MXPA01008918A - Oxamic acids and derivatives as thyroid receptor ligands - Google Patents

Abstract

The present invention provides novel compounds of Formula (I) and prodrugs thereof, geometric and optical isomers thereof, and pharmaceutically acceptable salts of such compounds, prodrugs and isomers, wherein R1 - R8 and W are as described herein. Pharmaceutical compositions containing such compounds, prodrugs, isomers or pharmaceutically acceptable salts thereof, and methods, pharmaceutical compositions and kits for treating obesity, hyperlipidemia, glaucoma, cardiac arrythmia, skin disorders, thyroid disease, hypothyroidism and related disorders and diseases such as diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesteremia, depression and osteoporosis are also provided.

Description

OXAMIC ACIDS AND DERIVATIVES AS LIGANDS OF THYROID RECEIVERS FIELD OF THE INVENTION The present invention relates to new thyroid receptor ligands and, more particularly, relates to novel oxamic acids and their derivatives, which are useful in the treatment of obesity, hyperlipidemia, glaucoma, cardiac arrhythmia, skin disorders, thyroid, hypothyroidism and disorders and related diseases such as diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, depression and osteoporosis. Also provided are methods, pharmaceutical compositions and kits ("kits") for the treatment of such diseases and disorders.

BACKGROUND OF THE INVENTION It is generally accepted that thyroid hormones, specifically biologically active iodothyronines, are critical for normal development and maintenance of metabolic homeostasis. Thyroid hormones stimulate the metabolism of cholesterol to bile acids and improve the lipolytic responses of fat cells to other hormones.

Thyroid hormones also affect cardiac function both directly and indirectly, for example, by increasing metabolic rate. For example, tachycardia, increased volume of strokes, higher cardiac indexes, cardiac hypertrophy, lower peripheral vascular resistance and higher pulse pressure are observed in patients with hyperthyroidism. Thyroid disorders are usually treated with replacement of hormones by the administration of thyroid hormones that occur naturally or thyromimetic analogues thereof that mimic the effects of thyroid hormones. Below are two thyroid hormones that occur naturally, namely thyroxine or 3,5,3 ', 5'-tetraiodido-L-thyronine (commonly called "T") and 3,5,3' -triyodo-L-thyronine (commonly referred to as "T3"): T T3 T3 is the most biologically active of the two and, as will be appreciated by the structural formulas provided above, differs from T4 by the absence of iodine in the 5 'position. T3 can be produced directly from the thyroid gland or, in peripheral tissues, by removing the iodine at the 5 'position by deiodinated enzymes. The thyromimetic analogs are often designed to be structurally similar to T3. In addition, metabolites of T3 that occur naturally are known. As discussed above, thyroid hormones affect cardiac function, for example, causing an increase in heart rate and, consequently, an increase in oxygen consumption. However, although the increase in oxygen consumption can produce certain desired metabolic effects, it puts the heart under an extra load, which, in some situations, can produce harmful side effects. Therefore, as is known in the art, as described by A.H. Underwood et al., In an article published in Nature, vol. 324: pp. 425-429 (1986), attempts have been made to synthesize analogs of thyroid hormones that function by reducing serum lipids and cholesterol without generating the adverse cardiac effects mentioned above. The patents of E.U.A. Nos. 4,766,121; 4,826,876; 4,910,305; and 5,061,798 describe certain thyroid hormone mimetics, particularly, 3,5-d, bromo-3 '- [6-oxo-3 (1H) -pyridazinylmethyl] thyronines. The patent of E.U. A. No. 5,284,971 discloses certain cholesterol-reducing thyromimetic agents, particularly, 4- (3-cyclohexyl-4-hydroxy or -methoxy-phenylsufonyl) -3,5-dibromo-phenylacetic compounds. The patents of E.U.A. Nos. 5,401,772; 5,654,468; and 5,569,674 disclose certain lipid reducing agents, particularly, heteroacetic acid derivatives, which compete with radiolabeled T3 in assays using rat liver nuclei and plasma membrane preparations. Certain oxamic acids and their derivatives are known in the art, for example, the U.S. No. 4,069,343 describes the use of certain oxamic acids to prevent immediate type hypersensitivity reactions; the patent of E.U.A. No. 4,554,290 describes the use of certain oxamic acids to combat pests in animals and plants; the patent of E.U. A. No. 5,401,772 discloses certain oxamic acids as lipid reducing agents; the patent of E.U.A. No. 5,232,947 describes the use of certain oxamic acids to improve brain damaged brain functions; and the brief description of the European patent invention published as EP 580,550 discloses certain oxamic acid derivatives as hypocholesterolemic agents. In addition, certain oxamic acid derivatives of thyroid hormones are known in the art. For example, N. Yokoyama et al., In an article published in the Journal of Medicinal Chemistry, 38 (4): 695-707 (1995), describes the substitution of a -CH2 group in a metabolite of T3 that is produced from natural form by a group -NH, resulting in -HNCOCO2H. Analogously, R.E. Steele et al., In an article published in International Congressional Service. { Atherosclerosis X) 1066: 321-324 (1995) and Z.F. Stephan et al., In an article published in Atherosclerosis, 126: 53-63 (1996), describe certain oxamic acid derivatives useful as lipid reducing thyromimetic agents free of undesirable cardiac activities. All documents cited here, including the above, are incorporated by reference in their entirety.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides compounds of formula I: (i) prodrugs thereof, geometric and optical isomers thereof and pharmaceutically acceptable salts of said compounds, said prodrugs and said isomers, wherein: each of R1, R2 and R3 is independently hydrogen, halogen, C-alkyl, -6) trifluoromethyl, -CN, -OCF3 or -O-C-? -6 alkyl; R4 is hydrogen, C1-12 alkyl optionally substituted with one to three substituents independently selected from the group Z, C2-12 alkenyl, halogen, -CN, aryl, heteroaryl, C3-cycloalkyl, heterocycloalkyl, -S (O) 2NR9R10 , -C (O) NR 9 R 10, - (C 1 .6 alkyl) -NR 9 R 10, -NR 9 C (O) R 10, -NR 9 C (O) NR 9 R 10, -NR 9 S (O) 2 R 10, - (C 1 -C 6 alkyl) -OR 11 , -OR11 or -S (O) aR12, with the proviso that, when R5 is not fluorine, R4 is -S (O) 2NR9R10, -C (O) NR9R10, - (C6-alkyl) -NR9R10, -NR9C (O) R10, -NR9C (0) NR9R10, -NR9S (O) 2R10, - (alkyl d-6) -OR11, -OR11 or -S (O) aR12; or R3 and R4 can be taken together to form a carbocyclic ring A of formula - (CH2) b- or a heterocyclic ring A selected from the group consisting of -Q- (CH2) C and - (CH2) jQ- (CH2) k -, wherein Q is O, S or NR17, each of said carbocyclic A and heterocyclic A rings optionally independently substituted with one or more substituents independently selected from C 1-4 alkyl, halide or oxo; R5 is fluorine, hydroxy, alkoxy G O OC (O) R9; or R4 and R5 can be taken together to form a heterocyclic ring B selected from the group consisting of -CR9 = CR10-NH, -N = CR9-NH, -CR9 = CH-O- and -CR9 = CH-S; R6 is hydrogen, halogen, C1-4 alkyl or trifluoromethyl; R7 is hydrogen or C-i-β alkyl; R8 is -OR9 or -NR19R20; R9 and R10, each time they appear, are independently (A) hydrogen, (B) C1-12 alkyl optionally substituted with one or more substituents independently selected from the group V, (C) C2-12 alkenyl, (D) C3 cycloalkyl -10 optionally substituted with one or more substituents independently selected from C.sub.-β alkyl, C 2-5 alkynyl, C 3-10 cycloalkyl, -CN, -NR 13 R 14, oxo, -OR 18, -COOR 18 or aryl optionally substituted with X and Y, (E) aryl optionally substituted with X and Y, or (F) het optionally substituted with X and Y; or R9 and R10, each time they appear, can be taken together to form a heterocyclic ring C which optionally also contains a second hetero group selected from the group consisting of -O-, -NR13- and -S-, and further is optionally substituted with one or more substituents independently selected from C1-5 alkyl, oxo, -NR13R14, -OR18, -C (0) 2R18, -CN, -C (O) R9, aryl optionally substituted with X and Y, het optionally substituted with X and Y, C5-6 spirocycloalkyl and a carbocyclic ring B selected from the group consisting of 5, 6, 7 or 8 membered carbocyclic rings, partially and fully saturated, unsaturated, including any bicyclic group wherein said carbocyclic ring B is condensed with a carbocyclic ring C selected from the group consisting of carbocyclic rings of 5, 6, 7 or 8 partially and fully saturated, and unsaturated members; R11 is C-? 12 alkyl optionally substituted with one or more substituents independently selected from the group V, C2-12 alkenyl, C3-10 cycloalkyl, trifluoromethyl, difluoromethyl, monofluoromethyl, aryl optionally substituted with X and Y, het optionally substituted with X and Y, -C (O) NR9R10 or -C (O) R9; R12 is C.sub.1-12 alkyl optionally substituted with one or more substituents independently selected from the group V, C2-12 alkenyl. C3-10 cycloalkyl, aryl optionally substituted with X and Y, or het optionally substituted with X and Y; R 13 and R 14, each time they occur, are independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, - (C 1-6 alkyl) -alkoxy C 1-6, aryl optionally substituted with X and Y, het optionally substituted with X and Y, - (C 1 .4 alkyl) -aryl optionally substituted with X and Y, - (C 1. 4 alkyl) -heterocycle optionally substituted with X and Y, - (C 4 alkyl) -hydroxy, (C 4 alkyl) -halo, - (C 1 .4 alkyl) -halo, - (C 1 alkyl) -poly-halo, - (C 1. 4 alkyl) -CONR 15 R 16 or cycloalkyl R15 and R16, each time they appear, are independently hydrogen, C1-6 alkyl, C3-10 cycloalkyl, or aryl optionally substituted with X and Y; R 7 is hydrogen, C, -6 alkyl, -COR 9 or -SO 2 R 9; R18 is hydrogen, C6-6 alkyl, C2-6 alkenyl > - (C 1 -C 6 alkyl) -Cl 6 alkoxy, aryl optionally substituted with X and Y, het optionally substituted with X and Y, - (C 4 alkyl) aryl optionally substituted with X and Y, - (alkyl) C1.4) -heterocycle optionally substituted with X and Y, - (C? -4 alkyl) -hydroxy, - (C? .4 alkyl) -halo, - (C? -4 alkyl) -poly-halo, - ( C 4 alkyl) -CONR 15 R 16, - (C 4 alkyl) - (C 1-4 alkoxy) or C 3-10 cycloalkyl; R19 is hydrogen or Ci-β alkyl; R20 is hydrogen or C-? 6 alkyl; W is O, S (O) d, CH2 or NR9; The group Z is C2-6 alkenyl, C2-6 alkynyl, halogen, -CF3, -OCF3, hydroxy, oxo, -CN, aryl, heteroaryl, C3-10 cycloalkyl, heterocycloalkyl, -S (0) aR12, -S ( O) 2NR9R10, -C (O) R9R10 and -NR9R10; The group V is halogen, -NR13R14, -OCF3, -OR9, oxo, trifluoromethyl, -CN, C3-10 cycloalkyl, aryl optionally substituted with X and Y, and het optionally substituted with X and Y; het, each time it appears, is a heterocyclic ring D selected from the group consisting of 4, 5, 6, 7 and 8 partially and fully saturated, unsaturated heterocyclic rings, containing from one to four heteroatoms independently selected from the group group consisting of N, O and S, and including any bicyclic group in which said heterocyclic ring D is fused with a benzene ring or a heterocyclic ring E selected from the group consisting of heterocyclic rings of 4, 5, 6, 7 and 8 partially and fully saturated, and unsaturated, members containing one to four heteroatoms independently selected from the group consisting of N, O and S; X and Y, each time they appear, are independently (A) hydrogen, (B) halogen, (C) trifluoromethyl, (D) -OCF3, (E) -CN, (F) C 1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OCF3, -CF3 and phenyl, (G) C-? --6 alkoxy, (H) aryl optionally substituted with one or more substituents independently selected from the group consisting of halogen, - OCF3, -CF3, C-alkyl and CM alkoxy. (I) -C (O) 2R13, (J) -C (O) NR13R14, (K) -C (O) R13, (L) -NR13C (O) NR13R14 and (M) -NR 3C (O) R14; or X and Y; each time they appear in the same variable, they can be taken together to form (a) a carbocyclic ring D of formula - (CHb.e- or (b) a heterocyclic ring F selected from the group consisting of -O (CH2) fO- , (CH2) gNH- and -CH = CHNH, each of a and d are independently 0, 1 or 2, b is 3, 4, 5, 6 or 7, each of c, f, g, j and k are independently 2, 3, 4, 5 or 6, and e is 3, 4, 5, 6, or 7. A preferred group of compounds and pharmaceutically acceptable salts of said compounds, referred to as group A, contain the compounds of formula I and the pharmaceutically acceptable salts of such compounds, as set forth above, wherein W is O. A preferred group of compounds and pharmaceutically acceptable salts of said group A compounds, designated group B, contains the compounds of formula I and the pharmaceutically acceptable salts of such compounds , as stated above, in which R1 is located in position 3, R2 is crazy It is located in the 5 position, R3 is located in the 2 'position, R4 is located in the 3' position, R5 is located in the 4 'position and R6 is located in the 5' position. A preferred group of pharmaceutically acceptable compounds and salts of such group B compounds, referred to as group C, contains the compounds of formula I and the pharmaceutically acceptable salts of such compounds, as set forth above, wherein R is hydrogen, or R3 and R4 are taken together to form a carbocyclic ring A of formula - (Chfe) ..- or a heterocyclic ring A selected from the group consisting of -Q- (CH2) cy- (CH2) jQ- (CH2) k-, in the Q is O, S or NR17, each of said carbocyclic rings A and heterocyclic A optionally independently substituted with one or more substituents independently selected from alkyl, halide or oxo, R5 is hydroxy, R6 is hydrogen and R7 is hydrogen. A preferred group of pharmaceutically acceptable compounds and salts of such group C compounds, referred to as group D, contains the compounds of formula I and pharmaceutically acceptable salts of such compounds, as set forth above, wherein each of R1 and R2 it is independently methyl, bromine or chlorine, and R8 is hydroxy, methoxy, ethoxy, ispropoxy, NH2 or NH (CH3). A preferred group of pharmaceutically acceptable compounds and salts of such group D compounds, designated as group E, contains the compounds of formula I and pharmaceutically acceptable salts of such compounds, as set forth above, wherein R4 is S (O) NR9R10, and R10 is hydrogen or methyl. Particularly preferred compounds of group E are compounds in which (a) R 1 is chlorine, R 2 is methyl, R 8 is ethoxy or hydroxy, R 9 is ethyl and R 10 is hydrogen, (b) R 1 is chlorine, R 2 is methyl, R 8 is ethoxy or hydroxy, R9 is n-butyl and R10 is hydrogen, (c) R1 is chloro, R2 is methyl, R8 is ethoxy or hydroxy, R9 is -CH2-cyclopropyl and R10 is hydrogen, and (d) R1 is chloro, R2 is methyl, R8 is isopropoxy or hydroxy, R9 is cyclopropyl and R10 is hydrogen; and pharmaceutically acceptable salts of said compounds. Another preferred group of compounds and pharmaceutically acceptable salts of such compounds of group D, called group F, contains the compounds of formula I and the pharmaceutically acceptable salts of such compounds, as set forth above, wherein R 4 is S (O) 2NR9R10 and R9 and R10 are taken together with the nitrogen atom to which they are attached to form N (CH2) 4, N (CH2) 5, morpholine or Particularly preferred compounds of the group F are those in which R9 and R10 are taken together with the nitrogen atom to which they are bound to form N (Ch A preferred group of compounds and pharmaceutically acceptable salts of such compounds of group E, called the group G, contains the compounds of formula I and pharmaceutically acceptable salts of such compounds, as set forth above, wherein R9 is hydrogen, isopropyl, -CH2-2-thienyl, -Chk-cyclopropyl, cyclopropyl, - (CH2) 2? H, exo-2-norbomyl, methyl, ethyl, 4-fluorophenyl, cyclobutyl, cyclopentyl, cyclohexyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-octyl or n-decyl.

