MX2008009703A - Spiro imidazole derivatives as ppar modulators - Google Patents

Abstract

The invention provides compounds (Ia), (Ib) and (Ic), pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of the Peroxisome Proliferator-Activated Receptor (PPAR) families.

Description

SPIRO-IMIDAZOL DERIVATIVES AS PPAR MODULATORS BACKGROUND OF THE INVENTION Field of the Invention The invention provides compounds, pharmaceutical compositions comprising these compounds, and methods for using such compounds for the purpose of treating or preventing diseases or disorders associated with the activity of the proliferator-activated receptor families. peroxisome (PPAR). Background Peroxisome proliferator-activated receptors (PPARs) are members of the super-family of nuclear hormone receptors, which are transcription factors activated by the ligand, which regulate gene expression. Certain receptors activated by the peroxisome proliferator are associated with a number of disease states, including dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, atherogenesis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin disorders, respiratory diseases, ophthalmic disorders, IBDs (irritable bowel disease), ulcerative colitis, and Crohn's disease. In accordance with the above, the molecules that regulate the activity of the peroxisome proliferator-activated receptors are useful as therapeutic agents in the treatment of these diseases. BRIEF DESCRIPTION OF THE INVENTION In one aspect, the present invention provides compounds selected from Formulas la, Ib, and le: Ib where: n is selected from 1, 2, 3, 4, and 5; m is selected from 1, 2, 3, 4, and 5; each is independently from hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted by halogen, alkoxy of 1 to 6 carbon atoms, and alkoxy of 1 to 6 carbon atoms substituted by halogen; R3 is selected from alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkyl of 1 to 6 carbon atoms substituted by halogen, alkenyl of 2 to 6 carbon atoms substituted by halogen, -XIXO, heteroaryl of 5 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms, and cycloalkyl of 3 to 12 carbon atoms-alkyl of 0 to 4 carbon atoms; wherein R2 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; R is selected from hydrogen and alkyl of 1 to 6 carbon atoms; R5 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; or R4 and R5, together with the carbon atom to which R4 and R5 are attached, form carbonyl; And it is selected from N and CH; Z is selected from a bond, -S (O) 0.2-, and -CR ,, R, 2-; wherein R and R 12 are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms; A and B are independently selected from CH and N; R6 and R7 are independently selected from hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted by halogen, alkoxy of 1 to 6 carbon atoms, and alkoxy of 1 to 6 atoms carbon replaced by halogen; R8 is selected from -X2C02Ri3, -X2CR 4Ri5X3C02Ri2, -X2SCR14R15X3C02R13l and -X2OCR14Ri5X3C02R13; wherein X2 and X3 are independently selected from a bond and alkylene of 1 to 4 carbon atoms; and R and R15 are independently selected from hydrogen, alkyl of 1 to 4 carbon atoms, and alkoxy of 1 to 4 carbon atoms; or Ri4 and R15, together with the carbon atom to which R14 and R15 are attached, form cycloalkyl of 3 to 12 carbon atoms; and R13 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; R9 and R10 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, and -OR16; wherein R16 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; and the N-oxide derivatives, the pro-drug derivatives, the protected derivatives, the individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates (e.g., hydrates) of these compounds. In a second aspect, the present invention provides a pharmaceutical composition containing a compound of Formula I, or an N-oxide derivative, individual isomers, and mixtures of isomers thereof; or a pharmaceutically acceptable salt thereof, mixed with one or more suitable excipients. In a third aspect, the present invention provides a method for the treatment of a disease in an animal wherein the modulation of peroxisome proliferator-activated receptor activity can prevent, inhibit, or decrease the pathology and / or symptomatology of the Disease, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula I or an N-oxide derivative, individual isomers and mixtures of isomers thereof, or a pharmaceutically acceptable salt thereof. In a fourth aspect, the present invention provides the use of a compound of Formula I in the manufacture of a medicament for the treatment of a disease in an animal wherein the activity of the peroxisome proliferator-activated receptor contributes to the pathology and / or symptomatology of the disease. In a fifth aspect, the present invention provides a process for the preparation of compounds of Formula I, and N-oxide derivatives, pro-drug derivatives, protected derivatives, individual isomers, and mixtures of isomers thereof, and the pharmaceutically acceptable salts thereof. DETAILED DESCRIPTION OF THE INVENTION Definitions "Alkyl", as a group and as a structural element of other groups, for example alkyl substituted by halogen and alkoxy, can be straight or branched chain. Alcoxyl of 1 to 6 carbon atoms includes methoxy, ethoxy, and the like. Alkyl substituted by halogen includes trifluoromethyl, pentafluoro-ethyl, and the like. "Aryl" means a fused monocyclic or bicyclic aromatic ring assembly, containing from 6 to 10 ring carbon atoms. For example, aryl can be phenyl or naphthyl, preferably phenyl. "Arylene" means a divalent radical derived from an aryl group. "Heteroaryl" is as defined for aryl, wherein one or more of the ring members is a heteroatom. For example, heteroaryl includes pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzo- [1, 3] -dioxole, imidazolyl, benzoimidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl, etc. "Aryl of 6 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms" means an aryl as described above, connected by means of an alkylene group. For example, aryl of 6 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms includes phenethyl, benzyl, etc. "Cycloalkyl" means a monocyclic, fused bicyclic, or bridged polycyclic, saturated or partially unsaturated ring assembly containing the number of ring atoms indicated. For example, cycloalkyl of 3 to 10 carbon atoms includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. "Hetero-cycloalkyl" means cycloalkyl, as defined in this application, with the understanding that one or more of the ring carbon atoms indicated, are replaced by a fraction selected from -O-, -N =, - NR-, -C (O) -, -S-, -S (O) -, or -S (0) 2-, wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, or a protecting group of nitrogen. For example, hetero-cycloalkyl of 3 to 8 carbon atoms, as used in this application to describe the compounds of the invention, includes morpholino, pyrrolidinyl, piperazinyl, piperidinyl, piperidinylone, 1,4-dioxa-8-aza-spiro - [4.5] -dec-8-ilo, etc. "Halogen" (or halo) preferably represents chlorine or fluorine, but may also be bromine or iodine. "Treat", "treating", and "treatment", refer to a method to alleviate or abate an illness and / or its combined symptoms.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention provides compounds, compositions, and methods for the treatment of diseases wherein the modulation of one or more PPARs can prevent, inhibit, or diminish the pathology and / or symptomatology of the disease, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula I. In one embodiment, with reference to the compounds of Formulas la, Ib, and le: n is selected from 1, 2, 3, and 4; m is selected from 1, 2, and 3; each phase is independently selected from hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted by halogen, alkoxy of 1 to 6 carbon atoms, and alkoxy of 1 to 6 atoms carbon replaced by halogen; R3 is selected from alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkyl of 1 to 4 carbon atoms substituted by halogen, alkenyl of 2 to 6 carbon atoms substituted by halogen, -X1C (0) R2, heteroaryl of 5 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms, and cycloalkyl of 3 to 12 carbon atoms-alkyl of 0 to 4 carbon atoms; wherein R2 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; R is selected from hydrogen and alkyl of 1 to 6 carbon atoms; R5 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; or R and R5, together with the carbon atom to which R4 and R5 are attached, form carbonyl; And it is selected from N and CH; Z is selected from a bond, -S (O) 0-2-. and -CR Ri2-; wherein R (1 and R12 are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms; A and B are independently selected from CH and N; R6 and R7 are independently selected from hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted by halogen, and alkoxy of 1 to 6 carbon atoms; R8 is selected from -X2CO2R131 -X2CR14R15X3CO2R121 -X2SC R14R15X3CO2 R13, and -X2OC i4Ri5X3C02R13 wherein X2 and X3 are independently selected from a bond and alkylene of 1 to 4 carbon atoms, and R14 and R15 are independently selected from hydrogen and alkyl of 1 to 4 carbon atoms; R13 is selected from of hydrogen and alkyl of 1 to 6 carbon atoms, and R9 and R10 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, and -OR16, wherein R16 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; to 6 carbon atoms In another embodiment, it is independently selected from hydrogen, halogen, methoxy, trifluoromethoxy, and trifluoromethyl; R3 is selected from isobutyl, cyclopropyl-methyl, cyclobutyl-methyl, isopentyl, butyl, cyclopentyl-methyl, 3-methyl-but-2-enyl, pentyl, 2,2-dimethyl-propyl, 4-fluoro-butyl, 2-eti I-butyl, 2-methyl-pentyl, cyclohexyl-methyl, 3,3-dimethyl-2-oxo-butyl, pyrrolyl-propyl, 3-trifluoromethyl-propyl, cyclohexyl-ethyl, 2-ethyl- hexyl, 2-methyl-butyl, 3,4,4-trifluoro-but-3-enyl, and 3,3-dimethyl-butyl; R4 and R5 are each hydrogen, or R4 and R5, together with the carbon atom to which R4 and R5 are attached, form carbonyl; and Z is selected from a bond, -S (0) 2- and -CH2-. In another embodiment, R8 is selected from -CH2C (0) OH, -CH (CH2) C (0) OH, -OC (CH2) 2C (0) OH, - (CH2) 2C (0) OH and -OCH2C (0) OH; and R9 and R10 are independently selected from hydrogen, halogen, methyl, methoxy, and trifluoromethyl. Preferred compounds of the invention are selected from: (3- {3-isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8- triaza-spiro- [4.5] -dec-8-yl-methyl.}. phenyl) -acetic; (3- {3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl} -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -decan-8} -sulfonyl.} -4-methyl-phenyl) -acetic; (3- {3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro [4.5] -dec-8- il.}.-phenyl) -acetic; 2- (4-. {3-Isobutyl-1- [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1,3-diaza-spiro- [4.5] -dec-7 acid -yl-methyl.}. -phenyl) -propionic; (3- { 3-cyclopropyl-methyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4,5] -dec- 8-yl.}. Phenyl) -acetic; acid { 3- [3-isobutyl-2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1,3,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic; 2- (2-. {3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1,3,8-triaza-spiro- [4,5] -d acid ec-8-i I.} - pyrimidin-4-yloxy) -2- methyl I -propionic acid; 2- (3. {3-Cyclobutyl-methyl-1 - [2- (2,4-dichloro-phenyl) -ethyl] -2,4-dioxo-1,3-diaza-spiro- [4.5] -dec-8-yl.}. -phenoxy) -2-methyl-pro-ion; acid { 3- [3-cyclopropyl-methyl-2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1,3,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic; (3. {3-cyclobutyl-methyl-2,4-dioxo-1 - [2- (4-trifluoromethyl-phenyl) -etl] -1, 3,8-triaza-spiro- [ 4.5] -dec-8-yl.}. Phenyl) -acetic; (3- {3-cyclobutyl-methyl-1 - [4- (4-methoxy-phenyl) -butyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec} -8-yl.}.-Phenyl) -acetic; acid 3-. { 3-isobutyl I- 1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec-8-yl-methyl} -benzoic; (2- { 3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4,5] -dec-8- il-methyl] -phenyl) -acetic; (3- {3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl} -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -decan-8} -sulfonol.} -4-methoxy-faith or I) -acetic; 3- (3. {3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec acid -8-yl.}.-Phenyl) -propionic; (3- {3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl} -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec-8} -yl.}. -phenoxy) -acetic; 2- (3. {3-isobuti I- 1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] - dec-8-yl.}. -phenoxy) -2-methyl-propionic; (5- { 3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1,3,8-triaza-spiro- [4,5] -dec-8 -yl.} -2-methyl-phenyl) -acetic; (3- {3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl} -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec-8} -yl.}. -5-methyl-phenyl) -acetic; acid (2-fluoro-5-. {3-isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec-8-yl.}. phenyl) -acetic; (5- { 3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1,3,8-triaza-spiro- [4,5] -dec-8 -yl.} -2-trifluoro-methyl-phenyl) -acetic; (5- { 3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1,3,8-triaza-spiro- [4,5] -dec-8 -yl.} -2-methoxy-phenyl) -acetic; 2- (3. {3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec acid -8-yl.}.-Phenyl) -2-methyl-propionic; (5- { 3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1,3,8-triaza-spiro- [4,5] -dec-8 -yl.} -2-methyl-phenoxy) -acetic; acid (2-chloro-5-. {3-isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-d -oxo-1, 3,8-triaza-spiro- [ 4.5] -dec-8-yl.}. -phenoxy) -acetic; 2- (5- { 3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec acid -8-yl.} -2-methyl-phenoxy) -2-methyl-propionic acid; 2- (2-Chloro-5-. {3-isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [ 4.5] -dec-8-yl.}. -phenoxy) -2-methyl-pro pion ico; 2- (2,3-difluoro-5-. {3-isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro acid - [4.5] -dec-8-yl.}. -phenoxy) -2-methyl-pro-ion; (3- {3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2-oxo-1,3,8-triaza-spiro- [4.5] -dec-8-yl} .}.-phenyl) -acetic; (6- { 3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4,5] -dec-8 -yl.} - pyridin-2-yl) -acetic; (2- {3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-l, 3,8-triaza-spiro- [4.5] -dec-8} -yl.} - pyridin-4-yl) -acetic; acid (5-. {3-cyclobutyl-1-methyl-1 - [2- (2,4-dichloro-phenyl) -ethyl] -2,4-dioxo-1,3,8-triaza-spiro- [4.5 ] -dec-8-yl.} -2-methyl-phenyl) -acetic; 2- (5-. {3-Cyclobutyl-methyl-1- [2- (2,4-dichloro-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec-8-yl.} -2-methyl-phenoxy) -2-methyl-propionic; acid (2-chloro-5-. {3-cyclobutyl-methyl-1 - [2- (2,4-dichloro-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro - [4.5] -dec-8-yl.}. -phenoxy) -acetic; 2- (2-Chloro-5-. {3-cyclobutyl-methyl-1- [2- (2,4-dichloro-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza -spiro- [4.5] -dec-8-il.}. -phenoxy) -2-methyl-propionic; (6- { 3-Cyclobutyl-methyl-1 - [2- (2,4-dichloro-phenyl) -ethyl] -254-dioxo-1, 3,8-triaza-spiro- [4.5] -dec acid -8-il.} -pi ri din -2- i I) -acetic; (4- { 3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1,3,7-triaza-spiro- [4.5] -dec-7 -yl-methyl.}. -phenoxy) -acetic; (3- {3-Cyclobutyl-methyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1,3,8-triaza-spiro- [4.5] -dec acid -8-yl.}.-Phenyl) -acetic; acid { 3- [1 - [2- (4-methoxy-phenyl) -ethyl] -3- (3-methyl-butyl) -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec -8-yl] -phenyl} -acetic; (3- {3-Butyl-1 - [2- (4-methoxy-phenyl) -ethyl} -2,4-dioxo-l, 3,8-triaza-spiro- [4.5] -dec-8} -yl.}.-phenyl] -acetic; 2 - (4-. {3- 3 i so bu ti I-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [ 4.5] -dec-8-yl.} - pyrimidin-2-yloxy) -2-methyl-propionic acid; 2- (6- { 3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4,5] -dec acid -8-yl.} - pyrimidin-4-yloxy) -2-methyl-propionic acid; 2- (4-. {3-Cyclobutyl-methyl-1 - [2- (2,4-dichloro-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [ 4.5] -dec-8-yl.} - pyrimidin-2-yloxy) -2-methyl-propionic acid; 2- (2-. {3-Cyclobutyl-methyl-1 - [2- (2,4-dichloro-phenyl) -ethyl] -2,4-dioxo-1,3,8-triaza-spiro- [ 4.5] -dec-8-yl.} - pi rimidin-4-yloxy) -2-methyl-propionic acid; 2- (6-. {3-Cyclobutyl-methyl-1 - [2- (2,4-dichloro-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [ 4.5] -dec-8-yl.} - pyrimidin-4-yloxy) -2-methyl-propionic; acid { 3- [3-Cyclobutyl-methyl-2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1,3,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic; acid { 3- [3-Cyclobutyl-methyl-2,4-dioxo-1- (4-trifluoromethyl-benzyl) -1,3,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic; acid { 3- [3-cyclopentyl-methyl-2,4-dioxo-1- (4-trifluoromethyl-benzyl) -1,3,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic; acid { 3- [3-cyclopentyl-methyl-2,4-dioxo-1- (4-trifluoromethoxy-benzyl) -1,3,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic; acid { 3- [1 - (2,4-bis-trifluoro-methyl-benzyl) -3-cyclopentyl-methyl-2,4-dioxo-1, 3,8-triaza-spiro- [4,5] -dec-8- il] -phenyl} -acetic; acid { 3- [3-Cyclobutyl-methyl-2,4-dioxo-1- (3-trifluoromethoxy-benzyl) -1,3,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic; (3- {3-cyclobutyl-methyl-2,4-dioxo-1 - [4- (4-trifluoromethyl-phenyl) -thiazol-2-yl-methyl] -1,8,8-triaza -spiro- [4.5] -dec-8-yl.}. -phenyl) -acetic; (3. {3-cyclopropyl-methyl-2,4-dioxo-1- [4- (4-trifluoromethyl-phenyl) -thiazol-2-yl-methyl-1,3,8-tr! aza-spiro- [4.5] -dec-8-yl.] -phenyl] -acetic; acid { 3- [3- (3-methyl-but-2-enyl) -2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1, 3,8-triaza-spiro- [4.5] -dec -8-yl] -phenyl} -acetic; acid { 3- [1 - [2- (4-bromo-phenyl) -2-hydroxy-ethyl] -3- (3-methyl-butyl) -2,4-dioxo-1, 3,8-triaza-spiro- [ 4.5] -dec-8-il} -phenyl} -acetic; acid { 3- [1 - [2- (4-chloro-phenyl) -2-hydroxy-ethyl] -3- (3-methyl-butyl) -2,4-dioxo-1, 3,8-triaza-spiro - [4.5] -dec-8-yl] -phenyl} -acetic; acid { 3- [2,4-dioxo-3-pentyl-1- (4-trifluoro-methoxy-benzyl) -1,3,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic; acid { 3- [3- (2, 2-di methyl-propic2,4-dioxo-1 - (4-trifluoro-methoxy-benzyl) -1, 3,8-triaza-spiro- [4.5] -dec-8-yl ] -phenyl.} -acetic acid: {. 3- [3- (2-ethyl-butyl) -2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1, 3,8- triaza-spiro- [4.5] -dec-8-yl] -phenyl.} -acetic acid: {. 3- [3- (4-fluoro-butyl) -2,4-dioxo-1 - (4- trifluoro-methoxy-benzyl) -1,8,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic acid; {3- [3- (4-methyl-pentyl ) -2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1,8,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic acid {3- [3-cyclohexyl-methyl-2,4-dioxo-1 - (4-trifluoro-methoxy-benzyl) -1, 3,8-triaza-spiro- [4.5] -dec-8-yl] -phenol; -acetic acid; {.3- [2,4-dioxo-3- (3-pyrrol-1-yl-propyl) -1- (4-trifluoro-methoxy-benzyl) - 1, 3,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl.} -acetic acid: {. 3- [3- (3,3-dimethyl-2-oxo-butyl) -2,4-dioxo-1 - (4-trifluoro-methoxy-benzyl) -1,8,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic acid; 3- [2,4-dioxo-3- (4,4,4-trifluoro-butyl) -1- (4 -trifluoro-methoxy-benzyl) -1,3,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic; acid { 3- [3- (2-cyclohexyl-ethyl) -2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1, 3,8-triaza-spiro- [4.5] -dec-8-yl ] -phenyl} -acetic; acid { 3- [3- (2-ethyl-hexyl) -2,4-dioxo-1 - (4-trifluoro-methoxy-benzyl) -1, 3,8-triaza-spiro- [4.5] -dec-8-yl ] -phenyl} -ac0tico; acid { 3- [3- (2-methyl-butyl) -2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1, 3,8-triaza-spiro- [4.5] -dec-8-yl ] -phenyl} -acetic; acid { 3- [2,4-dioxo-3- (3,4,4-trifluoro-but-3-enyl) -1 - (4-trifluoro-methoxy-benzyl) -1, 3,8-triaza-spiro- [ 4.5] -dec-8-yl] -phenyl} -acetic; acid { 3- [3- (3,3-dimethyl-butyl) -2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1, 3,8-triaza-spiro- [4.5] -dec-8 -yl] -phenyl} -acetic; acid { 3- [1- (2,4-dichloro-5-fluoro-benzyl) -3- (3,3-dimethyl-butyl) -2,4-iioxo-1, 3,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic; acid { 3- [1- (2,4-dichloro-5-fluoro-benzyl) -3- (4-fluoro-butyl) -2,4-dioxo-1, 3,8-triaza-spiro- [4,5] -dec -8-yl] -phenyl} -acetic; (3. {3-Cyclobutyl-methyl-1 - [2- (2,4-dichloro-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec-8-yl.}. phenyl) -acetic; (3- {3-cyclopentyl-methyl-2,4-dioxo-1 - [2- (4-trifluoromethyl-phenyl) -ethyl} -1,8,8-triaza-spiro- [4.5] -dec-8-yl.}. phenyl) -acetic; (3- {3-cyclopentyl-methyl-1 - [2- (2,4-dichloro-phenyl) -ethyl} -2,4-dioxo-1,3,8-triaza-sphero- [4.5] -dec-8-yl.}. phenyl) -acetic; (3- {3-cyclohexyl-methyl-1 - [2- (2,4-dichloro-phenyl) -ethyl] -2,4-dioxo-1,3,8-triaza-spiro- [4.5] -dec-8-yl.} l-phenyl) -acetic; and (3- { 1 - [2- (4-Chloro-phenyl) -ethyl] -3-cyclopentyl-methyl-2,4-dioxo-1,3,8-triaza-spiro- [4,5] - dec-8-yl.}. phenyl) -acetic. Additional preferred compounds of Formula I are detailed in the Examples below. Pharmacology and Utility The compounds of the invention modulate the activity of the peroxisome proliferator-activated receptors, and as such, are useful for the treatment of diseases or disorders wherein the peroxisome proliferator-activated receptors contribute to the pathology and / or symptomatology of the disease. This invention further provides compounds of this invention for use in the preparation of medicaments for the treatment of diseases or disorders wherein the peroxisome proliferator-activated receptors contribute to the pathology and / or symptomatology of the disease. Therefore, these compounds can be used for the treatment or prophylaxis of dyslipidemia, hyperlipidemia, hypercholesteremia, atherosclerosis, atherogenesis, hypertriglyceridemia, heart failure, hypercholesterolemia, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, cachexia, syndrome of waste by HIV, inflammation, arthritis, cancer, Alzheimer's disease, anorexia, anorexia nervosa, bulimia, skin disorders, respiratory diseases, ophthalmic disorders, IBDs (irritable bowel disease), ulcerative colitis, and Crohn's disease. Preferably, for the treatment or prophylaxis of dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, atherogenesis, hypertriglyceridemia, cardiovascular diseases, hypertension, obesity, inflammation, cancer, skin disorders, IBDs (irritable bowel disease), ulcerative colitis, and Crohn's disease. The compounds of the invention can also be used to treat critical long-term diseases, to increase muscle mass and / or muscle strength, to increase lean body mass, to maintain muscle strength and function in old age, to improve muscle power and muscle function, and to reverse or prevent frailty in old age. In addition, the compounds of the present invention can be used in mammals as hypoglycemic agents for the treatment and prevention of conditions wherein impaired glucose tolerance, hyperglycemia, and insulin resistance are involved, such as type 1 diabetes and type 1 diabetes. 2, impaired glucose metabolism (IGM), impaired glucose tolerance (IGT), impaired glucose in fasting (IFG), and syndrome X. Preferably, type 1 and type 2 diabetes, impaired glucose metabolism (IGM), impaired glucose tolerance (IGT), and impaired fasting glucose (IFG). In accordance with the foregoing, the present invention further provides a method for preventing or treating any of the diseases or disorders described above, in a subject in need of such treatment, which method comprises administering to this subject a therapeutically effective amount (see "Administration and Pharmaceutical Compositions ", below) of a compound of the invention or a pharmaceutically acceptable salt thereof. For any of the above uses, the required dosage will vary depending on the mode of administration, the particular condition to be treated, and the desired effect. The present invention also relates to: i) a compound of the invention or a pharmaceutically acceptable salt thereof, for use as a medicament; and ii) the use of a compound of the invention or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for preventing or treating any of the diseases or disorders described above. Administration and Pharmaceutical Compositions In general, the compounds of the invention will be administered in therapeutically effective amounts by any of the usual and acceptable modes known in the art, either alone or in combination with one or more therapeutic agents. A therapeutically effective amount can vary widely, depending on the severity of the disease, the age and general health of the subject, the potency of the compound used, and other factors. In general, it is indicated that satisfactory results are obtained systemically with daily dosages of approximately 0.03 to 2.5 milligrams / kilogram of body weight. An indicated daily dosage in the higher mammal, for example in humans, is in the range of about 0.05 milligrams to about 100 milligrams, conveniently administered, for example, in divided doses up to four times a day, or in a delayed form. Unit dosage forms suitable for oral administration comprise from about 1 to 50 milligrams of active ingredient. The compounds of the invention can be administered as pharmaceutical compositions by any conventional route, in particular enterally, for example orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions, topically, for example in the form of lotions, gels, ointments, or creams, or in a nasal or suppository form. Pharmaceutical compositions comprising a compound of the present invention in free form or in a pharmaceutically acceptable salt form, in association with at least one pharmaceutically acceptable carrier or diluent, can be manufactured in a conventional manner by mixing, granulating, or coating methods. . For example, the oral compositions may be tablets or gelatin capsules comprising the active ingredient together with: diluent, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine; b) lubricants, for example silica, talc, stearic acid, its magnesium or calcium salt, and / or polyethylene glycol; for tablets also c) binders, for example magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxy methyl cellulose, and / or polyvinyl pyrrolidone; if desired d) disintegrants, for example starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or e) absorbers, colorants, flavors, and sweeteners. The injectable compositions can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from emulsions or fat suspensions. The compositions can be sterilized and / or contain adjuvants, such as preservatives, stabilizers, wetting agents, or emulsifiers, solution promoters, salts for regulating the osmotic pressure, and / or pH regulators. In addition, they may also contain other therapeutically valuable substances. Formulations suitable for transdermal applications include an effective amount of a compound of the present invention, with a carrier. A vehicle can include absorbable pharmacologically acceptable solvents to aid passage through the skin of the host. For example, the transdermal devices are in the form of a patch comprising a backup member, a reservoir containing the compound optionally with carriers, optionally a rate control barrier for delivering the compound to the skin of the host at a controlled rate and previously determined for a prolonged period of time, and elements to secure the device to the skin. Transdermal matrix formulations can also be used. The formulations suitable for topical application, for example to the skin and eyes, are preferably aqueous solutions, ointments, creams, or gels well known in the art. These may contain solubilizers, stabilizers, tonicity improving agents, pH regulators, and preservatives. This invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound as described herein, in combination with one or more pharmaceutically acceptable carriers. The compounds of the invention can be administered in therapeutically effective amounts in combination with one or more therapeutic agents (pharmaceutical combinations). Accordingly, the present invention also relates to pharmaceutical combinations, such as a combined preparation or a pharmaceutical composition (fixed combination), which comprise: 1) a compound of the invention as defined above, or a pharmaceutically acceptable salt thereof; and 2) at least one active ingredient selected from: a) anti-diabetic agents, such as insulin, insulin derivatives and mimetics; insulin secretagogues, such as sulfonyl-ureas, for example Glipizide, Gliburide, and Amaryl; insulinotropic sulfonyl urea receptor ligands, such as meglitinides, for example nateglinide and repaglinide; insulin sensitizers, such as protein tyrosine-1B phosphatase inhibitors (PTP-1B), such as PTP-112; inhibitors of GSK3 (glycogen synthase kinase-3), such as SB-517955, SB-4195052, SB-216763, NN-57-05441, and NN-57-05445; RXR ligands, such as GW-0791 and AGN-194204; inhibitors of the sodium-dependent glucose co-transporter, such as T-1095; inhibitors of glycogen A phosphorylase, such as BAY R3401; biguanides, such as metformin; alpha-glucosidase inhibitors, such as acarbose; GLP-1 (glucagon-1 peptide), GLP-1 analogs, such as exendin-4, and GLP-1 mimetics; inhibitors of DPPIV (dipeptidyl-peptidase IV), such as DPP728, LAF237 (vildagliptin - Example 1 of International Publication Number WO 00/34241), MK-0431, saxagliptin, GSK23A; an AGE breaker, a thiazolidone derivative (glitazone), such as pioglitazone, rosiglitazone, or (R) -1 - acid. { 4- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-yl-methoxy] -benzenesulfonyl} -2,3-dihydro-1 H-indole-2-carboxylic acid described in Patent Application Number WO 03/043985, as the compound 19 of Example 4, a PPARy agonist which is not of the glitazone type, for example Gl- 262570; b) hypolipidemic agents, such as inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) -reductase, for example lovastatin, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, dalvastatin, atorvastatin , rosuvastatin, and rivastatin; squalene synthase inhibitors; ligands FXR (farnesoid X receptor) and LXR (liver X receptor); cholestyramine; fibrates; nicotinic acid, and aspirin; c) an anti-obesity agent or an appetite regulating agent, such as phentermine, leptin, bromocriptine, dexamfetamine, amphetamine, fenfluramine, dexfenfluramine, sibutramine, orlistat, dexfenfluramine, mazindol, phentermine, phendimetrazine, diethylpropion, fluoxetine, bupropion, topiramate, diethyl-propion, benzophetamine, phenyl-propanol-amine, or ecopipam, ephedrine, pseudo-ephedrine, or cannabinoid receptor antagonists; d) anti-hypertensive agents, for example cycle diuretics, such as ethacrynic acid, furosemide, and torsemide; diuretics, such as thiazide derivatives, chlorothiazide, hydrochlorothiazide, amiloride; angiotensin-converting enzyme (ACE) inhibitors, such as benazepril, captopril, enalapril, fosinopril, Msinopril, moexipril, perinodopril, quinapril, ramipril, and trandolapril; inhibitors of the Na-K-ATPase membrane pump, such as digoxin; neutralendopeptidase (NEP) inhibitors, for example, thiorphan, terteo-thiorphan, SQ29072; ECE inhibitors, for example SLV306; ACE / NEP inhibitors, such as omapatrilate, sampatrilate, and fasidotril; angiotensin II antagonists, such as candesartan, eprosartan, irbesartan, losartan, telmisartan, and valsartan, in particular valsartan; renin inhibitors, such as aliskiren, lerlaquirene, dilequirene, RO 66-1132, RO-66-1168; ß-adrenergic receptor blockers, such as acebulolol, atenolol, belaxolol, bisoprolol, meioprolol, nadolol, propranolol, solalol, and timolol; inolopic agents, such as digoxin, dobutamine, and milrinone; calcium channel blockers, such as amlodipine, bepridil, dilliazem, felodipine, nicardipine, nimodipine, nifedipine, nisoldipine, and verapamil; Aldosterone receptor antagonists; and inhibitors of aldosterone synthase; e) an HDL-increasing compound; f) a cholesterol absorption modulator, such as Zetia® and KT6-971; g) Apo-A1 analogs and mimetics; h) thrombin inhibitors, such as Ximelagatran; i) aldosterone inhibitors, such as anastrazole, fadrazole, or eplerenone; j) inhibitors of platelet accumulation, such as aspirin, clopidogrel bisulfate; k) estrogen, testosterone, a selective modulator of the estrogen receptor, a selective modulator of the androgen receptor; I) a chemotherapeutic agent, such as aromatase inhibitors, for example femara, anti-estrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule-active agents, alkylating agents, anti-neoplastic anti-metabolites, platinum compounds, compounds which decrease the activity of the protein kinase, such as an inhibitor of the tyrosine kinase receptor of the platelet-derived growth factor, preferably Imatinib ( {N- { 5- [4- (4-methyl- piperazino-methyl) -benzoyl-amido] -2-methyl-phenyl.} -4- (3-pyridyl) -2-pyrimidine-amine.).), described in European Patent Application Number EP-A-0 564 409, as Example 21, or 4-methyl-N- [3- (4-methyl-imidazol-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyridin-3-yl -pyrimidin-2-ylamino) -benzamide, described in Patent Application Number WO04 / 005281 as Example 92; and m) an agent that interacts with a 5-HT3 receptor and / or an agent that interacts with a 5-HT4 receptor, such as tegaserod, described in United States Patent Number 5510353 as Example 13, maleate tegaserod acid, cisapride, cilansetron; or in each case, a pharmaceutically acceptable salt thereof; and optionally a pharmaceutically acceptable carrier.

