1H NMR (500 MHz, CDCl3) δ 9.68 (s, 1H), 7.04 to 7.00 (m, 3H), 6.68 to 6.65 (m, 1H), 4.73 (s, 2H), 4.70 (s, 2H); 13 C NMR (125 MHz, CDCl 3) 195, 165.2, 145.3, 128.7, 124.7, 123.2, 117.6, 114.7, 67.6, 51.2; Analysis Calculated for C 10 H 9 NO 3: C, 62.82; H, 4.74; N, 7.33. Found: C, 62.85; H, 4.46; N, 7.22.

Step 4. Synthesis of 4- (2-oxo-propyl) -4H-benzo [1,41oxazin-3-one (Compound

rank 1-2 with the exception that 3-chloro-2-methylpropene was used instead of allyl bromide. Ozone was bubbled through an ice-solution (-70 ° C) of Compound 1-5 (30.0 g, 147 mmol) and Sudan III (trace) in dichloromethane (450 mL) for 1.5 h. Triphenylphosphine (46.3 g, 177 mmol) was added at a rate where the internal temperature was maintained at -70 ° C. The resulting solution was stirred at -70 ° C for 30 min, warmed to room temperature, and stirred for 1 h. Volatile materials were removed by evaporation to yield a crude residue, which was dissolved in dichloromethane and applied to a flash column for purification (1.36 kg 230-400 mesh silica gel, gradient elution with 0% EtOAc. 30% in hexane). Evaporation of appropriate fractions afforded Compound 1-6 as a white solid (13.0 g, 43%, melting point 74 to 76 ° C). 1H

NMR (300 MHz, CDCl 3) δ 7.04 to 6.95 (m, 3H), 6.64 to 6.59 (m, 1H), 4.69 (s, 4H), 2.26 (s, 3H ); 13 C NMR (75 Hz, CDCl 3) 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 +) mlz 206.1 (M + 1);

THE

1-5

1-6

m

Compound 1-5 was prepared by the same method as with Comp. Analysis calculated for C 11 H 11 NO 3: C, 64.38; H, 5.40; N, 6.83. Found:

C, 64.23; H, 5.12; N1 6.75.

Il 0

1I S

^ YNfO D O3, MeOH -78 ° C ^^^

1-7

2) DMS (60%)

1-8

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 used instead of Compound 1-1. Ozone (0.56 kg / cm 2) was slowly bubbled into an ice solution (-78 ° C) of Compound 1-7 (10 g, 54 mmol) in methanol (535 mL) for 90 min while the solution changed yellow to blue-green. Oxygen was bubbled through the solution until the solution turned yellow, and then dimethyl sulfide (5.3 mL, 73 mmol) was added dropwise at such a rate that the internal temperature was maintained at -78 ° C. The resulting solution was kept at 30 ° C for 18 h, then warmed to room temperature. The solvent was evaporated to yield a crude product, which was purified by silica gel column chromatography (gradient elution with 10 to -50% EtOAc in hexane). Evaporation of the appropriate fractions yielded 9 g of an oil which was treated with tetrahydrofuran (150 mL), water (50 mL), and 4 M HCl (20 mL). The resulting mixture was stirred for 1h at room temperature and treated with MTBE. The organic layer was washed with water, dried over sodium sulfate, filtered, and evaporated to yield a clear oil which was treated a second time with THF, water and 4 M HCl, and stirred for 2 h. Extraction again with MTBE, washing, drying, and evaporation provided Compound 1-8 as an oil (6.1 g, 60%). 1H NMR (300 MHz, CDCl3) δ 9.65 (s, 1H), 7.24 to 7.16 (m, 2H), 7.06 to 7.00 (m, 1H), 6.67 (d, J = 9.3 Hz, 1H), 4.71 (s, 2H), 3.01 to 2.95 (m, 2H), 2.77 to 2.71 (m, 2H); 13 C NMR (75Hz, CDCl 3) 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 +) mlz 190.11 (M + 1).

ΟΗΠ

THE

1-9 NHHCl

Borane pyridine complex,

N

EtOH (57%)

1-4

THE

Cpd 86

10

15

Caption: Borane Pyridine Complex

Step 6. Synthesis of 4-R 2- (4-phenyl-piperidin-1-yl) -ethyl-4H-benzo [1,4loxazin-3-one (Compound 86).

1993, to a solution of Compound 1-9 of 4-phenylpiperidine hydrochloride (290 mg, 1.5 mmol) and Compound 1-4 (300 mg, 1.5 mmol) in 10 mL of absolute ethanol was added BAP (154 pL, 1.5 mmol). After stirring for 2 hours, an additional equivalent of aldehyde Compound 1-4 and BAP was added. The reaction mixture was stirred overnight and concentrated to yield an oily residue. The residue was taken up in DCM, washed with saturated NaHCO 3 sodium bicarbonate solution and brine, dried over Na 2 SO 4, and concentrated. The residue was purified on silica gel (elution with 30% EtOAc in hexane) to yield Compound 86 as a glassy oil (287 mg, 57%) of a glassy oil. 1H NMR (300 MHz, CDCl3) δ 7.25 to 7.11 (m, 5H), 7.04 to 6.91 (m, 4H), 4.53 (s, 2H), 4.04 (m, 2H), 3.04 (m, 2H), 2.58 (m, 2H), 2.45 to 2.40 (m, 1H), 2.15 (t of d, J = 11 and 3 Hz, 2H), 1.83 to 1.64 (m, 4H); MS (ES +) mlz 337.2 (M + 1); Analysis Calculated for C21 H24 N2 O2 0.51 H2 O: C, 73.02; H, 7.29; N, 8.11. Found: C, 72.98; H, 7.11; N, 8.00.

Following the procedure of Synthetic Comm. 23 (6), 789-795, Xjo

Cpd 93

Caption: Compound 93

Step 7. Synthesis of 2-1- [2- (3-oxo-2,3-dihydro-benzo], 41-oxain-4-yl-ethin-piperidin-4-yl-benzoic acid methyl ester (compound 93).

Compound 93 was synthesized in the same manner as Compound 86 except that 2- (piperidin-4-yl) benzoic acid methyl ester was used instead of Compound 1-9 as a starting material. Compound 93 was purified on silica gel (elution with 50% EtOAc in hexane) to provide a glassy oil (25%). 1H NMR (300 MHz1 CDCl3) δ 7.77 (d, J = 7 Hz, 1H), 7.46 to 7.40 (m, 2H), 7.08 (m, 1H), 7.05 to 7, 00 (m, 4H), 4.60 (s, 2H), 4.12 (m, 2H), 3.89 (s, 3H), 3.42 to 3.31 (m, 1H), 3.12 (m, 2H), 2.69 (m, 2H), 2.27 (t of d, J = 11 and 3 Hz, 2H), 1.85 to 1.73 (m, 4H); MS (ES +) mlz 395.2 (M + 1).

Using the procedure of Example 1, other representative compounds of the present invention may be prepared: Cpt_Nome_MS

85 4- {2- [4- (4-chloro-phenyl) -piperidin-1-yl] -ethyl} -4H-371.2

benzo [1,4] oxazin-3-one

4- {2- [4- (4-Methoxy-phenyl) -piperidin-1-yl] -ethyl} -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-yl] -ethyl} -4H-355.2

benzo [1,4] oxazin-3-one

90 4- [2- (4-p-tolyl-piperidin-1-yl) ethyl] -4H-benzo [1,4] oxazin-3- 351.3

one

4- [2- (4-o-tolyl-piperidin-1-yl) ethyl] -4H-benzo [1,4] oxazin-3- 351.1

Cpt 92

Name

4- {2- [4- (3-chloro-phenyl) -piperidin-1-yl] -ethyl} -4H-benzo [1,4] oxazin-3-one

MS 371.2

Example 2

4- (4-chloro-phenyl) -1- [2- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) -acetic acid dimethylamide

ethyl] piperidine-4-carboxylic (Compound 115) Cl.

1 H-NMM, HOBt, HBTU,

dimethylamine, DMF, 18 h

(94%;

1-8

4M HCI / dioxane,

\ 1h (82%)

N

, N

Cpd 115

Caption: Dimethylamine / dioxane Step 1. Synthesis of 4- (4-Chlorophenyl) -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 cooled to a bath temperature Ice 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 to room temperature overnight, 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 Na 2 SO 4 and concentrated to afford Compound 2-2 (6.1 g, 17 mmol, 94%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.32 (d, J = 9 Hz1 2Η), 7.17 (d, J = 9 Hz, 2Η), 4.2 to 3.8 (br m, 2H ), 3.0 to 2.6 (br m, 2H), 2.96 (s, 3H), 2.80 (s, 3H), 2.25 (m, 2H), 2.1 to 1.7 (br m, 2H), 1.45 (s, 9H). 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 hydrogen chloride.

4 M hydrogen in dioxane (5 ml) and stirred at room temperature for 1 h. Concentration in vacuo afforded Compound 2-3-HCl (4.2 g, 14 mmol, 82%) as a white solid, which is employed below without purification. MS (ES +) mlz 267.1 (M + 1); Analysis Calculated for C 14 H 19 ClN 2 O-HCl-H 2 O; 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-r2- (2-oxo-3,4-dihydro-2H-guinolin-1-ID-ethyl-piperidine-4-carboxylic acid dimethylamide (compound 115) .

Compound 115 was prepared by the same method as Compound 86 except that Compound 2-3 was used instead of Compound 1-9 and Compound 1-8 was used instead of Compound 1-4. Compound 115 was isolated as a white solid (53%, melting point 243 at 245 ° C). 1H (300 MHz, CDCl3) δ 7.44 to 7.01 (m, 8H), 4.55 (m, 2H), 3.62 (m, 2H), 3.31 to 2.40 (m, 18H); MS (ES +) mlz 440.0 (M +1).

Using the procedure of Example 2, other compounds represented

The formulants of the present invention may be prepared:

Comp. MS Name

103 1- [2- (3-Oxo-2,3-dihydro-408.1 benzo [1,4] oxazin-4-yl) -ethyl] -4-phenylpiperidine-4-carboxylic acid dimethyl amide

104 1- [2- (3-oxo-2,3-dihydro-470.2 benzo [1,4] oxazin-4-yl) ethyl] -4-phenylpiperidine-4-carboxylic acid benzylamide

105 1- [2- (3-oxo-2,3-dihydro-484,3 benzo [1,4] oxazin-4-yl) ethyl] -4-phenylpiperidine-4-carboxylic acid phenethyl amide

106 1- [2- (3-Oxo-2,3-dihydro-498.1-benzo [1,4] oxazin-4-yl) -ethyl] -4-phenyl-piperidin-4-acid methylphenethyl-amide -carboxylic

107 1- [2- (3-Oxo-2,3-dihydro-498.1 benzo [1,4] oxazin-4-yl) ethyl] -4-phenyl acid (3-phenyl-propyl) -amide -piperidine-4-carboxylic

108 1- [2- (3-Oxo-2,3-dihydro-512.3 benzo [1,4] oxazin-4-yl) -ethyl] -4-phenyl acid (4-phenyl-butyl) -amide -piperidine-4-carboxylic

109 4- (4-chloro-phenyl) -1 - [2- (3-oxo-2,3-518,2-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] phenethyl amide -piperidine-4-carboxylic Comp. 110

Name

MS

1- [2- (6-Chloro-3-oxo-2,3-dihydro-476,2-benzo [1,4] oxazin-4-yl) -ethyl] -4- (4-chloro-phenyl) acid dimethylamide ) -piperidine-4-

carboxylic

111 4- (4-Chloro-phenyl) -1- [2- (6-methyl-3-456.1-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -acetamide dimethylamide ethyl] piperidine-4-

carboxylic

112 4- (4-Chloro-phenyl) -1 - [2- (6-fluoro-3-460-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] dimethylamide -piperidine-4-

carboxylic

113 4- (4-Chloro-phenyl) -1 - [2- (3-oxo-2,3-442,2-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidine acid dimethylamide -4-carboxylic