Particularly preferred compounds of group G are compounds in which (a) R 1 is chloro, R 2 is methyl, R 8 is hydroxy or ethoxy, R 9 is cyclopropyl and R 10 is hydrogen, (b) R 1 is methyl, R 2 is methyl, R 8 is hydroxy or ethoxy, R9 is cyclopropyl and R10 is methyl, (c) R1 is methyl, R2 is methyl, R8 is hydroxy or ethoxy, R9 is cyclobutyl and R10 is methyl, (d) R1 is methyl, R2 is methyl, R8 is hydroxy or ethoxy, R9 is cyclopropyl and R10 is hydrogen, and (e) R1 is methyl, R2 is methyl, R8 is hydroxy or ethoxy, R9 is cyclobutyl and R10 is hydrogen; and pharmaceutically acceptable salts of such compounds. A preferred group of pharmaceutically acceptable compounds and salts of such group D compounds, designated as group J, contains the compounds of formula I and the pharmaceutically acceptable salts of such compounds, as set forth above, wherein R 4 is -C (O ) NR9R10 and R10 is hydrogen, methyl or ethyl. A preferred group of a compound and pharmaceutically acceptable salts of such compounds of group J, called group K, contains the compounds of formula I and the pharmaceutically acceptable salts of such compounds, as set forth above in which R 9 is methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, n-pentyl, n-hexyl, 4-fluorophenyl, -CH2-2-thienyl, cyclopropyl, -CH2-cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclohexyl, endo -2-norbomil, exo-2-norbornyl, (S) -1-phenylethyl, (R) -1-phenylethyl, -CH2-2-chlorophenyl, -CH2-4-chlorophenyl, -CH2-4-fluorophenyl, -CH2 -3-chloro-4-fluorophenyl, -CH2-2-chloro-4-fluorophenyl, -CH2-2-fluoro-4-chlorophenyl, -CH2-3,4-difluorophenyl, -CH2-4-isopropylphenyl, -CH2- 2,3-dichlorophenyl, -CH2-2,4-dichlorophenyl, -CH2-3,4-dichlorophenyl, CH2-3-trifluorop.-ethyl-4-chlorophenyl, 4-phenyphenyl, 3- (2,4-dimethyl) pentyl , (R) -1- (1-naphthyl) ethyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, (R) -1- (2-naphthyl) ethyl), (R) -2- (l-naphthyl) ethyl, -CH (1-naphthyl), (R) -l-cyclohexylethyl, (S) -l-cyclohexylethyl, -CH2-3,4-methylenedioxyphenyl, - CH2-4-γ-butylphenyl, -CH2-2.3-dichlorophenyl, 1-indanyl, (R) -1-indanyl, (S) -1-indanyl, 5-indanyl, 1- (1, 2,3, 4-tetrahydronaphthyl) or (R) -1-cyclohexylethyl. Particularly preferred compounds of the group K are compounds in which (a) R 1 is chlorine, R 2 is chlorine, R 8 is hydroxy or ethoxy, R 9 is 3- (2,4-dimethyl) pentyl and R 10 is hydrogen, (b) R 1 is methyl, R 2 is methyl, R 8 is hydroxy or ethoxy, R 9 is cyclopropyl and R 10 is methyl, (c) R 1 is methyl, R 2 is methyl, R 8 is hydroxy or ethoxy, R 9 is cyclobutyl and R 10 is methyl, (d) R 1 is methyl, R 2 is methyl, R 8 is hydroxy or ethoxy, R 9 is 3- (2,4-d-methyl) pentyl and R 10 is hydrogen, (e) R 1 is methyl, R 2 is methyl, R 8 is hydroxy or ethoxy, R 9 is n-pentyl and R10 is methyl, (g) R1 is methyl, R2 is methyl, R8 is hydroxy or ethoxy, R9 is isopropyl and R10 is methyl, (h) R1 is methyl, R2 is methyl, R8 is hydroxy, ethoxy or NH2, R9 is cyclobutyl and R10 is methyl and (i) R1 is chloro, R2 is chloro, R8 is hydroxy or ethoxy, R9 is cyclobutyl and R10 is methyl; and the pharmaceutically acceptable salts of said compounds. Another preferred group of compounds and pharmaceutically acceptable salts of such compounds, designated as group L, contains the compounds of formula I and the pharmaceutically acceptable salts of such compounds, as discussed above, in the groups R4 is -C (0) NR9R10, and R9 and R10 are taken together with the nitrogen atom to which they are attached to form N (CH2) 7, N (CH2) 6, N (CH2) 5, N (CH2) 4, morpholine, A preferred group of pharmaceutically acceptable compounds and salts of such group D compounds, designated the M group, contains the compounds of formula I and pharmaceutically acceptable salts of such compounds, as set forth above, wherein R 4 is -CH 2 NR 9 R 10 and R 10 is hydrogen, methyl or -COCH3.

A preferred group of compounds and pharmaceutically acceptable salts of such compounds of group M, called group N, contains the compounds of formula I and the pharmaceutically acceptable salts of such compounds, as set forth above, wherein R9 is methyl, n- propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, exo-2-norbornyl, -CH2-4-fluorophenium, -CH2-4-chlorophenyl, -CH2-4-isopropylphenyl, -CH2-3.4-methylenedioxyphenyl, (R ) -1- (1-naphthyl) ethyl, (R) -1-phenylethyl, (S) -1-phenylethyl, (R) 1-cyclohexylethyl, 1- (1, 2,3,4-tetrahydronaphthyl), 1 - indanyl or -CH2- (1-naphthyl).

A preferred group of pharmaceutically acceptable compounds and salts of such compounds of the group M, called the O group, contains the compounds of formula I and the pharmaceutically acceptable salts of such compounds, as set forth above, in which R9 and R10 are taken together with the nitrogen atom to which they are bound to form N (CH2) 6, morpholine, A preferred group of pharmaceutically acceptable compounds and salts of such group D compounds, designated as group P, contains the compounds of formula I and the pharmaceutically acceptable salts of such compounds as set forth above, wherein R 4 is -NHCOR 9. A preferred group of compounds and pharmaceutically acceptable salts of such compounds of group P, designated group Q, contains the compounds of formula I and the pharmaceutically acceptable salts of such compounds, as set forth above, wherein R 9 is cyclopropyl or cyclobutyl. A preferred group of pharmaceutically acceptable compounds and salts of such group D compounds, referred to as the R group, contains the compounds of formula I and the pharmaceutically acceptable salts of such compounds, as set forth above, wherein R4 is -S ( O) 2R12 and R12 is 4-chlorophenyl, phenyl, 1-naphthyl, 2-naphthyl, CH2-cyclopropyl, isopropyl, CH2-cyclobutyl, CH2-cyclohexyl, cyclopentyl, CH2-4-fluorophenyl, 4-tolyl, methyl, ethyl, n-butyl, CH2-phenyl or n-propyl. Particularly preferred compounds of the R group are compounds in which (a) R1 is chloro, R2 is chloro, R8 is hydroxy or ethoxy, and R12 is ethyl, (b) R1 is chloro, R2 is chloro, R8 is hydroxy or ethoxy and R12 is -CH2- cyclobutyl, (c) R1 is chloro, R2 is chloro, R8 is hydroxy or ethoxy and R12 is -CH2- cyclohexyl, (d) R1 is chloro, R2 is chloro, R8 is hydroxy or ethoxy and R12 is cyclopentyl, (e) R1 is chloro, R2 is chloro, R8 is hydroxy or ethoxy and R12 is -CH2- cyclopropyl, (f) R1 is chloro, R2 is chloro, R8 is hydroxy or ethoxy and R12 is -CH2- cyclobutyl and (g) R1 is methyl, R2 is methyl, R8 is hydroxy or ethoxy, and R12 is -CH2-cyclopropyl; and the pharmaceutically acceptable salts of said compounds. A preferred group of compounds and pharmaceutically acceptable salts of such compounds of group B, called group S, contains the compounds of formula I and the acceptable pharmaceutical salts of such compounds, as set forth above, wherein each R1 and R2 is Independently methyl, bromine or chlorine, R3 is hydrogen, R4 and R5 are taken together to form R6 is hydrogen, R7 is hydrogen, R8 is ethoxy, hydroxy or NH2, and R10 is hydrogen or methyl.

A preferred group of compounds and pharmaceutically acceptable salts of such compounds of group D, called group T, contains the compounds of formula I and the pharmaceutically acceptable salts of such compounds, as set forth above in which R3 is hydrogen and R4 is - OR11. A preferred group of compounds and pharmaceutically acceptable salts of such compounds of group T, called group U, contains the compounds of formula I and the pharmaceutically acceptable salts of such compounds, as set forth above, wherein R 11 is phenyl, 4-chlorophenyl or 4-fluorophenyl. A preferred group of compounds and pharmaceutically acceptable salts of such compounds of group D, called group V, contains the compounds of formula I and the pharmaceutically acceptable salts of such compounds, as set forth above, wherein R3 is hydrogen and R4 is - (alkyl C? -6) -OR11. Particularly preferred compounds of group V are compounds wherein R 4 is -CH 2 -OR 11. A preferred group of pharmaceutically acceptable compounds and salts of such group V compounds, designated as group W, contains the compounds of formula I and pharmaceutically acceptable salts of such compounds, as set forth above, wherein R 11 is phenyl or fluorophenyl. A preferred group of pharmaceutically acceptable compounds and salts of such group D compounds, designated as group X, contains the compounds of formula I and the pharmaceutically acceptable salts of such compounds, as set forth above in which R3 and R4 are taken together to forming a carbocyclic ring A of the formula - (CH2) D- or a heterocyclic ring A selected from the group consisting of Q- (CH2) C and - (CH2) jQ- (CH2) k-, where Q is O, S or NR17, each of said carbocyclic A and heterocyclic A rings being optionally substituted independently with one or more substituents independently selected from C-alkyl. halide or oxo. A preferred group of compounds and pharmaceutically acceptable salts of such compounds of group X, designated group Y, contains the compounds of formula I and the pharmaceutically acceptable salts of such compounds, as set forth above in which R3 and R4 are taken together to form said carbocyclic ring A. A preferred group of compounds and pharmaceutically acceptable salts of such compounds of group Y, called group Z, contains the compounds of formula I and the pharmaceutically acceptable salts of such compounds, as set forth above, in the that R3 and R4 are taken together to form - (CH2) 3-, -CH2C (CH3) 2-CH2- or - (CH2) 4-. Particularly preferred compounds of group Z are compounds in which (a) R 1 is methyl, R 2 is methyl, R 8 is hydroxy or ethoxy and R 3 and R 4 are taken together to form - (CH 2) 3-, (b) R 1 is chlorine , R2 is methyl, R8 is hydroxy or ethoxy and R3 and R4 are taken together to form - (CH2) 3- and (c) R1 is methyl, R2 is methyl, R8 is hydroxy or ethoxy, and R3 and R4 are taken together to form (-CH2) 4-; and the pharmaceutically acceptable salts of said compounds. A preferred group of pharmaceutically acceptable compounds and salts of such compounds, referred to as the AA group, contains the compounds of formula I and the pharmaceutically acceptable salts of such compounds, as set forth above, wherein R8 is -OR9. A preferred group of pharmaceutically acceptable compounds and salts of such AA group compounds, designated AB group, contains the compounds of formula I and the pharmaceutically acceptable salts of such compounds, as set forth above, wherein R9 is C? Alkyl? ?2. A preferred group of compounds and pharmaceutically acceptable salts of such group AB compounds, designated AC group, contains the compounds of formula I and the pharmaceutically acceptable salts of such compounds, as set forth above, wherein R9 is methyl, aspropyl or ethyl. A preferred group of pharmaceutically acceptable compounds and salts of such AC group compounds, referred to as AD group, contains the compounds of formula I and pharmaceutically acceptable salts of such compounds, as set forth above, wherein R9 is ethyl. A preferred group of pharmaceutically acceptable salts of the compounds of formula I, and of the prodrugs and geometric and optical isomers thereof, contains the pharmaceutically acceptable salts of the compounds, prodrugs and geometric and optical isomers, the salt being a sodium salt or potassium. A preferred group of compounds of formula I, designated as group AE, includes the specific compounds: N- [3-chloro-4- (3-cyclopropylsulfamoyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -oxamic acid; N- [4- (3-cyclopropylsulphamoyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl-oxamic acid; N- acid. { 4- [3- (Cyclobutyl-methyl-carbamoyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl-oxamic; N- acid. { 3-chloro-4- [3- (cyclobutyl-methyl-carbamoyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -oxamic; N- [4- (7-hydroxy-indan-4-yloxy) -3,5-dimethyl-phenyl] -oxamic acid; N- acid. { 3,5-dichloro-4- [3- (cyclobutyl-methyl-carbamoyl) -4-hydroxy-phenoxy] -phenyl} -oxamic; N- [3,5-dichloro-4- (3-cyclopentanesulfonyl-4-hydroxy-phenoxy) -phenyl] -oxamic acid; N- [3,5-dichloro-4- (3-cyclopropyl-methanesulfonyl-4-hydroxy-phenoxy) -phenyl] -oxamic acid; N- [3,5-dichloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -oxamic acid;N- [4- (3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl-oxamic acid; N- [3-chloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -oxamic acid; N- [4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl-oxamic acid; N- [4- (3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl-oxamic acid; N- [3-chloro-4- (3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -oxamic acid; N- [3,5-dichloro-4- (3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -oxamic acid; N- [4- (3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-methyl-phenyl] -oxamic acid; N- [3-chloro-4- (3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -oxamic acid; N- [3,5-dichloro-4- (3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -oxamic acid; N- [3,5-dichloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy) -phenyl] -oxamic acid; N- acid. { 4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -oxamic; N- acid. { 3-Chloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -oxamic, and the prodrugs and geometric and optical isomers thereof, and the pharmaceutically acceptable salts of the compounds, prodrugs and sisomers. A preferred group of the pharmaceutically acceptable salts of the compounds, prodrugs and geometrical and optical isomers of the AE glove, designated AF group, contains the pharmaceutically acceptable salts of the compounds, prodrugs and geometric and optical isomers, the salt being a potassium salt or of sodium. A preferred group of the geometric and optical isomers and compounds of the group AE compounds, called the AG group, contains the ethyl esters of these compounds. A preferred group of pharmaceutically acceptable compounds and salts of such group B compounds, designated as group AH, contains the compounds of formula I and the pharmaceutically acceptable salts of such compounds, as set forth above, wherein R5 is fluorine. A preferred group of compounds and pharmaceutically acceptable salts of such compounds of group AH, called the Al group, contains the compounds of formula I and the pharmaceutically acceptable salts of such compounds, as set forth above, wherein R 4 is hydrogen, fluorine, chlorine, methyl or cyclobutyl-methyl-carbamoyl. A preferred group of pharmaceutically acceptable compounds and salts of such Al group compounds, designated as group AJ, contains the compounds of formula I and the pharmaceutically acceptable salts of such compounds, as set forth above, wherein each of R1 and R2 it is independently methyl or chlorine. A preferred group of compounds and pharmaceutically acceptable salts of such compounds of group JA, called group AK, contains the compounds of formula I and pharmaceutically acceptable salts of such compounds, as set forth above, in which both R and R2 are methyl . A preferred group of pharmaceutically acceptable compounds and salts of such compounds of group AJ, called the AL group, contains the compounds of formula I and the pharmaceutically acceptable salts of such compounds, as set forth above, in which both R 1 and R 2 are chloro . A preferred group of compounds and pharmaceutically acceptable salts of such compounds of group AJ, designated AM group, contains the compounds of formula I and the pharmaceutically acceptable salts of such compounds, as set forth above, wherein R7 is hydrogen and R8 is hydrogen or -OR9. A preferred group of compounds and pharmaceutically acceptable salts of such AM group compounds, called the AN group, contains the compounds of formula I and pharmaceutically acceptable salts of such compounds, as set forth above, wherein R9 is methyl or ethyl.