The most preferred combination components are tegaserod, imatinib, vildagliptin, metformin, a thiazolidone derivative (glitazone), such as pioglitazone, rosiglitazone, or (R) -1 - acid. { 4- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-yl-methoxy] -benzenesulfonyl} -2,3-dihydro-1 H-indole-2-carboxylic acid, a sulfonyl-urea receptor ligand, aliskiren, valsarians, orlistat, or a statin, such as pitavastatin, simvastatin, fluvastatin, or pravastatin. Preferably, the pharmaceutical combination contains a therapeutically effective amount of a compound of the invention as defined above, in combination with a therapeutically effective amount of another therapeutic agent, as described above, e.g., each in a therapeutic dose. effective, as reported in the technique. The combination components (1) and (2) can be administered together, one after the other, or separately in a combined unit dosage form or in two separate unit dosage forms. The unit dosage form can also be a fixed combination. The structure of the active agents identified by generic or commercial names, can be taken from the current edition of the standard compendium "The Merck Index", or from the Physician's Desk Reference, or from the databases, for example Patents International (for example, IMS World Publications), or Current Drugs. The corresponding content thereof is incorporated herein by reference. Any person skilled in the art is absolutely qualified to identify the active agents and, based on these references, in the same way is able to manufacture and test the indications and pharmaceutical properties in conventional test models, both in vitro and in vivo. In another preferred aspect, the invention relates to a pharmaceutical composition (fixed combination), which comprises a therapeutically effective amount of a compound as described herein, in combination with a therapeutically effective amount of at least one active ingredient selected from from groups a) to m) described above, or in each case, a pharmaceutically acceptable salt thereof. A pharmaceutical composition or combination as described herein, for the manufacture of a medicament for the treatment of dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin disorders, respiratory diseases, ophthalmic disorders, inflammatory bowel diseases, IBDs (irritable bowel disease), colitis ulcerative, Crohn's disease, conditions involving impaired glucose tolerance, hyperglycemia, and insulin resistance, such as type 1 and type 2 diabetes, impaired glucose metabolism (IGM), impaired glucose tolerance ( IGT), impaired fasting glucose (IFG), and syndrome X. These therapeutic agents include estrogen, testosterone, a selective estrogen receptor modulator, a selective androgen receptor modulator, insulin, insulin derivatives and mimetics; insulin secretagogues, such as sulfonyl-ureas, for example Glipizide and Amaril; insulinotropic sulfonyl urea receptor ligands, such as meglitinides, for example nateglinide and repaglinide; insulin sensitizers, such as inhibitors of protein tyrosine-1B phosphatase (PTP-1B), inhibitors of GSK-3 (glycogen synthase kinase-3), or RXR ligands; biguanides, such as metformin; alpha-glucosidase inhibitors, such as acarbose; GLP-1 (glucagon-1 type peptide), GLP-1 analogs, such as Exendin 4, and GLP-1 mimetics; inhibitors of DPPIV (dipeptidyl peptidase IV), for example isoleucine-thiazolidide; DPP728 and LAF237, hypolipidemic agents, such as inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) -reductase, for example lovastatin, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, dalvastatin , atorvastatin, rosuvastatin, fluindostatin, and rivastatin, inhibitors of squalene synthase, or ligands FXR (farnesoid X receptor) and LXR (liver X receptor), cholestyramine, fibrates, nicotinic acid, and aspirin. A compound of the present invention can be administered either simultaneously, before, or after the other active ingredient, separately by the same or different route of administration, or together in the same pharmaceutical formulation. The invention also provides pharmaceutical combinations, for example a kit, which comprise: a) a first agent that is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) At least one co-agent. The kit may comprise instructions for its administration. The terms "co-administration" or "combined administration", or the like, as used herein, are intended to encompass the administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens wherein the agents are not necessarily administered by the same route of administration or at the same time. The term "pharmaceutical combination", as used herein, means a product resulting from the mixture or combination of more than one active ingredient, and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, for example a compound of Formula I and a co-agent, are both administered to a patient in a simultaneous manner in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, for example a compound of Formula I and a co-agent, are both administered to a patient as separate entities, either concurrently, concurrently, or in sequence, without specific time limits, where this administration provides therapeutically effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, for example the administration of three or more active ingredients. Processes for the Preparation of the Compounds of the Invention The present invention also includes processes for the preparation of the compounds of the invention. In the reactions described, it may be necessary to protect the reactive functional groups, for example the hydroxyl, amino, imino, thio, or carboxyl groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups can be used in accordance with standard practice, for example, see TW Greene and PGM Wuts in "Protective Groups in Organic Chemistry," John Wiley and Sons, 1991. The compounds of Formula 4 can be prepared by proceeding as in Reaction Scheme 1: wherein m, R ,, F, 9, R10, and n are as defined for Formula I. Compounds of Formula 4 are prepared by the reaction of a compound of Formula 2 with a compound of Formula 3 in the presence of a suitable solvent (e.g., acetic acid, and the like), and a suitable reagent (e.g., trimethylsilyl cyanide, and the like). The reaction is carried out in the temperature range from about 0 ° C to about 50 ° C, and takes up to about 24 hours to be performed. The compounds of Formula 5 are prepared proceeding as in Reaction Scheme 2: where m, R (, R9, R10, and n are as defined for the Formula I. Compounds of Formula 5 are prepared by first forming an intermediate, by reacting a compound of Formula 4 with a suitable reagent (eg, chlorosulfonyl isocyanate, and the like), and a suitable solvent (per example, dichloromethane, and the like). The reaction is carried out in a temperature range from about 0 ° C to about 50 ° C, and takes up to about 2 hours to be performed. Secondly, the intermediate is treated with a suitable acid (for example, 1 M HCl in water, and the like), in a temperature range of about 80 ° C to about 120 ° C, and takes up to about 6 hours to be carried out. . The compounds of Formula 6 can be prepared by proceeding as in Reaction Scheme 3: wherein m, R ^ R3, R9, R10, and n are as defined for Formula I, and Q is a halogen, preferably Cl, I, or Br. The compounds of Formula 6 are formed by the reaction of a compound of Formula 5 with R3Q1, in the presence of a suitable solvent (e.g., dimethyl sulfoxide, and the like), and a suitable base (e.g., potassium carbonate, and the like). The reaction is carried out in the temperature range of about 25 ° C to about 75 ° C, and takes up to about 24 hours to be performed. The compounds of Formula 7 can be prepared by proceeding as in Reaction Scheme 4: wherein m, R ,, R3, R9, R10, and n are as defined for Formula I. Compounds of Formula 7 are prepared by deprotection of a compound of Formula 6 in the presence of a suitable solvent (per example, methanol, and the like), a suitable catalyst (e.g., palladium on carbon, and the like), a suitable acid (e.g., HCI, and the like), and a suitable reducing agent (e.g., hydrogen, and the like. The reaction is carried out in the temperature range from about 0 ° C to about 50 ° C, and takes up to about 24 hours to be carried out The compounds of Formula 9 can be prepared by proceeding as in Reaction Scheme 5: wherein R3 is as defined for Formula I; and Qi is a halogen, preferably Cl, I, or Br. Compounds of Formula 9 are formed by the reaction of a compound of Formula 8 with R3Q1, in the presence of a suitable solvent (e.g., N, N -dimethyl-formamide, and the like), and a suitable base (e.g., cesium bicarbonate, and the like). The reaction is carried out in the temperature range of about 25 ° C to about 75 ° C, and takes up to about 24 hours to be performed.