114 4- (4-Chloro-phenyl) -1 - [2- (3-oxo-2,3-458-dihydro-benzo [1,4] thiazin-4-yl) -ethyl] -piperidine-4-acid dimethylamide -carboxylic

Example 3

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)

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)

CO2Me

LiOH H2O1 THF / H2 O (98%)

Cpd 93

NMM, HOBt, HBTU, DMF,

phenylpropyl amine (64%)

Caption: phenylpropyl amine Step 1. Synthesis of 2- (1-R 2- (3-oxo-2,3-dihydro-benzon, 41oxazin-4-ID-ethin-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} -acetic acid methyl ester compound 93 Benzoic acid (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 at 40 ° C for 24 h, cooled to room temperature, adjusted to pH 3 with 1N HCl, and concentrated in vacuo. Purification by Gilson HPLC (10 to 90 gradient elution of H2O with 0.2% TFA buffer / acetonitrile with 0.1% TFA buffer) provided Compound 3-1 as a white solid (1.45 g , 2.93 mmol, 98%). 1H NMR (300 MHz, CDCl3) δ 8.71 (d, J = 5 Hz, 1H), 7.92 (m, 1H), 7.59-7 to 43 (m, 2H), 7.32 to 7 , 22 (m, 1H), 7.14 to 6.89 (m, 3H), 4.62 (s, 2H), 3.97 to 3.68 (m, 2H), 3.45 to 2.94 (m, 4H), 2.71 to 2.33 (m, 3H), 2.13 to 1.96 (m, 2H), 1.80 to 1.65 (m, 2H); MS (ES +) mlz 381.1 (M + 1). Step 2. Synthesis of 2- (1-R2- (3-oxo-2,3-dihydro-benzoH.41oxazin-4-yl) -ethyl-piperidin-4-yl) - N - (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 μί, 1.5 mmol), 1-hydroxybenzotriazole (6.3 mg, 0.047 mmol). ), and phenylpropylamine (70 μί, 0.49 mmol). The reaction mixture was cooled to 40 ° C in an ice bath, treated with HBTU (280 mg, 0.74 mmol), and stirred overnight, allowing it to warm to room temperature. The reaction mixture was poured into EtOAc (50 mL) and washed with 1 N sodium hydroxide solution (3x), 1 N hydrochloric acid solution (3x), and brine. The organic layer was dried over Na 2 SO 4 and concentrated to yield a crude product, which was purified on silica gel (elution with 90% EtOAc in hexane) to yield Compound 3 (125 mg, 0.25 mmol, 64%). ) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.37 to 6.98 (m, 13H), 5.97 (t, J = 6 Hz, 1H), 4.56 (s, 2H), 4.09 (t , J = 7Hz, 2H), 3.45 (t, J = 7Hz, 2H), 3.10 to 2.93 (m, 3H), 2.74 to 2.61 (m, 4H), 2 27 (t d, J = 8 and 3 Hz, 2H), 2.02 to 1.83 (m, 6H); MS (ES +) mlz 498.3 (M + 1); Analysis Calculated for C 31 H 35 N 3 O 3 -Ol H 2 O-0.62 HCl: 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.

Step 3. Synthesis of 2-Naphthalen-2-yl-ethylamine (Compound 3-3V

Non-commercially available arylethylamines were produced by the following procedure. 2-Naphthylacetonitrile Compound 3-2 (16.7 g, 0.10 mol) in anhydrous tetrahydrofuran (50 mL) was added to 1 M solution of BH3-THF (250 mL, 0.25 mol) over 10 min at room temperature. environment. The reaction proceeds with an induction period of 2 to 4 min. Following the addition, the mixture was heated under reflux and under argon for one hour (TLC of an extinguished aliquot showed no starting material). The reaction was cooled in an ice bath and 10% aqueous HCl (150 mL) was cautiously added 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 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 smaller volumes of the aqueous layer and simplifies amine extraction) and extracted with diethyl ether (4 x 250 mL). . The organic layer was washed with brine (50 mL), dried over sodium sulfate, and evaporated under reduced pressure below 40 ° C. The solvent was not completely removed to prevent product loss. TLC (85:15 CH-CI 3 Z MeOH, 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 volume of 300 mL. The white precipitate was collected by filtration, washed with ether, and vacuum dried to provide Compound 3-3 (22.3 g, 85%) as the oxalate salt (mp = 191 to 193 ° C). Analysis Calculated for C 12 H 13 N · 0.85 C 2 O 4 H 2: C, 66.42; H 5.98. Found: C, 66.67; H, 6.05. Compound 3-3 free base: 1H NMR (300 MHz, CDCl3) δ 7.83 to 7.77 (m, 3H), 7.65 (s, 1H), 7.49 to 7.40 (m, 2H) , 7.34 (d of d, J = 8.5 and 1.6 Hz, 1H), 3.06 (t, J = 7 Hz, 2H), 2.92 (t, J = 7 Hz, 2H) . Step 4. Synthesis of N- (2-Naphthalen-2-yl-ethin-2- {1- (2- (3-oxo-2,3-dihydro-benzo), 41-oxazin-4-yn-piperidin-4-yl) benzamide (Compound 20).

Compound 20 was prepared by the method of step 2 above except that Compound 3-3 was used instead of phenylpropylamine. MS (ES +) mlz 534.4 (M + 1).

Using the procedure of Example 3, other representative compounds of the present invention may be prepared:

Comp. MS Name

1 2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] - 484.4

piperidin-4-yl} -N-phenethyl benzamide

2 N-benzyl-2- {1 - [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -470.2

ethyl] -piperidin-4-yl} -benzamide

2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -512.4

piperidin-4-yl} -N- (4-phenylbutyl) benzamide

N-benzyl-N-methyl-2- {1- [2- (3-oxo-2,3-dihydro-484.4 benzo [1,4] oxazin-4-yl) ethyl] piperidin-4 il} benzamide

6 N- [2- (3-methoxy-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 -yl) 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) ethyl] -2- {1- [2- (3-oxo-2,3-dihydro-518 benzo [1,4] oxazin-4-yl) -benzamide ethyl] -piperidin-4-yl} -benzamide

N- [2- (3,4-dimethoxy-phenyl) ethyl] -2- {1- [2- (3-oxo-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-dihydro-532

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-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

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 Comp. MS Name

16 N- [2- (4-fluoro-phenyl) -ethyl] -2- {1- [2- (3-oxo-2,3-dihydro-502 benzo [1,4] oxazin-4-yl) -benzamide 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-Methyl-2- {1 - [2- (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-oxo-2,3-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

23 N- [2- (2,3-difluoro-phenyl) ethyl] -2- {1- [2- (3-oxo-2,3-dihydro-520.1 benzo [1,4] oxazin-4 -yl) ethyl] 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 benzamide

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-1-yl-2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4- 496.2

yl) ethyl] piperidin-4-yl} benzamide

2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-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

2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -477.2

piperidin-4-yl} -N- (2-pyrrolidin-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 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) ethyl] -483.8

piperidin-4-yl} phenyl) -3-phenylpropionamide

N- [2- (4-bromo-phenyl) -ethyl] -2- {1- [2- (3-oxo-2,3-dihydro-563.6 benzo [1,4] oxazin-4-yl ) -ethyl] -piperidin-4-yl} -benzamide Comp. MS Name

[4- (2- {1- [2- (3-Oxo-2,3-dihydro-551,7-acid) tert-butyl ester

benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) butyl] carbamic

36 N- (2-methoxy-ethyl) -2- {1- [2- (3-oxo-2,3-dihydro-438,3 benzo [1,4] oxazin-4-yl) -ethyl] -piperidin -4-yl} benzamide

37 N- (3-methoxypropyl) -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-hydroxypropyl) -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

42 2- {1 - [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) ethyl] -485.6

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] -471.2

piperidin-4-yl} -N-pyridin-3-ylmethyl benzamide

2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -470.8

piperidin-4-yl} -N-pyridin-4-ylmethyl benzamide

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

piperidin-4-yl} -N-thiophen-2-ylmethyl benzamide

2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -490.2

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-488.2 benzo [1,4] oxazin-4-yl) -benzamide ethyl] -piperidin-4-yl} -benzamide

49 N- (2-acetylaminoethyl) -2- {1- [2- (3-oxo-2,3-dihydro-465 benzo [1,4] oxazin-4-yl) ethyl] piperidin-4 -yl} -benzamide

4 - [(2- {1- [2- (3-Oxo-2,3-dihydro-577.4 benzo [1,4] oxazin-4-yl) -ethyl] -acetic acid tert-butyl ester piperidin-4-yl} -benzoylamino) -

methyl] piperidine-1-carboxylic

2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -5,55-piperidin-4-yl} -N- [3 - (2-oxo-pyrrolidin-1-yl) -propyl] -benzamide

2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -491.5

piperidin-4-yl} -N- (2-piperidin-1-yl-ethyl) benzamide Comp.

Name

MS

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-dihydro-592.2

benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzamide

N- [2- (3-naphthalen-1-yl-ureido) ethyl] -2- {1- [2- (3-oxo-2,3-dihydro-592.2

benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzamide

Example 4

4- [2- (5-chloro-2- {1- [2- (3-oxo-2,3-dihydroxy) -acetyl tert-butyl ester

benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) ethyl] piperazine-1

carboxylic acid (Compound 66)

Cl

cV0

COOMe

'N 4-1 Boc

PdCl 2 Clppf, K 2 CO 3, DMF, 90 ° C, 5 h (60%)

COOMe

PtO2, H2

(1: 1) EtOH / AcOH, h (93%)

COOMe

HCl in dioxane, h (93%)

COOMe

1-4 ^ CHO

CLT

Me4NBH (OAc) 3,

DCE1 TEA, 4 h (74%)

COOMe 3N NaOH, MeOH,

COOH

4-6

BocN

N

4-8

NH5

HOBT, HBTU, NMM1 DMF

O ^ N.

XO

Cpd 66

Caption: HCl in dioxane Step 1. Synthesis of 4- (4-Chloro-2-methoxycarbonyl-phenyl) -3,6-dihydro-2H-pyridine-1-carboxylic acid tert-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), boronate Compound 4-1 (6.00 g, 19.4 mmol), PdCl 2 dppf-CH 2 Cl 2 (1.06 g, 1.30 mmol) and K 2 CO 3 (8.9 g, 58.21 mmol) in DMF and EtOH (4: 1, 90 mL) were prepared in a thick wall tube. . The mixture was stirred under argon at room temperature for 5 to 10 min and the tube was closed and heated at 90 ° C for 5 h (4 to 16 h for other examples). The mixture was cooled to room temperature then filtered through a pad of Celite®, washing with EtOAc. The solvent was evaporated and purified by flash chromatography (gradient elution with 50% 5-EtOAc in heptane with 0.1% TEA). Compound 4-3 of desired product was isolated as yellow liquid (4.05 g, 60%). 1H NMR (300 MHz, CDCl3) 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 +) mlz 374.0 (M + Na).

Step 2. Synthesis of 4- (4-Chloro-2-methoxycarbonyl-phenyl) -piperidine-1-carboxylic acid tert-butyl ester (Compound 4-4). Compound 4-3 (2.73 g, 7.76 mmol), EtOH / AcOH (1: 1, 60 mL) and

PtO 2 (0.895 g) was stirred in a Parr apparatus (15 psig hydrogen) for 10 h. The reaction mixture was filtered through Celite®, washing with ethanol. The solution was concentrated, and the residue was diluted with dichloromethane and washed with saturated NaHCO 3. The aqueous layer was again extracted with dichloromethane, and the combined organic layers were dried over anhydrous Na 2 SO 4, filtered and concentrated. The product was purified by flash chromatography (gradient elution with 50% ethyl acetate (0.1% TEA) in heptane. Compound 4-4 of desired product was isolated as thick colorless oil (2.55 g, 93%) 1 H NMR (300 MHz, CDCl 3) δ 7.79 (d, J = 2.3 Hz, 1H), 7.43 (d of d, J = 8.5 and 2.3 Hz1 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 to 1.5 (m, 4H), 1.48 (s, 9H) MS (ES +) m / z 253.8 (M-Boc + 1) HRMS (FAB +) Calculated for C 18 H 23 CINO 4: 352.1316 Found: 352.1329 Step 3. Synthesis of 5-Chloro-2-pyridin-4-yl-benzoic acid methyl ester (Compound 4-5).