A preferred group of compounds of formula I, designated as the AO group, includes the specific compounds: N- [4- (4-fluoro-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid, N- [3,5-dichloro-4- (4-fluoro-phenoxy) -phenyl] -oxamic acid, N- [3,5-dichloro-4- (3,4-difluoro-phenoxy) -phenyl acid] -oxamic, N- [4- (3-methyl-4-fluoro-phenoxy) -3,5-dichloro-phenyl] -oxamic acid, N- [3,5-dichloro-4- (3-chloro-4 -fluoro-phenoxy) -phenyl] -oxamic, N- [4- (3,4-difluoro-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid, N- [4- (3-dichloro- 4-fluoro-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid, N- [4- (3-methyl-4-fluoro-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid, N-acid - [3,5-Dichloro-4- (4-fluoro-phenoxy) -pheny] -oxamic acid, N- [3,5-dichloro-4- (3,4-difluoro-phenoxy) -phenyl] - oxoamic, N- acid. { 4- [3- (Cyclobutyl-methyl-carbamoyl) -4-fluoro-phenoxy) -3,5-dimethyl-phenyl-oxamic acid, N- [4- (4-fluoro-phenoxy) -3,5-dimethyl- phenyl] -oxamic, and the prodrugs and geometric and optical isomers thereof, and the pharmaceutically acceptable salts of the compounds, prodrugs and isomers. A preferred group of the pharmaceutically acceptable salts of the compounds, prodrugs and geometrical and optical isomers of the group AO, called the AP group, contains the pharmaceutically acceptable salts of the compounds, prodrugs and geometric and optical isomers, the salt being a potassium salt or of sodium.

A preferred group of the compounds, and geometric and optical isomers thereof, of the group AO, called group AQ, contains the ethyl esters of those compounds. This invention provides methods of treating a condition selected from obesity, hyperlipidemia, glaucoma, cardiac arrhythmia, skin disorders, thyroid disease, hypothyroidism, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, depression and osteoporosis, in a mammal (including human), comprising administering to said mammal an effective amount of treatment of a compound of formula I, a prodrug thereof, a geometric or optical isomer thereof, or a pharmaceutically acceptable salt of such compound , such prodrug or such isomer, as described above. In another aspect, this invention provides methods of treating a condition selected from obesity, hyperlipidemia, glaucoma, cardiac arrhythmia, skin disorders, thyroid disease, hypothyroidism, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, depression and osteoporosis, in a mammal (including human), comprising administering to said mammal effective treatment amounts of a compound of formula I, a prodrug thereof, a geometric or optical isomer thereof, or a pharmaceutically acceptable salt of such compound, such prodrug or such isomer, as described above, and an anorectic agent.

In another aspect, this invention provides methods of treating a condition selected from obesity, hyperlipidemia, glaucoma, cardiac arrhythmia, skin disorders, thyroid disease, hypothyroidism, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, depression and osteoporosis, in a mammal (including human), comprising administering to said mammal effective treatment amounts of a compound of formula I, a prodrug thereof, a geometric or optical isomer thereof, or a pharmaceutically acceptable salt of such a compound, such prodrug or such isomer, as those described above, and a lipase inhibitor. In a preferred aspect, this invention provides methods of treating obesity in mammals (including humans), which comprise administering to said mammal an effective amount for the treatment of obesity of a compound of formula I, a prodrug thereof , of a geometrical or optical isomer thereof, or of a pharmaceutically acceptable salt of such compound, prodrug or isomers, as described above. In another aspect, this invention provides methods of treating obesity in mammals (including humans), which comprise administering to said mammal amounts effective for the treatment of obesity of a compound of formula I, a prodrug thereof, a geometrical or optical isomer thereof, or a pharmaceutically acceptable salt of such compound, prodrug or isomers, as described above, and an anorectic agent. In another aspect, this invention provides methods of treating obesity in a mammal (including a human), comprising administering to said mammal effective amounts for the treatment of obesity of a compound of formula I, a prodrug thereof, of a geometric or optical isomer thereof, or a pharmaceutically acceptable salt of such a compound, such prodrug or such isomer, as described above, and a lipase inhibitor. In another aspect, this invention provides pharmaceutical compositions comprising a compound of formula I, a prodrug thereof, a geometric or optical isomer thereof or a pharmaceutically acceptable salt of such a compound, prodrug or isomer, as described above., and a pharmaceutically acceptable carrier, diluent or excipient. In another aspect, this invention provides pharmaceutical compositions comprising a compound of formula I, a prodrug thereof, a geometric or optical isomer thereof, or a pharmaceutically acceptable salt of such a compound, prodrug or isomer, as described above, an agent anorexigen and a pharmaceutically acceptable carrier, diluent or excipient. In another aspect, this invention provides pharmaceutical compositions comprising a compound of formula I, a prodrug thereof, a geometric or optical isomer thereof, or a pharmaceutically acceptable salt of such a compound, prodrug or isomer, as described above, an inhibitor. of lipase and a pharmaceutically acceptable carrier, diluent or excipient. In another aspect, this invention provides pharmaceutical compositions for the treatment of a condition selected from obesity, hyperlipidemia, glaucoma, cardiac arrhythmia, skin disorders, thyroid disease, hypothyroidism, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, depression and osteoporosis, in a mammal (including a human), comprising a compound of formula I, a prodrug thereof, a geometric or optical isomer thereof, or a pharmaceutically acceptable salt of such a compound, prodrug or isomer, as described above, and a pharmaceutically acceptable carrier, diluent or excipient. In another aspect, this invention provides pharmaceutical compositions for the treatment of a condition selected from obesity, hyperlipidemia, glaucoma, cardiac arrhythmia, skin disorders, thyroid disease, hypothyroidism, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, depression and osteoporosis, in a mammal (including a human), comprising a compound of formula I, a prodrug thereof, a geometric or optical isomer thereof, or a pharmaceutically acceptable salt of such compound, prodrug or isomer, as described above, an anorectic agent and a pharmaceutically acceptable carrier, diluent or excipient. In another aspect, this invention provides pharmaceutical compositions for the treatment of a condition selected from obesity, hyperlipidemia, glaucoma, cardiac arrhythmia, skin disorders, thyroid disease, hypothyroidism, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, depression and osteoporosis, in a mammal (including a human), comprising a compound of formula I, a prodrug thereof, a geometric or optical isomer thereof, or a pharmaceutically acceptable salt of such compound, prodrug or isomer, as described above, a lipase inhibitor and a pharmaceutically acceptable carrier, diluent or excipient. In another preferred aspect, this invention provides pharmaceutical compositions for the treatment of obesity in a mammal (including a human), comprising a compound of formula I, a prodrug thereof, a geometrical or optical isomer thereof, or a salt pharmaceutically acceptable of such compound, prodrug or isomer, as described above, and a pharmaceutically acceptable carrier, diluent or excipient. In yet another aspect, this invention provides pharmaceutical compositions for the treatment of obesity in a mammal (including a human), comprising a compound of formula I, a prodrug thereof, a geometric or optical isomer thereof, or a salt pharmaceutically acceptable of such compound, prodrug or isomer, as described above, an anorectic agent and a pharmaceutically acceptable carrier, diluent or excipient. In another aspect, this invention provides pharmaceutical compositions for the treatment of obesity in a mammal (including a human), which comprise a compound of formula I, a prodrug thereof, a geometrical or optical isomer thereof, or a pharmaceutically acceptable salt of such a compound, prodrug or isomer, as described above, a lipase inhibitor and a carrier, diluent or pharmaceutically acceptable excipient. In another aspect, this invention provides kits for the treatment of a condition selected from obesity, hyperlipidemia, glaucoma, cardiac arrhythmia, skin disorders, thyroid disease, hypothyroidism, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, depression and osteoporosis, comprising: a first compound, said first compound being a compound of formula I, a prodrug thereof, a geometric or optical isomer thereof, or a pharmaceutically acceptable salt of such compound, prodrug or isomer, as described above , and a pharmaceutically acceptable carrier, excipient or diluent, in a first unit dosage form; a second compound, said second compound being an anorectic agent or a lipase inhibitor, and a pharmaceutically acceptable carrier, excipient or diluent, in a second unit dosage form; and a container. In another preferred aspect, this invention provides kits for the treatment of obesity comprising: a first compound, said first compound being a compound of formula I, a prodrug thereof, a geometric or optical isomer thereof, or a pharmaceutically acceptable salt of such compound, prodrug or isomer, as described above, and a pharmaceutically acceptable carrier, excipient or diluent, in a first unit dosage form; a second compound, said second compound being an anorectic agent or a lipase inhibitor, and a pharmaceutically acceptable carrier, excipient or diluent, in a second dosage form; and a container. Unless otherwise indicated, in this document "alkyl" means a straight or branched hydrocarbon chain radical, which includes, as the case may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl and the like; "alkenyl" means a linear or branched, unsaturated monovalent aliphatic radical; "alkoxy" means an alkyl radical that is attached to the rest of the molecule by oxygen, including, as the case may be, for example, methoxy; "alkynyl" means a straight or branched acyclic hydrocarbon radical with a triple bond, including, as the case may be, for example, acetylene; "carbocyclic" (carbocycle) means an unsaturated or partially or fully saturated ring, which only has carbon atoms in its nucleus, including, as the case may be, an aryl (an organic radical derived from an aromatic hydrocarbon by the elimination of an atom, for example, phenyl from benzene, also including, for example, naphthyl); "cycloalkane" means a saturated monocyclic hydrocarbon, including, as the case may be, for example, cyclohexane; "cycloalkyl" means a monocyclic or polycyclic radical derived from a cycloalkane, including, as the case may be, for example, cyclohexyl; "halo" or "halogen" means a radical derived from the elements fluorine, chlorine, bromine or iodine; "heterocyclic" ("heterocycle") means a radical derived from an unsaturated, or partially or fully saturated, monocyclic or polycyclic ring of different types of atoms, including aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms, being selected each heteroatom between O, S and N; examples of the heterocyclic groups include, for example, benzoimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, furyl, imidazolyl, indolyl, isoquinolyl, isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolyl, piperazinyl, piperidyl, pyranyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidyl , pyrrolyl, quinolyl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrahydrothienyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, thiomorpholinyl, thiophenyl and triazolyl; when the heterocyclic groups are specifically referenced or mentioned as substituents for the compounds of formula I, it is understood that, unless specifically indicated otherwise, all suitable isomers of such heterocyclic groups are included; a "hydrate" is a crystalline substance that contains one or more water molecules of crystallization, that is, a substance that contains water combined in molecular form; "pharmaceutically acceptable" means that the carrier, diluent, excipient, and / or salt must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof; The "pharmaceutically acceptable salts" of the compounds of this invention can be formed with the compounds themselves, prodrugs, for example, esters, isomers and the like, and include all pharmaceutically acceptable salts that are most often used in pharmaceutical chemistry; for example, the salts can be formed with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, carboxylic acids, sulphonic acids including agents such as naphthalene sulfonic acid, ethanesulfonic acid, hydroxyethane sulfonic acid, methanesulfonic acid ("mesylate"), benzenesulfonic ("besylate") and toluenesulfonic, eg, p-toluenesulfonic ("tosylate"), sulfuric acid, nitric acid, phosphoric acid, tartaric acid, pyrosulfonic acid, metaphosphoric acid, succinic acid, formic acid, phthalic acid, malic acid , maleic acid, lactic acid, ascorbic acid, glycolic acid, gluconic acid, mandelic acid, glutamic acid, aspartic acid, fumaric acid, pyluric acid, phenylacetic acid, pamoic acid, nicotinic acid and the like; Suitable pharmaceutically acceptable salts also include alkali metal salts (e.g., sodium and potassium salts), alkaline earth metal salts (e.g., magnesium and calcium salts), amine salts (e.g., ammonium, alkylammonium salts, dialkylammonium, trialkylammonium, tetraalkylammonium, diethanolamine, tri-ethanolamine and guanidinium); preferred salts include salts of organic acids selected from formic, acetic, trifluoroacetic, propionic, benzoic, citric, maleic, tartaric, methanesulfonic, benzenesulfonic or toluenesulfonic acids, salts of inorganic acids selected from hydrochloric, hydrobromic, sulfuric or phosphoric, selected amino acids between aspartic and glutamic, and sodium and potassium salts; A "polymorph" is a substance that occurs in two or more forms; a "prodrug" is a drug precursor which, after administration, releases the drug in vivo by means of some chemical or physiological processes (e.g., a prodrug, when brought to physiological pH or by a means of an enzymatic action it becomes the desired drug form); exemplary prodrugs, upon cleavage, release the corresponding free acid, and such hydrolyzable ester-forming moieties of the compounds of formula I include, but are not limited to, those having a carboxyl radical in which the free hydrogen has been replaced by alkyl (C1-C4), (C2-C) alkanoyloxymethyl, 1- (alkanoyloxy) ethyl having from 4 to 9 carbon atoms, 1-methyl-1- (alkanoyloxy) -ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having from 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl having from 5 to 8 carbon atoms. carbon, N- (alkoxycarbonyl) aminomethyl having from 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton -4-yl, di-N, N-alkylamino (C?-C2) (C2-C3) alkyl (such as b-dimethylaminoethyl), carbamoyl-(C1-C2) alkyl, NN-di-alkylcarbamoyl (C? -C2) -alkyl (C1-C2) and piperidino-, pyrrolidino- or morpholino-alkyl (C2C3); a "radical" is a group of atoms that behaves like a single atom in a chemical reaction, for example, an organic radical is a group of atoms that confers characteristic properties to the compound that contains it, or that is not altered during a series of reactions; a "solvate" is a molecular or ionic complex of molecules or ions of a solvent with the molecules or ions of a solute; a "solvate" in which the solvent is water, forms "hydrates" or hydrated ions; "Spirocycloalkyl" means cycloalkyl having a spiro junction (the union formed by a single atom which is the only common member of the rings); and "treatment" or "treating" includes, among others, preventive (for example, prophylactic), palliative and curative treatment.