The compounds of Formula 11 can be prepared by proceeding as in Reaction Scheme 6: wherein m, R3, R9, R10, and n are as defined for Formula I; and is a halogen, preferably Cl, I, or Br. The compounds of Formula 11 are formed by the reaction of a compound of Formula 9 with a compound of Formula 10, in the presence of a suitable solvent (e.g. , DMF, DME, and the like), and a suitable base (e.g., cesium carbonate, KF-AI203, and the like). The reaction mixture can be subjected to microwave radiation. The reaction is carried out in the temperature range of about 100 ° C to about 150 ° C, and takes up to about 30 minutes to be performed. The compounds of Formula 7 can be prepared by proceeding as in Reaction Scheme 6: (11) (7) wherein R ,, R3, R9, R10, and n are as defined for Formula I. Compounds of Formula 7 are prepared by deprotection of a compound of Formula 11 in the presence of a suitable solvent (e.g., dichloromethane, and the like), and a suitable acid (e.g., trifluoroacetic acid, and the like). The reaction is carried out in the temperature range from about 0 ° C to about 50 ° C, and takes up to about 5 hours to be performed. The compounds of Formula I, wherein Z is a bond, can be prepared by proceeding as in Reaction Scheme 7: wherein n, m, A, B, R ,, R3, R6, R7, R8, R9, and R10 are as defined for Formula I; and it is preferably chlorine, iodine, or bromine. The compounds of Formula I are prepared by the reaction of a compound of Formula 7 with a compound of Formula 12, in the presence of a suitable solvent (eg, 1,4-dioxane, and the like), a suitable catalyst (e.g., Pd2 (dba) 3, and the like), a suitable ligand (e.g., phosphine ligands, such as (dBU) 3PHBF3, and the like), a suitable inorganic base (e.g., cesium carbonate, and the like) ), under a suitable protective atmosphere (e.g., argon, and the like). The reaction is carried out in the temperature range from about 80 ° C to about 150 ° C, and takes up to about 24 hours to be performed. The compounds of Formula I, wherein Z is -S (O) 0-2- (SO2 shown), can be prepared by proceeding as in Reaction Scheme 8: wherein n, m, A, B, R ,, R3, R6, R7 > R8, R9, and R10 are as defined for Formula I. Compounds of Formula I are prepared by the reaction of a compound of Formula 7 with a compound of Formula 13, in the presence of a suitable solvent (per example, dichloromethane, and the like), a suitable organic base (e.g., triethylamine, and the like). The reaction is carried out in the temperature range from about 0 ° C to about 50 ° C, and takes up to about 24 hours to be performed. The compounds of Formula I, wherein Z is methylene, can be prepared by proceeding as in Reaction Scheme 9: where n, m, A, B, R ,, R3, R6, R7, Re. R9. and R10 are as defined for Formula I; and it's chlorine, bromine, or iodine. The compounds of Formula I are prepared by the reaction of a compound of Formula 7 with a compound of Formula 12, in the presence of a suitable solvent (for example, dichloromethane, and the like), a suitable base ( example, triethylamine, and the like). The reaction is carried out in the temperature range from about 0 ° C to about 50 ° C, and takes up to about 24 hours to be performed. The compounds of Formula I, wherein Z is a bond, can be prepared by proceeding as in Reaction Scheme 10: wherein n, m, A, B, R (, R3, R6, R7, Re. Ft9, and R10 are as defined for Formula I, and Q2 is chloro, bromo, or iodo.) Compounds of Formula I are prepared by the reaction of a compound of Formula 7 with a compound of Formula 14, in the presence of a suitable solvent (e.g., normal butanol, and the like), and a suitable base (e.g., di-isopropyl-ethyl-amine, and the like). The reaction is carried out in the temperature range of about 25 ° C to about 75 ° C, and takes up to about 24 hours to be performed. The compounds of Formula I, wherein R 1 is selected from and (and R 13 is alkyl of 1 to 6 carbon atoms), are converted to their corresponding acids (wherein R 13 is hydrogen), by means of a reaction of saponification The reaction proceeds in the presence of a suitable base (e.g., lithium hydroxide, or the like), and a suitable solvent mixture (e.g., tetrahydrofuran / water, or the like), and is carried out in the temperature range from about 0 ° C to about 50 ° C, taking up to about 30 hours to complete. The detailed reaction conditions are described in the Examples below. Additional Processes for the Preparation of the Compounds of the Invention A compound of the invention can be prepared as a pharmaceutically acceptable acid addition salt, by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of a compound of the invention can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Alternatively, the salt forms of the compounds of the invention can be prepared using the salts of the starting materials or the intermediates. The free acid or free base forms of the compounds of the invention can be prepared from the form of the base addition salt or the corresponding acid addition salt, respectively. For example, a compound of the invention in an acid addition salt form can be converted to the corresponding free base by treatment with a suitable base (for example, solution of ammonium hydroxide, sodium hydroxide, and the like). A compound of the invention in a base addition salt form can be converted to the corresponding free acid by treatment with a suitable acid (e.g., hydrochloric acid, etc.). The compounds of the invention in a non-oxidized form can be prepared from the N-oxides of the compounds of the invention by their treatment with a reducing agent (for example, sulfur, sulfur dioxide, triphenyl-phosphine, lithium borohydride). , sodium borohydride, phosphorus trichloride, tribromide, or the like), in a suitable inert organic solvent (eg, acetonitrile, ethanol, aqueous dioxane, or the like), from 0 ° C to 80 ° C. The pro-drug derivatives of the compounds of the invention can be prepared by methods known to those of ordinary skill in the art (for example, for further details, see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Volume 4 , page 1985). For example, appropriate pro-drugs can be prepared by reacting a non-derivatized compound of the invention with a suitable carbamylating agent (e.g., 1,1-acyloxy-alkyl-carbano-chlorhidate, para-nitrophenyl carbonate, or Similar). The protected derivatives of the compounds of the invention can be made by means known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protective groups and their removal can be found in TW Greene, "Protecting Groups in Organic Chemistry", 3rd Edition, John Wiley and Sons, Inc., 1999. The compounds of the present invention can be conveniently prepared, or can be formed, during the process of the invention, as solvates (eg, hydrates). The hydrates of the compounds of the present invention can be conveniently prepared by recrystallization from a mixture of aqueous / organic solvents., using organic solvents such as dioxin, tetrahydrofuran, or methanol.

The compounds of the invention can be prepared as their individual stereoisomers by reaction of a racemic mixture of the compound with an optically active resolving agent, to form a pair of diastereoisomeric compounds, the diastereomers are separated, and the optically pure enantiomers are recovered. Although the resolution of the enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of the invention, dissociable complexes (e.g., crystalline diastereomeric salts) are preferred. The diastereomers have different physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.), and can be easily separated by taking advantage of these differences. The diastereomers can be separated by chromatography, or preferably by separation / resolution techniques based on differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that does not result in racemization. A more detailed description of the techniques applicable to the resolution of the stereoisomers of the compounds can be found from their racemic mixture in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons , Inc., 1981. In summary, the compounds of Formula I can be made by a process that involves: (a) that of the reaction schemes detailed above; and (b) optionally converting a compound of the invention to a pharmaceutically acceptable salt; (c) optionally converting a salt form of a compound of the invention to a non-salt form; (d) optionally converting a non-oxidized form of a compound of the invention to a pharmaceutically acceptable N-oxide; (e) optionally converting an N-oxide form of a compound of the invention to its non-oxidized form; (f) optionally resolving an individual isomer of a compound of the invention from a mixture of isomers; (g) optionally converting a non-derivative compound of the invention into a pharmaceutically acceptable pro-drug derivative; and (h) optionally converting a pro-drug derivative of a compound of the invention to its non-derivatized form. As far as the production of the starting materials is not particularly described, the compounds are known or can be prepared in a manner analogous to methods known in the art, or as disclosed in the Examples below. I presented. One skilled in the art will appreciate that the above transformations are only representative of the methods for the preparation of the compounds of the present invention, and that other well known methods can be similarly employed. EXAMPLES The present invention is further exemplified, but not limited, by the following Intermediates and Examples, which illustrate the preparation of the compounds of Formula I according to the invention.

Step C Intermediate 5: 3-isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -1,8,8-triaza-spiro- [4.5] -decano-2,4-dione. Step A: The 1-benzyl-piperidin-4-one I (9.5 grams, 50 mmol) is dissolved in AcOH (75 milliliters), and cooled to 0 ° C. 4-Methoxy-phenethylamine (8.1 milliliters, 55 mmol) is added, followed by trimethylsilyl cyanide (6.7 milliliters, 50 mmol). The ice bath is removed, and the mixture is stirred at room temperature for 20 hours. The mixture is then poured into ice water, adjusted to a pH of 9 with aqueous ammonia, and extracted with dichloromethane twice. The organic layers are combined and concentrated. Recrystallization from ether gives 2 as a white solid. 1 H NMR (400MHz, CDCl 3) d = 7.26 (m, 5H), 7.07 (d, J = 8.5 Hz, 2H), 6.77 (d, J = 8.5 Hz, 2H), 3.72 (s, 3H), 3.46 (s) , 2H), 2.90 (t, J = 6.9 Hz, 2H), 2.70 (m, 4H), 2.27 (m, 2H), 1.91 (m, 2H), 1.69 (m, 2H). MS calculated for C22H28 30 (M + H +) 350.2, found 350.3. Step B: 1-Benzyl-4- [2- (4-methoxy-phenyl) -ethyl-amino] -piperidine-4-carbonitrile 2 (8.0 grams, 23 mmol) is dissolved in dichloromethane (100 milliliters), and cooled to 0 ° C. Chlorosulfonyl isocyanate (2.2 milliliters, 25 mmol) is added, the ice bath is removed, and the mixture is stirred at room temperature for 1 hour. Then the solvent is removed, 1 M HCl (100 milliliters) is added, and the mixture is heated to reflux for 3 hours. After adjusting the pH to 7, the mixture is extracted with dichloromethane three times. The solvent is removed, and the remainder is triturated with MeCN, to give 8-benzyl-1 - [2- (4-methoxy-phenyl) -ethyl] -1, 3,8-triaza-spiro- [4.5] - decane-2,4-dione 3 as a colorless solid. 1 H NMR (400MHz, CDCl 3) d = 7.33 (m.5H), 7.15 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 3.79 (s, 3H), 3.58 (s) , 2H), 3.36 (t, J = 7.9 Hz, 2H), 2.91 (t, J = 7.9 Hz, 2H), 2.76 (m, 4H), 1.88 (m, 2H), 1.60 (m, 2H). MS calculated for C23H28 3O3 (M + H +) 394.3, found 394.2. Step C: Hydantoin 3 (8.2 grams, 20.8 millimoles), 1-bromo-2-methyl-propane (2.83 milliliters, 26.1 millimoles) and potassium carbonate (3.7 grams, 27.1 millimoles), in dimethyl sulfoxide (50 milliliters) , they are stirred for 12 hours at 50 ° C. The mixture is cooled to room temperature, diluted with EtOAc, and washed with H20 three times, and with brine once. The organic layer is dried (MgSO 4), filtered, and concentrated. The residue is purified by flash chromatography (EtOAc / hexanes gradient), to give 8-benzyl-3-isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -1, 3,8- triaza-spiro- [4.5] -decano-2,4-dione 4 as a white solid: 1 H NMR (400 MHz, CDCl 3) d = 7.32 (m, 5 H), 7.13 (d, J = 8.7 Hz, 2 H), 6.83 (d, J = 8.7 Hz, 2H), 3.78 (s, 3H), 3.58 (s, 2H), 3.38 (t, J = 7.8 Hz, 2H), 3.30 (d, J = 7.4 Hz, 2H), 2.92 (t, J = 7.8 Hz, 2H), 2.75 (m, 4H), 2.08 (m, 1H), 1.87 (m, 2H), 1.49 (m, 2H), 0.90 (d, J = 6.7 Hz, 6H) . MS calculated for C27H36 3O3 (M + H +) 450.3, found 450.2.

Step D: Hydantoin 4 (0.25 grams, 0.56 mmol) is dissolved in MeOH (25 milliliters). A catalytic amount of palladium (10 percent on carbon, 50 milligrams) is added, followed by a catalytic amount (3 drops) of concentrated HCl. The mixture is placed under a hydrogen atmosphere, and stirred at room temperature for 20 hours. The mixture is filtered over Celite, washed with MeOH, and dried in vacuo to provide 3-isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -1,3,8-triaza-spiro- [4.5] -decano-2,4-dione 5 (220 milligrams, quantitative), as a colorless crystal: 1 H-NMR (400MHz, CDCl 3) d = 7.14 (d, J = 8.5 Hz, 2H), 6.78 (d, J = 8.5 Hz, 2H), 3.72 (s, 3H), 3.57 (m, 2H), 3.42 (t, J = 7.3 Hz, 2H), 3.34 (m, 2H), 3.27 (d, J = 7.4 Hz, 2H), 2.93 (t, J = 7.3 Hz, 2H), 2.36 (m, 2H), 2.04 (m, 1H), 1.45 (m, 2H), 0.86 (d, J = 6.7 Hz, 6H). MS calculated for C20H30N3O3 (M + H +) 360.2, found 360.2.

Intermediate 10: 3-isobuti I- 1 - [2- (4-methoxy-phenyl) -etl] -1,3,7-triaza-spiro- [4.5] -decano-2,4-dione . Step A: 1-Benzyl-3-pyridinone hydrochloride hydrate 6 (3.0 grams, 13.3 mmol) is dissolved in AcOH (30 milliliters), and cooled to 0 ° C. 4-Methoxy-phenethyl-amine (2.1 milliliters, 14.6 millimoles) is added, followed by trimethyl-cyanide cyanide (2.4 milliliters, 13.3 millimoles). The ice bath is removed, and the mixture is stirred at room temperature for 20 hours. The mixture is then poured into ice water, adjusted to a pH of 9 with aqueous ammonia, and extracted with dichloromethane twice. The organic layers are combined and concentrated to give a brown oil, which is used directly in the next step without purification. MS calculated for C22H28 3O (M + H +) 350.2, found 350.2. Step B: 1-benzyl-3- [2- (4-methoxy-phenyl) -ethyl-amino] -piperidine-3-carbonitrile 7 (13.3 mmol) is dissolved in dichloromethane (50 milliliters), and cooled to 0 ° C. Chlorosulfonyl isocyanate (1.3 milliliters, 14.6 millimoles) is added, the ice bath is removed, and the mixture is stirred at room temperature for 2 hours. The solvent is then removed, 1 M HCl (100 milliliters) is added, and the mixture is heated to reflux for 3 hours. After adjusting the pH to 7, the mixture is extracted with dichloromethane three times. The solvent is removed, and the residue is purified on reverse phase HPLC (gradient of H20 / MeCN), to give 7-benzyl-1 - [2- (4-methoxy-phenyl) -ethyl] -1,3, 7-triaza-spiro- [4.5] -decano-2,4-dione 8 as a colorless oil. 1 H-NMR (400MHz, CDCl 3) d = 7.16 (m, 5H), 7.08 (d, J = 8.8 Hz, 2H), 6.76 (d, J = 8.8 Hz, 2H), 3.98 (m, 1H), 3.70 ( s, 3H), 3.65 (m, 1H), 3.39 (d, J = 13.3 Hz, 1H), 3.33 (d, J = 13.3 Hz, 1H), 2.90 (m, 1H), 2.78 (m, 1H), 2.67 (m, 1H), 2.53 (d, J = 12.0 Hz, 1H), 2.46 (d, J = 12.0 Hz, 1H), 2.13 (m, 1H), 1.79 (m, 3H), 1.62 (m, 1H) ). MS calculated for C23H28 3O3 (M + H +) 394.3, found 394.2. Step C: Hydantoin 8 (1.2 grams, 3.0 millimoles), 1-bromo-2-methyl-propane (0.39 milliliters, 3.6 millimoles) and potassium carbonate (0.54 grams, 3.9 millimoles) in dimethyl sulfoxide (10 milliliters), they are stirred for 12 hours at 50 ° C. The mixture is cooled to room temperature, diluted with EtOAc, and washed with H20 three times, and with brine once. The organic layer is dried (MgSO4), filtered, and concentrated, to provide 7-benzyl-3-isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -1, 3,7-triaza -spiro- [4.5] -decano-2,4-dione 9 as a colorless oil, which is used directly in Step D: 1 H-NMR (400MHz, CDCl 3) d = 7.26 (m, 5H), 7.16 ( d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 4.00 (m, 1H), 3.80 (s, 3H), 3.79 (m, 1H), 3.52 (d, J = 13.2 Hz, 1H), 3.40 (d, J = 13.2 Hz, 1H), 3.29 (d, J = 7.6 Hz, 2H), 3.00 (m, 1H), 2.89 (m, 1H), 2.76 (m, 1H), 2.55 (m, 2H), 2.05 (m, 1H), 1.91 (m, 3H), 1.62 (m, 2H), 0.87 (d, J = 6.4 Hz, 6H). MS calculated for C27H36N303 (M + H +) 450.3, found 450.3. Step D: Hydantoin 9 (0.25 grams, 0.56 mmol) is dissolved in AcOH (20 milliliters). A catalytic amount of palladium (aMO percent on charcoal is added, 50 milligrams), and the mixture is pressurized to 60 psi (4.2 kg / cm2) of hydrogen, and stirred for 20 hours. The mixture is filtered on Celite, neutralized with aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic fraction is washed with brine, dried (MgSO 4), filtered, and evaporated, to give 3-isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -1, 3,7- triaza-spiro- [4.5] -decano-2,4-dione 10 as a colorless crystal: 1 H-NMR (400MHz, CDCl 3) d = 7.06 (d, J = 8.8 Hz, 2H), 6.77 (d, J = 8.8 Hz, 2H), 3.72 (s, 3H), 3.63 (s, 1H), 3.35 (m, 2H), 3.28 (d, J = 7.2 Hz, 2H), 3.02 (m, 1H), 2.85 (t, J = 7.6 Hz, 2H), 2.68 (m, 2H), 2.47 (m, 1H), 2.05 (m, 2H), 1.65 (m, 2H), 0.83 (d, J = 6.8 Hz, 6H). MS calculated for C20H30 3O3 (M + H +) 360.2, found 360.2.

Step C 1 »Intermediate 13: 3-isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -1,8,8-triaza-espyro- [4,5] -decan-2-one. Step A: Intermediate 4 (45 milligrams, 0.1 millimoles) is dissolved in MeOH (1.5 milliliters), and cooled to 0 ° C. Sodium borohydride (100 milligrams, 2.5 mmol) is added, and the mixture is stirred at 0 ° C for 30 minutes, and then stirred for 48 hours at room temperature. Crude 8-benzyl-4-hydroxy-3-isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -1,8,8-triaza-spiro- [4.5] -decan-2-one 11 is used in the next step without further purification. MS calculated for C27H38N303 (M + H +) 452.3, found 452.3. Step B: Intermediate 11 is dissolved in trifluoroacetic acid (1.5 milliliters), and cooled to 0 ° C. Sodium borohydride (40 milligrams, 1.0 mmol) is added, and the mixture is stirred at room temperature for 5 hours. Then the reaction mixture is poured into ice water, and extracted with EtOAc twice. The organic layers are combined, washed with water, and concentrated to provide 12 as a white solid. 1 H-NMR (400MHz, CDCl 3) d = 7.38-7.30 (m, 5H), 7.14 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 3.77 (s, 3H), 3.52 (s, 2H), 3.21 (t, J = 8.0 Hz, 2H), 3.09 (s, 2H), 2.98 (d, J = 7.5 Hz, 2H), 2.88 (m, 2H), 2.80 (d, J = 8.0 Hz, 2H), 1.99 (m, 2H), 1.84 (m, 3H), 1.37 (m, 2H), 0.90 (d, J = 6.7 Hz, 6H). MS calculated for C22H28N30 (M + H *) 436.3, found 436.3.