Compound 4-4 (40 mg, 0.11 mmol), dioxane (3 mL), 4N HCl in dioxane (3 mL) and a drop of anisole was added and stirred at room temperature for 2 h. 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 +) mlz 253.7 (M + 1).

Step 4. Synthesis of 5-Chloro-2- (1- (2- (3-oxo-2,3-dihydro-benzoH. 41oxazin-4-yl) -etin-piperidin-4-yl) -benzoic acid methyl ester (Compound 4-6).

Intermediate 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 HCl salt of compound 4-5 to yield the free amine.

Benzoxazinone aldehyde compound 1-4 (0.52 g, 2.8 mmol) was added at room temperature and stirring was continued for 45 min. Tetramethylammonium triacetoxyborohydride was added and the reaction mixture was stirred for 2 h, quenched with NH40H / H20 (1: 1, 5 mL), washed with NH40H: H20 (1: 1, 2 χ 10 mL), dried over anhydrous Na 2 SO 4, filtered, concentrated and purified by flash chromatography (gradient elution with 25-100% EtOAc in 0.1% TEA heptane). Product Compound 4-6 was isolated as white solid (0.86 g, 74%). 1H NMR (300 MHz, CDCl3) δ 7.77 (m, 1H), 7.45 to 7.30 (m, 2H), 7.07 to 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 to 1.6 (m, 4H); MS (ES +) mlz 429.0 (M + 1). Step 5. Synthesis of 5-Chloro-2-R1- (2- (3-oxo-2,3-dihydro-benzo1,41oxazin-4-yl) -ethyl-piperidin-4-yl] -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 room temperature, and stirred for 24 hours. H. The reaction was neutralized with 2N hydrochloric acid solution (7 mL, 14 mmol) and purified by HPLC and RP (gradient elution with 15 to 90% acetonitrile in water, each containing 0.1% TFA). Lyophilization provided Product Compound 4-7 as a white solid (trifluoroacetate salt, 0.62 g, 64%). 1H NMR (300 MHz1 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 to 7.06 (m, 3H), 4.70 (s, 2H), 4.33 (m, 2H), 3.86 to 3.20 (m, 7H), 2.04 to 1.86 (m, 4H); MS (ES +) mlz 414.9 (M + 1); Analysis Calculated for C 22 H 23 ClN 2 O 4 • JSCF 3 CO 2 H: C, 50.05; H, 4.08, N, 4.60. Found: C, 50.11; H, 4.23; N, 4.56.

Step 6. Synthesis of 4-R 2- (5-Chloro-2- (1-f- (3-oxo-2,3-dihydro-benzo [1141oxazin-4-yl) -ethyl) -butyric acid tert-butyl ester piperidin-4-yl) -benzoylamino) -ethin-piperazine-1-carboxylic (Compound 66). A solution of compound 4-7 (0.24 g, 0.58 mmol) in dimethyl

formamide (3 mL) was combined with N-methylmorpholine (0.19 mL, 1.74 mmol), 1-hydroxybenzotriazole (0.04 g, 0.29 mmol), O-benzotriazol-1-yl- / V hexafluorophosphate Tb / tetramethyluronium (HBTU, 0.26 g, 0.70 mmol) and Compound 4-8 (0.16 g, 0.70 mmol). The reaction mixture was stirred overnight at room temperature, quenched with saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by RP HPLC (gradient elution with 60% acetonitrile in water, each with 0.1% TFA) and lyophilized to afford Compound 66 as white solid (trifluroacetate salt, 0.26 g, 72%). 1H NMR (300 MHz, DMSO) δ 7.58 to 7.53 (m, 2H), 7.37 (d, J = 8.5 Hz, 1H), 7.30 (m, 1H), 7.12 at 7.05 (m, 3H), 4.70 (s, 2H), 4.3 to 3.1 (m, 21H), 2.0 to 1.8 (m, 4H), 1.42 (s 9H); MS (ES +) mlz 626.1 (M + 1); Analysis Calculated for C33 H44 ClN5 O5 -6.6CF3 CO2 H: 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 representative compounds of the present invention may be prepared: Comp. MS Name

5-Chloro-2- {1- [2- (3-oxo-2,3-429-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-acid methyl ester il} benzoic

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 Comp. MS Name

58 4 - [(5-chloro-2- {1 - [2- (3-oxo-611.3-acid) tert-butyl ester

2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-yl} -benzoylamino) -methyl] -piperidine-1-carboxylic acid

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

60 [4- (5-Chloro-2- {1- [2- (3-oxo-585.3-acid) tert-butyl ester

2,3-dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) butyl] carbamic

61 5-chloro-N- (2-naphthalen-2-yl-ethyl) -2- {1- [2- (3-oxo-2,3-dihydro-568

benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzamide

62 5-chloro-N- [2- (1H-indol-3-yl) ethyl] -2- {1- [2- (3-oxo-2,3-557

dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzamide

63 - 4 - [(5-Chloro-2- {1 - [2- (3-oxo-2,3- 645,3 acid) benzyl ester

dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino (o) methyl] piperidine-1-carboxylic

64 N- (1-benzoyl-piperidin-4-ylmethyl) -5-chloro-2- {1- [2- (3-oxo-615.3

2) 3-dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzamide

65 5-Chloro-N- [1- (3,3-dimethyl-butyryl) -piperidin-4-ylmethyl] -2- {1-609.2 [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-2-one

4-yl} benzamide

67 4 - [(5-chloro-2- {1- [2- (3-oxo-2,3- 644,2-acid) benzylamide

dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) methyl] piperidine-1-carboxylic

68 4- [2- (5-Chloro-2- {1 - [2- (3- 625.2 oxo-2,3-dihydro-benzo [1,4] oxazin-4-acid) tert-butyl ester yl) -ethyl] -piperidin-4-yl} -

benzoylamino) ethyl] piperidine-1-carboxylic

69 [4- (5-Chloro-2- {1 - [2- (3-oxo-2,3-619,2-acid) benzyl ester

dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) butyl] carbamic

70 [5- (5-Chloro-2- {1 - [2- (3-oxo-599.2-acid) tert-butyl ester

2,3-dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) pentyl] carbamic

71 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 Comp. MS Name

72 5-chloro-2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl)-665,2-ethyl] -piperidin-4-yl} -benzamide N- (1-phenylmethanesulfonyl-piperidin-4-one

ylmethyl) benzamide

73 5-chloro-2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -526

ethyl] -piperidin-4-yl} -N- (2-piperazin-1-yl-ethyl) -benzamide

74 [6- (5-chloro-2- {1 - [2- (3-oxo-623.2) acid tert-butyl ester

2,3-dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) hexyl] carbamic

75 [5- (5-Chloro-2- {1- [2- (3-oxo-2,3-633 acid benzyl ester)

dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) pentyl] carbamic

76 5-chloro-N- [5- (3,3-dimethyl-butyrylamino) -pentyl] -2- {1 - [2- (3- 597.2 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-2,3-632.1

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) -653.3

ethyl] -piperidin-4-yl} -N- (5-phenylmethanesulfonylamino-pentyl) -benzamide

{2- [2- (5-Chloro-2- {1 - [2- (3-601,21-oxo-2,3-dihydro-benzo [1,4] oxazin-4 acid) tert-butyl ester -yl) -ethyl] -piperidin-4-yl} -

benzoylamino) ethoxy] ethyl} carbamic

80 5-chloro-N- [5- (3-isopropyl ureido) pentyl] -2- {1- [2- (3-oxo 584.1

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) -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 [1,4] 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-597.3-acid) tert-butyl ester

3,4-dihydro-2H-quinolin-1-yl) ethyl] piperidin-4-yl} benzoylamino) pentyl] carbamic

Example 5

[5- (5-Chloro-2- {8- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -acetate-tert-butyl ester 8-aza-bicyclo [3.2.1] oct-3-yl} -benzoylamino) -pentyl] -carbamic (Compound 100)

[5- (5-Chloro-2- {2,6-dimethyl-1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-acid) tert-butyl ester Carbamic (yl) -ethyl] -1,2,3,6-tetrahydro-pyridin-4-yl} -benzoylamino) (Compound 102)

Hn

-Ç

NH5

5-2

Step 1. Synthesis of [5- (5-Chloro-2- (8- [2- (3-oxo-2,3-dihydro-benzon, 41oxazin-4-yl) -etin-8-yl) -t-tert-butyl ester] aza-bicyclor3.2.11oct-3-yl (benzoylamino) pentyl-1-carbamic (Compound 100) Compound 100 was made using the methods described for Compound 66 (Example 4) except 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 Hudlicky1 BE Maryanoff1 Can. J.Chem. 2006, 84, 555-560. 1H NMR (300 MHz1 CDCl3) δ 7.6 to 7.0 (m , 7H), 4.61 (s, 2H), 4.7 to 4.3 (m, 2H), 4.16 (m, 2H), 3.7 to 2.8 (m, 7H), 2, 5 to 1.3 (m, 14H), 1.88 (s, 9H) MS (ES +) mlz 625.3 (M + 1) HRMS (FAB +) Calculated for C34H45CIN405 + 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 similar manner to Hall, Η. K. Jr .; J. Am. Chem. Soc., 1957, 79, 5444-5447. Step 2a: In a mixture of diethyl acetonecarboxylate (103.6 g, 0.512 mol) and acetaldehyde (45.3 g, 1.33 mol) ammonia gas was bubbled until this liquid was saturated at -30 ° C. The solution was stored in a freezer overnight. The yellow suspension was dissolved in dichloromethane (15 mL), filtered through silica gel and washed with EtOAc. The organic layer was concentrated to afford 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 overnight. Water was evaporated to yield 2,6-Dimethyl-4-piperidone / HCl, which was used for the next step without further purification. Step 2c: 2,6-Dimethyl-4-piperidone HCl salt (25.0 g, 0.153 mol) was partitioned between dioxane (250 mL) and H 2 O (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 room temperature overnight. The reaction mixture was evaporated to remove dioxane. The residue was extracted with Et 2 O and the organic layer was washed with brine and dried over sodium sulfate. After evaporation, the crude product was purified by chromatography (gradient elution 9 to 14% EtOAc in hexane) to yield Compound 5-3 as a white solid (18.0 g, 52%, 70: Trans: cis) (based on NMR spectra of Compound 5-3 trans reported in Beak, P .;

Lee, W. K .; J. Org. Chem. 1993, 58, 1109-1117). MS (ES +) mlz 128 (M-Boc + 1).

Trans compound 5-3: 1 H NMR (300 MHz, CDCl 3) 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), 13 C NMR (75 MHz, CDCl3) δ 208.11, 154.59, 80.06, 46.70, 44.37, 28.66, 22, 90

Compound Cys 5-3: 1 H NMR (300 MHz, CDCl 3) 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, 2Hax, 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, 2CH 3), 13 C NMR (75 Hz, CDCl 3) 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-H 2 S 4 -gtaborolan-2-D-Se-dihydro-H-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 the 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%, melting point 84 to 85 ° 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%).

Compound 5-4 (trans): 1 H NMR (300 MHz, CDCl 3) δ 6.58 (m, 1H),

4.23 to 4.14 (m, 2H), 2.41 to 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); 13 C NMR (75 Hz, CDCl 3) 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 (EI +) mlz 337 (M +); HRMS (EI +) Calculated for C 18 H 32 NO 4 B :; 337.2424. Found: 337.2433; Rf: 0.52 (pentane / EtOAc, 9: 1); Analysis Calculated for C 18 H 32 NO 4 B: C, 64.10; H, 9.56. Found: C, 64.15; H, 9.80. Compound 5-4 (trans and useful in a ratio of 2.25: 1): 1 H NMR (300 MHz, CDCl 3) δ 6.58 (m, 0.7H), 6.39 (m, 0.3H), 4.56 to 4.31 (m, 0.6H), 4.23 to 4.14 (m, 1.4H), 2.41 to 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, 2.1 H); 13 C NMR (75 Hz, CDCl 3) 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 (EI +) mlz 337 (M +); HRMS (EI +) Calculated for C 18 H 32 NO 4 B :; 337.2424. Found: 337.2424; Rf: 0.52 and 0.46 (pentane / EtOAc, 9: 1); Analysis Calculated for C 18 H 32 NO 4 B: C, 64.10; H, 9.56. Found: C, 63.97; H, 9.75. Step 4. Synthesis of R5- (5-Chloro-2- (2,6-dimethyl-1- [2- (3-oxo-2,3-dihydro-benzof 1,4] oxazin-4-yl) tert-butyl ester] -etin-1,2,3,6-tetrahydropyridin-4-yl) benzoylamino) pentincarbamic (Compound 102).