DETAILED DESCRIPTION OF THE INVENTION Unless otherwise indicated, throughout this document: ° C means degrees centigrade,% means percentage, Cale, means calculated data, cm means centimeter, DDE is diethyl ether, DME is dimethyl ether, DMF is dimethylformamide, DMSO is dimethisulfoxide, DTT is dithiothreitol, EtOAc is ethyl acetate, EtOH is ethanol, Found means found data, g is gram or grams, h is hour or hours, kg is kilogram or kilograms, KOH is potassium hydroxide, I is liter or liters , M is molar (concentration), MeOH is methanol, mg is milligram or milligrams, min is minute or minutes, ml is milliliter or milliliters, mm is millimole or millimoles, mM is millimolar (concentration), EM is mass spectrum, N is normal (concentration), NaOH is sodium hydroxide, nM is nanomolar (concentration), NMR is proton nuclear magnetic resonance spectrum, psi is pounds per square inch, TA is room temperature, TEA is triethylamine, TFA is trifluoroacetic acid, THF is tetrahydrofuran , μg is microgram or micrograms, and μl is microliter or microliters.

As described herein, all the times reference is made to a compound within the scope of formula I, it will be understood to include all active forms of such compounds, including, for example, their free form, eg, the form of base or free acid and also all prodrugs, polymorphs, hydrates, solvates, stereoisomers, for example, diastereomers and enantiomers and the like, and all pharmaceutically acceptable salts as described above. It will also be appreciated that suitable active metabolites of the compounds within the scope of formula I, in any suitable form, are also included in the present invention. More specifically, certain compounds suitable for use in the present invention, such as, for example, certain compounds of formula I, may have asymmetric centers and, therefore, exist in different enantiomeric forms. All suitable optical isomers and stereoisomers of such compounds, and mixtures thereof, are considered within the scope of the invention. With respect to such compounds, the present invention includes the use of a racemate, a single enentiomeric form, a single diastereomeric form, or mixtures thereof, as appropriate. However, such compounds can also exist with tautomers. Accordingly, the present invention relates to the use of all such suitable tautomers and mixtures thereof. In addition, those skilled in the art will readily recognize that physiologically active compounds having accessible hydroxy groups are often administered in the form of pharmaceutically acceptable esters. The compounds of this invention can be administered as esters, formed on the hydroxy groups. Although the mechanism has not yet been investigated and no limitation is desired by any theory, it is believed that such esters are cleaved metabolically in the body, and that the actual drug is the hydroxy compound itself. As is known for a long time in pharmaceutical chemistry, it is possible to adjust the speed or duration of the reaction of the compound by choosing suitable ester groups. From this description, those skilled in the art will understand how to prepare the compounds of the present invention using any suitable known method. In addition, the reaction schemes of the present invention illustrate the preparation of the compounds of the present invention and, unless otherwise indicated, R 1, R 2, R 3, R 4, R 6, R 7, R 9, R 10, X and Y in the reaction schemes are as described above, Q of compound 14 of scheme A is preferably sodium or potassium, X1 of schemes D, I and L is preferably halide or sulfonate, and T of schemes K and L is as described below. In addition, the examples provided in this document further illustrate the preparation of the compounds of the present invention. The present invention also includes isotopically-labeled compounds, which are identical to those mentioned in formula I except for the fact that one or more atoms are replaced by an atom having an atomic mass or a mass number different from the atomic mass or the number of mass normally found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P , 35S, 18F and 36CI, respectively. The compounds of the present invention, the prodrugs thereof and the pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms, are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example, those in which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and / or tissue substrate distribution assays. Particularly preferred are the tritiated isotopes, ie, 3H and carbon-14, ie 14C, for their ease of preparation and detectability. In addition, replacement with heavier isotopes such as deuterium, ie 2H, can produce certain therapeutic advantages resulting from increased metabolic stability, for example, a longer half-life in vivo or the requirement of a lower dosage and, therefore, can Prefer in some circumstances. The isotopically-labeled compounds of formula I of this invention and the prodrugs thereof can be prepared, in general, by performing the procedures described in the scheme and / or in the examples shown below, by replacing an unlabelled reagent isotopically by a Isotopically-labeled reagent easily available.

The starting materials for each synthesis scheme and for each example provided by this description are commercially available or can be prepared according to procedures known to those skilled in the art, as described, for example, in United States patents. United Nos. 5,401, 772; 5,569,674; and 5,654,468, and in the European patent specification published as EP 580,550, mentioned above. The compounds of the present invention can be prepared from a common intermediate 1 as described below 1 which can be synthesized according to any suitable procedure known in the art. More specifically, those skilled in the art will understand, based on the present disclosure, how to prepare the common intermediate 1 wherein W is oxygen, (S? 2) d, CH2 or NR9, where d and R9 are as described above. It is particularly preferred that W is oxygen. For example, the common intermediate 1 in which W is oxygen ("1 (a)") can be prepared by (a) coupling a 4-nitrophenol (or a corresponding thiophenol) 2 with a bis-aryl iodonium tetrafluoroborate 3 at about RT in a suitable organic solvent such as, for example, dichloromethane, chloroform, DMF or DMSO, in the presence of a suitable copper catalyst such as, for example, bronze copper, and a suitable base such as, for example, TEA , potassium t-butoxide or sodium hydride (J. Med. Chem. 38: 695-707 (1995)); (b) 4 5 1 (a) the coupling of a 4-halonitrobenzene 4 (M is halogen), such as, for example, a 4-iodonitrobenzene, a 4-bromonitrobenzene or a 4-chloronitrobenzene, with a phenol (or a thiophenol) such as, for example, a 4-fluorophenol, at a suitable elevated temperature (greater than about 120 ° C, eg, at about 130 ° C), in the presence of a suitable base such as, for example, potassium carbonate, hydroxide potassium or potassium t-butoxide, in an inert polar solvent such as, for example, DMSO or N-methylpyrrolidone (NMP); or (c) 6 2 1 (a) coupling (at RT in dichloromethane) a phenylboronic acid 6 with a 4-nitrophenol 2 in the presence of copper (II) acetate and a suitable base such as, for example, TEA, pyridine or a mixture of ASD and pyridine. (Tetrahedron, Lett., 39: 2933-2936, 2937-2940 (1988)). The embodiments of the present invention wherein the R4 substituent of a compound of formula I is located at the 3 'position and is sulfonamide, amide, eg, carboxamide, methylamino, carbamoyl or sulphamoyl, aryloxy, eg, phenyloxy or benzyloxy , phenylsulfone or alkylsulfone, can be prepared, for example, according to schemes A and B, C and D, E, F, G and J, H and I, respectively, provided by the present disclosure set forth below. In addition, a compound of formula I in which R4 is located in the 3 'position and R3 is located in the 2' position and taken together are indanyl or tetrahydronaphthalyl can be prepared according to schemes K and L, also provided by the present description exposed later. In addition, a compound of formula I in which R4 is located in the 3 'position and R5 is located in the 4' position, R4 and R5 are taken together to form an indolyl, can be prepared according to scheme M, provided more ahead. In addition, a compound of formula I in which R5 is located at the 4 'position and is fluorine, can be prepared according to scheme N, given below. In schemes A and C described below, the starting material ("A") is the common intermediate 1 in which R5 is located at the 4 'position and is methoxy or ("MeO"). In schemes E, H and I described below, the starting material ("B") is the common intermediate 1 in which R5 is located at the 4 'position and is MeO and R4 is located at the 3' position and It is hydrogen. In scheme N, the starting material ("C") is compound 5 wherein R5 is in the 4 'position and is fluorine. It will be understood that the following schemes are provided for illustrative purposes only and that they do not limit the invention, which is defined by the claims.

SCHEME A LCISO3H 2. NH2R9 H 2. NHR9R10 R10X1, base 8 SCHEME A (CONTINUED) 8 reduction (CO2Et) 2 or CICOCO2Et 11 SCHEME A (CONTINUED) eleven NaOH 12 11 MHR19R20 13 SCHEME A (CONTINUED) 12 Salt formation 14 SCHEME B aldehyde / ketone, NaBH4 base fifteen (CO2Et) 2 16 NaOH 17 SCHEME C formylation 18 oxidation 19 1. BBr3 2. H2 3. (C02Et) 2 SCHEME C (CONTINUED) coupling conditions / NHR9R10 21 NaOH 22 D SCHEMA 19 coupling conditions NH2R9 iento 23 NHR9R10 R10X1, base 24 1. BBr3 2. H2 3. (C02Et) 2 21 SCHEME E B 1. BBr3 2. H2 3. (C02Et) 2 formylation 26 NHR9R10 NaBH3CN 27 SCHEME F HN03 acetic acid 29 15 R10COCI base 20 NaO H 32 SCHEME F (CONTINUED) 29 R10SO2CI base 31 NaOH 50 ° C 33 SCHEME G 37 thioanisole, TFA, TA, 4 hours 37 Pheniboronic acid or • L I + BF > - 1. BBr3, 2. H2, 10% Pd / C, 3. (C02Et) 2 SCHEME H B Eaton Et Reagent SCHEME I 1. CIS02OH 2. Na2S03, base, H20 1. BBr3, 2. H2, 3. CICOC02Et SCHEME J 18 BBr. 49 SEMICL, base 50 DIBALH 51 SCHEME J (CONTINUED) 51 ArilOH Mitsunobu conditions 52 Acid conditions 53 SCHEME J (CONTINUED) 53 hydrogenation 54 55 SCHEME K 56 57 potassium t-butoxide, DMSO 60-80 ° c (o) potassium carbonate methyl ethyl ketone, reflux 58 1. BBr3, dichloromethane, 0 ° C to RT 2. H2 > Pd / C 15 59 diethyl oxalate, heat or 20 chloroethyl oxalate 60 SCHEME K (CONTINUED) 60 ammonia, methanol 62 60 NaOH, EtOH, H2O 61 SCHEME L 63 lithium hexamethyldisilazane lithium hexamethyldisilazane R22X1 BCI3, dichloromethane SCHEME M 67 68 K2C03 NMP 69 1. H2, 2. CICOC02Et, THF 3. KOH, MeOH-H20 70 SCHEME N 71 KOH NMP, 130 ° C 72 1. H2, 15 2. CICOC02Et, THF 3. KOH, MeOH-H20 73 By scheme A: The nitro intermediate A can be converted to 3'-sulfonamide 7 or 8 by reaction of the 3'-chlorosulfonylated intermediate of A and a primary or secondary amine in a suitable solvent such as, for example, dichloromethane , THF, MeOH, EtOH or acetonitrile, in the presence of a suitable base such as, for example, TEA or diisopropylethylamine. The chlorosulfonylation of A can be carried out by stirring a solution of A in a pure chlorosulfonic acid at a temperature of about 0 ° C to approximately 25 ° C. Sulfonamide 7 can be converted to sulfonamide 8 by alkylation. A preferred alkylation process uses a suitable alkylating agent such as, for example, an alkyl halide, in the presence of a suitable base such as, for example, potassium carbonate, sodium hydride, potassium t-butoxide, NaOH or KOH, in a Suitable organic solvent such as, for example, acetone, THF, DMSO, 2-propanol or an aqueous solution of MeOH. The demethylation of 8 to the phenol 9 can be carried out by reaction of 8 with a suitable boron trihalide such as, for example, boron tribromide or boron trichloride, in a suitable organic solvent such as, for example, dichloromethane or chloroform. The nitro reduction of 9 giving the aniline 10 can be performed using procedures well known in the art such as, for example, hydrogenation or reduction with zinc powder or tin (II) chloride.

Aniline 10 can be converted to oxamate 11 by reaction of 10 with diethyl oxalate at about 120 ° C, for a period of about 5 to about 24 hours, or with ethyl oxalyl chloride at about RT in an appropriate anhydrous aprotic solvent. such as, for example, DEE, dichloromethane, chloroform or THF. Oxamate 11 can be converted to oxamic acid 12 and oxamide 13 using conventional procedures well known in the related art. For example, ester 11 can be hydrolyzed to give acid 12 using suitable aqueous alkalis such as, for example, alkali metal carbonates or hydroxides in an aqueous solution of MeOH. The oxamide 13 can be synthesized by reacting the ester 11 with an amine in a suitable solvent such as, for example, dichloromethane, chloroform, THF or MeOH. The acid 12 can be converted into salts 14 such as, for example, metal or ammonium salts, by treating 12 with an equivalent amount of the corresponding base such as, for example, alkali or ammonium hydroxides, by exchange with salts of carboxylic acids or alkaline siroxides, or by ion exchange processes known in the art.

By Scheme B: The primary aniline 10 can be converted to the secondary aniline 15 according to procedures well known in the art for the conversion of a primary amine to a secondary amine such as, for example, by reductive alkylation. A preferred reductive alkylation process employs an aldehyde or a ketone and a reducing agent in a suitable solvent, and is best performed in the presence of molecular sieves of about 3A. Preferred reducing agents are sodium cyanoborohydride, sodium triacetoxyborohydride and sodium borohydride. The preferred organic solvents are EtOH and MeOH. The resulting aniline can be converted to oxamate 16 and then to acid 17 by, for example, procedures analogous to those previously described in Scheme A discussed above.

By Scheme C: The nitro intermediate A can be converted to aldehyde 18 by formylation. A preferred formylation process can be performed by reacting A with hexamethylenetetramine at about 65 ° C in a suitable solvent such as, for example TFA The aldehyde 18 can be oxidized to the carboxylic acid 19 by procedures well known in the art, for example, Jones oxidation. Preferred oxidation processes include Jones oxidation and those employing sodium hypochlorite. The reaction of aldehyde 18 with Jones reagent (chromic acid / aqueous sulfuric acid) in acetone yields carboxylic acid 19.

The compound 19 of the nitro-containing carboxylic acid can be converted to oxamate 20 in three steps (demethylation, nitro reduction and oxamate formation) by, for example, procedures analogous to those described in Scheme A given above. Oxamate 20 can be converted to the 3'-carboxamide derivative 21 according to procedures known in the art. For example, the use of a chloride or acid anhydride (symmetrical or mixed) of 20 with an amine in a suitable dry aprotic solvent such as, for example, dichloromethane, THF, DME or DEE, in the presence of a base such as TEA , dimethylaminopyridine or pyridine, are two commonly used procedures. Another method utilizes the reaction of 20 and the required amine in an aprotic solvent with any of the conventional carbodiimide coupling reagents such as, for example, dicyclohexylcarbodiimide, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinolone and benzotriazole hexafluorophosphate. -1-Clyoxyl (dimethylamino) -phosphonium. The ester 21 can be hydrolyzed to give the oxamic acid 22 by, for example, a procedure analogous to that described in Scheme A discussed above.

By Scheme D: Amide 23 can be prepared by the reaction of a (symmetrical or mixed) acid chloride or anhydride of 19 with a primary amine in a suitable solvent such as, for example, dichloromethane, THF, DME or DEE, in the presence of a base such as, for example, ASD, DMAP or pyridine. The amide 23 can be alkylated to the amide 24 by reacting a carboxamide anion of 23 with a suitable alkylating agent such as, for example, an alkyl halide. The carboxamide anion of 23 can be generated in DMF with a suitable base such as, for example, sodium hydride or potassium hydride. The alkylation of 23 can also be carried out by phase transfer catalysis without solvent or with a suitable solvent such as, for example, DMF or DMSO. The phase transfer reaction uses tetrabutylammonium bromide ("TBAB") as a phase transfer agent and potassium carbonate, KOH or NaOH as the base. Amide 24 can be converted into the corresponding compound 21, for example, in three steps, by procedures analogous to those described in Scheme A discussed above.

By scheme E: Compound B can be converted to oxamate 25, for example, in three steps, by procedures analogous to those described in Scheme A given above. The formylation of 25 can be carried out by a formylation process analogous to that described in Scheme C given above.