Step C: Hydantoin 12 (35 milligrams, 0.08 mmol) is dissolved in MeOH. A catalytic amount of palladium (10 percent on carbon, 50 milligrams) is added, followed by a catalytic amount (3 drops) of concentrated HCl. The mixture is placed under a hydrogen atmosphere, and stirred at room temperature for 20 hours. The mixture is filtered over Celite, washed with MeOH, and dried in vacuo to provide 3-isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -1,8,8-triaza-spiro- [4.5] -decan-2-one 13 (22 milligrams, quantitative), as a colorless crystal: MS calculated for C20H32N3O2 (M + H +) 346.2, found 346.2. 17 Intermediate 17: 3-propyl-1- (4-trifluoro-methoxy-benzyl) -1,3,8-triaza-spiro- [4.5] -decano-2,4-dione. Step A: A well stirred solution of 14 (2 grams, 7.4 mmol) in?,? - anhydrous dimethyl formamide (10 milliliters) is treated with CsHC03 (2.16 grams, 11.1 mmol), and 1-iodo-2-methyl- propane (2.0 grams, 11.1 millimoles). The reaction mixture is heated at 65 ° C for 8 hours. The reaction mixture is cooled and quenched with water, and extracted with EtOAc. The organic layer is washed once with 3N NaOH, water, brine, dried over Na2SO4, and concentrated to give the 3-isobutyl-2,4-dioxo-1,3,8-triaza-spiro tert-butyl ester. - [4.5] -decano-8-carboxylic acid 15 as a white solid. LC / MS (M + H +) = 326.2. Step B: A well-stirred solution of 15 (0.15 grams, 0.46 millimoles) in anhydrous N, N-dimethylformamide (1 milliliter) is treated with Cs2C03 (0.18 grams, 0.55 millimoles) and 1-bromo-methyl-4-trifluoro -methoxy-benzene (0.176 grams, 0.69 millimoles). The reaction mixture is irradiated in a microwave oven at 120 ° C for 20 minutes. The reaction mixture is directly purified by LC / MS preparation, using a gradient of MeCN / water of 90 to 10 percent. The solvent is removed in vacuo to provide 3-isobutyl-2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1,3,8-triaza-spiro- [4.5] - terbutil-ester. decan-8-carboxylic acid 16. 1 H-NMR (400 MHz, CDCl 3) d 7.23 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 4.42 (s, 2H), 3.97 -3.94 (bm, 2H), 3.42-3.30 (m, 2H), 3.30 (d, J = 8.0 Hz, 2H) 2.05 (quintet, J = 8.0 Hz, 1H), 1.68-1.64 (m, 2H) 1.49- 1.46 (m, 2H), 1.38 (s, 9H), 0.85 (d, J = 8.0Hz, 6H). MS (M + H +) = 500.3. Step C: 3-Isobutyl-2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1,3,8-triaza-spiro- [4,5] -decan-8-carboxylic acid terbutyl ester 16 (0.15 grams, 0.3 mmol) is dissolved in dichloromethane (1 milliliter), and treated with a 50 percent solution of trifluoroacetic acid / trichloromethane (2 milliliters). The reaction mixture is stirred at room temperature for 1 hour. The solvent is removed under vacuum to provide 17 as a trifluoroacetic acid salt in a quantitative yield. LC / MS (M + H +) = 400.2. 18 Intermediate 18: 3-cyclobutyl-methyl-1 - [2- (2,4-dichloro-phenyl) -ethyl] -1,3,8-triaza-espyro- [4,5] -decano-2,4 -Diona. Following the procedure of Intermediary 5, except that using 2,4-dichloro-phenethyl-amine to replace 4-methoxy-phenethylamine, and using (bromo-metit) -cyclobutane to replace 1-bromo-2 -methyl-propane, prepare the title compound as a clear liquid: 1 H NMR (400 MHz, CDCl 3) d = 7.38 (s, 1 H), 7.18 (s, 2 H), 3.52 (d, J = 7.4 Hz, 2 H) , 3.41 (t, J = 7.5 Hz, 2H), 3.34 (m, 2H), 3.11 (t, J = 7.3 Hz, 2H), 2.97 (m, 2H), 2.68 (m, 1H), 1.99 (m, 4H), 1.75 (m, 4H), 1.44 (d, J = 13.7 Hz, 2H). MS calculated for C2oH26Cl2N302 (M + H +) 410.1, found 410.1. 31 Intermediate 31: Ethyl ester of (3-bromo-methyl-phenyl) -acetic acid. Ethyl-m-tolyl acetate 30 (2.00 grams, 11.2 mmol) is dissolved in carbon tetrachloride (30 milliliters). NBS (1.90 grams, 10.7 millimoles) is added, followed by benzoyl peroxide (266 milligrams, 1.1 millimoles). The mixture is heated at 75 ° C overnight. The mixture is diluted with dichloromethane, and washed with water and saturated aqueous NaHCO3. The residue is purified by flash chromatography (EtOAc / hexanes gradient), to give the (3-bromo-methyl-phenyl) -acetic acid ethyl ester 31 as a colorless oil: 1 H NMR (400MHz, CDCl 3) d = 7.36-7.22 (m, 4H), 4.48 (s, 2H), 4.16 (q, J = 7.1 Hz, 2H), 3.61 (s, 2H), 1.26 (t, J = 7.1 Hz, 3H). MS calculated for CiiH13Br02 (M + H +) 257.0, found 257.0.

Intermediate 33: Methyl ester of (2-chloro-methyl-phenyl) -acetic acid. Isocromanone 32 (1.9 grams, 13 mmol) is dissolved in MeOH (15 milliliters), and cooled to 0 ° C. Thionyl chloride (2 milliliters, 27.3 mmol) is added, and the solution is stirred at room temperature for 48 hours. The solvent is removed in vacuo, the remainder is dissolved in dichloromethane and washed with water and saturated aqueous NaHCO3. The organic layer is dried (MgSO 4), filtered, and concentrated. Purification by flash chromatography (gradient of EtOAc / hexanes) gives the methyl ester of (2-chloro-methyl-phenyl) -acetic acid 33 as a colorless oil: 1 H NMR (400MHz, CDCl 3) d = 7.39-7.26 (m, 4H), 4.68 (s, 2H), 3.82 (s, 2H), 3.70 (s, 3H). MS calculated for C10HnO2 (M-CI +) 163.1, found 163.1.

Intermediate 36: 2- (3-Bromo-phenyl) -2-methyl-propionic acid methyl ester. Step A: 3-Bromo-phenyl-acetic acid 34 (1.17 grams, 5.44 mmol) is dissolved in MeOH (15 milliliters) containing catalytic amounts of thionyl chloride (0.2 milliliters). The solution is stirred at room temperature overnight. The solvent is evaporated, and the remainder is dissolved in dichloromethane, and washed with water and saturated aqueous NaHCO3. The organic layer is dried (MgSO 4), filtered, and concentrated, to provide the methyl ester 35 as an oil: 1 H NMR (400MHz, CDCl 3) d = 7.44 (s, 1H), 7.40 (ddd, J = 2.0 , 2.4, 6.8 Hz, 1H), 7.20 (m, 2H), 3.70 (ss, 3H), 3.59 (s, 2H). MS calculated for C9H10BrO2 (M + H +) 229.1, found 229.0 Step B: Intermediary 35 (1.0 grams, 4.4 mmol) is dissolved in N, N-dimethylformamide (10 milliliters), and cooled to 0 ° C. Sodium hydride (60 percent dispersion, 1.6 grams, 22.0 mmol) is added slowly, and the mixture is stirred at 0 ° C until the evolution of gas ceases. Then methyl iodide (1.5 milliliters, 22.0 mmol) is added, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is carefully quenched with MeOH (5 milliliters) with stirring over an ice bath. Water is added, and the mixture is extracted with EtOAc twice. The combined organic layers are washed with water and brine, dried over MgSO4, and concentrated. The crude residue is purified by flash chromatography on silica (gradient of EtOAc / hexanes), to give 2- (3-bromo-phenyl) -2-methyl-propionic acid methyl ester 36 as a clear liquid : 1 H NMR (400MHz, CDCl 3) d = 7.48 (t, J = 1.9 Hz, 1H), 7.37 (m, 1H), 7.25 (m, 1H), 7.19 (t, J = 7.8 Hz, 1H), 3.66 ( s, 3H), 1.56 (s, 6H). MS calculated for C H ^ BrOz (M + H +) 257.0, found 257.0 37 Intermediate 37: (5-Bromo-2-methoxy-phenyl) -acetic acid methyl ester. Following the procedure of Intermediary 36, Step A, except that using the (5-bromo-2-methoxy-phenyl) -acetic acid to replace the 3-bromo-phenyl-acetic acid, the title compound is prepared as a transparent liquid: 1H NMR (400MHz, CDCI3) d = 7.35 (dd, J = 2.5 Hz, J = 8.7 Hz, 1H), 7.30 (d, J = 2.5 Hz, 1H), 6.74 (d, J = 8.7 Hz, 1H), 3.80 (s, 3H), 3.69 (s, 3H), 3.59 (s, 2H). MS calculated for C10H12BrO3 (M + H +) 259.0, found 259.0. 38 Intermediary 38: (5-Chloro-2-fluoro-phenyl) -acetic acid methyl ester. Following the procedure of Intermediary 36, Step A except that using the (5-chloro-2-fluoro-phenyl) -acetic acid to replace the 3-bromo-phenyl-acetic acid, the title compound is prepared as a clear liquid: 1H NMR (400MHz, CDCl 3) d = 7.27-7.20 (m, 2H), 7.00 (t, J = 8.9 Hz, 1H), 3.72 (s, 3H), 3.64 (s, 2H). MS calculated for C9H9CIF02 (M + H +) 203.0, found 203.0. aa Intermediate 39: (5-Chloro-trifluoromethyl-phenyl) -acetic acid methyl ester. Following the procedure of Intermediary 36, Step A, except that using the (5-chloro-2-trifluoro-methyl-phenyl) -acetic acid to replace the 3-bromo-phenyl-acetic acid, the title compound is prepared as a clear liquid: 1H NMR (400MHz, CDCI3) d = 7.59 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 3.80 (s, 2H), 3.72 (s, 3H). MS calculated for C10H9CIF2O2 (M-F +) 233.0, found 233.0. 40 Intermediate 40: 2- (4-bromo-methyl-phenyl) -propionic acid methyl ester. Following the procedure of Intermediary 36, Step A, except that using 2- (4-bromo-methyl-phenyl) -propionic acid to replace 3-bromo-phenyl-acetic acid, the title compound is prepared as a clear liquid : 1 H NMR (400MHz, CDCl 3) d = 7.31 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H) .4.43 (s, 2H), 3.68 (q, J = 7.2 Hz, 1H), 3.61 (s, 3H), 1.45 (d, J = 7.2 Hz calculated for CH ^ BrOa (M + H +) 257.0, found 257.0 41 Intermediate 41: 3- (3-bromo-phenyl) -propionic acid methyl ester. Following the procedure of Intermediary 36, Step A, except that using the 3- (3-bromo-phenyl) -propionic acid to replace the 3-bromo-phenyl-acetic acid, the title compound is prepared as a clear liquid: MS calculated for C10H BrO2 (M + H +) 243.0, found 243.0.

Intermediate 43: (3-bromo-phenoxy) -acetic acid methyl ester.

The 3-bromo-phenol 42 (1.72 grams, 10 mmol), together with the bromo-methyl acetate (1.01 milliliters, 11 mmol), are dissolved in MeCN (600 milliliters). K2C03 (2.07 grams, 15 mmol) is added, and the mixture is stirred at 50 ° C overnight. After the insoluble salts are filtered and washed with MeCN, the solvent is removed, and the remainder is taken up in EtOAc, and subsequently washed with water and brine. The organic layer is dried (MgSO4), filtered, and concentrated to give 43 as a colorless semi-solid: MS calculated for C9H10BrO3 (M + H +) 245.0, found 244.9. 44 Intermediate 44: (5-Chloro-2-methyl-phenoxy) -acetic acid methyl ester. Following the procedure of Intermediary 43, except that using 5-chloro-2-methyl-phenol to replace the 3-bromo-phenol, prepare the title compound as a white solid: H NMR (400MHz, CDCl 3) d = 7.07 (d, J - 8.0 Hz, 1H), 6.89 (dd, J = 1.9 Hz, J = 8.0 Hz, 1H), 6.68 (d, J = 1.9 Hz, 1H), 4.64 (s, 2H), 3.82 (s) , 3H), 2.24 (s, 3H). MS calculated for C10H12CIO3 (M + H +) 215.0, found 215.0. 46 Intermediate 45: (5-bromo-2-chloro-phenoxy) -acetic acid methyl ester. Following the procedure of Intermediary 43, except that using 5-bromo-2-chloro-phenol to replace 3-bromo-phenol, prepare the title compound as a white solid: 1 H NMR (400MHz, CDCl 3) d = 7.27 (d, J = 8.4 Hz, 1H), 7.11 (dd, J = 2.1 Hz, J = 8.4 Hz, 1H), 6.99 (d, J = 2.1 Hz, 1H), 4.73 (s, 2H), 3.85 (s) , 3H). MS calculated for C9H9BrCl03 (M + H +) 278.9, found 279.0 46 Intermediate 46: 2- (3-Bromo-phenoxy) -2-methyl-propionic acid methyl ester. Following the procedure of Intermediary 43, except that using a, b-dimethyl-methyl bromo acetate to replace methyl bromide-acetate, and heating under reflux, the title compound is prepared as a clear liquid: MS calculated for CH ^ BrOs (M + H +) 273.0, found 273.0. 47 Intermediate 47: 2- (5-Chloro-2-methyl-phenoxy) -2-methyl-propionic acid methyl ester. Following the procedure of Intermediary 43, except that using a, b-dimethyl-methyl bromo acetate to replace methyl bromide-acetate, and heating under reflux, the title compound is prepared as a clear liquid: 1 H NMR ( 400MHz, CDCI3) d = 7.06 (d, J = 8.0 Hz, 1H), 6.87 (dd, J = 2.0 Hz, J = 8.0 Hz, 1H), 6.62 (d, J = 2.0 Hz, 1H), 3.80 (s) , 3H), 2.18 (s, 3H), 1.60 (s, 6H). MS calculated for C12H16Cl03 (M + H +) 243.1, found 243.1. 48 Intermediate 48: 2- (5-Bromo-2,3-difluoro-phenoxy) -2-methyl-propionic acid methyl ester. Following the procedure of Intermediary 43, except that using 5-bromo-2,3-difluoro-phenol to replace 5-chloro-2-methyl-phenol, the title compound is prepared as a clear liquid: 1 H NMR (400 MHz) , CDCl 3) d = 7.05 (m, 1H), 6.91 (m, 1H), 3.80 (s, 3H), 1.60 (s, 6H). MS calculated for C11H12BrF203 (M + H +) 309.0, found 309.0.

Intermediate 49: 2- (5-Bromo-2-chloro-phenoxy) -2-methylpropionic acid methyl ester. Following the procedure of Intermediary 43, except that using 5-bromo-2-chloro-phenol to replace 5-chloro-2-methyl-phenol, the title compound is prepared as a clear liquid: 1 H NMR (400MHz, CDCl 3 ) d = 7.23 (d, J = 8.5 Hz, 1H), 7.09 (dd, J = 2.0 Hz, J = 8.5 Hz, 1H), 7.03 (d, J = 2.0 Hz, 1H), 3.81 (s, 3H) , 1.62 (s, 6H). MS calculated for CnH ^ BrClOa (M + H +) 307.0, found 307.0. 34 Step A 50 Intermediary 50: Terbutil-ester of (3-bromo-phenyl) -acetic acid. To a solution of 34 (11.2 grams, 51.6 millimoles) and Boc20 (25 grams, 114.5 millimoles) in 525 milliliters of tBuOH, DMAP (1.9 grams) is added. The reaction mixture is stirred overnight, and verified by thin layer chromatography until complete. After evaporation of the solvent, the product is purified by a short column of silica gel (from 5 to 10 centimeters) to 10 percent EtOAc, to provide the terbutil-ester of the acid (3-bromo-phenyl) - acetic 50 pure as a colorless oil. 1 H NMR (400MHz, CDCl 3) d 7.36 (m, 1 H), 7.34-7.30 (m, 1H), 7.15-7.11 (m, 2H), 3.42 (s, 2H), 1.17 (s, 9H).

Intermediate 53: (5-Bromo-2-methyl-phenyl) -acetic acid methyl ester. Step A: In a flame-dried flask, isoamyl nitrate (2.16 milliliters, 16 millimoles) is dissolved in dry MeCN (6 milliliters). Then add copper chloride (Cu (II) CI2) 1.74 grams, 13 mmol) and vinylidene chloride (12.9 milliliters, 16 mmol). Slowly add 5-bromo-2-methyl-aniline 51 (2.00 grams, 11 mmol) over a period of 10 minutes, while the mixture is maintained at room temperature with a water bath. The reaction mixture is stirred at room temperature overnight, then poured into 20 percent ice cold aqueous HCI (80 milliliters). After stirring for 30 minutes, it is extracted with ether twice, the combined organic layers are washed with 20 percent aqueous HCl, water, and brine, dried over MgSO4, and concentrated. Step B: Crude 4-b'romo-1-methyl-2- (2,2,2-trichloro-ethyl) -benzene 52 from Step A is dissolved in MeOH (2 milliliters), and cooled to 0 ° C. . A solution of 30 percent NaOMe in MeOH (8.5 milliliters) is slowly added, and then the mixture is refluxed for 5 hours. After cooling down to 0 ° C, concentrated H2SO4 (1.6 milliliters) is added, and the mixture is refluxed for 1 hour. The reaction mixture is cooled to room temperature, water is added, and extracted with dichloromethane three times. The combined organic layers are washed with water and brine, dried over MgSO4, and concentrated. The residue is purified by flash chromatography on silica (gradient of EtOAc / hexanes), to give the methyl ester of (5-bromo-2-methyl-phenyl) -acetic acid 53 as an oil: 1 H NMR (400MHz, CDCI3) d = 7.34 (d, J = 2.0 Hz, 1H), 7.30 (dd, J = 2.0 Hz, J = 8.1 Hz, 1H), 7.05 (d, J = 8.1 Hz, 1H), 3.70 (s, 3H ), 3.60 (s, 2H), 2.25 (s, 3H). MS calculated for C 0H12BrO2 (M + H +) 243.0, found 243.0.