Compound 5-4, as a mixture of eis and trans isomers, was converted to Compound 5-6 by the methods described for C conversion of Compound 4-1 to Compound 4-3, except that Compound 5-5 of triflate was used instead of arylbromide Compound 4-2. Compound 5-6 was converted to compound 102 in several steps by the methods described for converting Compound 4-4 to Compound 66 (Example 4) using 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, CDCl3) δ 7.55 (d, J = 2.2 Hz, 1H), 7.31 (d of d, J = 8.2 and 2.2 Hz, 1H), 7.10 at 6.91 (m, 5H), 6.06, 5.67 (m, 1H), 4.60 (s, 2H), 4.01 (m, 2H), 3.4 to 2.0 (m , 10H), 1.56 (s, 9H), 1.6 to 1.3 (m, 6H), 1.19 (d, J = 6.7Hz, 3H), 1.05 (d, J = 6 , 6Hz, 3H); MS (ES +) mlz 624.9 (M + 1). Using the procedure of Example 5, other compounds represented

The formulants of the present invention may be prepared: Comp. MS Name

94 4- [2- (5-Chloro-2- {8- [2- (3-oxo-649.8 2,3-dihydro-benzo [1,4] oxazin-4-acid) tert-butyl ester yl) -ethyl] -8-aza-bicyclo [3.2.1] oct-2-en-3-yl} -benzoylamino) -ethyl] -piperazine-

1-carboxylic Comp. MS Name

95 [5- (5-chloro-2- {8- [2- (3-oxo-622,8-acid) tert-butyl ester

2,3-dihydro-benzo [1,4] oxazin-4-yl) ethyl] -8-aza-bicyclo [3.2.1] oct-2-en-3-yl} -benzoylamino) -pentyl] -carbamic

96 4- [2- (2- {8- [2- (3-oxo-2,3-618,5-dihydro-benzo [1,4] oxazin-4-yl) -ethyl) tert-butyl ester ] -8-aza-bicyclo [3.2.1] oct-3-

yl} -benzoylamino) -ethyl] -piperazine-1-carboxylic

97 [5- (2- {8- [2- (3-oxo-2,3-dihydro-591.5-acid) tert-butyl ester

benzo [1,4] oxazin-4-yl) ethyl] -8-aza-bicyclo [3.2.1] oct-3-yl} benzoylamino) pentyl] carbamic

98 [5- (2- {8- [2- (3-Oxo-2,3-dihydro-581.5-acid) tert-butyl ester

benzo [1,4] oxazin-4-yl) ethyl] -8-aza-bicyclo [3.2.1] oct-3-yl} benzoylamino) pentyl] carbamic

99 4- [2- (2- {8- [2- (3-oxo-2,3-618,5-dihydro-benzo [1,4] oxazin-4-yl) -ethyl) tert-butyl ester ] -8-aza-bicyclo [3.2.1] oct-3-

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] oxazin-3-one (Compound 116)

Cpd 116

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 stir bar. The flask was purged with N 2 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 isopropoxide (IV) titanium (2.83 g, 10 mmol). The mixture was heated in an oil bath at 50 ° C for 1.5 h, when the reaction was judged complete by TLC. The reaction mixture was cooled to room temperature 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 h, 1N sodium hydroxide solution (28 mL) was added and a large amount of white solid was formed. It was diluted with H 2 O (10 mL) and stirred vigorously with CH 2 Cl 2 (50 mL). The suspension was filtered through a pad of Celite® (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 (Na 2 SO 4), concentrated, and purified by flash silica gel chromatography (50 g, elution with 20% EtOAc in hexanes, 1000 mL). The eluent was collected in 50 mL fractions. Fractions 7 to 11 were combined and concentrated to afford Compound 116 as a colorless oil (0.30 g, 39%). R1 = 0.49 (30% EtOAc / hexanes); 1H NMR (300 MHz1 CDCl3) δ 7.32 to 7.25 (m, 2H), 7.21 to 7.16 (m, 3H), 7.11 to 6.99 (m, 4H), 4.66 at 4.55 (m, 2H), 4.11 to 3.94 (m, 2H), 3.10 to 2.97 (m, 2H), 2.78 to 2.74 (m, 1H), 2 57 to 2.32 (m, 3H), 1.86 to 1.59 (m, 4H), 1.02 (d, J = 9.2 Hz, 3H); 13 C NMR (75 MHz, CDCl 3): 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-H-methyl-2- (3-oxo-2,3-dihydro-benzof 1,41oxazin-4-yn-H-piperidin-4-yl) -N- (1-phenylmethanesulfonyl-piperidin -4-ylmethyl) benzamide (Compound 84)

Bochn

H2N

Bochn

alpha-toluenesulfonyl chloride, DIPEA, DCM

N

4 M HCI / dioxane,

N

I

"N 'H

7-1

ι

S = O

S = O Cl

Cl

N

Boc 7-4

COOMe

1st NaOH, MeOH

N

Boc 7-5

CO2H

7-3, HBTU1 HOBt1

NMM1 DMF

Caption: alpha-toluenesulfonyl chloride / dioxane

Step 1. Synthesis of (1-phenylmethanesulfonyl-piperidine-4ylmethyl) -carbamic acid tert-butyl ester (Compound 7-2).

(50 mL) and treated with DIPEA (2.44 mL, 14.0 mmol). The reaction mixture was placed in an ice bath before addition of alpha-toluenesulfonyl chloride (890 mg, 4.67 mmol). The reaction mixture was allowed to warm to room temperature over a period of 48 h. The reaction was poured into 50 ml of dichloromethane and washed with 1 N hydrochloric acid solution (2 χ 30 mL), 1 N sodium hydroxide solution (2 χ 30 mL), and brine (50 mL). The organic layer was dried over sodium sulfate and concentrated to yield Compound 7-2 (1.1 g, 64%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.38 (m, 5H), 4.60 (bs, NH), 4.20 (s, 2H), 3.65 (d, J = 12 Hz, 2H), 2.97 (t, J = 6Hz, 2H), 2.53 (m, 2H), 1.63 (d, J = 12Hz, 2H), 1.43 (m & s, 10H), 1.12 ( m, 2H); MS (ES +) mlz 269.1 (M-Boc + 1).

Step 2. Synthesis of (1-phenylmethanesulfonyl-piperidin-4-yl) methylamine hydrochloride (Compound 7-3).

Compound 7-1 (1.00 g, 4.67 mmol) was dissolved in dichlorome. 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 h before concentration to a yield of Compound 7-3-HCl as a white solid. 1H NMR (300 MHz, DMSO d6) δ 7.38 (m, 5H), 4.39 (s, 2H), 3.57 (d, J = 12 Hz -1 2H), 2.70 to 2.63 (m , 4H), 1.77 to 1.60 (m, 3H), 1.12 (m, 2H); MS (ES +) mlz 269.1 (M + 1).

Step 3. Synthesis of 4- {4-Chloro-2 - [(1-phenylmethanesulfonyl-piperidin-4-ylmethyl) -carbamoyl-phenyl) -piperidine-1-carboxylic acid tert-butyl 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 at reflux for 18 h, cooled to room temperature and concentrated to yield 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 cooled 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 DMF. . Once the solution was equilibrated to ice bath temperature, HBTU (263 mg, 0.696 mmol) was added and stirring was continued in an ice bath for 4 h. The reaction mixture was diluted with 50 mL 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 yield Compound 7-6 (0.26 g, 75% crude yield) and was used as is for the next reaction. MS (ES +) mlz 489.9 (M-Boc + 1).

Step 4. Synthesis of 5-Chloro-2- (1-methyl-2- (3-oxo-2,3-dihydro-benzoyl-1,4-oxazin-4-yl) -etin-piperidin-4-yl) -N- ( 1-phenylmethanesulfonyl-piperidin-4-ylmethyl) -benzamide (Compound 84).

Compound 7-6 (0.26 g, 0.44 mmol) was dissolved in dioxane (2 mL) and treated with a 4 M solution of hydrogen chloride in dioxane (1 mL, 4 mmol). This solution was stirred at room temperature for 2 h, 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 afford the intermediate piperidine as a clear oil. Compound 1-6 (182 mg, 0.883 mmol) was combined with intermediate piperidine and titanium (IV) isopropoxide (1.0 mL, 3.3 mmol) and heated at 50 ° C for 1.5 h. The reaction mixture was cooled to room temperature and a suspension of sodium borohydride (171 mg, 4.62 mmol) in absolute ethanol (1 mL) was added. After an additional 15 min absolute ethanol (10 mL) was added. After 20 h, the reaction mixture was poured into 1 N sodium hydroxide solution (20 mL) and the solids were filtered. The basic filtrate was diluted with 50 mL EtOAc and separated. The EtOAc layer was washed with 1 N NaOH (2 x 20 mL), dried over sodium sulfate and concentrated to a glassy oil. The oil was purified on reverse phase HPLC (35 to 90% acetonitrile gradient in water, both with 0.2% TFA) to yield Compound 84 (17.7 mg, 5% over 3 steps). 1H NMR (300 MHz, CDCl3) δ 7.46 to 7.39 (m, 7H), 7.25 to 7.00 (m, 5H), 6.01 (t, J = 7 Hz, NH), 4 , 62 (m, 2H), 4.6 to 4.3 (m, 2H), 4.22 (s, 2H), 3.8 to 2.7 (m, 12H), 2.6 to 1.2 (m, 8H), 1.34 (d, J = 6.7 Hz, 3H); MS (ES +) mlz 679.2 (M + 1). Biological Examples Example 1

Calcium Flow Test

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 cyclic agonist peptide. (Ac) -CFWK (2-Nal) C-NH 2 (FLIPR EC50 = 0.54 ± 0.2 nM, rU-11 Ki = 0.12 ± 0.05 nM) at 1 nM (WA Kinney, HR Almond, Jr., J. Qi, CE Smith, RJ Santulli, L. de Garavilla, P. Andrade-Gordon, DS Cho, AM Everson, MA Feinstein, PA Leung, E. E. Maryanoff, Angew. Chem., Intl Ed. 2002, 41, 2940-2944) in rat GPR14 transfected CHO cells (U-11 receptor) (M. Tal, DA Ammar, M. Karpuj, V. Krizhanovsky, M. Naim, DA Thompson, Biochem, Biophys, Res. Commun., 1995, 209, 752-759, A. Marcheese, M. Heiber, T. Nguyen, H. H. Heng, VR Saldivia, R. Cheng, M. Murphy, LC Tsui, X. Shi. P. Gregor, Genomics 1995, 29, 335-344).