The aldehyde 26 can be converted, for example, to the methylamino derivative 27 by methods known in the art. A preferred process uses reductive amination. For example, the reductive amination can be carried out by reacting the aldehyde 26 with an amine and a reducing agent in a suitable solvent, and it is best carried out in the presence of 3A molecular sieves. Preferred reducing agents are sodium cyanoborohydride, sodium triacetoxyborohydride and sodium borohydride. Preferred organic solvents include EtOH, MeOH and 1,2-dichloroethane.

By Scheme F: Oxamate 25 can be converted to nitro compound 28 by nitration. The nitro compound 28 can be reduced to the corresponding aniline 29 by, for example, catalytic hydrogenation or chemical reduction with zinc powder or tin (II) chloride. Acylation of 29 with carbonyl chloride in the presence of a suitable base such as, for example, TEA or N, N-diisopropylethylamine, produces diacylated compound 30. Diacylated oxamate 30 can be converted to oxamic acid 32 by hydrolysis with a base suitable, such as, for example, NaOH or KOH, in an aqueous solution of MeOH. Sulfonylation of 29 with sulfonyl chloride in the presence of a suitable base such as, for example, TEA or N, N-diisopropylethylamine, produces the disulfonylated compound 31. The hydrolysis of 31 with a suitable base such as, for example, NaOH or KOH, in an aqueous solution of MeOH at about 50 ° C, produces oxamic acid 33.

By scheme G: Benzyl ether 37 can be converted to phenol 38 by debenzylation. Treatment of 37 with thioanisole in TFA at room temperature produces 38. The conversion of 38 into phenyl ether 39 can be accomplished by coupling 38 with arylodonium tetrafluoroborate and copper bronze in the presence of triethylamine in dichloromethane or coupling 38 with arylboronic acid and copper (II) acetate in the presence of a suitable base such as, for example, TEA, pyridine, or a mixture of TEA and pyridine. The conversion of 39 into oxamate 40 can be carried out, for example, in three steps (demethylation, nitro reduction and oxamate formation) according to procedures analogous to those described in Scheme A discussed above. The oxamic acid 41 is prepared by alkaline hydrolysis of the ester 40.

By scheme H: The treatment of B with an arylsulfonic acid in the presence of Eaton's reagent at an elevated temperature produces a 3'-aryl sulfone 42.

Demethylation of 42 followed by hydrogenation and subsequent reaction with ethyl oxalyl chloride provides oxamate 43. Oxamate 43 can be hydrolyzed to oxamic acid 44 using a base, such as, for example, NaOH or KOH.

By Scheme I: The nitro B compound can be converted to 3'-sulfinic acid 45 by treatment with chlorosulfonic acid followed by reduction with sodium sulfite in the presence of a base such as, for example, sodium bicarbonate or NaOH. Treatment of the sulfinic acid with an alkyl halide in the presence of a base such as, for example, NaOH, KOH, potassium t-butoxide, sodium hydride or sodium methoxide, provides the alkyl sulfone 46. The nitro compound 46 can be converted into oxamate 47 by demethylation, hydrogenation and oxamate formation. Hydrolysis of oxamate 47 under basic conditions yields oxamic acid 48.

By Scheme J: Methyl ester 18 can be converted to phenol 49 using procedures analogous to those described in Scheme A. Phenol 49 can be protected as trimethylsilylethoxymethyl ether 50 by treatment with a strong base such as, for example, sodium hydride or potassium t-butoxide in an aprotic solvent, for example, THF, followed by treatment with trimethylsilylethoxymethyl chloride ("SEMCL"). The treatment of the aldehyde 50 with a reducing agent such as, for example, diisobutylaluminum hydride ("DIBALH") in an aprotic solvent, for example, dichloromethane or THF, produces 51. The reaction of alcohol 51 with a suitable phenol using an azodicarbonyl compound, for example, 1,1 '- (azodicarbonyl) dlpiperidine or diethylazodicarboxylate and a phosphine such as, for example , triphenyl- or tributylphosphine in an aprotic solvent, eg, THF or toluene, provides ether 52. Removal of the "SEM" protecting group present at 52 under acidic conditions such as, for example, sulfuric acid or mineral acid in a solvent alcohol, for example, MeOH or EtOH or, alternatively, under conditions mediated by fluoride (tetrabutylammonium fluoride / THF, hydrogen fluoride / acetonitrile) produces phenol 53. Reduction of the nitro group present at 53 by heating to reflux in acetic acid with a pulverized metal, for example, zinc or iron, provides the amine 54. The conversion of the oxamate 55 and the oxamic acids and associated oxamides is carried out using analogous methods. to those detailed in Scheme A.

By Scheme K: Compounds 56-62 can be prepared according to procedures analogous to those described above according to procedures well known in the art. Those skilled in the art will understand by the present description and, in particular, by scheme A, how to convert compound 62 to the detailed oxamate derivatives in the complete K.T scheme, as described above when R3 and R4 are taken together, a carbocyclic ring A of formula - (CH2) D- or a heterocyclic ring A selected from the group consisting of -Q- (CH2) C- and - (CH2) jQ- (CH2) k-, where b, Q , c, j and k as described above, and each of said carbocyclic A and heterocyclic A rings being optionally substituted independently with one or more substituents (e.g., R21, R22) independently selected from C-, halide or oxo alkyl, as also described above.

By scheme L: The exhaustive treatment of 63 with a strong base such as, for example, lithium hexamethyldisilizone, lithium diisopropylamide or potassium t-butoxide and a suitable alkyl halide in an aprotic solvent, eg, THF, produces the bis-alkylated intermediate 65. This process is carried out in stages when R21 and R22 are different, and in a single reaction flask when R21 and R22 are the same. One of the methyl ethers present in 65 can be selectively deprotected using boron trichloride or aluminum chloride in an aprotic solvent, for example, dichloromethane or toluene. The reduction of the ketone functionality present in 66 can be carried out by treatment with a hydrosilane, preferably triethylsilane, in the presence of an acid, for example, methanesulfonic acid or TFA, with or without a solvent present. The solvents may be protic or aprotic, with dichloromethane being preferred. Those skilled in the art will understand by the present disclosure how to convert the resulting reduced compounds into the desired oxamate derivatives. T is as described for scheme K.

By scheme M: Indole 69 can be prepared by coupling the commercially available 5-hydroxy indole 67 with 4-iodonitrobenzene 68 at about 125 ° C in the presence of potassium carbonate for about 3 h. The nitro compound 69 is converted to the desired compound 70 by hydrogenation and oxamate formation.

By Scheme N: The diaryl ether 72 is prepared by coupling commercially available fluorophenol 71 with 4-halonitrobenzene 4 at 130 ° C in NMP in the presence of KOH. The oxamic acid 73 is synthesized from the nitro compound 72 by hydrogenation, acylation and hydrolysis. In the preparation of the compounds of formula I it is indicated that, as will be appreciated by those skilled in the art, some of the methods useful for the preparation of such compounds, for example, as exemplified by the J and L schemes described above, they may require the protection of a particular functionality, for example, to prevent the interference of such functionality in reactions from other sites within the molecule or to preserve the integrity of such functionality. The need and type of such protection is easily determined by one skilled in the art, and will vary depending, for example, on the nature of the functionality and the conditions of the selected preparation process. See, for example, T.W. Greene, Protective Groups in Organic Synthesis. John Wiley & Sons, New York, 1991. Protective groups suitable for any particular functionality include those which do not substantially undergo chemical reactions under the described reaction conditions and which can be substantially removed without chemically altering other functionalities of any given intermediate of the compound of formula I, or of the compound of formula I itself. The protecting group can be removed when desired in any given preparation process., for example, at a later stage. Some compounds of formula I of this invention are acidic and form a salt with a pharmaceutically acceptable cation. Some compounds of formula I of this invention are basic and form a salt with a pharmaceutically acceptable anion. All such salts are within the scope of this invention and can be prepared by conventional procedures such as the combination of the acidic and basic entities, usually in a stoichiometric ratio, in an aqueous, non-aqueous or partially aqueous medium, as appropriate. The salts are recovered by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent, in the case of aqueous solutions, by lyophilization, as appropriate. The compounds can be obtained in crystalline form by a solution in a suitable solvent (s) such as ethanol, hexanes or water / ethanol mixtures. Preferred anorectic agents of the compositions, methods and kits of this invention include phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a neuropeptide Y antagonist, a cholecystokinin A agonist, a monoamine reuptake inhibitor, a sympathomimetic agent, an agent serotonergic, a dopamine agonist, an agonist or mimetic of the melanocyte-stimulating hormone receptor, a cannabinoid receptor agonist, an analogue of the melanocyte-stimulating hormone, an antagonist of the melamine-concentrating hormone, the OB protein, a Leptin analogue, "a galanin antagonist and an orexin receptor antagonist." A preferred monoamine reuptake inhibitor is sibutramine Preferred serotonergic agents include dexfenfluramine and fenfluramine A preferred dopamine agonist is bromocriptine. The preferred lipase inhibitor is tetrahydrolipstatin. Suitable anorectic agents for the compositions, methods and kits of this invention can be prepared using methods known to those skilled in the art, for example, phentermine can be prepared as described in US Pat. 2,408,345; Sibutramine can be prepared as described in the US patent. No. 4,929,629; Fenfluramine and dexfenfluramine can be prepared as described in the U.S.A. No. 3,198,834; and bromocriptine can be prepared as described in the US patents. A. Nos. 3,752,814 and 3,752,888. Suitable lipase inhibitors can be prepared using methods known to those skilled in the art, for example, tetrahydrolipstatin. { lactone of 1, 3 (2S, 3S, 5S) -5 - [(S) -2-formamido-4-methyl-valeryloxy] -2-hexyl-3-hydroxy-hexadecanoic acid} it can be prepared as described, for example, in the US patents. Nos. 5,274,143; 5,420,305; 5,540,917; and 5,643,874. The administration of a compound, prodrug, isomer or pharmaceutically acceptable salt of the present invention and an anorectic agent or lipase inhibitor, as the case may be, according to this invention, can be sequential in time or simultaneous, with the simultaneous procedure. For sequential administration, a compound, a prodrug, an isomer or a pharmaceutically acceptable salt of the present invention and an anorectic agent or a lipase inhibitor, as the case may be, can be administered in any order. In addition, for sequential administration, the compound, prodrug, isomer or pharmaceutically acceptable salt of the present invention and the anorectic agent (or the lipase inhibitor as the case may be), can be administered in any order. It is generally preferred that such administration be oral. It is even more preferred that the administration be oral and simultaneous. However, for example, if the subject to be treated can not swallow or absorption is impeded or is undesirable for another reason, parenteral or transdermal administration will be appropriate. When the administration is sequential, the administration of a compound, prodrug, isomer or pharmaceutically acceptable salt of the present invention and an anorectic agent or a lipase inhibitor, as the case may be, can be carried out by the same procedure or by different procedures. The dose of a compound, prodrug, isomer or pharmaceutically acceptable salt of this invention to be administered to a human or animal is very variable and is subject to the judgment of the corresponding physician or veterinarian. As will be understood by those skilled in the art, it may be necessary to adjust the dose of a compound, prodrug or isomer of this invention when administered in the form of a salt, for example, when the salt-forming moiety has an appreciable molecular weight. . The general range of effective administration rates of the compounds, prodrugs, isomers or pharmaceutically acceptable salts of this invention is from about 0.001 mg / kg of body weight to about 100 mg / kg of body weight of the subject per day. A preferred range of effective administration rates of the compounds, prodrugs, isomers or pharmaceutically acceptable salts of this invention is from about 0.01 mg / kg of body weight to about 50 mg / kg of body weight of the subject per day. Although it may be practical to administer the daily dose of a compound, prodrug, isomer or pharmaceutically acceptable salt of this invention, in portions, at diversion times of the day, in any given case, the amount of the compound, prodrug, isomer or pharmaceutically acceptable salt administered it will depend on factors such as the solubility of the pharmaceutically acceptable compound, prodrug, isomer or sai of this invention, the formulation used and the route of administration (e.g., orally, transdermally, parenterally or topically). The doses of the compounds, prodrugs, isomers and pharmaceutically acceptable salts of the present invention can be administered to humans by any suitable route, with oral administration being preferable. Individual tablets or capsules should generally contain from about 0.1 mg to about 100 mg of the compound, prodrug, isomer or pharmaceutically acceptable salt of this invention, in a suitable pharmaceutically acceptable carrier, diluent or excipient. The dose for intravenous administration is generally within the range of about 0.1 mg to about 100 mg per individual dose as required. For intranasal or inhalant administration, the dose is generally formulated as a solution of about 0.1% to about 1% (w / v). In practice, the doctor will determine the most appropriate actual dose for an individual patient, and this will vary, for example, with the age, weight and response of the particular patient. The above dosages are illustrative of the average case but, of course, there may be individual cases where higher or lower dosage ranges are required, and all such doses of compounds, prodrugs, isomers and pharmaceutically acceptable salts of this invention are within the scope of the present invention. In aspects of the present invention comprising anorectic agents, any suitable dose of such agents can be used. The dose of the anorectic agent is generally in the range of from about 0.01 to about 50 mg / kg of subject body weight per day, preferably from about 0.1 to about 10 mg / kg of subject body weight per day, administered individually or as a divided dose. For example, when the anorectic agent is phentermine, the dose of phentermine is from about 0.01 to 50 mg / kg of subject body weight per day, preferably from about 0.1 to about 1 mg / kg of subject body weight per day. In addition, when the anorectic agent is sibutramine, the dosage range is from about 0.01 to about 50 mg / kg of subject body weight per day, preferably from about 0.1 to about 1 mg / kg of subject body weight per day.; when the anorectic agent is dexfenfluramine or fenfluramine, the dosage range is from about 0.01 to about 50 mg / kg of subject body weight per day, preferably from about 0.1 to about 1 mg / kg of subject body weight per day, and when the anorectic agent is bromocriptine, the dosage range is from about 0.01 to about 10 mg / kg of subject body weight per day, preferably from about 0.1 to about 10 mg / kg of subject body weight per day. In practice, the physician will determine the actual dose of the most appropriate anorectic agent for an individual patient and this will vary, for example, with the age, weight and response of the particular patient. The above doses of anorectic agents are exemplary but, of course, there may be individual cases where higher or lower dosage ranges of such anorectic agents are required, and all such doses are within the scope of the present invention. In aspects of the present invention comprising lipase inhibitors, any suitable dose of a lipase inhibitor can be used. The dose of the lipase inhibitor is generally in the range of from about 0.01 to about 50 mg / kg of subject body weight per day, preferably from about 0.05 to about 10 mg / kg of subject body weight per day, administered in a single dose or in divided doses. For example, when the lipase inhibitor is tetrahydrolipstatin, the dose of tetrahydrolipstatin is preferably 0.05 to 2 mg / kg of body weight of the subject per day. In practice, the physician will determine the actual dose of the lipase inhibitor most suitable for an individual patient, and this will vary, for example, with the age, weight and response of the particular patient. The above doses of lipase inhibitors are illustrative but, of course, there may be individual cases where higher or lower dosage ranges of such lipase inhibitors are required, and all such doses are within the scope of the present invention. Any suitable route of administration can be used in the present invention. It is usually preferred to administer the compounds, prodrugs, isomers and pharmaceutically acceptable salts of this invention orally for reasons of convenience; however, they can be administered, for example, percutaneously or as suppositories for absorption by the rectum, as desired in a given case. As described above, administration can be carried out in a single dose or in multiple doses, as appropriate. The compounds, prodrugs, isomers and pharmaceutically acceptable salts of this invention can be administered alone, and are preferably administered as pharmaceutical compositions comprising a pharmaceutically acceptable carrier, excipient or diluent. The pharmaceutical compositions of the invention will comprise a suitable amount of a compound, prodrug, isomer and pharmaceutically acceptable salt of this invention, i.e., an amount sufficient to provide the desired dose. The compounds, prodrugs, isomers and pharmaceutically acceptable salts of this invention can be administered in a wide variety of different dosage forms, that is, they can be combined with various inert pharmaceutically acceptable carriers in any suitable form. Such vehicles include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. The pharmaceutical compositions may be formulated so as to contain a daily dose, or a convenient fraction of a daily dose, in a dosage form, which may be a single tablet or capsule or a convenient volume of a liquid. In the present invention, all common types of pharmaceutical compositions including tablets may be used., pills, hard candies, chewable tablets, granules, powders, sprays, capsules, pills, microcapsules, solutions, parenteral solutions, troches, injections (for example, intravenous, intraperitoneal, intramuscular or subcutaneous), suppositories, elixirs, syrups and suspensions. For parenteral administration, the compounds, prodrugs, isomers and pharmaceutically acceptable salts of this invention can be used as solutions in sesame or peanut oil, or as aqueous solutions (eg, aqueous propylene glycol), as the case may be, but It is best to use them in the form of a sterile aqueous solution that may contain other substances; for example, enough salts or glucose to make the solution isotonic, adjusting and buffering the pH of the solution conveniently when necessary, and surfactants such as, for example, hydroxypropylcellulose. Such oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. Such aqueous solutions are suitable for intravenous injection purposes.