M Intermediate 58: (3-bromo-5-methyl-phenyl) -acetic acid methyl ester. Step A: 5-bromo-meta-xylene 54 (1.85 grams, 10 mmol), N-bromo-succinimide (0.78 grams, 10 mmol), and AIBN (0.11 grams, 0.7 mmol), are suspended in CCI4 (20 milliliters) ). The reaction mixture is refluxed for 2 hours, and then the solids are filtered and the remainder is concentrated to give 1-bromo-3-bromo-methyl-5-methyl-benzene (2.7 grams, quantitative) as a solid white: MS calculated for C8H9Br2 (M + H +) 262.9, found 281.0. Step B: Intermediary 55 (2.70 grams, 10 mmol) is dissolved in dimethyl sulfoxide (10 milliliters), and cooled to 0 ° C. Then sodium cyanide (0.98 grams, 20 mmol) is added, and the mixture is stirred at room temperature for 1 hour. Acetonitrile (10 milliliters) is added, and the mixture is heated to reflux for 90 minutes. It is then diluted with H20, and extracted with ether three times. The combined organic layers are washed with H20 and brine, dried over MgSO4, and concentrated to provide (3-bromo-5-methyl-phenyl) -acetonitrile 56 as a reddish oil. MS calculated for C9H9BrN (M + H +) 210.0, found 210.0. Step C: A high pressure tube is loaded with KaOH (2.24 grams, 40 millimoles) dissolved in H20 (20 milliliters). Add Intermediary 56 (approximately 10 millimoles) in isopropanol (10 milliliters), seal the tube, and heat at 120 ° C overnight. The mixture is then stirred at room temperature for 62 hours. After the isopropanol is evaporated, the residue is acidified with 6M HCl to a pH of 2, and extracted with ether three times. The combined organic layers are washed with H20, dried over MgSO4, and concentrated to give the (3-bromo-5-methyl-phenyl) -acetic acid as a reddish solid. MS calculated C9H10BrO2 (M + H +) 229.0, found 228.9. Step D: (3-Bromo-5-methyl-phenyl) -acetic acid 57 is dissolved in MeOH (20 milliliters) containing catalytic amounts of thionyl chloride (0.2 milliliters). The solution is stirred at room temperature overnight. The solvent is evaporated, the rest is dissolved in dichloromethane, and washed with water and saturated aqueous NaHCO3. The organic layer is dried (MgSO 4), filtered, and concentrated. The residue is purified by flash chromatography on silica (EtOAc / hexanes gradient), to give the methyl ester of (3-bromo-5-methyl-phenyl) -acetic acid 58 as an oil: 1 H NMR (400MHz, CDCI3) d = 7.24 (s, 2H), 7.02 (s, 1H), 3.71 (s, 3H), 3.56 (s, 2H), 2.32 (s, 3H). MS calculated for C10H12BrO2 (M + H +) 243.0, found 243.0 Intermediate 59: Ethyl ester of (2-chloro-pyridin-4-yl) -acetic acid. The 2-chloro-4-methyl-pyridine 59 (1.06 grams, 8.33 mmol) is dissolved in tetrahydrofuran (18 milliliters), and cooled to -78 ° C. Slowly add LDA (10 milliliters, 20 millimoles) over a period of 15 minutes, and stir at -78 ° C for another 15 minutes. Then diethyl carbonate (1.2 milliliters, 10 millimoles) is added slowly over a period of 5 minutes, and stirred at -78 ° C for another 15 minutes. The mixture is then heated to 0 ° C, and stirred at this temperature for 4 hours. After quenching with a saturated solution of ammonium chloride (250 milliliters), the solution is extracted with EtOAc three times. The combined organic layers are washed with H20, dried over Na2SO4, and concentrated. The residue is purified by flash chromatography on silica (gradient EtOAc / hexanes), to give the ethyl ester of (2-chloro-pyridin-4-yl) -acetic acid 60 as an orange liquid: 1 H NMR ( 400MHz, CDCI3) d = 8.32 (d, J = 5.1 Hz, 1H), 7.27 (d, J = 4.0 Hz, 1H), 7.15 (d, J = 5.0 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.60 (s, 2H), 1.26 (t, J = 7.1 Hz, 3H). MS calculated for C9HHCINO2 (M + H +) 200.0, found 200.1. 61 Intermediate 6: (6-Chloro-pyridin-2-yl) -acetic acid ethyl ester. Following the procedure of Intermediary 60, except that using 6-chloro-2-methyl-pyridine to replace 2-chloro-4-methyl-pyridine, the title compound is prepared as a clear liquid: 1 H NMR ( 400MHz, CDCI3) d = 7.63 (t, J = 7.8 Hz, 1H), 7.24 (m, 2H), 4.18 (q, J = 7.1 Hz, 2H), 3.82 (s, 2H), 1.26 (t, J = 7.1 Hz, 3H). MS calculated for C9HHCl O2 (M + H +) 200.0, found 200.1.

Intermediate 63: (3-Chloro-sulfonyl-4-methyl-phenyl) -acetic acid methyl ester. The p-tolyl-acetic acid methyl ester 62 (1.0 grams, 6.09 mmol) is dissolved in dichloromethane (4 milliliters), and cooled to 0 ° C. Chlorosulfonic acid (10 milliliters) is added dropwise with stirring over a period of 1 hour. The mixture is warmed to room temperature, and stirred for 1 hour. The reaction mixture is diluted with EtOAc, and washed with saturated Na 2 CO 3 and brine. The organic layer is separated, dried (MgSO 4), filtered, and concentrated, to give the crude product, which is purified from chromatography on silica gel (EtOAc / hexane gradient), to give the compound of title 63 as an oil: 1 H NMR (400MHz, CDCl 3) d = 7.89 (d, J = 1.6 Hz, 1H), 7.48 (dd, J = 1.6 Hz, J = 7.6 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 3.66 (s, 3H), 3.63 (s, 2H), 2.70 (s, 3H); MS calculated for C10H11O4S (M-CI +) 227.04, found 227.00. 64 Intermediate 64: (3-Chloro-sulfonyl-4-methoxy-phenyl) -acetic acid methyl ester. The Intermediary 64 is prepared in accordance with the patent literature, British Patent Number GB 2378179.

Intermediates 66 and 67: 2- (2-Chloro-pyrimidin-4-yloxy) -2-methyl-propionic acid methyl ester and 2- (4-chloro-pyrimidin-2-yloxy) -methyl ester - 2-methyl-propionic. The 2,4-dichloro-pyrimidine 65 (0.90 grams, 6.0 mmol) is dissolved in N, N-dimethyl formamide (36 milliliters). Methyl ester of 2-hydroxyisobutyrate (2.13 grams, 18.0 mmol) and Cs2CO3 (7.8 grams, 24 mmol) are added, and the mixture is subjected to microwave irradiation (120 ° C, 5 minutes). Then it is diluted with EtOAc and washed with H20 three times, and then with brine. The organic layer is dried over MgSO4 and concentrated. The residue is purified by flash chromatography on silica (EtOAc / hexanes gradient), to provide the regioisomers 66 and 67 in a ratio of 3: 1 as clear oils: 66: 1 H-NMR (400MHz, CDCl 3) d = 8.24 (d, J = 5.8 Hz, 1H), 6.61 (d, J = 5.8 Hz, 1H), 3.66 (s, 3H), 1.63 (s, 6H). MS calculated for C9H12CIN203 (M + H +) 231.1, found 231.0. 67: 1 H-NMR (400MHz, CDCl 3) d = 8.26 (d, J = 5.4 Hz, 1H), 6.90 (d, J = 5.4 Hz, 1H), 3.61 (s, 3H), 1.65 (s, 6H) . MS calculated for C9H12CIN203 (M + H +) 231.1, found 231.0. 68 69 Intermediate 69: 2- (6-Chloro-pyrimidin-4-loxy) -2-methyl-propionic acid methyl ester. The 4,6-dichloro-pyrimidine 68 (0.90 grams, 6.0 mmol) is dissolved in N, N-d-methyl-formamide (36 milliliters). Methyl ester of 2-hydroxyisobutyrate (2.13 grams, 18.0 mmol) and CS2CO3 (7.8 grams, 24 mmol) are added, and the mixture is heated at 50 ° C for 12 hours. Then it is diluted with EtOAc, and washed with H20 three times, and then with brine. The organic layer is dried over MgSO4 and concentrated. The residue is purified by flash chromatography on silica (gradient EtOAc / hexanes), to give 69 as a clear oil: 1 H NMR (400MHz, CDCl 3) d = 8.48 (s, 1H), 6.79 (s, 1H) , 3.67 (s, 3H), 1.68 (s, 6H). MS calculated for C9H12Cl 203 (M + H +) 231.1, found 231.0.

Intermediate 72: [3- (2,4-Dioxo-1, 3,8-triaza-spiro- [4.5] -dec-8-yl) -phenyl] -acetic acid terbutyl ester. Step A: To a solution of 4-piperidone monohydrate hydrochloride 70 (2.5 grams, 16.42 mmol) in anhydrous dioxane (50 milliliters), and under a nitrogen atmosphere, Cs2C03 (11.75 grams, 36.13 mmol), terbutil is added. - (3-bromo-phenyl) -acetic acid ester (4.9 grams, 18.1 mmol), and bis- (triterbutyl-phosphine) -palladium. The flask is covered with a septum, and evacuated three times. The reaction mixture is stirred in an oil bath at 85 ° C for 12 hours, and after this time, the reaction mixture is cooled, diluted with a saturated solution of NH 4 Cl (80 milliliters), and extracted with EtOAc. (100 milliliters, twice). The combined organic layers are washed once with NH 4 Cl, brine, and dried over Na 2 SO 4. The crude product is purified by short chromatography with Si02 (hexane-EtOAc, 9: 1 to 8: 2 as eluent), to provide 1.27 grams of the [3- (4-oxo-piperidin-1-yl) -phenyl] -acetic acid tert-butyl ester 71 as a yellow oil. 1 H NMR (400MHz, CDCl 3) d 7.24 (t, J = 8.0 Hz, 1H), 6.92-6.86 (m, 2H), 6.80 (d, J = 4.0 Hz, 1H), 3.61 (t, J = 8.0 Hz, 4H), 3.49 (s, 2H), 2.55 (t, J = 8.0 Hz, 4H). MS (m / z) (M + 1) + 290.2. Step B: A well stirred solution of 71 (0.3 grams, 1.04 millimoles) in 6.5 milliliters of 95 percent EtOH and 0.5 milliliters of H2O, is treated with (NH4) 2C03 (1.84 grams, 19.2 millimoles) and NaCN (0.2 grams) , 4.1 millimoles). The reaction mixture is heated in a sealed tube at 85 ° C for 12 hours. After this time, the reaction is allowed to cool, is diluted with H20, and extracted with EtOAc (60 milliliters, twice). The combined organic layers are washed once with brine, dried over Na 2 SO, and evaporated, to give 0.76 grams of 72 as a white solid, which is used without further purification. 1 H NMR (400 MHz, CD 3 OD) d 7.19 (t, J = 8.0 Hz, 1 H), 6.93-6.90 (m, 2 H), 6.75 (d, J = 8.0 Hz, 1 H), 3.68-3.63 (m, 2 H), 3.48 (s, 2H), 3.12 (m, 2H), 2.17-2.09 (m, 2H), 1.43 (s, 9H).

MS (m / z) (M + 1) + 360.2.

Example A1 Acid (3-. {3-isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec-8 -yl-methyl.}. phenyl) -acetic. Step A: 3-Butyl-1 - [2- (4-methoxy-phenyl) -ethyl] -1,8,8-triaza-spiro- [4,5] -decano-2,4-dione 5 (30 milligrams, 0.08 millimoles) is dissolved in dichloromethane (2.5 milliliters). Triethylamine (53 microliters, 0.24 mmol) and (3-bromo-methyl-phenyl) -acetic acid methyl ester (22 milligrams, 0.09 mmol) are added successively, and the mixture is stirred at room temperature night. The solvent is removed in vacuo to give the ethyl ester of (3- {3-isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3, Crude 8-triaza-spiro- [4.5] -dec-8-yl-methyl.}. Phenyl) -acetic, which is used without further purification in Step B. Step B: Ethyl-3-ethyl ester - { 3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec-8-il- crude methyl.}. phenyl) -acetic is dissolved in tetrahydrofuran (1 milliliter), a solution of LiOH 1 in H20 (0.6 milliliter) is added, and the mixture is stirred for 12 hours at 50 ° C. The mixture is acidified with 1 M HCl (0.8 milliliters), and extracted with dichloromethane twice. The organic layer is washed with brine, dried (MgSO4), filtered, concentrated, and purified on reverse phase HPLC (gradient of H20 / MeCN), to give the title compound as a colorless solid: 1 H NMR ( 400MHz, CDCI3) d = 7.35 (m, 3H), 7.23 (s, 1H), 7.07 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 8.6 Hz, 2H), 4.11 (s, 2H) , 3.75 (s, 3H), 3.62 (s, 2H), 3.44 (m, 4H), 3.35 (t, J = 7.1 Hz, 2H), 3.30 (d, J = 7.4 Hz, 2H), 2.90 (m, 2H), 2.33 (m, 2H), 2.06 (m, 1H), 1.40 (m, 2H), 0.89 (d, J = 6.7 Hz, 6H). MS calculated for C29H38N305 (M + H +) 508.3, found 508.4.

Bl Example B1. Acid (3-. {3-isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -decan-8 -sulfonyl.} -4-methyl-phenyl) -acetic.

Step A: 3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -1,8,8-triaza-spiro- [4,5] -decano-2,4-dione 5 (18 milligrams, 0.05 mmol) is dissolved in dichloromethane (0.5 milliliters). Triethylamine (14 microliters, 0.10 mmol) and (3-chlorosulfonyl-4-methyl-phenyl) -acetic acid methyl ester (16 milligrams, 0.06 mmol) are added successively, and the mixture is stirred at room temperature. environment for 8 hours. The solvent is removed in vacuo to give the methyl ester of (3- {3-isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1,3, Crude 8-triaza-spiro- [4.5] -decan-8-sulfonyl.} -4-methyl-phenyl) -acetic, which is used without further purification in Step B. Step B: The methyl ester of the acid (3- { 3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4,5] -decan-8- The crude sulfonyl, 4-methyl-phenyl-acetic acid is dissolved in tetrahydrofuran (1 milliliter), a solution of 1 M LiOH in H20 (0.6 milliliter) is added, and the mixture is stirred for 12 hours at room temperature. The mixture is acidified with 1M HCl (0.8 milliliters), and extracted with dichloromethane twice. The organic layer is washed with brine, dried (MgSO4), filtered, concentrated, and purified on reverse phase HPLC (gradient of H20 / MeCN), to give the title compound as a colorless solid: 1 H NMR ( 400MHz, CDCI3) d = 7.80 (d, J = 1.6 Hz, 1H), 7.37 (dd, J = 1.6 Hz, J = 7.8 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.12 (d , J = 8.5 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 3.79 (s, 3H), 3.75 (m, 2H), 3.68 (s, 2H), 3.40 (m, 2H), 3.34 (t, J = 7.0 Hz, 2H), 3.28 (d, J = 7.4 Hz, 2H), 2.93 (t, J = 7.4 Hz, 2H), 2.58 (s, 3H), 2.04 (m, 1H), 1.90 (m, 2H), 1.43 (d, J = 13.7 Hz, 2H), 0.87 (d, J = 6.7 Hz, 6H). MS calculated for C29H38 3O7S (M + H +) 572.2, found 572.2.

Example C1. Acid (3-. {3-isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec-8 -yl.}.-phenyl) -acetic. Step A: A sealed and flame-dried tube is loaded with 3-isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -1,8,8-triaza-spiro- [4,5] -decano -2,4-diona 5 (75 milligrams, 0.21 millimoles), (3-bromo-phenyl) -acetic acid methyl ester (72 milligrams, 0.31 millimoles), (tBu) 3PHBF3 (6 milligrams, 0.021 millimoles) and Cs2C03 (137 milligrams, 0.42 millimoles). 1,4-dioxane (1.1 milliliters) is added, and the tube is purged with argon. Then Pd2 (dba) 3 (10 milligrams, 0.011 mmol) is added, and the mixture is heated at 120 ° C overnight. The mixture containing the methyl ester of (3- {3-isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1,3,8-triaza- crude spiro- [4.5] -dec-8-yl.}. phenyl) -acetic is used without further purification in Step B. Step B: To the reaction mixture from Step A, tetrahydrofuran (3 milliliter) is added.; a solution of 1 M LiOH in H20 (1 milliliter) is added, and the mixture is stirred for 12 hours at room temperature. The mixture is acidified with 1M HCl (1.2 milliliters), and extracted with dichloromethane twice. The organic layer is washed with brine, dried (MgSO4), filtered, concentrated, and purified on reverse phase HPLC (gradient of H20 / MeCN), to give the title compound as a colorless solid: 1 H NMR ( 400MHz, CDCI3) d = 7.40-7.18 (m, 4H), 7.13 (d, J = 8.5 Hz, 2H), 6.82 (d, J = 8.5 Hz, 2H), 3.93 (t, J = 11.9 Hz, 2H) , 3.77 (s, 3H), 3.65 (s, 2H), 3.54 (m, 2H), 3.43 (t, J = 7.1 Hz, 2H), 3.34 (d, J = 7.4 Hz, 2H), 2.96 (t, J = 7.4 Hz, 2H), 2.43 (m, 2H), 2.11 (m, IH), 1.51 (d, J = 14.0 Hz, 2H), 0.92 (d, J = 6.7 Hz, 6H). MS calculated for C28H36N305 (M + H +) 494.3, found 494.2.

Example D1. 2- (4- [3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1,3-diaza-spiro- [4.5] -dec-7-yl acid -methyl.} -phenyl) -propionic. Step A: 3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -1,7,7-triaza-spiro- [4.5] -decano-2,4-dione 10 (15 milligrams, 0.04 millimoles) is dissolved in dichloromethane (2.5 milliliters). Triethylamine (17 microliters, 0.12 mmol) and 2- (3-bromo-methyl-phenyl) -propionic acid methyl ester (12 milligrams, 0.04 mmol) are added in succession, and the mixture is stirred at room temperature. overnight. The solvent is removed under vacuum to provide 2- (4. {3-isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1-methyl ester. Crude 3-diaza-spiro- [4.5] -dec-7-yl-methyl.}. Phenyl) -propionic, which is used without further purification in Step B. Step B: The methyl ester of the 2-acid (4- { 3-Butyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1,3-diaza-spiro- [4.5] -dec-7-yl -methyl.) -phenyl) -propionic crude is dissolved in tetrahydrofuran (1 milliliter); a solution of 1M LiOH in H20 (0.6 milliliter) is added, and the mixture is stirred for 12 hours at 50 ° C. The mixture is acidified with 1 M HCl (0.8 milliliters), and extracted with dichloromethane twice. The organic layer is washed with brine, dried (MgSO4), filtered, concentrated, and purified on reverse phase HPLC (gradient of H20 / MeCN), to give the title compound as a colorless solid: 1 H NMR ( 400MHz, CDCI3) d = 7.40 (d, J = 6.8 Hz, 2H), 7.27 (d, J = 6.0 Hz, 2H), 7.13 (d, J = 6.8 Hz, 2H), 6.85 (d, J = 6.0 Hz , 2H), 4.45 (m, 1H), 4.33 (m, 1H), 3.87 (s, 3H), 3.64 (m, 1H), 3.40 (m, 4H), 3.10 (m, 2H), 2.93 (m, 1H), 2.78 (s, 3H), 2.52 (m, 1H), 2.15 (m, 1H), 2.00 (m, 2H), 1.72 (m, 1H), 1.61 (m, 3H), 0.95 (s, 6H) ). MS calculated for C30H40 3O5 (M + H +) 522.3, found 522.3.

Example E1. Acid (3-. {3-cyclopropyl-methyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec -8-yl.}.-Phenyl) -acetic. Step A: 8-Benzyl-1 - [2- (4-methoxy-phenyl) -ethyl] -1,8,8-triaza-spiro- [4,5] -decano-2,4-dione (39 milligrams, 0.1 millimoles) is dissolved in acetonitrile (0.5 milliliters). Cyclopropylmethyl bromide (0.2 mmol), sodium iodide (30 milligrams, 0.2 mmol), and cesium carbonate (65 milligrams, 0.2 mmol) are added at room temperature. The mixture is heated in oil at 80 ° C for 16 hours. The reaction is judged complete by LC / MS. The solid is filtered, and the solvent is removed from the mixture to provide 8-benzyl-1 - [2- (4-methoxy-phenyl) -ethyl] -1,8,8-triaza-spiro- [4.5] - crude decane-2,4-dione, which is used without further purification in Step B. Step B: 8-Benzyl-1 - [2- (4-methoxy-phenyl) -ethyl] -1, 3.8 -triaza-spiro- [4.5] -decano-2,4-dione crude is dissolved in MeOH (1 milliliter), and stirred with Pd (OH) 2 (approximately 10 milligrams), in the presence of 1 atmosphere of hydrogen during 16 hours at room temperature. After filtration and concentration, the crude product of 3-cyclopropyl-methyl-1 - [2- (4-methoxy-phenyl) -ethyl] -1,8,8-triaza-spiro [4.5 is obtained. ] -decano-2,4-dione, and used without further purification in Step C. Step C: 3-Cyclopropyl-methyl-1 - [2- (4-methoxy-phenyl) -ethyl] -1, 3 , Crude 8-triaza-spiro- [4.5] -decano-2,4-dione is dissolved in 1,4-dioxane (0.3 milliliter). Tert-butyl 3-bromo-phenyl-acetate 50 (40 milligrams, 0.15 millimoles) and cesium carbonate (65 milligrams, 0.2 millimoles) are added at room temperature. The resulting mixture is purged under a stream of nitrogen, and Pd (PtBu3) 2 (5 milligrams, 0.01 mmol) is introduced under nitrogen. The reaction mixture is heated in oil at 110 ° C for 16 hours. The mixture is purified by flash chromatography on silica gel (15 percent EtOAc / hexanes), to give (3- {3-cyclopropyl-methyl-1 - [2- (4-cyclopropyl) -3- -methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec-8-yl.}. -phenyl) -acetic acid, as a colorless oil. Step D: (3. {3-Cyclopropyl-methyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2-tert-butyl ester, 4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec-8-il} -phenyl) -acetic acid is treated with trifluoroacetic acid at room temperature to provide (3- ({(3- ({3-cyclopropyl-methyl-1 - [2- (4-methoxy-phenyl)} acid. -etl] -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec-8-yl.}. -phenyl) -acetic acid as a trifluoroacetic acid salt, which is purify by LC / MS preparation (20 to 100 percent MeCN / H20). 1 H NMR (400 MHz, CDCl 3) d 7.62 (s, 1 H), 7.53 (d, J = 8.3 Hz, 1 H), 7.48 ( t, J = 8.2 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.15 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 4.16 (t, J = 11.7 Hz, 2H), 3.77 (s, 3H), 3.72 (s, 2H), 3.58 (d, J = 12 Hz, 2H), 3.47 (t, J = 7.2 Hz, 2H), 3.41 (d, J = 7.3 Hz, 2H), 2.99 (t, J - 7 Hz, 2H), 2.64 (t, J = 13 Hz, 2H), 1.56 (dt, J = 14.2, 2 Hz, 2H), 1.2 (m, 1H), 0.55 (m, 2H), 0.37 (m, 2H), LC / MS (M + H +): 492.2.