To derive these cells, the complete rat UII coding sequence (Genbank Accession No. U32673) was amplified by rat heart marathon-Ready cDNA nested PCR. PCR was performed using DNA polymerase PFU (Stratagene) following conditions suggested by a manufacturer. PCR products were cloned into EcoR I and Xba I digested pcD-NA3 (Invitrogen). Clones containing rat U II receptor were verified by complete sequencing of the U II receptor insert to ensure a lack of errors. introduced by PCR. The constructed vector was transfected into CHO cells by use of lipofectamine (GIBCO BRL). CHO cells with high expression of rat U II receptor were selected and established as stable cell lines by use of G418. CHO cells were seeded into 25,000 cells per well in 96-well clear-bottom microtiter plates 24 h 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 proprietary tincture of the Molecular Devices (FLIPR) Calcium Assay Kit prepared in assay buffer (Hanks Balanced Salts Solution, 20 mM HEPES, 0.1% BSA, probed at 2.5 mM, pH 7.4), and incubated for 1 h at 37 ° C. Calcium mobilization determinations were performed at room temperature (23 ° C). The use of rat GPR14 was considered acceptable because human U II has similar affinity for human or rat GPR14 in transfected cells (SA Douglas, H. H. Ohlstein, Trends Cardiovasc. Med. 2000, 10, 229 - 237). The resulting data are shown in Table 3. Example 2

Human Radioland Binding Assay

Human Skeletal Muscle Myoblasts (HSMM) were obtained from Cambrex, and were cultured according to the manufacturer's instruction. Cell viability was examined by trypan blue exclusion. Cells in less than 4 passages were used in all studies. For (125I) -U Il binding experiments (described in: "Characterization of Functional Urotensin Il Receptors in Human Skeletal Muscle Myoblasts: Comparison with Angiotensin Il Receptors" J. Qi1 LK Minor, C. Smith, B1 Hu1 J. Yang1 P. Adrade-Gordon, B. Damiano, Peptides 2005, 26, 683-690), HSMM were seeded in 12-well Costar plates in complete medium for 48 h to achieve 70% confluence. The binding medium used was Dulbecco's modified Eagles® (DMEM) medium containing 2 mg / ml BSA and 25 mM HEPES (pH 7.4). 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 M (125 I) -U II and compounds for 3 h. Cells were washed 4x with binding medium and solubilized in 1% SDS and 0.5N NaOH. Radioactivity was quantified by gamma counting.

Radiolabelled (125 I) -U Il specifically and saturated bound to intact adherent HSMM. Binding assays were performed at 25 ° C to lower nonspecific (125 I) -U II uptake by cells that are seen at 37 ° C. Using this method, non-specific binding was below 10% total binding. Saturation data analysis using the nonlinear 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 Hill's slope near the unit. Based on the number of cells in a cell and Bmax value, the number of HSMM UT receptors was 2311 ± 236 per cell (N = 3 experiments). A time course experiment demonstrated that (125 I) -U II binding to HSMM reached steady state within 3 h, and remained constant for up to 5 hours, the longest time measured. Human U II, when added at time 0, efficiently removed (125 I) -U II specific binding with a Ki of 0.425 ± 0.096 nM (N = 3 experiments). The resulting data are shown in Table 4. Table 3 In Vitrode Evaluation of Mouse U11 Receptors Using FLIPR *

IC50 Cpt (μΜ) IC50 Cpt (μΜ) 1 7.5 59 10 2 7.9 60 0.5 3 4.2 61 2 4 3.1 62 0.9 11 63 0.4 6 10 64 0.52 7 19 65 0.33 8 14 66 0.02 9 3.2 67 0.21 13 68 0.1 11 5.4 69 0.15 12 10 70 0.03 13 8 71 0.27 14 4 72 0.05 8 73 1.9 16 8 74 0.05 17 7 75 0.04 18 15 76 0.15 19 6 77 0.03 2 78 0.1 21 9 79 0.037 22 13 80 0.21 23 7 81 0.53 24 12 82 0.17 4 83 0.36 26 2 84 2 27 43 85 18 28 9 86 24 29 20 87 47 32 88 28 31 13 89 23 32 14 90 15 33 4 91 21 Cpt IC50 (μΜ) Cpt IC50 ( μΜ) 34 3 92 20 3 93 32 36 25 94 0.29 37 30 95 0.64 38 23 96 3.5 39 32 97 5.4 40 4 98 1.6 41 21 99 1.1 42 20 100 0, 45 43 18 101 19 44 21 102 7.6 45 16 103 24 46 6 104 26 47 7 105 7 48 43 106 14 49 38 107 9.1 50 2.5 108 8.8 51 22 109 5 52 16 110 11 53 18 111 8 54 7 112 5 55 2 113 4.4 56 8 7 57 1.3 21 58 0.60 70

* inhibition of acetyl cyclic-induced Ca2 + mobilization [Cys-Phe-Trp-Lys- (2-Nal) -Cys] -NH2 (FLIPR) in rat U11 receptor-transfected CHO cells referenced in: " Structure-Function Analysis of Urotensin Il and Its Use in the Construction of a Ligand-Receptor Working Model "WA Kinney, HR Almond, Jr., J. Q1 CE Smith, RJ Santulli, L. de Garavilla, P. Andrade-Gordon, DS Cho1 AM Everson, MA Feinstein, PA Leung, Β. E. Maryanoff Angewandte Chemie, Int. Ed. 2002, 41, 2940-2944. Table 4

In Vitro Evaluation of Human Ull Receptor Binding *

Cpt Ki (μΜ) Cpt Ki (M) 1 2.9 70 25 3 0.33 72 0.03 0.72 74 0.1 26 0.75 75 0.03 34 0.62 76 0.04 0.59 77 0.04 50 0.43 78 0.04 55 0.84 79 0.05 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 0.05 95 1.3 65 0.03 98 1.4 66 0.06 99 1.4 67 0.03 100 1.2 68 0.05 113 1.7 69 0.06

* (125I) -U Il binding experiments are described in: "Characterization of Functional Urotensin Il Receptors in Human Skeletal Muscle Myoblasts: Comparison with Angiotensin Il Receptors" J. Qi1 LK Minor, C. Smith , H. 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 purposes of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and / or modifications as falling within the scope of the following claims and their equivalents.

All publications described in the above specification are hereby incorporated by reference in their entirety.

Claims (42)