The compounds, prodrugs, isomers and pharmaceutically acceptable salts of this invention can also be administered topically, and this can be achieved by means of, for example, creams, jellies, ointments, lotions, gels, pastes, ointments and the like, in accordance with conventional pharmaceutical practice. The compounds, prodrugs, isomers and pharmaceutically acceptable salts of this invention can also be administered transdermally (e.g., by the use of a patch). Any suitable formulation for transdermal application comprising a compound of the present invention can be employed, and such formulations will generally also contain a suitable transdermal vehicle, for example, a pharmacologically acceptable absorbable solvent to promote and assist in the passage of the compounds through the skin of the subject. For example, suitable transdermal devices may comprise the form of a bandage having a support member and a reservoir containing the subject compound. Such bandage type transdermal devices may also include suitable excipients, barriers to control the speed, and means for securing the transdermal device to the skin of the subject. As will be described in detail below, the pharmaceutical compositions may be prepared by methods commonly employed using conventional organic or inorganic additives, such as an excipient (eg, sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate). or calcium carbonate), a binder (eg, cellulose, hypromellose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose or starch), a disintegrant (eg, starch, carboxymethylcellulose, hydroxypropylstarch, low substituted hydroxypropylcellulose, bicarbonate sodium, calcium phosphate or calcium citrate), a lubricant (for example, magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate), a flavoring agent (for example, citric acid, menthol, glycine or orange powder), a preservative (eg, sodium benzoate, sodium bisulfite, methylparaben op ropilparaben), a stabilizer (eg, citric acid, sodium citrate or acetic acid), a suspending agent (eg, hypromellose, polyvinylpyrrolidone or aluminum stearate), a dispersing agent (eg, hydroxypropyl methylcellulose), a diluent (eg. example, water), a coloring agent, an emulsifying agent and a base wax (for example, cocoa butter, white petrolatum or polyethylene glycol). Any of the compounds, prodrugs, isomers or pharmaceutically acceptable salts of this invention can be easily formulated in the form of tablets, capsules and the like. It is preferable to prepare solutions from water-soluble salts, such as the hydrochloride salt. In general, all pharmaceutical compositions are prepared according to standard procedures in pharmaceutical chemistry. Capsules can be prepared by mixing a compound, prodrug, isomer or pharmaceutically acceptable salt of the invention with a suitable diluent and introducing the appropriate amount of the mixture into capsules. Typical diluents include inert powdered substances such as starch of many different types, cellulose powder, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, cereal flours and similar edible powders. The tablets can be prepared by direct compression, wet granulation or dry granulation. Their formulations usually incorporate diluents, binders, lubricants and disintegrants, as well as a compound, prodrug, isomer or pharmaceutically acceptable salt of this invention. Common diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives can also be used. Common tablet binders include substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Also suitable are natural and synthetic gums, including gum arabic, alginates, hypromellose, polyvinyl pyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders. In a tablet formulation, a lubricant is generally needed to prevent the tablets and punches from adhering to the matrix. The lubricant is selected from slippery solids such as talcum, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.

Tablet disintegrants include substances that swell when wetted causing the tablet to disintegrate and release a compound, prodrug, isomer or pharmaceutically acceptable salt of this invention. These agents include starches, clays, celluloses, algines and gums. More particularly, corn and potato starch, hypromellose, agar, bentonite, wood cellulose, natural powder sponge, cation exchange resin, alginic acid, guar gum, citrus pulp and carboxymethylcellulose, for example, as well as lauryl sulfate can be used. sodium The tablets are often coated with sugar as a flavoring and sealant, or with film-forming protective agents to modify the dissolution properties of the tablet. The compounds, prodrugs, isomers and pharmaceutically acceptable salts of this invention can also be formulated in the form of chewable tablets by the use of large amounts of pleasant tasting substances such as mannitol in the formulation, as is well established in the art. When it is desired to administer a compound, prodrug, isomer or pharmaceutically acceptable salt of this invention as a suppository, any suitable base can be used. Cocoa butter is a traditional suppository base that can be modified by adding waxes to raise its melting point. Water-miscible suppository bases comprising, in particular, polyethylene glycols of various molecular weights are widely used. As discussed above, the effect of a compound, prodrug, isomer or pharmaceutically acceptable salt of this invention can be delayed or prolonged by an appropriate formulation. For example, slowly dissolving granules of a compound, prodrug, isomer or pharmaceutically acceptable salt of this invention can be prepared and incorporated into a tablet or capsule. The technique can be improved by manufacturing granules of different dissolution rates and filling the capsules with a mixture of the granules. The tablets or capsules may be coated with a film that resists dissolution for a predictable period of time. Parenteral preparations can also be made long-term by dissolving or suspending a compound, prodrug, isomer or pharmaceutically acceptable salt of this invention, as the case may be, in oily or emulsified vehicles that allow only slow dispersion in the serum. The compounds, prodrugs, isomers and pharmaceutically acceptable salts of this invention may also be administered to a mammal other than a human. The method of administration and the dose to be administered to such a mammal will depend, for example, on the animal species and the disease or disorder to be treated. The compounds, prodrugs, isomers and pharmaceutically acceptable salts of this invention can be administered to animals in any suitable form, for example, orally, parenterally or transdermally, in any suitable form such as, for example, a capsule, bolus, tablet. , granules, for example, prepared by mixing a compound, prodrug, isomer or pharmaceutically acceptable salt of this invention with a suitable diluent such as carbowax or carnauba wax, together with a lubricant, liquid potion or paste, for example, prepared by dispersion of a compound, prodrug, isomer or pharmaceutically acceptable salt of this invention in a pharmaceutically acceptable oil such as peanut oil, sesame oil or corn oil. The compounds, prodrugs, isomers and pharmaceutically acceptable salts of this invention can also be administered to animals in the form of an implant. Such formulations are prepared in a conventional manner in accordance with standard veterinary practice. Alternatively, the compounds, prodrugs, isomers and pharmaceutically acceptable salts of this invention can be administered with water, for example, in the form of a liquid or water-soluble concentrate. In addition, the compounds, prodrugs, isomers and pharmaceutically acceptable salts of this invention, for example, within the pharmaceutical compositions of the invention, can be administered in the animal's food, for example, a concentrated feed additive or premix can be prepared to be mixed with the normal food of the animal, commonly together with a suitable vehicle for it. The vehicle facilitates the uniform distribution of a compound, prodrug, isomer or pharmaceutically acceptable salt of this invention, for example, in the finished food with which the premix is mixed. Suitable carriers include, but are not limited to, liquids, for example, water, oils such as soy, corn, cottonseed or volatile and solid organic solvents, for example, a small portion of the food or various suitable foods including alfalfa, soybeans, cottonseed oil, linseed oil, corn cobs, corn, molasses, urea, bone and mineral mixtures. As the present invention has an aspect that relates to the treatment of the diseases / conditions described herein with a combination of active ingredients that can be administered separately, the invention also relates to a combination of the separate pharmaceutical compositions in the form of a kit . The kit comprises two separate pharmaceutical compositions: a compound of the formula I or a prodrug thereof, a geometric or optical isomer thereof or a salt of such a compound, prodrug or isomer, and a second compound as described above. The kit comprises a container for containing the separate compositions, such as a divided bottle or a divided sheet container. Typically, the kit comprises instructions for the administration of the separated compounds. The shape of the kit is particularly advantageous when the separate components are preferably administered in different dosage forms (eg, oral and parenteral), administered at different dosage intervals, or when the corresponding physician wishes to assess the individual components of the combination.

An example of such a case is the so-called blister. Blisters are well known in the packaging industry and are widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules and the like). Blisters generally consist of a sheet of relatively rigid material covered with a sheet of preferably transparent plastic material. During the packaging process, cavities are formed in the plastic sheet. The cavities have the size and shape of the tablets or capsules to be packaged. Then, the tablets or capsules are placed in the cavities and the sheet of relatively rigid material is sealed with the plastic sheet on the side of the sheet opposite the direction in which the cavities were formed. As a result, the tablets or capsules are sealed in the cavities between the plastic sheet and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister by manually pressing on the cavity, thereby forming an opening in the sheet at the cavity site. The tablet or capsule can then be withdrawn through said opening. It may be desirable to provide a reminder in the set, for example, in the form of numbers near the tablets or capsules, the numbers corresponding to the days of the regimen in which the tablets or capsules so specified should be ingested. Another example of such a reminder is a calendar printed on the card, for example, as indicated below: "First week, Monday, Tuesday, ... etc ... Second week, Monday Tuesday, ..." etc. Other variations of reminders will be evident. A "daily dose" may be a single tablet or capsule or several tablets or capsules to be taken on a given day. In addition, a daily dose of the compound of Formula I, of a prodrug thereof, of a geometric or optical isomer of the mimes or of a pharmaceutically acceptable salt of such a compound, prodrug or isomer, may consist of a tablet or capsule, while a The daily dose of the second compound may consist of several tablets or capsules and vice versa. The reminder should reflect this. In another specific embodiment of the invention, a dispenser designed to deliver the daily doses, one at a time, in the desired order of use is provided. Preferably, the dispenser has a reminder, so that it further facilitates compliance with the regime. An example of such a reminder is a mechanical counter that indicates the number of daily doses that have been delivered. Another example of such a reminder is a battery operated microchip memory, coupled to a liquid crystal display, or a reminder auditory signal that, for example, shows the data of the last daily dose taken and / or remembers when it should Take the next dose. The utility of the compounds of formula I or their isomers, or pharmaceutically acceptable salts of such compounds or isomers, can be demonstrated by the activity in at least one of the two assays described below.

TEST 1 Oxygen Consumption As will be appreciated by those skilled in the related art, during a higher energy expenditure the animals generally consume more oxygen. In addition, metabolic fuels such as, for example, glucose and fatty acids are oxidized to CO2 and H20 with the joint heat release, which is commonly referred to in the thermogenesis art. Thus, measurement of oxygen consumption in animals, including humans and companion animals, is an indirect measure of thermogenesis. Those skilled in the related art commonly use indirect calorimetry in animals, for example, in humans, to measure such energy expenditure. Those skilled in the art understand that increased energy expenditure and the concomitant combustion of metabolic fuels resulting in the production of heat can be effective with respect to the treatment, for example, of obesity. As is well known to those skilled in the art, thyroid hormones affect cardiac function, for example, by causing an increase in heart rate and, consequently, an increase in oxygen consumption with concomitant production of heat. The ability of the compounds, their isomers and the pharmaceutically acceptable salts of said compounds and isomers of this invention to generate a thermogenic response can be demonstrated according to the following protocol.

A. Experimental. This in vivo analysis is designed to evaluate the efficiency and cardiac effects of compounds that are agonists of tissue-selective thyroid hormones. The measured efficacy endpoints are the total body oxygen consumption and the activity of the mitochondrial alpha-glycerophosphate dehydrogenase ("mGPDH") hepatic. The cardiac endpoints that are measured are cardiac weight and cardiac mGPDH activity. The protocol involves: (a) administering the drug to obese Zucker rats for approximately 6 days, (b) measuring oxygen consumption and (c) collecting the tissue for mitochondria preparation and then assaying the enzyme activity.

B. Preparation of the Rats. Male obese Zucher rats having a range of body weights of about 400 g to about 500 g are enclosed for a period of about 3 to about 7 days, in individual cages under laboratory conditions conventionally before the start of the study. A compound of formula I, or an isomer thereof, or a pharmaceutically acceptable salt of such compound or isomer, vehicle or sodium salt of T3, is administered by oral gavage as a single daily dose administered between about 3 p.m. and approximately 6 p.m., for approximately 6 days. A compound of formula I, an isomer thereof or a pharmaceutically acceptable salt of such compound or isomer, or the sodium salt of T3, is dissolved in a suitably small volume of NaOH of about 1 N and then brought to an adequate volume with approximately 0.01 N NaOH containing approximately 0.25% hypromellose (10: 1, 0.01 N NaOH / HM: 1 N NaOH). The dosage volume is about 1 ml.

C. Oxygen consumption. Approximately 1 day after the last dose of the compound is administered, the oxygen consumption is measured using an open circuit, indirect calorimeter (Oxymax, Columbus Instruments, Columbus, OH 43204). The Oxymax gas sensors are calibrated with N2 gas and a gaseous mixture (approximately 0.5% C02, approximately 20.5% of 02 and approximately 79% of N2) before each experiment. The rats are removed from their cages and their body weights are recorded. The rats are placed in sealed chambers (43 x 43 x 10 cm) of the Oxymax, the chambers are placed on the activity monitors and the air flow passing through the chambers is set at a value of approximately 1. 6 l / min. at approximately 1.7 l / min.

The Oxymax software then calculates the oxygen consumption (ml / kg / h) by the rats based on which air through the chambers and the difference in oxygen content in the inlet and outlet holes. The activity monitors have 15 beams of infrared light at a distance of approximately one inch on each axis; Ambulatory activity is recorded when two consecutive beams are broken and the results are recorded as quantities. Oxygen consumption and ambulatory activity are measured approximately every 10 minutes for a period of approximately 5 hours to approximately 6.5 hours. Resting oxygen consumption is calculated in individual rats by averaging the values, excluding the first 5 values and the values obtained during the periods of time in which the ambulatory activity exceeded a value of approximately 100.

ASSAY 2 Union to the Thyroid Hormone Receptors The ability of a compound of formula I, an isomer thereof or a pharmaceutically acceptable salt of such a compound or isomer ("thyromimetic test compounds") to bind to thyroid hormone receptors can be demonstrated in the following protocol.