Example F1. Acid { 3- [3-Butyl-2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1,3,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic. Step A: To a solution of 17 (0.103 grams, 0.19 millimoles) in anhydrous dioxane (1 milliliter), and under a nitrogen atmosphere, add Cs2C03 (0.16 grams, 0.49 millimoles), the terbutil-acid ester (3 -bromo-phenyl) -acetic 50 (0.074 grams, 0.27 millimoles), and Pd (PtBu3) 2 (0.03 grams, 0.06 millimoles). The bottle is covered with a septum, and evacuated three times. The reaction mixture is stirred in an oil bath at 85 ° C for 12 hours. The reaction mixture is cooled, diluted with a saturated solution of ammonium chloride (5 milliliters), and extracted with EtOAc (10 milliliters, twice). The organic layer is washed once with NH 4 Cl, brine, and dried over Na 2 SO 4. The crude product is purified by LC / MS preparation (from 20 to 100 percent MeCN / H20), to provide the terbutil-ester of the acid. { 3- [3-isobutyl-2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1,3,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic. LC / MS (M + H +) = 590.3. Step B: The terbutil-ester of the acid. { 3- [3-isobutyl-2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1,3,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic is dissolved in dichloromethane (1 milliliter), and treated with a 50 percent solution of trifluoroacetic acid / dichloromethane (2 milliliters). The reaction mixture is stirred at room temperature for 3 hours. The solvent is removed under vacuum to provide the F1 as a trifluoroacetic acid salt in a quantitative yield. 1 H NMR (400 MHz, CD 3 OD) d 7.45-7.21 (m, 8 H), 4.63 (s, 2 H), 4.04-3.98 (bm, 2 H), 3.67 (m, 4 H), 3.40 (d, J = 8.0 Hz, 2H), 2.38 (dt, J = 4.0 and 16.0 Hz, 2H), 2.10 (quintet, J = 8.0 Hz, 1H), 1.94-1.90 (m, 2H), 0.95 (d, J = 8.0Hz, 6H). LC / MS (M + H +) = 534.3. < xi Example G1. 2- (2-. {3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1,3,8-triaz-a-spiro- [4,5] - dec-8-yl.} - pyrimidin-4-yloxy) -2-methyl-propionic acid. Step A: 3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -1,8,8-triaza-spiro- [4,5] -decano-2,4-dione (72 milligrams, 0.20 millimoles) is dissolved together with the 2- (2-chloro-pyrimidin-4-yloxy) -2-methyl-propionic acid methyl ester (48 milligrams, 0.20 mmol) and di-isopropyl-ethyl-amine (52 microliters) , 0.30 millimoles) in normal butanol (0.8 milliliters). The solution is heated at 50 ° C for 12 hours, then diluted with EtOAc, and washed with water twice. The organic layer is separated and concentrated to give methyl 2- (2. {3-isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo- Crude 1, 3,8-triaza-spiro- [4.5] -dec-8-yl.} - pyrimidin-4-yloxy) -2-methyl-propionic acid. Step B: To the crude product of Step A, tetrahydrofuran (3 milliliters) is added; a solution of 1 M LiOH in H20 (1 milliliter) is added, and the mixture is stirred for 12 hours at room temperature. The mixture is acidified with 1 M HCl (1.2 milliliters), and extracted with dichloromethane twice. The organic layer is washed with brine, dried (MgSO4), filtered, concentrated, and purified on reverse phase HPLC (gradient of H20 / MeCN), to give the title compound as a white solid: 1 H NMR ( 400MHz, CDCI3) d = 8.12 (d, J = 6.4 Hz, 1H), 7.08 (d, J - 8.5 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 6.21 (d, J = 6.4 Hz , 1H), 4.34 (m, 2H), 3.80 (s, 3H), 3.65 (m, 2H), 3.50-3.00 (m, 4H), 2.95 (m, 2H), 2.07 (m, 1H), 2.00- 1.20 (m, 4H), 1.70 (s, 6H), 0.91 (d, J = 6.7 Hz, 6H). MS calculated for C28H38N506 (M + H +) 540.3, found 540.3. se 89 Bl Example H1. 2- (3. {3-Cyclobutyl-methyl-1 -. {2- (2,4-dichloro-phenyl) -ethyl] -2,4-dioxo-1,3-diaza-spiro- [ 4.5] -dec-8-yl.}. -phenoxy) -2-methyl-propionic acid. Step A: The 3-bromo-anisole (2.0 milliliters, 15.8 millimoles) is dissolved in dry tetrahydrofuran (20 milliliters), and cooled to -78 ° C. N-butyl lithium (1.6M solution in hexane, 10.5 milliliters, 16.8 millimoles) is added dropwise, with stirring, for 5 minutes. Stirring is continued at -78 ° C for another 45 minutes, to provide a suspension. In a separate dry flask, 1,4-dioxa-spiro- [4.5] -decan-8-one 80 (2.67 grams, 17.1 mmol) is dissolved in dry tetrahydrofuran (15 milliliters), and cooled to -78 ° C. . The suspension prepared above is added cold by means of a cannula to the ketone solution; The resulting mixture is stirred at -78 ° C for 15 minutes, and then at room temperature for 30 minutes. Treatment with 5 milliliters of a saturated aqueous solution of NH 4 Cl, followed by concentration, treatment with 1 N HCl, and extraction with ethyl acetate, and then washing with water and brine, drying over MgSO 4, concentration and chromatography on silica gel ( 10 to 90 percent EtOAc / hexane), provide 8- (3-methoxy-phenyl) -1,4-dioxa-spiro- [4.5] -decan-8-ol 81 as a clear, thick oil: 1H NMR ( 400 MHz, CDCI3) d = 7.27 (t, J = 7.9 Hz, 1H), 7.10 (m, 2H), 6.80 (dd, J = 2.4, 8.2 Hz, 1H), 3.99 (m, 4H), 3.82 (s) , 3H), 2.13 (m, 4H), 1.81 (d, J = 12.1 Hz, 2H), 1.69 (d, J = 12.0, 2H). Step B: The 8- (3-methyl-phenyl) -1,4-dioxa-spiro- [4.5] -decan-8-ol 81 (1.57 grams, 5.9 mmol) is dissolved in benzene (40 milliliters). P-Toluenesulfonic acid monohydrate (0.14 grams, 0.74 millimoles) is added; the flask is adapted with a Dean-Stark trap, and heated to 105 ° C (bath temperature). After 3 hours, the mixture is cooled, diluted with ethyl acetate, and washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, and concentrated to provide the 8- (3-methoxy-phenyl) -1, 4-dioxa-spiro- [4.5] -dec-7-ene 82 as an oil (quantitative): MS calculated for C15H1903 (M + H +) 247.1, found 247.1; 1 H NMR (400 MHz, CDCl 3) d = 7.22 (t, J = 7.9 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 6.93 (t, J = 2.2 Hz, 1H), 6.78 (dd, J = 2.2, 7.9 Hz, 1H), 5.99 (m, 1H), 4.03 (s, 4H), 3.81 (s, 3H), 2.65 (m, 2H), 2.47 (m, 2H), 1.92 (m, 2H) ).

Step C: The 8- (3-methoxy-phenyl) -1,4-dioxa-spiro- [4.5] -dec-7-ene 82 (from Step B above) is dissolved in ethyl acetate (60 milliliters). Palladium black (5 percent on carbon, 0.22 grams, 21 mole percent) is added, and the mixture is degassed and stirred under 50 psi (3.5 kg / cm2) of hydrogen for 3 hours. Filtration and concentration give 8- (3-methoxy-phenyl) -1,4-dioxa-spiro- [4.5] -decano-83 as an oil (1.31 grams, quantitative): MS calculated for C15H2103 (M + H +) 249.1, found 249.1; 1 H NMR (400 MHz, CDCl 3) d = 7.21 (t, J = 7.9 Hz, 1H), 6.83 (d, J = 7.9 Hz, 1H), 6.79 (t, J = 2.2 Hz, 1H), 6.74 (dd, J = 2.2, 7.9 Hz, 1H), 3.98 (s, 4H), 3.80 (s, 3H), 2.53 (m, 1H), 1.85 (m, 4H), 1.69 (m, 4H). Step D: The 8- (3-methoxy-phenyl) -1,4-dioxa-spiro- [4.5] -decano-83 (1.3 grams, 5 mmol) is dissolved in acetone (30 milliliters) and aqueous HCI 4N (10.0 milliliters) , 40 millimoles). The mixture is heated to reflux for 2.5 hours. Cooling and concentration, followed by extraction with ethyl acetate, washing the extracts with saturated aqueous NaHCO3, water, and brine, drying over Na2SO4, and concentration, provide an oil. Purification on silica gel yields 4- (3-methoxy-phenyl) -cyclohexanone 84 as a clear oil, which is eventually converted to a white solid: MS calculated for Ci3H1702 (M + H +) 205.1, found 205.1; H NMR (400 MHz, CDCl 3) d = 7.25 (t, J = 7.9 Hz, 1H), 6.84 (d, J = 7.9 Hz, 1H), 6.79 (s, 1H), 6.78 (dd, J = 2.2, 7.9 Hz, 1H), 3.81 (s, 3H), 3.01 (tt, J = 3.4, 12.1 Hz, 1H), 2.51 (m, 4H), 2.23 (m, 2H), 1.93 (m, 2H). Step E: 4- (3-methoxy-phenyl) -cyclohexanone 84 (0.55 grams, 2.7 mmol) is dissolved in AcOH (10 milliliters), and cooled to 10 ° C. 2,4-Dichloro-phenethyl-amine (0.50 milliliters, 3.3 mmol) is added, followed by trimethyl-silyl cyanide (0.50 milliliters, 3.7 mmol). The ice bath is removed, and the mixture is stirred at room temperature for 20 hours. The mixture is poured into ice water, adjusted to a pH of 9 using aqueous ammonia, and extracted with EtOAc twice. The organic extracts are combined, then washed with saturated NaHCO3, water, and brine, dried over MgSO4, and concentrated, to provide an oil. Chromatography on silica gel (10 to 50 percent EtOAc / hexanes) gives 85 as an oil (0.67 grams, 1.66 millimoles). MS calculated for C22H25Cl2 2O (M + H +) 403.1, found 403.0; 1 H NMR (400 MHz, CDCl 3) d = 7.39 (s, 1 H), 7.23 (t, J = 7.9 Hz, 1 H), 7.20 (s, 2 H), 6.82 (d, J = 7.9 Hz, 1 H), 6.77 ( s, 1H), 6.76 (dd, J = 2.2, 7.9 Hz, 1H), 3.80 (s, 3H), 3.06 (t, J = 7.2 Hz, 2H), 2.93 (t, J = 7.2 Hz, 2H), 1.96 (m, 2H), 1.83 (m, 2H), 1.57 (m, 2H). Step F: The chlorosulfonyl isocyanate (0.2 milliliter, 2.3 mmol) was dissolved in dichloromethane (10 milliliters), and cooled to 0 ° C. 1 - [2- (2,4-Dichloro-phenyl) -ethyl-amino] -4- (3-methoxy-phenyl) -cyclohexane-carbonitrile 85 (0.67 grams, 1.66 mmol) is added dropwise, with stirring, As a solution in dichloromethane (10 milliliters), the ice bath is removed, and the mixture is stirred at room temperature for 1 hour. The solvent is removed, 1 M HCl (40 milliliters) is added, and the mixture is heated at reflux for 3.5 hours. Cooling to room temperature, followed by vacuum filtration, washing the white solid with water, and air drying, provide 1 - [2- (2,4-dichloro-phenyl) -ethyl] -8- (3-methoxy) phenyl) -1,3-diaza-spiro- [4.5] -decano-2,4-dione 86 (0.52 grams, 1.16 mmol): MS calculated for C23H25Cl2N2O3 (M + H +) 447.1, found 447.1; 1 H NMR (400 MHz, DMSO-d 6) d = 10.82 (s, 1 H), 7.61 (s, 1 H), 7.41 (s, 2 H), 7.22 (t, J = 7.9 Hz, 1 H), 6.81 (d, J = 7.8 Hz, 1H), 6.72 (m, 2H), 3.73 (s, 3H), 3.36 (t, J = 7.2 Hz, 2H), 2.99 (t, J = 7.2 Hz, 2H), 2.15 (m, 2H) ), 1.85 (m, 2H), 1.68 (m, 4H). Step G: 1 - [2- (2,4-Dichloro-phenyl) -ethyl] -8- (3-methoxy-phenyl) -1, 3-diaza-spiro- [4.5] -decano-2,4- diona 86 (0.52 grams, 1.16 millimoles), bromo-methyl-cyclobutane (0.175 milliliters, 1.56 millimoles), and potassium carbonate (0.32 grams, 2.32 millimoles) in dry dimethyl sulfoxide (5.0 milliliters), are stirred for 3 hours at 50 ° C. The mixture is cooled to room temperature, diluted with water, and extracted with dichloromethane (three times). The combined extracts are washed with 1N HCl, H20 (three times), and brine, dried over MgSO4, and concentrated, to provide 3-cyclobutyl-methyl-1 - [2- (2,4-dichloro-phenyl) -ethyl] -8- (3-methoxy-phenyl) -1, 3-diaza-spiro- [4.5] -decano-2,4-dione 87 (0.65 grams, quantitative), as a clear, thick oil: MS calculated for C28H33CI2N2O3 (M + H +) 515.1, found 515.1; 1 H NMR (400 MHz, CDCl 3) d = 7.40 (d, J = 1.7 Hz, 1 H), 7.21 (m, 3 H), 6.88 (d, J = 7.9 Hz, 1 H), 6.83 (t, J = 2.2 Hz, 1H), 6.75 (dd, J = 2.2, 7.9 Hz, 1H), 3.80 (s, 3H), 3.54 (d, J = 7.4 Hz, 2H), 3.41 (t, J = 7.2 Hz, 2H), 3.13 ( t, J = 7.2 Hz, 2H), 2.71 (septet, J = 7.7 Hz, 1H), 2.38 (m, 3H), 2.02 (m, 2H), 1.88 (m, 2H), 1.77 (m, 6H), 1.62 (m, 2H). Step H: 3-Cyclobutyl-methyl-1 - [2- (2,4-dichloro-phenyl) -ethyl] -8- (3-methoxy-phenyl) -1,3-diaza-spiro- [4.5] - decane-2,4-dione 87 (0.65 grams, 1.2 mmol) is dissolved in dry dichloromethane. Clean boron tribromide (0.50 milliliters, 5.2 mmol) is added, and the mixture is stirred at room temperature for 1.5 hours. The reaction mixture is poured onto ice, and extracted with dichloromethane (three times). The combined extracts are washed with saturated aqueous NaHCO3, dried over MgSO4, and concentrated to provide a crystal. Treatment with acetonitrile and concentration provide 3-cyclobutyl-methyl-1- [2- (2,4-dichloro-phenyl) -ethyl] -8- (3-hydroxy-phenyl) -1,3-diaza-spiro - [4.5] -decano-2,4-dione 88 as a white solid (0.56 grams, quantitative): MS calculated for (M + H +) 501.1, found 501.1; 1 H NMR (400 MHz, CDCl 3) d = 7.40 (d, J = 1.7 Hz, 1 H), 7.20 (m, 2 H), 7.17 (t, J = 7.9 Hz, 1 H), 6.85 (d, J = 7.9 Hz, 1H), 6.77 (t, J = 2.2 Hz, 1H), 6.68 (dd, J = 2.2, 7.9 Hz, 1H), 3.55 (d, J = 7.4 Hz, 2H), 3.41 (t, J = 7.2 Hz, 2H), 3.12 (t, J = 7.2 Hz, 2H), 2.71 (septet, J = 7.7 Hz, 1H), 2.38 (m, 3H), 2.02 (m, 2H), 1.87 (m, 2H), 1.77 ( m, 6H), 1.60 (m, 2H). Step I: 3-Cyclobutyl-methyl-1 - [2- (2,4-dichloro-phenyl) -ethyl] -8- (3-hydroxy-phenyl) -1,3-diaza-spiro- [4.5] - decane-2,4-dione 88 (0.28 grams, 0.56 mmol) is dissolved in dichloromethane (3 milliliters) and ACN (6 milliliters). 2-Bromo-2-methylpropionic acid methyl ester (0.09 milliliters, 0.7 millimoles) and Cs2CO3 (0.38 grams, 1.17 millimoles) are added, and the suspension is stirred vigorously at 60 ° C for 4 hours. Cooling, addition of a small amount of silica gel, and filtration, followed by concentration, give ester 89 as a thick oil: MS calculated for C32H39Cl2N205 (M + H +) 601.1, found 601.0; 1 H-NMR (400 MHz, CDCl 3) d = 7.40 (d, J = 1.7 Hz, 1H), 7.21 (m, 2H), 7.15 (t, J = 7.9 Hz, 1H), 6.91 (d, J = 7.9 Hz, 1H), 6.80 (t, J = 2.2 Hz, 1H), 6.62 (dd, J = 2.25 7.9 Hz, 1H), 3.79 (s, 3H), 3.54 (d, J = 7.4 Hz, 2H), 3.41 (t, J = 7.2 Hz, 2H), 3.12 (t, J = 7.2 Hz, 2H), 2.70 (septet, J = 7.7 Hz, 1H), 2.36 (m, 3H), 2.02 (m, 2H), 1.86 (m, 2H), 1.76 (m, 6H), 1.69 (m, 2H), 1.69 (s, 6H). Step J: 2- (3. {3-Cyclobutyl-methyl-1 - [2- (2,4-dichloro-phenyl) -ethyl] -2,4-dioxo-1,3-methyl acid ester -diaza-spiro- [4.5] -dec-8-yl.}. -phenoxy) -2-methyl-propionic acid 89 (from Step I above) is dissolved in DME (2 milliliters). Solid lithium hydroxide monohydrate (0.10 grams, excess) is added, followed by water (0.50 milliliters). The mixture is stirred at 60 ° C overnight. Cooling, adjustment of pH to 2 using 1N HCl, and extraction with dichloromethane (three times), followed by drying over MgSO4 and concentration, provide a resin. Treatment with diethyl ether and hexane, followed by concentration under a high vacuum, affords 2- (3. {3-cyclobutyl-methyl-1 - [2- (2,4-dichloro-phenyl) -ethyl) ] -2,4-dioxo-1, 3-diaza-spiro- [4.5] -dec-8-yl.}. -phenoxy) -2-methyl-propionic of Example H1 as a solid: MS calculated for C31H37CI2N205 (M + H +) 587.1, found 587.1; 1 H NMR (400 MHz, CDCl 3) d = 7.41 (d, J = 1.7 Hz, 1 H), 7.21 (m, 2 H), 7.18 (t, J = 7.9 Hz, 1 H), 6.90 (d, J = 1.9 Hz, 1H), 6.82 (t, J = 2.2 Hz, 1H), 6.65 (dd, J = 2.2, 7.9 Hz, 1H), 3.54 (d, J = 7.4 Hz, 2H), 3.41 (t, J = 7.2 Hz, 2H), 3.13 (t, J = 7.2 Hz, 2H), 2.70 (septet, J = 7.7 Hz, 1H), 2.36 (m, 3H), 2.02 (m, 2H), 1.88 (m, 2H), 1.77 ( m, 6H), 1.70 (m, 2H), 1.69 (s, 6H).