1. Compound of Formula (I): <formula> formula see original document page 102 </formula> 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-tetrahydropyridinyl; Y is selected from the group consisting of CH2, O and S; Li is absent or selected from the group consisting of -C (O) O-R 1, -C (O) N (R 5) -R 1 and -NHC (O) -R 1; L2 is C1-Salquila; L3 is absent or is -C (O) N (R5) -R7; R1 is selected from the group consisting of C1-alkyl, C1-alkoxy, aryl, C1-8 alkyl, C3-4 cycloalkyl, C3-4-cycloalkyl-C1-8 alkyl, heterocyclyl, heteroarycyl-C1-alkyl, heteroaryl and heteroaryl-C1-8 alkyl. wherein C1-Salkyl is optionally substituted with one, two or three substituents each selected from the group consisting of C1-Salcoxy, halogen, hydroxy and -NHR6, wherein C1-Salcoxy is optionally substituted with one, two or three substituents each. one selected from the group consisting of C1-Salcoxy, halogen, hydroxy and -NHR6, wherein each example of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of C1-Salkyl, C1-Salcoxy, halogen and wherein each example of heterocyclyl is optionally substituted by oxo, C 1-8 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-8 alkyl-N (R 5) carbonyl, arylcarbonyl, aryl Cvealkylcarbonyl, aryl-C 1-8 alkoxycarbonyl, aryl-N (R5) - Carbonyl aryl-C 1-8 alkyl-N (R 5) -carbonyl or aryl-C 1-8 alkylsulfonyl; R 2 is one, two or three substituents each selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 alkoxy and halogen; R3 is one, two or three substituents each selected from the group consisting of hydrogen and C1-4 alkyl; R4 is one, two or three substituents each selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 alkoxy, hydroxy and halogen; R5 is selected from the group consisting of hydrogen and C1-4 alkyl; R 6 is selected from the group consisting of C 1-8 alkylcarbonyl, C 1-8 alkoxycarbonyl, C 1-8 alkyl-N (R 5) carbonyl, arylcarbonyl, arylC 1-8 alkylcarbonyl, arylC 1-8 alkoxycarbonyl, aryl-N (R5) -carbonyl, aryl-C1-8 alkyl-N (R5) -carbonyl and BN1-Cl-SalkylSulfonyl; and, R 7 is selected from the group consisting of C 1-8 alkyl, aryl, C 1-8 alkyl aryl, C 3-14 cycloalkyl, C 3-14 cycloC 1-8 alkylalkyl, heterocyclyl, heterocyclylC 1-8 alkyl, heteroaryl and heteroarylC -8 alkyl. The compound of claim 1, wherein Ring A is piperidinyl. The compound of claim 1, wherein Ring A is 8-aza-bicyclo [3.2.1] oct-2-enyl. The compound of claim 1, wherein Ring A is 8-aza-bicyclo [3.2.1] octyl. The compound of claim 1, wherein Ring A is 1,2,3,6-tetrahydropyridinyl. The compound of claim 1, wherein Y is CH 2. The compound of claim 1, wherein Y is O. The compound of claim 1, wherein Y is S. The compound of claim 1, wherein R 1 is selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, aryl C 1-8 alkyl, C 3-14 cycloalkyl, C 3-14 CycloC 1-8 alkyl, heterocyclyl, heterocyclyl-C 1-8 alkyl and heteroarylC 1-8 alkyl, wherein C 1-8 alkyl is optionally substituted with a substituent selected from the group consisting of C 1-8 alkoxy, hydroxy and -NHR 6, wherein C 1-8 alkoxy is optionally substituted with -NHR 6, wherein each example Aryl is optionally substituted with one, two or three substituents each selected from the group consisting of C1-8 alkoxy, halogen and halo-C1-8 alkyl, and wherein each example of heterocyclyl is optionally substituted with oxo, C1-8 alkyl. carbonyl, C 1-6 alkoxycarbonyl, arylcarbonyl, arylC 1-8 alkoxycarbonyl, arylC 1-8 alkyl-N (R 5) -carbonyl or arylC 1-8 alkylsulfonyl. The compound of claim 9, wherein R1 is selected from the group consisting of C1-Salkyl, C1-8 alkoxy, phenyl-C1-8 alkyl, naphthyl-C1-8 alkyl, indanyl, cyclopropyl-C1-8 alkyl, cyclohexyl-C1-6. 8alkyl, 1,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-C 1-8 alkyl, piperidinyl-C 1-8 alkyl, piperazinyl-C 1-8 alkyl, furanyl-C 1-8 alkyl, thienyl-C 1-8 alkyl, imidazolyl-C 1-8 alkyl pyridinyl-C1-8 alkyl and indolyl-C1-8 alkyl, wherein each example of phenyl is optionally substituted with one, two or three substituents each selected from the group consisting of C1-8 alkoxy, chloro, fluoro, bromo and halo Wherein each example of 1,2,3,4-tetrahydro-isoquinolinyl, pyrrolidin-C 1-8 alkyl, piperidinyl-C 1-8 alkyl, and piperazinyl-C 1-8 alkyl is optionally substituted with oxo, C 1-8 alkylcarbonyl, C 1-8 alkoxycarbonyl, arylcarbonyl, arylC 1-8 alkoxycarbonyl, arylC 1-8 alkyl-N (R 5) carbonyl or arylC 1-8 alkylsulfonyl. The compound of claim 1, wherein R2 is a substituent selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 alkoxy and halogen. The compound of claim 1, wherein R 3 is one or two substituents each selected from the group consisting of hydrogen and C 1-4 alkyl. The compound of claim 1, wherein R 4 is a substituent selected from the group consisting of hydrogen, C 1-8 alkyl and halogen. The compound of claim 1, wherein R 5 is hydrogen. The compound of claim 1, wherein R 5 is C 1-4 alkyl. The compound of claim 1, wherein R 6 is selected from the group consisting of C 1-8 alkylcarbonyl, CT-alkoxycarbonyl, C 1-6 alkyl-N (R 5) -carbonyl, aryl-C 1-8 alkoxycarbonyl, aryl-N (R 5) -carbonyl, aryl-C 1-8 alkyl-N (R 5) -carbonyl and aryl-C 1-8 alkylsulfonyl. The compound of claim 1, wherein R6 is selected from the group consisting of C1-8 alkylcarbonyl, C1-4 alkoxycarbonyl, C1-8 alkyl-N (R5) carbonyl, phenyl-C1-6 alkoxycarbonyl, phenyl-N (R5 ) -carbonyl, phenylC 1-8 alkyl-N (R 5) -carbonyl and phenylC 1-8 alkyl sulfonyl. The compound of claim 1, wherein R7 is selected from the group consisting of C1-Salquyl and aryl-C1-8 alkyl. The compound of claim 1, wherein R7 is selected from the group consisting of C1-Salquila and phenyl-Cvealquila. 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-tetrahydropyridinyl; R 1 is selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkyl aryl, C 3-14 cycloalkyl, C 3 -MycicloalkylC 1-8 alkyl, heterocyclyl, heterocyclyl C 1-8 alkyl and Itheroaryl-C 1-6 alkyl wherein C 1-8 alkyl is optionally substituted with a substituent selected from the group consisting of C 1-8 alkoxy, hydroxy and -NR 6, wherein C 1-8 alkoxy is optionally substituted with -NHR 6, wherein each example of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of C1-8 alkoxy, halogen and Ilyo-C1-Salkyl, and wherein each example of heterocyclyl is optionally substituted with oxo, C1-Salkyl-Carbonyl, C1-Alkoxycarbonyl, arylcarbonyl, aryl-C1-8 alkoxycarbonyl, aryl-C1-4 alkyl-N4 -carbonyl or aryl-C1-alkylsulfonyl; R2 is a substituent selected from the group consisting of hydrogen, C1-8 alkyl, C1-Salcoxy and halogen; R3 is one or two substituents each selected from the group consisting of hydrogen and C1-4 alkyl; R4 is a substituent selected from the group consisting of hydrogen, C1-4 alkyl and halogen; R 6 is selected from the group consisting of C 1-8 alkylcarbonyl, C 1-8 alkoxycarbonyl, C 1-8 alkyl-N (R 5) -carbonyl, aryl-C 1-8 alkoxycarbonyl, aryl-N (R 5) -Carbonyl-aryl-C 1-4. 8-alkyl-N (R5) -carbonyl and aryl-C1-8 alkylsulfonyl; and R7 is selected from the group consisting of C1-8 alkyl and aryl-C1-8 alkyl. The compound of claim 20, wherein R 1 is selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, phenyl-C 1-8 alkyl, naphthyl-C 1-8 alkyl, indanyl, cyclopropyl-C 1-6 alkyl, cyclohexyl-C 1-8 alkyl, 1,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-C 1-6 alkyl, piperidinyl-C 1-8 alkyl, Piperazinyl-C 1-6 alkyl, furanyl C 1-8 alkyl, thienyl C 1-8 alkyl, imidazolyl C 1-8 alkyl, pyridinyl-C 1-6 C 1-8 alkyl and indolyl C 1-8 alkyl, wherein each example of phenyl is optionally substituted by one, two or three substituents each selected from the group consisting of C 1-8 alkoxy, chloro, fluoro, bromo and halo C 1-8 alkyl, and wherein each example of 1,2,3,4-tetrahydro-isoquinolinyl, pyrrolidin-C 1-8 alkyl, piperidinyl-C 1-8 alkyl, piperazinyl-C 1-8 alkyl is optionally substituted by oxo, C 1-8 alkylcarbonyl, C 1-8 alkoxycarbonyl, arylcarbonyl, arylC 1-8 alkoxycarbonyl, arylC 1-8 alkyl-N (R 5) -carbonyl or arylC 1-8 alkylsulfonyl; R6 is selected from the group consisting of C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-8 alkyl-N (R5) carbonyl, phenyl-C1-8 alkoxycarbonyl, phenyl-N (R5) carbonyl, phenylC1 -8alkyl-N (R5) -carbonyl and phenyl-C1-8alkylsulfonyl; and R7 is selected from the group consisting of C1-8 alkyl and phenyl-C1-8 alkyl. Compound of Formula (Ia): and forms thereof, wherein Y is selected from the group consisting of CH 2, O and S; L1 is absent or selected from the group consisting of -C (O) O-R1, -C (O) N (R5) -R1 and -NHC (O) -R1; L 2 is Cvealquila; L3 is absent or is -C (O) N (R5) -R7; R1 is selected from the group consisting of C1-Salkyl, C1-8 alkoxy, aryl, aryl-C1-4 alkyl, C3 -4-cycloalkyl, heterocyclyl, heterocyclyl-C1-6 alkyl, heteroaryl and heteroaryl-C1-4 alkyl, wherein C 1-8 alkyl is optionally substituted with one, two or three substituents each selected from the group consisting of C 1 -Salcoxy, halogen, hydroxy and -NHR 6, wherein C 1 -Salcoxy is optionally substituted with one, two or three substituents each selected from the group consisting of C1-Salcoxy, halogen, hydroxy and -NHR6, wherein each example of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of C1-Salkyl, C1-8 alkoxy, halogen and halo Wherein each example of heterocyclyl is optionally substituted by oxo, C1-Salkyl-Carbonyl, C3 -alkoxycarbonyl, C1-Alkyl-N (R5) -carbonyl, arylcarbonyl, aryl-C3 -alkylcarbonyl aryl-C 1-6 alkoxycarbonyl, aryl-N (R 5) -Carb onyl, aryl-C 1-4 alkyl-N-R 2 -carbonyl or aryl-C 1-6 alkylsulfonyl; R2 is one, two or three substituents each selected from the group consisting of hydrogen, C1-Salquila, C1-Salcoxy and halogen; R3 is one, two or three substituents each selected from the group consisting of hydrogen and C1-4 alkyl; R4 is one, two or three substituents each selected from the group consisting of hydrogen, C1-4 alkyl, C1-8 alkoxy, hydroxy and halogen; R5 is selected from the group consisting of hydrogen and C1-4 alkyl; R6 is selected from the group consisting of C1-8 alkylcarbonyl, C1-8 alkoxycarbonyl, C1-8 alkyl-N (R5) -carbonyl, arylcarbonyl, aryl-C1-8alkylcarbonyl, aryl-C1-8alkoxycarbonyl, aryl-N (R 5) -carbonyl, aryl-C 1-8 alkyl-N (R 5) -carbonyl and aryl-C 1-8 alkylsulfonyl; and, R 7 is selected from the group consisting of C 1-8 alkyl, aryl, C 1-8 alkyl, C 3-14 cycloalkyl, C 3-14 cycloC 1-8 alkyl, heterocyclyl, heterocyclyl-C 1-8 alkyl, heteroaryl and heteroaryl-C 1-8 alkyl . The compound of claim 22, wherein R 2 is selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, phenyl-C 1-8 alkyl, naphthyl-C 1-8 alkyl, indanyl, Cyclopropyl-C 1-8 alkyl, C 1 -C 8 -alkyl, 1,2,3,4-tetrahydro-isoquinolinyl, Pyrrolidinyl-C1-Saalkyl, piperidinyl-C1-alkyl, piperazinyl-C1-alkyl, furanyl-C1-8 alkyl, thienyl-C1-alkyl, imidazolyl-C1-alkyl, pyridinyl, Cvealkyl and Indo-C1-Cl-Alkyl, wherein C1-8 alkyl is optionally substituted with a substituent selected from the group consisting of C1-Salcoxy, hydroxy and -NR6, wherein C1-Salcoxy is optionally substituted with -NHR6, where each The phenyl example is optionally substituted with one, two or three substituents each selected from the group consisting of C1-Salcixi, chloro, fluoro, bromo and halo-C1.8alkyl, and each example of 1,2,3, 4-Tetrahydro-isoquinolinyl, pyrrolidin-C4-salquyl, Pipendinyl-C1-Salquila, Piperazinyl-C1-Salquila is optionally substituted with xyl, C 1-6 alkylcarbonyl, C 1-4 alkoxycarbonyl, arylcarbonyl, aryl-C 1-6 alkoxycarbonyl, aryl-C 1-8 alkyl-N (R 5) carbonyl or aryl-C 1-8 alkylsulfonyl; R2 is a substituent selected from the group consisting of hydrogen, C1-Salquila, C1-Salcoxy and halogen; R3 is one or two substituents each selected from the group consisting of hydrogen and C1-4 alkyl; R4 is a substituent selected from the group consisting of hydrogen, C1-6 alkyl and halogen; R5 is selected from the group consisting of hydrogen and C1-4alkyl; R 6 is selected from the group consisting of C 1-8 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-8 alkyl-N (R 5) -carbonyl, phenylC 1-8 alkoxycarbonyl, phenyl-N (R 5) -carbonyl, phenyl -C 1-8 alkyl-N (R 5) -carbonyl and phenylC 1-4 alkylsulfonyl; and R7 is selected from the group consisting of C1-8 alkyl and phenyl-C1-8 alkyl. Compound of Formula (Ib): and forms thereof, wherein 15 Y is selected from the group consisting of CH 2, O and S; Li is absent or selected from the group consisting of -C (O) O-R 1, -C (O) N (R 5) -R 1 and -NHC (O) -R 1; L2 is C1-Salquila; L3 is absent or is -C (O) N (R5) -R7; R 1 is selected from the group consisting of C 1-4 alkyl, C 1-8 alkoxy, aryl, C 1-4 alkyl, C 3-4 cycloalkyl, C 3 -Mycicloalkyl-C 1-6 alkyl, heterocyclyl, heterocyclyl C 1-6 alkyl, heteroaryl and heteroaryl C 1-4 alkyl; C1-Salkyl is optionally substituted with one, two or three substituents each selected from the group consisting of C1-Saloxy, halogen, hydroxy and -NHR6, wherein C1-8 alkoxy is optionally substituted with one, two or three substituents each selected from the group consisting of C1-8 alkoxy, halogen, hydroxy and -NHR6, wherein each example of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of C1-8 alkyl, C1-Salcoxy, halogen and halo. Wherein each example of heterocyclyl is optionally substituted by oxo, C1-8 alkylcarbonyl, C1-8 alkoxycarbonyl, C1-Alkyl-N (R5) -carbonyl, arylcarbonyl, aryl-C1-6 alkyl. 