A. Preparation of Nuclear Extracts of Insect Cells. High Five cell pellets (BTI-TN-5B1-4, catalog number B855-02, Invitrogen®, Carlsbad, Calif.) Obtained approximately 48 hours after a baculovirus infection (GibcoBRL®, Gaithersburg, Maryland) expressing TRa or human TRβ, in ice-cold Sample Buffer (10 mM Tris, pH 8.0; 1 mM MgCl 2; 1 mM DTT; 0.05% Tween 20; 1 mM 4- (2-aminoethyl) -benzenesulfonyl fluoride; 25 μg / ml leupeptin). After approximately 10 minutes of incubation on ice, the suspension was homogenized by 20 strokes with a Dounce homogenizer (VWR® Scientific Products, West Chester, Pennsylvania) and centrifuged at 800xg for approximately 15 minutes at 4 ° C. The pellet (cores) was suspended in a hypertonic buffer (0.4 M KCl, 10 mM Tris, pH 8.0, 1 mM MgCl 2, 1 mM DTT, 0.05% Tween 20) and incubated for approximately 30 minutes on ice. The suspension was centrifuged at 100,000xg for approximately 30 minutes at 4 ° C. The supernatant (nuclear extract) was stored in aliquots of 0.5 ml at -80 ° C.

B. Union test. The competitive binding assays performed to measure the interaction of the test thyromimetic compounds with the thyroid hormone receptors a1 and ß1 (TRa and TRβ) are carried out according to the following protocol.

Thyromimetic test compound solutions are prepared (concentration of the final 20 mM compound) using 100% DMSO as solvent. Each compound is serially diluted in an assay buffer (5 mM Tris-HCl, pH 8.0, 50 mM NaCl, 2 mM EDTA, 10% glycerol (v / v), 1 mM DTT, "assay buffer") contains 0.4 nM 125I-T3 (specific activity of approximately 200 Ci / mmol) to produce solutions ranging in concentration of the compound from about 10 μM to about 0.1 nM. The nuclear extract of High Five insect cells containing TRa or TRβ is diluted to a total protein concentration of 0.0075 mg / ml using the assay buffer as a diluent. One volume (100 μl) of each dilution of thyromimetic compound (containing 0.4 nM 125I-T3) is combined with an equal volume (100 μl) of diluted nuclear extract containing TRa1 or TRβ1, and incubated at RT for approximately 90 minutes . A 150 μl sample of the binding reaction is removed and placed in a 96-well filter plate (Millipore®, Bedford, Massachusetts) which had been pre-washed with an ice-cold assay buffer. The plate is subjected to vacuum filtration using a filtration nozzle (Millipore®). Each well is washed five times by the addition of 200 μl of ice-cold assay buffer and subsequent vacuum filtration. The plate is removed from the vacuum filtration nozzle, the bottom of the plate is dried briefly on paper towels and then 25 μl of Wallac® scintillation cocktail (EG &G Wallac®, Gaitersburg, Maryland) Optiophase Supermix a each well, the top of the plate is covered with a plastic sealing tape (Microplte Press-on Adhesive Sealing Film, Packard® Instrument Co., Inc., Downers Grove, Illinois) and the radioactivity is quantified using a scintillation counter of 96-well Wallac® Microbeta plates. The following examples are provided for illustrative purposes only and do not limit the invention, which is defined by the claims.

EXAMPLE 1 Acid N-. { 3.5-dichloro-4- [4-hydroxy-3- (pyrrolidine-1-sulfonyl) -phenoxy] -phenyl> - oxmic Step A 2 ', 6'-dichloro-4-methoxy-4'-nitrophenol ether was prepared by coupling 2,6-dichloro-4-nitrophenol with (4,4'-dimethoxydiphenyl) yodon tetrafluoroborate. or in the presence of copper powder and TEA according to the procedure described in J. Med. Chem., 38: 695-707 (1995).

Step B A solution of pure 2 ', 6'-dichloro-4-methoxy-4'-nitrodiphenyl ether (500 mg, 1.6 mmol) at 0 ° C was treated with chlorosulfonic acid (877 ml, 7.5 mmol) and the mixture of reaction immediately took on a dark brown color.

The mixture was stirred for 5 minutes at 0 ° C and allowed to warm to RT. After stirring for 30 minutes at RT, the reaction mixture was slowly added dropwise in 100 ml of ice water with stirring. The brown precipitate was extracted with ethyl acetate (3 x 75 ml). The combined organic extracts were washed with sodium bicarbonate (1 x 100 ml), water (1 x 100 ml), dried and concentrated to give a brown solid. The crude product was used in the next step without further purification. NMR (400 MHz, CDCl 3) d 8.32 (s, 2H), 7.40 (d, 1 H), 7.20-7.25 (dd, 1 H), 7.09 (d, 1 H), 4.04 (s, 3H), calculated MS : 410.9, Found: 392.1 [M-1 for 5- (2,6-dichloro-4-nitro-phenoxy) -2-methoxy-benzenesulfonic acid].

Step CA: a solution of 5- (2,6-dichloro-4-nitro-phenoxy) -2-methoxy-benzenesulfonyl chloride (200 mg, 0.48 mmol) in 5 ml of CH2Cl2 at RT was added pyrrolidine (85 ml, 1.0 mmoles). After stirring for 2 h at RT, the reaction mixture was quenched with 1 N HCl (5 mL) and extracted with CH2Cl2 (3 x 10 mL). The combined extracts were washed with 1 N HCl (3 x 5 mL) and saturated aqueous NaHCO 3 (2 x 5 mL), dried and concentrated. The residue was purified by preparative TLC (Hexane: EtOAc = 2: 1) yielding a white solid. NMR (400 MHz. CDCl 3) d 8.30 (s, 2H), 7.39 (d, 1 H), 7.02-7.05 (dd, 1 H), 6.95-6.98 (d, 1 H), 3.91 (s, 3H), 3.35-3.38 (m, 4H), 1.82-1.87 (m, 4H), Calculated MS: 446.0, Found: 447.0 (M + 1).

Step DA A solution of 1- [5- (2,6-dichloro-4-nitro-phenoxy) -2-methoxy-benzenesulfonyl-pyrrolidine (178.5 mg, 0.4 mmol) in 8 ml of chloroform at RT was added dropwise. drop boron tribromide (1 N in CH2Cl2, 2.4 ml, 2.4 mmol). After stirring for 16 h at RT, the reaction mixture was quenched with 10 ml of water. The mixture was stirred for 1 h at RT, extracted with CH2Cl2 (1 x 5 mL) and EtOAc (2 x 10 mL). The combined organic extracts were dried and concentrated. The product was used in the next step without further purification. NMR (400 MHz, CD3OD) d 8.31 (s, 2H), 7.09 (d, 1 H), 6.96-7.02 (m, 2H), 3.28-3.31 (m, 4H), 1.79-1.82 (m, 4H), Calculated MS: 432.0, Found: 431.1 (M-1).

Step E A mixture of 4- (2,6-dichloro-4-nitro-phenoxy) -2- (pyrrolidine-1-sulfonyl) -phenol (166 mg, 0.38 mmol) and Pd catalyst at approximately 10% / C ( 17 mg) in a mixture of EtOAc (5 ml) and MeOH (10 ml) was hydrogenated at 275.79 kPa at RT for 1 h. The solution was filtered through Celite® and concentrated to give a brown solid. The product was used in the next step without further purification.

NMR (400 MHz, CDCl 3) d 8.34 (s, 2H), 6.96-7.22 (S broad + m, 5H), 3.19 (m, 4H), 1.73 (m, 4H). Calculated MS: 402, Found: 401.1 (M-1).

Step F A mixture of 4- (4-amino-2,6-dichloro-phenoxy) -2- (pyrrolidine-1-sulfonyl) -phenol (154 mg, 0.38 mmol) and diethyl oxalate (1.49 g, 10.2 mmol) it was stirred at 120 ° C for 4 h. Excess diethyl oxalate was removed by vacuum distillation. The residue was purified by preparative TLC (0.5% MeOH in CH2Cl2) giving an off-white solid. NMR (400 MHz, CDCl 3) d 9.06 (s, 1 H), 8.60 (s, 1 H), 7.76 (s, 2 H), 7.03-7.06 (dd, 1 H), 6.96-6.98 (d, 1 H), 6.90 (d, 1H), 4.36-4.40 (q, 2H), 3.18-3.21 (m, 4H), 1.74-1.78 (m, 4H), 1.39 (t, 3H). Calculated MS: 502, Found: 501.1 (M-1).

Stage G To a solution of ethyl ester of N- acid. { 3,5-dichloro-4- [4-hydroxy-3- (pyrrolidine-1-sulfonyl) -phenoxy] -phenyl} -oxamic (10 mg, 0.02 mmol) in a mixture of H20 (0.5 ml) and MeOH (0.5 ml) were added 2 drops of KOH 3 N. The reaction mixture was stirred at RT for 2 h, acidified with 1 N HCl and extracted with EtOAc (4 x 5 mL). The combined organic extracts were dried and concentrated to yield the title compound as an off-white solid. NMR (400 MHz, CD3OD) d 7.96 (s, 2H), 7.02-7.06 (m, 2H), 6.95-6.98 (d, 1 H), 3.28-3.31 (m, 4H), 1.78-1.81 (m, 4H) ). Calculated MS: 474.3, Found: 473.1 (M + 1). Using the appropriate starting materials, Examples 1-1 to 1-57 were prepared in a manner analogous to that described in Example 1.

EXAMPLE 1-1 N- [4- (3-Cyclopropylsulfamoyl-4-hydroxy-phenoxy) -3,5-dimethyl-l-f-enyl] -oxamic acid ethyl ester Calculated MS: 448.5, Found: 447.3 (M-1).

EXAMPLE 1-2 N- [4- (4-Hydroxy-3-methylsulfamoyl-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid ethyl ester Calculated MS: 422.5, Found: 421.3 (M-1).

EXAMPLE 1-3 Ethyl ester of N- acid. { 4- [3- (4-fluoro-phenylsulfamoyl) -4-hydroxy-phenoxy-3,5-dimethyl-phenyl} -oxamic Calculated MS: 502.5, Found: 501.1 (M-1).

EXAMPLE 1-4 N- [4- (3-dimethylsulfamoyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid ethyl ester Calculated MS: 436.5, Found: 435.3 (M-1).

EXAMPLE 1-5 N-acid ethyl ester. { 4- [3- (cyclopropyl-methyl-sulfamoyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl] -oxamic Calculated MS: 462.5, Found: 461.2 (M-1).

EXAMPLE 1-6 Ethyl ester of N- acid. { 4- (3- (cyclobutyl-methyl-sulfamoyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl] -oxamic acid Calculated MS: 476.6, Found: 475.3 (M-1).

EXAMPLE 1-7 N- [4- (3-Cyclobutylsulfamoyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl-oxamic acid ethyl ester Calculated MS: 462.5, Found: 461.2 (M-1).

EXAMPLE 1-8 N- [4- (3-Cyclopentylsulfamoyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid ethyl ester Calculated MS: 476.6, Found: 475.3 (M-1).

EXAMPLE 1-9 Ethyl ester of N- acid. { 4-.4-hydroxy-3- (pyrrolidine-1-sulfonyl) -phenoxy '| -3,5-dimethyl-phenyl} -oxamic Calculated MS: 462.5, Found: 461.3 (M-1).

EXAMPLE 1-10 N- acid ethyl ester. { 4- [4-hydroxy-3- (p.peridine-1-sulfonyl) -phenoxy-3,5-dimethyl-phenyl} -oxamic Calculated MS: 476.6, Found: 475.2 (M-1).

EXAMPLE 1-11 N- [4- (3-Cyclohexyl-sulfamoyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid ethyl ester Calculated MS: 490.6, Found: 489.3 (M-1).

EXAMPLE 1-12 N- [4- (4-Hydroxy-3-propylsulfamoyl-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid ethyl ester Calculated MS: 450.5, Found: 449.3 (M-1).

EXAMPLE 1-13 N- [4- (3-Butylsulfamoyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid ethyl ester Calculated MS: 464.5, Found: 463.3 (M-1).

EXAMPLE 1-14 Acid N-. { 4- [3- (cyclopropyl-methyl-sulfamoyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -oxamic Calculated MS: 434.5, Found: 433.3 (M-1).

EXAMPLE 1-15 N- (4- [3- (Cyclobutyl-methyl-sulfamoyl) -4-hydroxy-phenoxy-3,5-dimethyl-phenyl} -oxamic acid Calculated MS: 448.5, Found: 447.3 (M-1).

EXAMPLE 1-16 N- [4- (3-Cyclopropylsulfamoyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid Calculated MS: 420.4, Found: 419.3 (M-1).

EXAMPLE 1-17 N- [4- (3-Cyclobutylsulfamoyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid Calculated MS: 434.5, Found: 433.2 (M-1).

EXAMPLE 1-18 N- [3-Chloro-4- (3-cyclopropylsulfamoyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -oxarnic acid ethyl ester Calculated MS: 468.1, Found: 466.5 (M-1).

EXAMPLE 1-19 N- [3-Chloro-4- (3-cyclobutylsulfamoyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -oxamic acid ethyl ester Calculated MS: 482.1, Found: 480.4 (M-1).

EXAMPLE 1-20 N- [3-Chloro-4- (3-cyclopentylsulfamoyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -oxamic acid ethyl ester Calculated MS: 496.2, Found: 494.9 (M-1).

EXAMPLE 1-21 N-f3-Chloro-4- (3-cyclohexylsulfamoyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -oxamic acid ethyl ester Calculated MS: 510.2, Found: 508.8 (M-1).

EXAMPLE 1-22 N- [3-Chloro-2- (4-hydroxy-3-sulfamoyl-phenoxy) -5-methyl-phenyl] -oxamic acid ethyl ester Calculated MS: 428.1, Found: 426.7 (M-1).

EXAMPLE 1-23 Ethyl ester of N- acid. { 3-Chloro-4- [4-hydroxy-3- (piperidine-1-sulfonyl) -phenoxy] -5-methyl-phenyl} -oxamic Calculated MS: 496.1, Found: 495.1 (M-1).

EXAMPLE 1-24 Ethyl ester of N- acid. { 3-Chloro-4- [3- (4-fluoro-phenylsulfamoyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -oxamic Calculated MS: 522.1, Found: 520.4 (M-1).

EXAMPLE 1-25 N- [3-Chloro-4- (3-dimethylsulfamoyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -oxamic acid ethyl ester Calculated MS: 456.1, Found: 457.3 (M + 1).

EXAMPLE 1-26 N- [3-Chloro-4- (4-hydroxy-3-methylsulfamoyl-phenoxy) -5-methyl-phenyl] -oxamic acid ethyl ester Calculated MS: 442.1, Found: 441.2 (M-1).

EXAMPLE 1-27 N- [3-Chloro-4- (4-hydroxy-3-propylsulfamoyl-phenoxy) -5-methyl-phenyl] -oxamic acid ethyl ester.

Calculated MS: 470.1, Found: 469.2 (M-1).

EXAMPLE 1-28 N- [3-Chloro-4- (4-hydroxy-3-pentylsulfamoyl-phenoxy) -5-methyl-phenyl] -oxamic acid ethyl ester Calculated MS: 498.2, Found: 497.2 (M-1).

EXAMPLE 1-29 N- [3-Chloro-4- (3-hexylsulfamoyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -oxamic acid ethyl ester Calculated MS: 512.2, Found: 511.2 (M-1).

EXAMPLE 1-30 N-f3-chloro-4- (4-hydroxy-3-octylsulfamoyl-phenoxy) -5-methyl-phenyl] -oxamic acid ethyl ester Calculated MS: 540.3, Found: 539.2 (M-1).

EXAMPLE 1-31 N- [3-Chloro-4- (3-decylsulfamoyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -oxamic acid ethyl ester Calculated MS: 568.3, Found: 567.3 (M-1).