Example 11: Acid. { 3- [3-cyclopropyl-methyl-2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1,3,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic. Step A: To a well stirred solution of Intermediary 72 (0.17 grams, 0.47 millimoles) in?,? - anhydrous dimethyl formamide (5 milliliters), CsHC03 (0.14 grams, 0.7 millimoles) and bromo-methyl-cyclopropane ( 0.095 grams, 0.7 millimoles). The reaction mixture is evacuated three times, and irradiated in a microwave oven at 130 ° C for 20 minutes. The reaction mixture is cooled, diluted with water, and extracted with EtOAc twice. The organic layers are combined, washed with a 5 percent Na2CO3 solution, brine, and concentrated to provide [3- (3-cyclopropyl-methyl-2,4-dioxo-1, 3-tert-butyl ester. , 8-triaza-spiro- [4.5] -dec-8-yl] -phenyl] -acetic acid as a white solid, which is used without further purification MS (m / z) (M + 1) + 414.3. B: To a well-stirred solution of [3- (3-cyclopropyl-methyl-2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec-8-yl) - tert-butyl ester phenyl] -acetic crude (20 milligrams, 0.048 millimoles) in anhydrous MeCN (1 milliliter), Cs2C03 (19 milligrams, 0.058 millimoles) and 1-bromo-methyl-4-trifluoro-methoxy-benzene (12.5 microliters, 0.77) are added. millimoles) The reaction mixture is evacuated three times and irradiated in a microwave oven at 130 ° C for 30 minutes.The reaction mixture is purified directly by LC / MS preparation, using a gradient of 90 MeCN / H20 to 10 percent The solvent is removed in vacuo to propo Rotate the terbutil-ester of the acid. { 3- [3-cyclopropyl-methyl-2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1,3,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic. MS (m / z) (M + 1) + 602.3. NB: KF-AI203 can be used instead of Cs2C03. Step C: A solution of the terbutil-ester of the acid. { 3- [3-cyclopropyl-methyl-2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1,3,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic in dichloromethane (1 milliliter) is treated with a 50 percent solution of trifluoroacetic acid in dichloromethane (2 milliliters). The reaction mixture is stirred at room temperature for 1 hour. The solvent is removed in vacuo, and the crude product is purified by LC / MS preparation, using a gradient of MeCN / H20 of 90 to 10 percent. Removal of the solvent gives the title compound 11 as the trifluoroacetic acid salt. H NMR (400MHz, CD3OD) d 7.41 (d, J = 8.0Hz, 2H), 7.29 (t, J = 8.0Hz, 1H), 7.23 (d, J = 8.0Hz, 2H), 7.07-7.04 (m, 2H), 6.95-6.94 (m, 2H), 4.61 (s, 2H), 3.73-3.63 (m, 4H), 3.54 (s, 2H), 3.41 (d, J = 4.0Hz, 2H), 2.24-2.17 (m, 2H), 1.82-1.79 (m, 2H), 1.43 (s, 9H), 1.22-1.18 (m, 2H), 0.55-0.51 (m, 1H), 0.38-0.34 (m, 2H). MS (m / z) (M + l) + 532.0.

Example J1. Acid (3- { 3-cyclobutyl-methyl-2,4-dioxo-1 - [2- (4-trifluoromethyl-phenyl) -ethyl] -1,8,8-triaza-spiro- [4.5] -dec-8-M.}.-phenyl) -acetic. Step A: To a stirred solution of 72 (0.4 grams, 1.1 mmol) in anhydrous N, N-dimethylformamide (5 milliliters), CsHC03 (0.32 grams, 1.6 mmol) and bromo-methyl-cyclobutane (0.23 grams) are added. , 1.6 millimoles). The reaction mixture is evacuated three times, and irradiated in a microwave oven at 130 ° C for 20 minutes. The reaction mixture is cooled, diluted with water, and extracted with EtOAc twice. The organic layers are combined, washed with a 5 percent Na2CO3 solution, brine, and concentrated to provide [3- (3-cyclobutyl-methyl-2,4-dioxo-1, 3-tert-butyl ester. , 8-triaza-spiro- [4.5] -dec-8-yl) -phenyl] -acetic acid as a white solid, which is used without further purification. 1 H NMR (400MHz, CDCl 3) d 7.17-7.13 (m, 1H), 6.79-6.73 (m, 3H), 5.89 (bs, 1H), 3.65-3.61 (m, 2H), 3.47 (d, J = 4.0Hz , 2H), 3.42 (s, 2H), 2.94-2.88 (m, 2H), 2.63 (quintet, J = 8.0Hz, 1H), 2.19- 2.12 (m, 2H), 1.97-1.90 (m, 2H), 1.81-1.65 (m, 6H), 1.37 (s, 9H). MS (m / z) (M + 1) + 428.3. Step B: To a solution of [3- (3-cyclobutyl-methyl-2-tert-butyl ester, 4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec-8-yl) -phenyl] -acetic acid (22 milligrams, 0.05 millimoles) in anhydrous DME (2 milliliters), is added 2- Methanesulfonic acid (4-trifluoro-methyl-phenyl) -ethyl ester (30 milligrams, 0.1 mmol) and KF-AI203 (0.2 grams). The reaction mixture is stirred in an oil bath at 80 ° C for 8 hours. After this time, the reaction mixture is filtered and purified directly by LC / MS preparation, using a gradient of MeCN / H20 of 90 to 10 percent, to provide the terbutil-ester of the acid (3- { 3-Cyclobutyl-methyl-2,4-dioxo-1 - [2- (4-trifluoromethyl-phenyl) -ethyl] -1,8,8-triaza-spiro- [4.5] -dec-8-yl}-phenyl) -acetic. MS (m / z) (M + 1) + 600.2. Step C: (3- {3-Cyclobutyl-methyl-2,4-dioxo-1 - [2- (4-trifluoromethyl-phenyl) -ethyl} -, 3-8- ter-butyl ester triaza-spiro- [4.5] -dec-8-yl.} - phenyl) -acetic, is converted to the title compound of (3- {3-cyclobutyl-methyl-2,4-dioxo-1 acid. - [2- (4-trifluoromethyl-phenyl) -ethyl] -1,8,8-triaza-spiro- [4.5] -dec-8-yl.} - phenyl) -acetic acid as a trifluoric acid salt -acetic, following the same procedure as described in Step C for the preparation of Example 11. 1 H NMR (400MHz, CD3OD) d 7.59 (d, J = 8.0Hz, 2H), 7.43 (d, J = 8. OH , 1H), 7.22 (t, J = 8.0Hz, 1H), 6.96-6.81 (m, 3H), 3.63-3.57 (m, 2H), 3.52-3.45 (m, 6H), 3.08-3.04 (m, 2H ), 2.71-2.63 (m, 1H), 2.05-2.00 (m, 4H), 1.89-1.87 (m, 2H), 1.80-1.77 (m, 2H), 0.91-0.98 (m, 2H). MS (m / z) (MH-1) + 544.3.

Example K1: Acid (3- {3-cyclobutyl-meth] -1- [4- (1-methoxy-phenyl) -butyl] -2,4-dioxo-1,3,8-triaza- spiro- [4.5] -dec-8-yl.} - phenyl) -acetic. Step A: To a well-stirred solution of 72 (0.4 grams, 1.1 mmol) in anhydrous dimethyl formamide (5 milliliters), CsHC03 (0.32 grams, 1.6 mmol) and bromo-methyl-cyclobutane (0.23 grams, 1.6 mmol) are added. ). The reaction mixture is evacuated three times, and irradiated in a microwave oven at 130 ° C for 20 minutes. The reaction mixture is cooled, diluted with water, and extracted with EtOAc twice. The organic layers are combined, washed with a 5 percent Na2CO3 solution, brine, and concentrated to provide [3- (3-cyclobutyl-methyl-2,4-dioxo-1, 3-tert-butyl ester. , 8-triaza-spiro- [4.5] -dec-8-yl) -phenyl] -acetic acid as a white solid, which is used without further purification. 1 H NMR (400MHz, CDCl 3) d 7.17-7.13 (m, 1H), 6.79-6.73 (m, 3H), 5.89 (bs, 1H), 3.65-3.61 (m, 2H), 3.47 (d, J = 4.0Hz , 2H), 3.42 (s, 2H), 2.94-2.88 (m, 2H), 2.63 (quintet, J = 8.0Hz, 1H), 2.19-2.12 (m, 2H), 1.97-1.90 (m, 2H), 1.81-1.65 (m, 6H), 1.37 (s, 9H). MS (m / z) (M + 1) + 428.3. Step B: (3- {3-Cyclobutyl-methyl-1- [4- (4-methoxy-phenyl) -butyl] -2,4-dioxo-1, 3,8-triaza terbutil-ester -spiro- [4.5] -dec-8-yl.}. - phenyl) -acetic is prepared from the [3- (3-cyclobutyl-methyl-2,4-dioxo-1,3 acid, tert-butyl ester, 8-triaza-spiro- [4.5] -dec-8-yl) -phenyl] -acetic, using the same procedure described in Step B for the preparation of J1. The reaction mixture is purified by LC / MS preparation, using a gradient of MeCN / H20 of 90 to 10 percent. The solvent is removed in vacuo to provide the title compound. MS (m / z) (M + 1) + 590.2. Step C: (3- {3-Cyclobutyl-methyl-1- [4- (4-methoxy-phenyl) -butyl] -2,4-dioxo-3-tert-butyl ester, 3,8 -triaza-spiro- [4.5] -dec-8-yl.} - phenyl) -acetic is converted to the title compound of the acid (3- {3-cyclobutyl-methyl-1 - [4- (4 -methoxy-phenyl) -butyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec-8-yl.}. -phenyl) -acetic acid as a trifluoroacetic acid salt , following the same procedure as described in Step C for the preparation of Example 11. 1 H NMR (400MHz, CDCl 3) d 7.59 (s, 1H), 7.53-7.50 (m, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0Hz, 1H), 7.09 (d, J = 8.0Hz, 2H), 6.82 (d, J = 8.0Hz, 2H), 4.20 (t, J = 12.0Hz, 2H), 3.78 (s, 3H), 3.68-3.66 (m, 3H), 3.55 (d, J = 8.0Hz, 2H), 3.29 (t, J = 8.0Hz, 2H), 2.83 (dt, J = 4.0 and 12.0Hz, 2H), 2.67 (quintet, J = 12.0Hz, 1H), 2.58 (t, J = 8.0Hz, 2H), 2.05-1.98 (m, 2H), 1.89-1.73 (m, 6H ), 1.66-1.60 (m, 4H). MS (m / z) (M + 1) + 534.2. By repeating the procedures described in the above Examples, using the appropriate starting materials, the following compounds of Formula I are obtained, as identified in Table 1.

Table 1 Transcription Assay Transfection assays are employed to evaluate the ability of the compounds of the invention to modulate the transcription activity of the peroxisome proliferator-activated receptors. Briefly stated, expression vectors are introduced for chimeric proteins that contain the yeast GAL4 DNA binding domain fused to the ligand binding domain (LBD) of either PPARO, PPARa, or ????? ?, by means of transient transfection, in mammalian cells, together with a reporter plasmid, wherein the luciferase gene is under the control of a GAL4 binding site. After exposure to a peroxisome proliferator-activated receptor modulator, the transcription activity of peroxisome proliferator-activated receptor varies, and this can be monitored by changes in luciferase levels. If the transfected cells are exposed to a peroxisome proliferator-activated receptor agonist, peroxisome proliferator-activated receptor-dependent transcription activity increases, and luciferase levels rise. 293T human embryonic kidney cells (8x106) are seeded in a 175 square centimeter flask one day before the start of the experiment, in 10 percent fetal bovine serum, penicillin / streptomycin / 1 percent fungizome, and DMEM medium. Cells are harvested by washing with phosphate-buffered serum (30 milliliters), and then dissociated using trypsin (0.05 percent); 3 milliliters). The trypsin is inactivated by the addition of the assay medium (DMEM, CA-dextran-fetal bovine serum (5 percent)). The cells are centrifuged and resuspended at 170,000 cells / milliliter. A transfection mixture is prepared from the ligand binding domain expression plasmid of GAL4-PPAR (1 microgram), the luciferase reporter plasmid-UAS (1 microgram), fugen (ratio of 3: 1, 6 microliters), and medium without serum (200 microliters), and incubated for 15 to 40 minutes at room temperature. The transfection mixtures are added to the cells to give 0.16M cells / milliliter, and then the cells (500 microliters / well) are applied to white solid 384 treated plates treated with CT. The cells are further incubated at 37 ° C, with 0.5% C02, for 5 to 7 hours. A series of 12-point dilutions (triple serial dilutions) is prepared for each test compound in dimethyl sulfoxide, with an initial compound concentration of 10 μ ?. The test compound (500 nanoliters) is added to each well of cells in the assay plate, and the cells are incubated at 37 ° C, with 5.0 percent C02, for 18 to 24 hours. The cell lysis regulator / luciferase assay, Bright-Glo ™ (25 percent; 25 microliters; Promega) is added to each well. After an additional incubation for 5 minutes at room temperature, the luciferase activity is measured. The crude luminescence values are normalized by dividing them by the value of the dimethyl sulfoxide control present in each plate. The standardized data are analyzed, and the dose response curves are adjusted using the Prism Graph adjustment program. The EC50 is defined as the concentration at which the compound elicits a response that is halfway between the maximum and minimum values. The relative efficiency (or percentage of efficacy) is calculated by comparing the response elicited by the compound with the maximum value obtained for a reference PPAR modulator. The compounds of Formula I, in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, for example, as indicated by the in vitro tests described in this application. The compounds of the invention preferably have an EC50 for ????? and / or PPARa, and / or PPARy, of less than 5?, More preferably less than 1?, More preferably less than 500 nM, and most preferably less than 100 nM. The compounds of the invention preferably have an EC5o for PPARO that is less than or equal to that for PPARa, which in turn has an EC50 that is at least 10 times lower than for PPARy. It is understood that the Examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes will be suggested in light thereof for those skilled in the art, and that they should be included within the spirit and scope of this application, and within the scope of the appended claims. All publications, patents, and patent applications cited herein are incorporated herein by reference for all purposes.

Claims (18)

1. A compound selected from the, Ib, and it: Ib where: n is selected from 1, 2, 3, 4, and 5; m is selected from 1, 2, 3, 4, and 5; each Ri is independently from hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted by halogen, alkoxy of 1 to 6 carbon atoms, and alkoxy of 1 to 6 carbon atoms replaced by halogen; R3 is selected from alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkyl of 1 to 6 carbon atoms substituted by halogen, alkenyl of 2 to 6 carbon atoms substituted by halogen, -X1C ( 0) R2, heteroaryl of 5 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms, and cycloalkyl of 3 to 12 carbon atoms-alkyl of 0 to 4 carbon atoms; wherein R2 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; R 4 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; R5 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; or R4 and R5, together with the carbon atom to which R4 and R5 are attached, form carbonyl; And it is selected from N and CH; Z is selected from a bond, -S (O) 0.2-, and -CRnR12-; wherein R1 (and R12 are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms; A and B are independently selected from CH and N; R6 and 7 are independently selected from hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted by halogen, alkoxy of 1 to 6 carbon atoms, and alkoxy of 1 to 6 atoms carbon replaced by halogen; R8 is selected from -X2CO2R13, -X2CR14R15 X3C02Ri2, -X2SCR14R15X3C02R13, and -X2OCR14R15X3C02R13; wherein X2 and X3 are independently selected from a bond and alkylene of 1 to 4 carbon atoms; and Ri and R15 are independently selected from hydrogen, alkyl of 1 to 4 carbon atoms, and alkoxy of 1 to 4 carbon atoms; or Ri and R15, together with the carbon atom to which R14 and R15 are attached, form cycloalkyl of 3 to 12 carbon atoms; and R13 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; R9 and R10 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, and -OR16; wherein R16 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; and the pharmaceutically acceptable salts, hydrates, solvates, isomers, and prodrugs thereof.

2. The compound of claim 1, wherein: n is selected from 1, 2, 3, and 4; m is selected from 1, 2, and 3; each is independently selected from hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted by halogen, alkoxy of 1 to 6 carbon atoms, and alkoxy of 1 to 6 carbon atoms replaced by halogen; R3 is selected from alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkyl of 1 to 4 carbon atoms substituted by halogen, alkenyl of 2 to 6 carbon atoms substituted by halogen, -X ^ OJRa, heteroaryl of 5 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms, and cycloalkyl of 3 to 12 carbon atoms-alkyl of 0 to 4 carbon atoms; wherein R2 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; R 4 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; R5 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; or R4 and R5, together with the carbon atom to which R and R5 are attached, form carbonyl; And it is selected from N and CH; Z is selected from a bond, -S (O) 0-2-, and -CR R12-; wherein R (1 and R12 are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms; A and B are independently selected from CH and N; R6 and 7 are independently selected from hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted by halogen, and alkoxy of 1 to 6 carbon atoms; R8 is selected from -X2C02Ri3, -X2CR14R15X3 C02R12, -X2SCR14Ri5 3C02R13, and -X2OCR14R15X3C02R13; wherein X2 and X3 are independently selected from a bond and alkylene of 1 to 4 carbon atoms; and R 4 and R 15 are independently selected from hydrogen and alkyl of 1 to 4 carbon atoms; R13 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; and R9 and R10 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, and -ORi6; wherein R16 is selected from hydrogen and alkyl of 1 to 6 carbon atoms.

3. The compound of claim 2, wherein: Ri is independently selected from hydrogen, halogen, methoxy, trifluoromethoxy, and trifluoromethyl; R3 is selected from isobutyl, cyclopropyl-methyl, cyclobutyl-methyl, isopentyl, butyl, cyclopentyl-methyl, 3-methyl-but-2-enyl, pentyl, 2,2-dimethyl-propyl, 4-fluoro-butyl, 2-ethyl-butyl, 2-methyl-pentyl, cyclohexyl-methyl, 3,3-dimethyl-2-oxo-butyl, pi r rol i lp-pyre, 3-trifluoromethyl-propyl, cyclohexyl-ethyl, 2- ethyl hexyl, 2-methyl-butyl, 3,4,4-trifluoro-but-3-enyl, and 3,3-dimethyl-butyl; R and R5 are each hydrogen, or R4 and R5I together with the carbon atom to which R and R5 are attached, form carbonyl; and Z is selected from a bond, -S (0) 2- and -CH2-.