8alkylcarbonyl, arylC 1-6 alkoxycarbonyl, aryl N (R 5) -Carbonyl, aryl-C 1-8 alkyl-N (R 5) -carbonyl or aryl-C 1-6 alkylsulfonyl; R2 is one, two or three substituents each selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 alkoxy and halogen; R3 is one, two or three substituents each selected from the group consisting of hydrogen and C1-4 alkyl; R4 is one, two or three substituents each selected from the group consisting of hydrogen, C1-8 alkyl, C1-Salcoxy, hydroxy and halogen; R5 is selected from the group consisting of hydrogen and C1-4 alkyl; Re is selected from the group consisting of C1-6 alkylcarbonyl, C1-4 alkoxycarbonyl, C1-C1-6 alkyl-N (R5) -Carbonyl, arylcarbonyl, aryl-C1-6 alkylcarbonyl, aryl-C1-4 alkoxycarbonyl, aryl- N (R 5) -carbonyl, BriI-C 1 -Salkyl-N (R 5) -carbonyl and aryl-C 1-8 alkylsulfonyl; and, R 7 is selected from the group consisting of C 1-8 alkyl, aryl, aryl-C 1-4 alkyl, C 3-14 cycloalkyl, C 3-4 cycloalkyl-C 1-8 alkyl, heterocyclyl, heterocyclyl-C 1-8 alkyl, heteroaryl and heteroaryl-C 1. 8alkyl. The compound of claim 24, wherein R1 is selected from the group consisting of C1-Salkyl, C1-Salcoxy, phenyl-C1-4 alkyl, naphthyl-C1-6 alkyl, indanyl, cyclopropyl-C1-4 alkyl, cyclohexyl-C1-4 alkyl, 2,3,4-Tetrahydro-isoquinolinyl, Pyrrolidinyl-Cl-Salkyl, Piperidinyl-C 1-8 alkyl, Piperazinyl-C 1-6 alkyl, Furanyl-C 4 -alkyl, ^ eniI-C1-Alkyl, imidazolyl-C 1-4 alkyl, Pyridinyl-C 1-4 alkyl and IndoI-C1-Sa-alkyl, wherein C1-Salkyl is optionally substituted with a substituent selected from the group consisting of C1-8 alkoxy, hydroxy and -NR6, where C1-8 alkoxy is optionally substituted with -NHR6, where each example of phenyl is optionally substituted with one, two or three substituents each selected from the group consisting of C 1-8 alkoxy, chloro, fluoro, bromo and halo-C 1-8 alkyl, and each example of 1,2,3,4 -tetrahydro-isoquinolinyl, pyrrolidin-C1-8 alkyl, piperidinyl-C1-8 alkyl, piperazinyl-C1-8 alkyl is optionally substituted by oxo, C 1-8 alkylcarbonyl, C 1-8 alkoxycarbonyl, arylcarbonyl, arylC 1-8 alkoxycarbonyl, arylC 1-8 alkyl-N (R 5) -carbonyl or arylC 1-8 alkylsulfonyl; R2 is a substituent selected from the group consisting of hydrogen, C1-8 alkyl, C1-6 alkoxy and halogen; R3 is one or two substituents each selected from the group consisting of hydrogen and C1-4 alkyl; R4 is a substituent selected from the group consisting of hydrogen, C1-8 alkyl and halogen; C 1-8 alkoxycarbonyl, C 1-8 alkyl-N (R 5) -carbonyl, phenylC 1-8 alkoxycarbonyl, phenyl-N (R 5) -carbonyl, phenylC 1-8 alkyl-N (R 5) -carbonyl and phenyl -C 1-8 alkylsulfonyl; and R5 is selected from the group consisting of hydrogen and C1-4 alkyl; R6 is selected from the group consisting of C1-8 alkylcarbonyl, R7 is selected from the group consisting of C1-8 alkyl and phenyl-C1-8 alkyl. Compound of Formula (Ic): R 2 is and forms thereof, wherein Y is selected from the group consisting of CH 2, O and S; L 1 is absent or selected from the group consisting of -C (O) O-R 1, -C (O) N (R 5) -R 1 and -NHC (O) -R 1; L2 is C1-6 alkyl; L3 is absent or is -C (O) N (R5) -R7; R1 is selected from the group consisting of C1-8 alkyl, C1-8 alkoxy, aryl, aryl-C1-8 alkyl, C3-4 cycloalkyl, C6-cycloalkyl-C1-alkyl, heterocyclyl, heterocyclyl-C1-8 alkyl, heteroaryl and heteroaryl-C1-8 alkyl wherein C 1-8 alkyl is optionally substituted with one, two or three substituents each selected from the group consisting of C 1-8 alkoxy, halogen, hydroxy and -NHR 6, wherein C 1-8 alkoxy is optionally substituted with one, two or three substituents each one selected from the group consisting of C 1-8 alkoxy, halogen, hydroxy and -NHR 6, wherein each example of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, halogen and halo-C1-8 alkyl, and wherein each example of heterocyclyl is optionally substituted by oxo, C1-8 alkylcarbonyl, C1-8 alkoxycarbonyl, C1-8-alkyl N (R5) -carbonyl, arylcarbonyl, aryl- C 1-6 alkylcarbonyl, arylC 1-8 alkoxycarbonyl, aryl-N (R 5 ) -Carbonyl, aryl-C 1-4 alkyl-NR 6 -carbonyl or aryl-C 1-8 alkylsulfonyl; R2 is one, two or three substituents each selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 alkoxy and halogen; R3 is one, two or three substituents each selected from the group consisting of hydrogen and C-Malkyl; R 4 is one, two or three substituents each selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 alkoxy, hydroxy and halogen; R5 is selected from the group consisting of hydrogen and C1-4 alkyl; R 6 is selected from the group consisting of C 1-8 alkylcarbonyl, C 1-8 alkoxycarbonyl, C 1-8 alkyl-N (R 5) carbonyl, arylcarbonyl, arylC 1-8 alkylcarbonyl, aryl-C 1-4 alkoxycarbonyl, aryl-N (R5) -carbonyl, aryl-C1-8 alkyl-N (R5) -carbonyl and aryl-C1-8 alkylsulfonyl; and, R 7 is selected from the group consisting of C 1-8 alkyl, aryl, aryl-C 1-8 alkyl, C 3-14 cycloalkyl, C 3-14CycloalkylC 1-8 alkyl, heterocyclyl, heterocyclyl-C 1-8 alkyl, heteroaryl and heteroaryl-C 1-6 alkyl. The compound of claim 26, wherein R 1 is selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, phenyl-C 1-8 alkyl, naphthyl-C 1-6 alkyl, indanyl, cyclopropyl-C 1-8 alkyl, cyclohexyl-C 1-8 alkyl, 1, 2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-C 1-8 alkyl, piperidinyl-C 1-8 alkyl, piperazinyl-C 1-8 alkyl, furanyl-C 1-8 alkyl, thienyl-C 1-8 alkyl, imidazolyl-C 1-8 alkyl, pyridinyl-C 1-4. C 1-8 alkyl and indolyl-C 1-8 alkyl, wherein C 1-8 alkyl is optionally substituted with a substituent selected from the group consisting of C 1-8 alkoxy, hydroxy and -NR 6, wherein C 1-8 alkoxy is optionally substituted with -NHR 6, wherein each The example phenyl is optionally substituted by one, two or three substituents each selected from the group consisting of C1-Saloxy, chloro, fluoro, bromo and halo-C1-8 alkyl, and wherein each example is 1.2.3, 4-Tetrahydro-isoquinolinyl, pyrrolidin-C 1-8 alkyl, piperidinyl-C 1-8 alkyl, piperazinyl-C 1-8 alkyl is optionally substituted with oxo, C 1-8 alkylcarbonyl, C 1-8 alkoxycarbonyl, arylcarbonyl, arylC 1-8 alkoxycarbonyl, arylC 1-8 alkyl-N (R 5) -carbonyl or aryl-C 1-8 alkylsulfonyl; R2 is a substituent selected from the group consisting of hydrogen, C1-8 alkyl, C1-Salcoxy and halogen; R3 is one or two substituents each selected from the group consisting of hydrogen and C1-4 alkyl; R4 is a substituent selected from the group consisting of hydrogen, C1-8 alkyl and halogen; R5 is selected from the group consisting of hydrogen and C1-4 alkyl; R 6 is selected from the group consisting of C 1-8 alkylcarbonyl, C 1-8 alkoxycarbonyl, C 1-8 alkyl-N (R 5) -carbonyl, phenyl-C 1-8 alkoxycarbonyl, phenyl-N (R 5) -carbonyl, phenyl -C 1-8 alkyl-N (R 5) -carbonyl and phenylC 1-8 alkylsulfonyl; and R7 is selected from the group consisting of C1-8 alkyl and phenyl-C1-8 alkyl. Compound of Formula (Id): and forms thereof, wherein Y is selected from the group consisting of CH2, O and S; L1 is absent or selected from the group consisting of -C (O) O-R1, -C (O) N (R5) -R1 and -NHC (O) -R1; L2 is C1-Salquila; L3 is absent or is -C (O) N (R5) -R7; R 1 is selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, aryl, C 1-8 arylC 1-8 alkyl, C 3-14 cycloC 1-8 alkylalkyl, heterocyclyl, heterocyclyl-C 1-6 alkyl, heteroaryl and heteroaryl-C 1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one, two or three substituents each selected from the group consisting of C1-8 alkoxy, halogen, hydroxy and -NHR6, wherein C1-Salcoxy is optionally substituted with one, two or three substituents each. one selected from the group consisting of C1-Salcoxy, halogen, hydroxy and -NHR6, wherein each example of aryl is optionally substituted with one, two or three substituents each selected from the group consisting of C1-Salkyl, C1-8 alkoxy, halogen and wherein each example of heterocyclyl is optionally substituted by oxo, C1-8 alkylcarbonyl, C1-8alkoxycarbonyl, C1-8alkyl-N (R5) carbonyl, arylcarbonyl, arylcarbonyl, C 1-8 alkylcarbonyl, aryl-C 1-8 alkoxycarbonyl, aryl-N (R 5) -C arbonyl, aryl-C 1-8 alkyl-N (R 5) -carbonyl or aryl-C 1-8 alkylsulfonyl; R2 is one, two or three substituents each selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 alkoxy and halogen; R3 is one, two or three substituents each selected from the group consisting of hydrogen and C1-4 alkyl; R4 is one, two or three substituents each selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 alkoxy, hydroxy and halogen; R5 is selected from the group consisting of hydrogen and C1-4 alkyl; R 6 is selected from the group consisting of C 1-8 alkylcarbonyl, C 1-8 alkoxycarbonyl, C 1-8 alkyl-N (R 5) -carbonyl, arylcarbonyl, aryl-C 1-8 alkylcarbonyl, aryl-C 1-8 alkyloxy carbonyl, aryl-N (R5) -carbonyl, aryl-C1-8 alkyl-N (R5) -carbonyl and aryl-C1-8 alkylsulfonyl; and, R 7 is selected from the group consisting of C 1-8 alkyl, aryl, aryl-C 1-8 alkyl, C 3 -Mycicloalkyl, C 3-14 cycloalkyl-C 1-8 alkyl, heterocyclyl, heterocyclyl-C 1-8 alkyl, heteroaryl and heteroaryl-C 1-8 alkyl. The compound of claim 28, wherein R 1 is selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, phenyl-C 1-6 alkyl, naphthyl-C 1-8 alkyl, indanyl, cyclopropyl-C 1-8 alkyl, cyclohexyl-C 1-4. 8alkyl, 1,2,3,4-tetrahydro-isoquinolinyl, pyrrolidinyl-C 1-8 alkyl, piperidinyl-C 1-8 alkyl, piperazinyl-Cvealkyl, furanyl-C 1-8 alkyl, thienyl-C 1-6 alkyl, imidazolyl C 1-8 alkyl, pyridinyl C1-8 alkyl and indolyl-C1-8 alkyl, wherein C1-8 alkyl is optionally substituted with a substituent selected from the group consisting of C1-8 alkoxy, hydroxy and -NR6, where C1-8 alkoxy is optionally substituted with -NHR6, in which whereas each example of phenyl is optionally substituted with one, two or three substituents each selected from the group consisting of C1-8 alkoxy, chloro, fluoro, bromo and halo-C1-8 alkyl, and wherein each example is 1.2, 3,4-Tetrahydro-isoquinolinyl, pyrrolidin-C 1-8 alkyl, piperidinyl-C 1-8 alkyl, piperazinyl-C 1-6 alkyl is optionally substituted by oxo, C 1-6 alkylcarbonyl, C 1-8 alkoxycarbonyl, arylcarbonyl aryl-C 1-8 alkoxycarbonyl, aryl-C 1-8 alkyl-N (R 5) -carbonyl or aryl-C 1-8 alkylsulfonyl; R2 is a substituent selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 alkoxy and halogen; R3 is one or two substituents each selected from the group consisting of hydrogen and C1-4 alkyl; R4 is a substituent selected from the group consisting of hydrogen, C1-8 alkyl and halogen; R5 is selected from the group consisting of hydrogen and C1. 4alkyl; R6 is selected from the group consisting of C1-Alkylcarbonyl, C1-8 alkoxycarbonyl, C1-8alkyl-N (R5) carbonyl, phenylCvealcoxycarbonyl, phenyl-N (R5) carbonyl, phenylC1 .8-alkyl-N (R5) -carbonyl and phenyl-C1-8 alkylsulfonyl; and R7 is selected from the group consisting of C1-Salquila and phenyl-C-1-8 alkyl. 30. Compound selected from the group consisting of: Level 12- {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-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} - / V- (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-methyl-2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4 - yl) ethyl] piperidin-4-yl} benzamide, 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, N- [2- (2,4-dichloro-phenyl) ethyl] -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) -ethyl] -piperidin-4-yl} -benzamide, Level 1 N- [2- (4-chloro-phenyl) -ethyl] -2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-i 1} -benzamide, N- [2- (3,4-dimethoxy-phenyl) -ethyl] -2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-2-one 4-yl) ethyl] piperidin-4-yl} benzamide, N- [2- (3,4-dichloro-phenyl) ethyl] -2- {1- [2- (3-oxo-2, 3-Dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-yl} -benzamide, N- [2- (4-chloro-phenyl) -1-methyl-ethyl] -2 - {1- [2- (3-Oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -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-one yl} -benzamide, N- [2- (4-methoxy-phenyl) -ethyl] -2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-one yl) -ethyl] -piperidin-4-yl} -benzamide, N- [2- (2-methoxy-phenyl) -ethyl] -2- {1- [2- (3-oxo-2,3-dihydro] benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzamide, 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, N- [2- (3,5-dimethoxy-phenyl) -benzamide 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-dihydro-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-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-yl } -benzamide, N- [2- (2,5-difluoro-phenyl) -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-phenyl) 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- (1H-indol-3-yl) -benzamide ethyl] -2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-yl} -benzamide, Level 1 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-4-yl} -N- (2-phenyl-propyl) -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 1,3-dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} -N- (2-pyrrolidin-1-yl-ethyl) benzamide, N-cyclohexylmethyl-2-one {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} -benzamide, N- (2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-yl} -phenyl) -3-phenyl-2-one propionamide, [4- (2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidine-acid-tert-butyl ester 4-yl} -benzoylamino) -butyl] -carbamic, N- (2-methoxy-ethyl) -2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazinyl] 4-yl) -ethyl] -piperidin-4-yl} -benzamide, N- (3-methoxy-propyl) -2- {1- [2- (3-oxo-2,3-dihydro-benzo [1, 4] ox azin-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-yl) 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] benzamide2- {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) -ethyl] -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-ylmethyl-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, Level 1 -2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-yl } -N-thiophen-2-ylmethyl-benzam Acid, -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-yl} benzamide, N- (2-acetylaminoethyl) -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) acid tert-butyl ester -dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-yl} -benzoylamino) -methyl] -piperidine-1-carboxylic, -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) -propyl] -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-benzo [1,4] oxazin-3-one, N- [2- (3-naphthalen-2-yl-ureido) ethyl] -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) ethyl] -2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-yl} -benzamide, 5-chloro acid methyl ester -2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-yl} -benzoic, -5-chloro- 2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-yl} -N-phenethyl-benzamide ester of 4 - [(5-chloro-2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-2-acid tert-butyl 4-yl} -benzoylamino) -methyl] -piperidine-1-carboxylic, -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) tert-butyl ester -2,3-dihydro-benzo [1,4] oxazin-4-yl) ethyl] -piperidin-4-yl} -benzoylamino) -butyl] -carbamic, -5-chloro-N- (2-naphthalene) 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, Level 1 benzyl ester of 4 - [(5-chloro-2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-yl} acid -benzoylamino) methyl] piperidine-1-carboxylic, N- (1-benzoyl-piperidin-4-ylmethyl) -5-chloro-2- {1- [2- (3-oxo-2,3-dihydroxy) benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzamide, -5-chloro-N- [1- (3,3-dimethylbutyryl) piperidin-4-ylmethyl ] -2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-yl} -benzamide, tert-ester 4- [2- (5-chloro-2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-yl butyl 4-yl} -benzoylamino) -ethyl] -piperazine-1-carboxylic acid 4 - [(5-chloro-2- {1- [2- (3-oxo-2,3-dihydro-benzo [1 4,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) methyl] piperidin-1-carboxylic acid 4- [2- (5-chloro-2) tert-butyl ester - {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-yl} -benzoylamino) -ethyl] -piperidine-1 -carboxylic, [4- (5-chloro-2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -benzyl ester 1] -piperidin-4-yl} -benzoylamino) -butyl] -carbamic acid [5- (5-chloro-2- {1- [2- (3-oxo-2,3-methyl) -butyl ester] dihydro-benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) pentyl] carbamic -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-2-one piperidin-4-ylmethyl) benzamide, -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, [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, -5-chloro-N- [5- (3,3-dimethyl-butyrylamino) -pentyl] -2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-2-one 4-yl) ethyl] piper idin-4-yl} benzamide, Level 1 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-phenylmethanesulfonylamino-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] -acetamide ethyl} -carbamic, -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-benzo [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-acid tert-butyl ester yl} -benzoylamino) -pentyl] -carbamic, -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-benzo [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-one, -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-dihydroxy) methyl ester benzol [1,4] oxain-4-yl-ethyl] -piperidin-4-yl-benzoic acid 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 ] -pi perazine-1-carboxylic acid, Level 1 [5- (5-chloro-2- {8- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazinecarboxylic acid) tert-butyl ester 4- [2- (4-yl) -ethyl] -8-aza-bicyclo [3.2.1] oct-2-en-3-yl} -benzoylamino) -pentyl] -carbamic acid tert-butyl ester 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 [5- (2- {8- [2- (3-oxo-2,3-dihydro-benzo [1,4]) tert-butyl ester oxazin-4-yl) ethyl] -8-aza-bicyclo [3.2.1] oct-3-yl} -benzoylamino) -pentyl] -carbamic acid [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, 4- [2- (2- {8- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) acid tert-butyl ester -ethyl] -8-aza-bicyclo [3.2.1] oct-3-yl} -benzoylamino) -ethyl] -piperazine-1-carboxylic acid [5- (5-chloro-2-yl) tert-butyl ester {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 4- [2- (3-phenyl-8-aza-bicyclo [3.2.1] oct-8-yl) ethyl] - 4H-benzo [1,4] oxazin-3-one, [5- (5-chloro-2- {2,6-dimethyl-1- [2- (3-oxo-2), tert-butyl ester 3-Dihydro-benzo [1,4] oxazin-4-yl) ethyl] -1,2,3,6-tetrahydropyridin-4-yl} -benzoylamino) pentyl] -carbamic acid dimethyl amide 1 - [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -4-phenylpiperidine-4-carboxylic acid 1- [2- ( 3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) ethyl] -4-phenylpiperidine-4-carboxylic acid 1- [2- (3- oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -4-phenyl-piperidine-4-carboxylic acid 1- [2- (3- (3-methyl) -phenyl] -amide oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -4-phenyl-piperidine-4-carboxylic acid 1- [2- (2-phenyl-propyl) -amide 1- (3-Oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -4-phenyl-piperidine-4-carboxylic acid, (4-phenyl-butyl) -amide [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -4-phenyl-2-one piperidine-4-carboxylic acid 4- (4-chloro-phenyl) -1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -acetamide ethyl] -piperidine-4-carboxylic acid, Level 1 1- (e-chloro-S-oxo-S-dihydro-benzothloxy oxazin-10-ethyl-H-chloro-phenyl-piperidine) dimethylamide carboxylic acid 4- (4-chloro-phenyl) -1- [2- (6-methyl-3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] dimethylamide -piperidine-4-carboxylic acid 4- (4-chloro-phenyl) -1- [2- (6-fluoro-3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-acid) dimethylamide yl) ethyl] piperidine-4-carboxylic acid 4- (4-chloro-phenyl) -1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4) acid dimethylamide -yl) ethyl] piperidine-4-carboxylic acid 4- (4-chloro-phenyl) -1- [2- (3-oxo-2,3-dihydro-benzo [1,4] thiazinecarboxylic acid) dimethylamide 4-yl) -ethyl] -piperidine-4-carboxylic acid 4- (4-chloro-phenyl) -1- [2- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) -dimethylamide yl) ethyl] piperidine-4-carboxylic acid, and 4- [2- (4-phenyl-piperidin-1-yl) propyl] -4H-benzo [1,4] oxazin-3-one. The compound of claim 30, wherein the compound is selected from the group consisting of: Level 2 -2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazinyl). 4-yl) -ethyl-piperidin-4-yl} - [[(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- (1H-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-2,3-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) tert-butyl ester ) -ethyl] -piperidin-4-yl} -benzoylamino) -butyl] -carbamic acid, 4 - [(2- {1- [2- (3-oxo-2,3-dihydroxy) tert-butyl ester benzo [1,4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) methyl] piperidin-1-carboxylic N- [2- (3-naphthalen-1-yl urea] ) -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, Level 2 4 - [(5-chloro-2) acid tert-butyl ester - {1- [2- (3-oxo-2,3-dihydro-benzothiyl] -oxoxin-1-O-ethyl-piperidin-1-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} acid -benzoylamino) -butyl] -carbamic, -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, 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-dimethylbutyryl) piperidin-4-ylmethyl] -2- {1 - [2- (3-Oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-yl} -benzamide, 4- [Acid tert-butyl ester 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 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 4- [2- (5-chloro-2- {1- [2] tert-butyl ester - (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-yl} -benzoylamino) -ethyl] -piperidine-1-carboxylic acid benzyl ester [4- (5-chloro-2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-yl acid } -benzoylamino) -butyl] -carbamic, [5- (5-chloro-2- {1- [2- (3-oxo-2,3-dihydro-benzo [1,4]) acid tert-butyl ester oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) pentyl] carbamic -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, Level 2 [6- (5-chloro-2- {1- [2- (3-oxo-2,3-dihydro-benzo [1] tert-butyl ester) , 4] oxazin-4-yl) ethyl] piperidin-4-yl} benzoylamino) hexyl] carbamic acid [5- (5-chloro-2- {1- [2- ( 3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-yl} -benzoylamino) -pentyl] -carbamic, -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-phenylmethanesulfonylamino-pentyl) benzamide, {2- [2- (5-chloro-2) acid tert-butyl ester - {1- [2- (3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-yl} -benzoylamino) -ethoxy] -ethyl } -carbamic, -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-benzo [1,4] oxazin-4-yl) -ethyl] -piperidin-4-yl} -N- [5- (3-phenethyl-ureido) -pentyl] -benzamide ester of [5- (5-Chloro-2- {1- [2- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) -ethyl] -piperidin-4-yl} acid tert-butyl -benzoylamino) pentyl] carbamic, -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- (5-chloro-2- {8- [2] acid tert-butyl ester - (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 and [5- (5-chloro-2- {8- [2- (3-oxo-2,3-dihydro-benzo [1, 4] oxazin-4-yl) ethyl] -8-aza-bicycl [3.2.1] oct-2-en-3-yl} -benzoylamino) -pentyl] -carbamic. A pharmaceutical composition comprising the compound of claim 1 or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. 33. A method of treating or preventing a disease or condition in a patient whose disease or condition is affected by urotensin II receptor antagonism, the method of which comprises administering to the patient in need of such treatment or preventing an amount of the compound of claim 1 or a form thereof. A method for treating or ameliorating an Urotensin II mediated disorder in a patient in need thereof comprising administering to the patient an effective amount of the compound of Claim 1 or a form thereof. The method of claim 34, wherein the Urotensin II-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 insufficiency, renal insufficiency caused by drug-induced toxicity, nephrotoxicity and diarrhea caused by antineoplastic agents, nephrotoxicity caused by radiocontrast and aminoglycoside agents, post-myocardial infarction, pulmonary hypertension, pulmonary fibrosis, resistance - insulin therapy and impaired glucose tolerance, diabetes, diabetic complications, diabetic nephropathy, pain, Alzheimer's disease, seizures, depression, migraine, psychosis, anxiety, neuromuscular deficit and stroke. The method of claim 34, wherein the Urotensin II-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. 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. cerebral. The method of claim 34, wherein said effective amount is from about 0.001 mg / kg / day to about 300 mg / kg / day. The method of claim 36, wherein the urotensin II mediated disorder is heart failure. Use of the compound of claim 1 for the manufacture of a medicament for treating or ameliorating a Urotensin II-mediated disorder in a patient in need thereof. The use of claim 39, wherein the Urotensin II-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 insufficiency, renal insufficiency caused by drug-induced toxicity, nephrotoxicity and diarrhea caused by antineoplastic agents, nephrotoxicity caused by radiocontrast and aminoglycoside agents, post-myocardial infarction, pulmonary hypertension, pulmonary fibrosis, resistance - insulin therapy and impaired glucose tolerance, diabetes, diabetic complications, diabetic nephropathy, pain, Alzheimer's disease, seizures, depression, migraine, psychosis, anxiety, neuromuscular deficit and stroke. The use of claim 40, wherein the Urotensin II-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. cerebral. The use of claim 41, wherein the urotensin II-mediated disorder is heart failure.