4. The compound of claim 3, wherein: R8 is selected from -CH2C (0) OH, -CH (CH2) C (0) OH, -OC (CH2) 2 C (0) OH, - ( CH2) 2C (0) OH and -OCH2C (0) OH; and R9 and R10 are independently selected from hydrogen, halogen, methyl, methoxy, and trifluoromethyl. The compound of claim 1, selected from: (3- {3-isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1,3, 8-triaza-spiro- [4.5] -dec-8-yl-methyl.} - phenyl) -acetic; (3- {3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl} -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -decan-8} -sulfonyl.} -4-methyl-phenyl) -acetic; (3- {3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl} -2,4-dioxo-1, 3,8-triaza-spiro [4.5] -dec-8} -yl.}.-phenyl) -acetic; 2- (4-. {3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1,3-diaza-spiro- [4.5] -decyclic acid 7-yl-methyl.}. Phenyl) -propionic; (3- { 3-cyclopropyl-methyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4,5] -dec- 8-yl.}. Phenyl) -acetic; acid { 3- [3-isobutyl-2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1,3,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic; 2- (2-. {3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] ] -dec-8-yl.} - pyrimidin-4-yloxy) -2-methyl-propionic; 2- (3. {3-Cyclobutyl-methyl-1 - [2- (2,4-dichloro-phenyl) -ethyl] -2,4-dioxo-1,3-diaza-spiro- [4.5] -dec-8-yl.}. -phenoxy) -2-methyl-propionic; acid { 3- [3-cyclopropyl-methyl-2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1,3,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic; (3- {3-cyclobutyl-methyl-2,4-dioxo-1 - [2- (4-trifluoromethyl-phenyl) -ethyl} -1,8,8-triaza-spiro- [4.5] -dec-8-yl.}. phenyl) -acetic; (3- ({3-cyclobutyl-methyl-1- [4- (4-methoxy-phenyl) -butyl] -2,4-dioxo-1,3,8-triaza-spiro- [4,5] -dec} -8-yl.}.-Phenyl) -acetic; acid 3-. { 3- isobuti I- 1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec-8-yl-methyl} -benzoic; (2- { 3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4,5] -dec-8- il-methyl] -phenyl) -acetic; (3- {3-Isobutyl-1- [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1,3,8-triaza-spiro- [4.5] -decan-8} -sulfonyl) -4-methoxy-phenyl) -acetic; 3- (3. {3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec acid -8-yl.}.-Phenyl) -propionic; (3- {3-Isobutyl-1- [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec-8} -yl.}. -phenoxy) -acetic; 2- (3. {3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4,5] -dec acid -8-yl.}. -phenoxy) -2-methyl-propionic; (5- { 3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1,3,8-triaza-spiro- [4,5] -dec-8 -yl.} -2-methyl-f e ni I) -acetic; (3- ({3- Isobutyl) 1-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -decide 8-yl.} - 5-methyl-phenyl) -acetic; acid (2-fluoro-5-. {3- isobuti 1-1 - [2- (4-metoxyphenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4.5 ] -dec-8-yl.}. phenyl) -acetic; (5- { 3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec-8 -yl.} -2-trifluoro-methyl-phenyl) -acetic; (5- { 3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1,3,8-triaza-spiro- [4,5] -dec-8 -yl.} -2-methoxy-phenyl) -acetic; 2- (3. {3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec acid -8-yl.}.-Phenyl) -2-methyl-propionic; (5- { 3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1,3,8-triaza-spiro- [4,5] -dec-8 -yl.} -2-methyl-phenoxy) -acetic; acid (2-chloro-5-. {3-isobutyl-1- [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec-8-yl.}. -phenoxy) -acetic; 2- (5- { 3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4,5] -dec acid -8-yl.} -2-methyl-phenoxy) -2-methyl-propionic acid; 2- (2-Chloro-5-. {3-isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [ 4.5] -dec-8-yl.}. -phenoxy) -2-methyl-propionic; 2- (2,3-difluoro-5-. {3-isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro acid - [4.5] -dec-8-yl.}. -phenoxy) -2-methyl-propionic; (3- {3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2-oxo-1,3,8-triaza-spiro- [4.5] -dec-8-yl} .}.-phenyl) -acetic; (6- { 3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4,5] -dec-8 -yl.} - pyridin-2-yl) -acetic; (2- {3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-l, 3,8-triaza-spiro- [4.5] -dec-8} -yl.} - pyridin-4-yl) -acetic; (5-. {3-Cyclobutyl-methyl-1 - [2- (2,4-dichloro-phenyl) -ethyl] -2,4-dioxo-1,3,8-triaza-spiro- [4.5 ] -dec-8-yl.} -2-methyl-phenyl) -acetic; 2- (5-. {3-Cyclobutyl-methyl-1 - [2- (2,4-dichloro-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec-8-yl.} -2-methyl-phenoxy) -2-methyl-propionic; acid (2-chloro-5-. {3-cyclobutyl-methyl-1 - [2- (2,4-dichloro-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro - [4.5] -dec-8-yl.}. -phenoxy) -acetic; 2- (2-Chloro-5-. {3-cyclobutylmethyl 1-1 - [2- (2,4-dichloro-phenyl) -etl] -2,4-dioxo-1,3, 8-triaza-spiro- [4.5] -dec-8-yl.}. -phenoxy) -2-methyl-pro-ion; (6- { 3-Cyclobutyl-methyl-1 - [2- (2,4-dichloro-phenyl) -ethyl] -254-dioxo-1, 3,8-triaza-spiro- [4.5] -dec acid -8-il.} -pi ri din -2- i I) -acetic; (4- { 3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1, 3,7-triaza-spiro- [4.5] -dec-7 -yl-methyl.}. -phenoxy) -acetic; (3- {3-Cyclobutyl-methyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1,3,8-triaza-spiro- [4.5] -dec acid -8-yl.}.-Phenyl) -acetic; acid { 3- [1 - [2- (4-methoxy-phenyl) -ethyl] -3- (3-methyl-butyl) -2,4-dioxo-1, 3,8-triaza-spiro- [4,5] -dec -8-yl] -phenyl-acetic; (3- {3-Butyl-1 - [2- (4-methoxy-phenyl) -ethyl} -2,4-dioxo-l, 3,8-triaza-spiro- [4.5] -dec-8} -yl.}.-phenyl) -acetic; 2- (4-. {3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1,3,8-triaza-spiro- [4.5] -dec acid -8-yl.} - pyrimidin-2-yloxy) -2-methyl-propionic; 2- (6- { 3-Isobutyl-1 - [2- (4-methoxy-phenyl) -ethyl] -2,4-dioxo-1,3,8-triaza-espyro- [4,5] -dec-8-il.} -pi ri m idin-4- i loxi) -2-metl-propion ico; 2- (4-. {3-Cyclobutyl-methyl-1 - [2- (2,4-dichloro-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [ 4.5] -dec-8-yl.} - pyrimidin-2-yloxy) -2-methyl-propionic; 2- (2-. {3-Cyclobutyl-methyl-1 - [2- (2,4-dichloro-phenyl) -ethyl] -2,4-dioxo-1,3,8-triaza-spiro- [ 4.5] -dec-8-yl.} - pyrimidin-4-yloxy) -2-methyl-propionic; 2- (6- { 3-Cyclobutyl-methyl-1 - [2- (2,4-dichloro-phenyl) -ethyl] -2,4-dioxo-1,3,8-triaza-spiro- [ 4.5] -dec-8-yl.} - pyrimidin-4-yloxy) -2-methyl-propionic; acid { 3- [3-Cyclobutyl-methyl-2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1,3,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic; acid { 3- [3-Cyclobutyl-methyl-2,4-dioxo-1- (4-trifluoromethyl-benzyl) -1,3,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic; acid { 3- [3-cyclopentyl-methyl-2,4-dioxo-1- (4-trifluoromethyl-benzyl) -1,3,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic; acid { 3- [3-cyclopentyl-methyl-2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1, 3,8-triaza-spiro- [4.5] -dec-8-yl] -phen L} -acetic; acid { 3- [1 - (2,4-bis-trifluoro-methyl-benzyl) -3-cyclopentyl-methyl-2,4-dioxo-1, 3,8-triaza-spiro- [4,5] -dec-8- il] -phenyl} -acetic; acid { 3- [3-cyclobutyl-methyl-2,4-dioxo-1- (3-trifluoro-methoxy-benzyl) -1, 3,8-triaza-spiro- [4.5] -dec-8-yl] -phen l} -acetic; (3- {3-cyclobutyl-methyl-2,4-dioxo-1 - [4- (4-trifluoromethyl-phenyl) -thiazol-2-yl-methyl] -1,8,8-triaza -spiro- [4.5] -dec-8-yl.}. -phenyl) -acetic; (3- {3-cyclopropyl-methyl-2,4-dioxo-1 - [4- (4-trifluoromethyl-phenyl) -thiazol-2-yl-methyl-1,3,8-triaza- spiro- [4.5] -dec-8-yl.} - phenyl) -acetic; acid { 3- [3- (3-methyl-but-2-enyl) -2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1, 3,8-triaza-spiro- [4.5] -dec -8-yl] -phenyl} -acetic; acid { 3- [1 - [2- (4-bromo-phenyl) -2-hydroxy-ethyl] -3- (3-methyl-butyl) -2,4-dioxo-1, 3,8-triaza-spiro- [ 4.5] -dec-8-il} -phenyl} -acetic; acid { 3- [1 - [2- (4-chloro-phenyl) -2-hydroxy-ethyl] -3- (3-methyl-butyl) -2,4-dioxo-1, 3,8-triaza-spiro- [ 4.5] -dec-8-yl] -phenyl} -acetic; acid { 3- [2,4-dioxo-3-pentyl-1- (4-trifluoro-methoxy-benzyl) -1,3,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic; acid { 3- [3- (2,2-dimethyl-propyl) -2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1, 3,8-triaza-spiro- [4.5] -dec-8 -yl] -phenyl} -acetic; acid { 3- [3- (2-ethyl-butyl) -2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1, 3,8-triaza-spiro- [4.5] -dec-8-yl ] -phenyl} -acetic; acid { 3- [3- (4-Fluoro-butyl) -2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1, 3,8-triaza-spiro- [4.5] -dec-8-yl ] -phenyl} -acetic; acid { 3- [3- (4-methyl-pentyl) -2,4-dioxo-1 - (4-trifluorop-methoxy-benzyl) -1, 3,8-triaza-spiro- [4.5] -dec-8-yl ] -phenyl} -acetic; acid { 3- [3-cyclohexyl-methyl-2,4-dioxo-1- (4-trif-1-methoxy-benzyl) -1,8,8-triaza-spiro- [4.5] -dec-8-yl] - fenl} -acetic; acid { 3- [2,4-dioxo-3- (3-pyrrol-1-yl-propyl) -1 - (4-trifluoro-methoxy-benzyl) -1,3,8-triaza-espirro- [4.5 ] -dec-8-yl] -phenyl} -acetic; acid { 3- [3- (3,3-Dimethyl-2-oxo-butyl) -2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1, 3,8-triaza-spiro- [ 4.5] -dec-8-yl] -phenyl} -acetic; acid { 3- [2,4-dioxo-3- (4,4,4-trifluoro-butyl) -1 - (4-trifluoro-methoxy-benzyl) -1, 3,8-triaza-spiro- [4.5] -dec -8-yl] -phenyl} -acetic; acid { 3- [3- (2-cyclohexyl-ethyl) -2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1, 3,8-triaza-spiro- [4.5] -dec-8-yl ] -phenyl} -acetic; acid { 3- [3- (2-ethyl-hexyl) -2,4-dioxo-1 - (4-trifluoro-methoxy-benzyl-l, 3,8-triaza-spiro- [4.5] -dec-8-yl) ] -phenyl.} -acetic acid; {. 3- [3- (2-methyl-butyl) -2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1, 3,8- triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic acid: {.3- [2,4-dioxo-3- (3,4,4-trifluoro-but-3-) enyl) -1- (4-trifluoro-methoxy-benzyl) -1,8,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic acid; 3- (3,3-dimethyl-butyl) -2,4-dioxo-1- (4-trifluoro-methoxy-benzyl) -1, 3,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl.} -acetic acid; {. 3- [1 - (2,4-dichloro-5-fluoro-benzyl) -3- (3,3-dimethyl-butyl) -2,4-dioxo-1 , 3,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic acid: {. 3- [1- (2,4-dichloro-5-fluoro-benzyl) - 3- (4-Fluoro-butyl) -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec-8-yl] -phenyl} -acetic acid (3-. { 3-Cyclobutyl-methyl-1 - [2- (2,4-dichloro-phenyl) -ethyl] -2,4-dioxo-1, 3,8-triaza-spiro- [4.5] -dec-8-il .}.-phenyl) -acetic acid (3- {3-cyclopentyl-methyl-2,4-dioxo-1 - [2- (4-trif luoro-methyl-phenyl) -ethyl] -1,8,8-triaza-spiro- [4.5] -dec-8-yl} phenyl) -acetic; (3- {3-cyclopentyl-methyl-1 - [2- (2,4-dichloro-phenyl) -ethyl] -2,4-dioxo-1,3,8-triaza-spiro- [4.5] -dec-8-yl.}. phenyl) -acetic; (3- {3-cyclohexyl-methyl-1 - [2- (2,4-dichloro-phenyl) -ethyl] -2,4-dioxo-1,3,8-triaza-spiro- [4.

5] -dec-8-yl.} l-phenyl) -acetic; and (3- { 1 - [2- (4-Chloro-phenyl) -ethyl] -3-cyclopentyl-methyl-2,4-dioxo-1,3,8-triaza-spiro- [4,5] - dec-8-yl.}. phenyl) -acetic.

6. A method for the treatment of a disease or disorder in an animal wherein the modulation of peroxisome proliferator-activated receptor activity can prevent, inhibit, or diminish the pathology and / or symptomatology of the disease, which method comprises administering to the animal a therapeutically effective amount of a compound of claim 1.

7. The method of claim 6, wherein the peroxisome proliferator activated receptor activity is at least one peroxisome proliferator-activated receptor selected from PPARa. , PPARó, and PPARy.

The method of claim 7, wherein the peroxisome proliferator activated receptor activity is both PPARa and PPARα.

The method of claim 6, wherein the disease or disorder is selected from dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, atherogenesis, hyperglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, cachexia, inflammation, arthritis, cancer, anorexia, anorexia nervosa, bulimia, Alzheimer's disease, skin disorders, respiratory diseases, ophthalmic disorders, irritable bowel diseases, ulcerative colitis, Crohn's disease, type 1 diabetes, type diabetes 2, and syndrome X.

10. The method of claim 6, wherein the disease or disorder is selected from HIV wasting syndrome, long-term critical illness, decreased muscle and / or muscle strength, decreased lean body mass, strength maintenance and function. muscle in old age, muscle power and decreased muscle function, and frailty in old age.

11. The use of a compound according to any of claims 1 to 5, in the manufacture of a medicament for the treatment of a disease in an animal wherein the activity of the peroxisome proliferator-activated receptor contributes to the pathology and / or symptomatology of the disease.

The use of claim 11, wherein the peroxisome proliferator activated receptor activity is at least one peroxisome proliferator-activated receptor selected from PPARa, PPAR5, and PPARy.

The use of claim 12, wherein the activity of the peroxisome proliferator-activated receptor is both PPARa and PPARα.

14. A pharmaceutical composition, which comprises a therapeutically effective amount of a compound of any of claims 1 to 5, in combination with one or more pharmaceutically acceptable excipients.

15. A pharmaceutical combination, especially a pharmaceutical composition, which comprises: 1) a compound of any of claims 1 to 5, or a pharmaceutically acceptable salt thereof; and 2) at least one active ingredient selected from: a) anti-diabetic agents, such as insulin, insulin derivatives and mimetics; insulin secretagogues, such as sulfonyl-ureas, for example Glipizide, Gliburide, and Amaryl; insulinotropic sulfonyl urea receptor ligands, such as meglitinides, for example nateglinide and repaglinide; insulin sensitizers, such as protein tyrosine-1B phosphatase inhibitors (PTP-1B), such as PTP-112; inhibitors of GSK3 (glycogen synthase kinase-3), such as SB-517955, SB-4195052, SB-216763, NN-57-05441, and NN-57-05445; RXR ligands, such as GW-0791 and AGN-194204; inhibitors of the sodium-dependent glucose co-transporter, such as T-1095; inhibitors of glycogen A phosphorylase, such as BAY R3401; biguanides, such as metformin; alpha-glucosidase inhibitors, such as acarbose; GLP-1 (glucagon-1 peptide), GLP-1 analogs, such as exendin-4, and GLP-1 mimetics; Peptidyl peptidase IV inhibitors, such as DPP728, vildagliptin, MK-0431, saxagliptin, GSK23A; an AGE breaker; a thiazolidone derivative (glitazone), such as pioglitazone, rosiglitazone, or (R) -1- acid. { 4- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-yl-methoxy] -benzenesulfonyl} 2,3-dihydro-1 H-indole-2-carboxylic acid, a PPARγ agonist not of the glitazone type, for example GI-262570; b) hypolipidemic agents, such as inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) -redue, for example lovastatin, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, dalvastatin, atorvastatin , rosuvastatin, and rivastatin; squalene synthase inhibitors; ligands FXR (farnesoid X receptor) and LXR (liver X receptor); cholestyramine; fibrates; nicotinic acid, and aspirin; c) an anti-obesity agent or appetite regulating agent, such as phentermine, leptin, bromocriptine, dexamfetamine, amphetamine, fenfluramine, dexfenfluramine, sibutramine, orlistat, dexfenfluramine, mazindol, phentermine, phendimetrazine, diethylpropion, fluoxetine, bupropion , topiramate, diethyl-propion, benzophetamine, phenyl-propanol-amine, or ecopipam, ephedrine, pseudo-ephedrine, or cannabinoid receptor antagonists; d) anti-hypertensive agents, for example cycle diuretics, such as ethacrynic acid, furosemide, and torsemide; diuretics, such as thiazide derivatives, chlorothiazide, hydrochlorothiazide, amiloride; angiotensin-converting enzyme (ACE) inhibitors, such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perinodopril, quinapril, ramipril, and trandolapril; inhibitors of the Na-K-ATPase membrane pump, such as digoxin; neutralendopeptidase (NEP) inhibitors, for example, thiorphan, terteo-thiorphan, SQ29072; ECE inhibitors, for example SLV306; ACE / NEP inhibitors, such as omapatrilate, sampatrilate, and fasidotril; angiotensin II antagonists, such as candesartan, eprosartan, irbesartan, losarian, telmisartan, and valsaran, in particular valsartan; renin inhibitors, such as aliskiren, terlaquirene, ditequirene, RO 66-1132, RO-66-1168; ß-adrenergic receptor blockers, such as acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol, and timolol; inotropic agents, such as digoxin, dobutamine, and milrinone; calcium channel blockers, such as amlodipine, bepridil, diltiazem, felodipine, nicardipine, nimodipine, nifedipine, nisoldipine, and verapamil; Aldosterone receptor antagonists; and inhibitors of aldosterone synthase; e) an HDL-increasing compound; f) a cholesterol absorption modulator, such as Zetia® and KT6-971; g) Apo-A1 analogs and mimetics; h) thrombin inhibitors, such as Ximelagatran; i) aldosterone inhibitors, such as anastrazole, fadrazole, or eplerenone; j) inhibitors of platelet accumulation, such as aspirin, clopidogrel bisulfate; k) estrogen, testosterone, a selective modulator of the estrogen receptor, a selective modulator of the androgen receptor; I) a chemotherapeutic agent, such as aromatase inhibitors, for example femara, anti-estrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule-active agents, alkylating agents, anti-neoplastic anti-metabolites, platinum compounds, compounds that decrease the activity of the protein kinase, such as an inhibitor of the tyrosine kinase receptor of the platelet-derived growth factor, preferably Imatinib, or 4-methyl-N- [3- (4-methyl-imidazol-1) -yl) -5-trifluoro-methyl-phenyl] -3- (4-pyridin-3-yl-pyrimidin-2-yl-amino) -benzamide; and m) an agent that interacts with a 5-HT3 receptor and / or an agent that interacts with a 5-HT4 receptor, such as tegaserod, tegaserod acid maleate, cisapride, cilansetron; or in each case, a pharmaceutically acceptable salt thereof; and optionally a pharmaceutically acceptable carrier.

16. A pharmaceutical composition according to claim 14, or a combination according to claim 15, for the treatment or prevention of dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis , cancer, Alzheimer's disease, skin disorders, respiratory diseases, ophthalmic disorders, inflammatory bowel diseases, IBDs (irritable bowel disease), ulcerative colitis, Crohn's disease, conditions where impaired glucose tolerance is involved, hyperglycemia, and insulin resistance, such as type 1 and type 2 diabetes, impaired glucose metabolism (IGM), impaired glucose tolerance (IGT), impaired fasting glucose (IFG), and syndrome X.

17. A compound according to any one of claims 1 to 5, or a pharmaceutical composition according to to claim 10, or a combination according to claim 11, for use as a medicament.

18. The use of a compound according to any of claims 1 to 5, or a pharmaceutical composition according to claim 14, or a combination according to claim 15, for the manufacture of a medicament for the treatment or prevention of dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin disorders, respiratory diseases, ophthalmic disorders, inflammatory bowel diseases, IBDs (irritable bowel disease), ulcerative colitis, Crohn's disease, conditions where impaired glucose tolerance, hyperglycemia, and insulin resistance are involved, such as type 1 and type 2 diabetes, metabolism impaired glucose (IGM), impaired tolerance to glucose lucosa (IGT), impaired glucose in fasting (IFG), and syndrome