EXAMPLE 1-32 N- [4- (3-Butylsulfamoyl-4-hydroxy-phenoxy) -3-chloro-5-methyl-phenyl] -oxamic acid ethyl ester Calculated MS: 484.2, Found: 483.2 (M-1).

EXAMPLE 1-33 'Ethyl ester of N- acid. { 3-chloro-4- [3- (ethyl-methyl-sulfamoyl) -4-hydroxy-phenoxy] -5-methyl-phenyl] -oxamic Calculated MS: 470.1, Found: 469.2 (M-1).

EXAMPLE 1-34 Ethyl ester of N- acid. { 3-Chloro-4- [4-hydroxy-3- (methyl-propyl-sulfamoyl) -phenoxy] -5-methyl-phenyl} -oxamic Calculated MS: 484.2, Found: 483.2 (M-1).

EXAMPLE 1-35 Ethyl ester of N- acid. { 4- [3- (Butyl-methyl-s-l-heamoyl) -4-hydroxy-phenoxy] -3-chloro-5-methyl-phenyl} -oxamic Calculated MS: 498.2, Found: 497.2 (M-1).

EXAMPLE 1-36 Ethyl ester of N- acid. { 3-chloro-4- [4-hydroxy-3- (morpholine-4-sulfonyl) -phenoxy] -5-methyl-phenyl} -oxamic Calculated MS: 498.1, Found: 497.2 (M-1).

EXAMPLE 1-37 Ethyl ester of N- acid. { 3-Chloro-4- [3- (cyclopropylmethyl-sulfamoyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -oxamic Calculated MS: 482.1, Found: 481.2 (M-1).

EXAMPLE 1-38 Ethyl ester of N- acid. { 3-Chloro-4- [4-hydroxy-3- (2-hydroxy-ethylsulfamoyl) -phenoxy] -5-methyl-phenyl} -oxamic Calculated MS: 472.1, Found: 471.2 (M-1).

EXAMPLE 1-39 N- [3-Chloro-4- (3-cyclopropylsulphamoyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -oxamic acid isopropyl ester Calculated MS: 482.1, Found: 481.2 (M-1).

EXAMPLE 1-40 N- [3-Chloro-4- (3-cyclopropylsulfamoyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -oxamic acid Calculated MS: 440.1, Found: 439.2 (M-1).

EXAMPLE 1-41 N- [3-Chloro-4- (3-cyclobutylsulfamoyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -oxamic acid Calculated MS: 454.1, Found: 452.8 (M-1).

EXAMPLE 1-42 N- [3-Chloro-4- (3-cyclopentylsulfamoyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -oxamic acid Calculated MS: 468.1, Found: 466.9 (M-1).

EXAMPLE 1-43 N- [3-Chloro-4- (3-cyclohexylsulfamoyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -oxamic acid Calculated MS: 482.1, Found: 481.0 (M-1).

EXAMPLE 1-44 N- [3-Chloro-4- (4-hydroxy-3-sulfamoyl-phenoxy) -5-methyl-phenyl] -oxamic acid Calculated MS: 400.0, Found: 398.9 (M-1).

EXAMPLE 1-45 Acid N-. { 3-Chloro-4-f3- (4-fluoro-phenylsulfamoyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -oxamic Calculated MS: 494.1, Found: 493.1 (M-1).

EXAMPLE 1-46 N- [3-Chloro-4- (4-hydroxy-3-propylsulfamoyl-phenoxy) -5-methyl-phenyl] -oxamic acid Calculated MS: 442.1, Found: 441.2 (M-1).

EXAMPLE 1-47 N- [4- (3-Butylsulfamoyl-4-hydroxy-phenoxy) -3-chloro-5-methyl-phenyl] -oxamic acid Calculated MS: 456.1, Found: 455.1 (M-1).

EXAMPLE 1-48 N- Acid. { 3-chloro-4-f4-hydroxy-3- (morpholine-4-sulfonyl) -phenoxy-5-methyl-phenyl} -oxamic Calculated MS: 470.1, Found: 469.2 (M-1).

EXAMPLE 1-49 Ethyl ester of N- acid. { 3.5-dichloro-4- [4-hydroxy-3- (y-pyrrolidine-1-sulfonyl) -phenoxy] -phenyl} -oxamic Calculated MS: 502.0, Found: 501.1 (M-1).

EXAMPLE 1-50 Ethyl ester of N- acid. { 3.5-dichloro-4- [3- (3,4-dihydro-1H-isoquinoline-2-sulfonyl) -4-hydroxy-phenoxy] -phenyl} -oxamic Calculated MS: 564.1 Found: 562.8 (M-1).

EXAMPLE 1-51 Ethyl ester of N- [3,5-dichloro-4- (3-cyclobutylsulfamoyl-4-hydroxy-phenoxy-phenyl] -oxamic acid ethyl ester Calculated MS: 502.0 Found: 500.3 (M-1) EXAMPLE 1-52 Ethyl ester of N- acid. { 4- [3- (bicyclo [2.2.1] hept-2-ylsulfamoyl) -4-hydroxy-phenoxy] -3,5-dichloro-phenyl} -oxamic Calculated MS: 542.0 Found: 540.6 (M-1) EXAMPLE 1-53 N- (3,5-Dichloro-4-. {4-hydroxy-3 - [(thiophen-2-ylmethyl) -sulfamoyl] -phenoxy] -phenyl) -oxamic acid ethyl ester Calculated MS: 544.0 Found: 542.3 (M-1) EXAMPLE 1-54 N- [3,5-Dichloro-4- (4-hydroxy-3-isopropylsulfamoyl-phenoxy) -phenyl] -oxamic acid ethyl ester Calculated MS: 490.0 Found: 488.9 (M-1) EXAMPLE 1-55 N- [3,5-Dichloro-4- (3-dimethylsulphamoyl-4-hydroxy-phenoxy) -phenyl] -oxamic acid ethyl ester Calculated MS: 476.1 Found: 475.1 (M-1) EXAMPLE 1-56 N- Acid. { 3.5-dichloro-4- [4-hydroxy-3- (pyrrolidine-1-sulfonyl) -phenoxy] -phenyl} - oxmic Calculated MS: 474.1 Found: 473.1 (M-1) EXAMPLE 1-57 N- [3,5-Dichloro-4- (4-hydroxy-3-isopropylsulfamoyl-phenoxy) -phenyl] -oxamic acid Calculated MS: 462.0 Found: 461.1 (M-1) EXAMPLE 2 Ethyl ester of N- acid. { 3.5-dichloro-4- [3- (3,3-dimethyl-piperidine-1-carbonyl) -4-hydroxy-phenoxy] -phenyl} -oxamic Step A A mixture of 2 ', 6'-dichloro-4-methoxy-4'-nitrodiphenyl ether (5.0 g, 16 mmol), TFA (50 ml) and hexamethylenetetramine (3.35 g, 24 mmol) was stirred at 70 ° C. for 3 h giving a yellow solution. The TFA was removed by a rotavap giving a viscous yellow oil which was diluted with H2O (100 ml) and stirred at RT for 0.5 h. Saturated aqueous NaHC 3 (300 mL) was added and the mixture was extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (200 ml), dried and concentrated to give a yellow solid. Calculated MS: 341.0 Found: 340.4 (M-1).

Step B To a solution of 5- (2,6-dichloro-4-nitro-phenoxy) -2-methoxy-benzaldehyde (1.0 g, 2.9 mmol) in acetone (30 ml) was added Jones's reagent (3.0 ml) slowly. The resulting solution was stirred at RT for 1 h and quenched with isopropanol (4 mL). The solid was removed by filtration through Celite®. The bluish solution was concentrated giving a yellow solid with a blue supernatant. The solid was dissolved in EtOAc and dried over Na 2 SO 4, filtered and concentrated. The resulting yellow oily solid was partially dissolved in EtOAc (25 mL) and extracted with saturated aqueous NaHCOs (5 x 75 mL). The combined aqueous extracts were acidified with 2N HCi, extracted with EtOAc (4 x 100 mL), dried and concentrated to give a yellow solid. MS Calculated: 356.9 Found: 357.8 (M-1).

Step CA: a solution of 5- (2,6-dichloro-4-nitro-phenoxy) -2-methoxy-benzoic acid (0.81 g, 2.3 mmol) in chloroform (20 ml) at RT, was added dropwise tribromide ( 1 N in CH2Cl2, 4.5 mL, 4.5 mmol). The resulting mixture was stirred at RT for 1 h and quenched with H20 (20 mL). After stirring at RT for 0.5 h, the aqueous phase was basified with saturated aqueous NaHCOs (4 x 50 mL). The organic phase was extracted with saturated aqueous NaHCO 3 (4 x 50 ml). The combined aqueous extracts were acidified with concentrated HCl to give a white precipitate which was extracted with EtOAc (4 x 100 mL). The combined organic extracts were dried and concentrated to give a yellowish white solid. MS Calculated: 342.9 Found: 341.8 (M-1).

Step DA A solution of 5- (2,6-dichloro-4-nitro-phenoxy) -2-hydroxybenzoic acid (0.69 g, 2 mmol) in a mixture of EtOAc (4 mL) and MeOH (12 mL) was added. 10% Pd / C (70 mg). The solution was hydrogenated at 275.79 kPa of pressure at RT for 2 h and then filtered through Celite®. The filtrate was concentrated. The product was used in the next step without further purification. MS Calculated: 312.9 Found: 311.9 (M-1).

Step E A mixture of 5- (2,6-dichloro-4-amino-phenoxy) -2-hydroxybenzoic acid (0.63 g, 2 mmol) and diethyl oxalate (4.4 g, 30 mmol) was stirred at 140 ° C for 3 h. The excess diethyl oxalate was removed in vacuo to give a brown oily solid which was triturated with hexanes to remove the residual diethyl oxalate. The chestnut solid was collected by filtration and washed with C ^ C ^ / hexanes (5% CH2Cl2 in hexanes). The product was used in the next step without further purification. Calculated MS: 413.0, Found: 411.8 (M-1).

Step FA: a solution of 5- [2,6-dichloro-4- (ethoxyoxalylamino) -phenoxy] -2-hydroxy-benzoic acid (29 mg, 0.07 mmol) in THF at RT was added thionyl chloride (25 mg , 0.21 mmol). The resulting mixture was stirred at 60 ° C for 1 h and concentrated in vacuo to give the acid chloride as a tan solid. The acid chloride was dissolved in chloroform (0.5 ml) and to the solution was added diisopropylethylamine (18 mg, approximately 0.14 mmol) and 3,3-dimethylpiperidine (9.4 mg, 0.083 mmol). The resulting mixture was stirred at RT for 17 h and concentrated. The crude product was purified by preparative TLC (6% acetone in CH 2 Cl 2) to give the title compound as a white solid. Calculated MS: 509.4 Found: 507.2 (M-1). Using the appropriate starting materials, examples 2-1 to 2-109 were prepared in a manner analogous to that described in example 2.

EXAMPLE 2-1 Ethyl ester of N- acid. { 4- [3- (3,4-dihydro-1H-isoquinoline-2-carbonyl) -4-hydroxy-phenoxy] -3,5-d-methyl-phenyl} -oxamic Calculated MS: 488.6 Found: 486.6 (M-1).

EXAMPLE 2-2 Ethyl ester of N- acid. { 4- [3- (3,4-dihydro-2H-quinoline-1-carbonyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -oxamic Calculated MS: 488.6 Found: 486.5 (M-1).

EXAMPLE 2-3 Ethyl ester of N- acid. { 4- [3- (2,3-D-Hydro-indol-1 -carbonyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -oxamic Calculated MS: 474.5 Found: 473.3 (M-1).

EXAMPLE 2-4 N- (4- [3- (3,3-Dimethyl-piperidine-1-carbonyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -oxamic acid ethyl ester Calculated MS: 468.6 Found: 466.7 (M-1).

EXAMPLE 2-5 Ethyl ester of N- acid. { 4- [4-hydroxy-3- (3-methyl-3-phenyl-piperidine-1-carbonyl) -phenoxy] -3,5-dimethyl-phenyl} -oxamic Calculated MS: 530.6 Found: 528.7 (M-1).

EXAMPLE 2-6 Ethyl ester of N- acid. { 4- [3-azepane-1-carbonyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -oxamic Calculated MS: 454.5 Found: 453.2 (M-1).

EXAMPLE 2-7 Ethyl ester of N- acid. { 4- [4-hydroxy-3- (1-naphthalen-1-yl- (1 R) -ethylcarbamoyl) -phenoxy] -3,5-dimethyl-phenyl} -oxamic Calculated MS: 526.6 Found: 525.2 (M-1).

EXAMPLE 2-8 Ethyl ester of N- acid. { 4- [4-hydroxy-3- (1-phenyl- (1R) -ethylcarbamoyl) -phenoxy] -3,5-dimethyl-phenyl} -oxamic Calculated MS: 476.5 Found: 475.2 (M-1).

EXAMPLE 2-9 N- acid ethyl ester. { 4- [3- (biciclof2.2.1] hept-2-ylcarbamoyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -oxamic Calculated MS: 466.5 Found: 465.2 (M-1).

EXAMPLE 2-10 Ethyl ester of N- acid. { 4- [3- (4-chloro-benzylcarbamoyl) -4-hydroxy-eneoxi] -3,5-dimethyl-phenyl} -oxamic Calculated MS: 497.0 Found: 495.2 (M-1).

EXAMPLE 2-11 N- acid ethyl ester. { 4- [3- (1-cyclohexyl- (1R) -ethylcarbamoyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -oxamic Calculated MS: 482.6 Found: 483.3 (M + 1).

EXAMPLE 2-12 Ethyl ester of N- acid. { 4- [4-hydroxy-3- (1-naphthalen-2-yl- (1 R) -ethylcarbamoyl) -phenoxy] -3,5-dimethyl-phenyl} -oxamic Calculated MS: 526.6 Found: 525.4 (M-1).

EXAMPLE 2-13 N- [4- (3-Cyclobutylcarbamoyl-4-hydroxy-phenoxy] -3,5-dimethyl-phenyl] -oxamic acid ethyl ester Calculated MS: 426.5 Found: 525.3 (M-1).

EXAMPLE 2-14 N- [4- (3-Cyclopentylcarbamoyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl ethyl ester ethyl ester} -oxamic Calculated MS: 440.5 Found: 439.3 (M-1).

EXAMPLE 2-15 Ethyl ester of N- acid. { 4- [4-hydroxy-3- (1-isopropyl-2-methyl-propylcarbamoyl) -phenoxy] -3,5-dimethyl-phenyl} -oxamic Calculated MS: 470.6 Found: 469.2 (M-1).

EXAMPLE 2-16 Ethyl ester of N- acid. { 4- [4-Hydroxy-3- (pyrrolidine-1-carbonyl) -phenoxy] -3,5-dimethyl-phenyl} -oxamic Calculated MS: 426.5 Found: 425.3 (M-1).

EXAMPLE 2-17 N- acid ethyl ester. { 4-f4-hydroxy-3- (morpholine-4-carbonyl) -phenoxy] -3,5-dimethyl-phenyl} -oxamic Calculated MS: 442.5 Found: 441.3 (M-1).

EXAMPLE 2-18 N- Acid. { 4- [4-hydroxy-3- (1-naphthalen-1-yl- (1 R) -ethylcarbamoyl) -phenoxy] -3,5-dimethyl-phenyl} -oxamic Calculated MS: 498.5 Found: 497.2 (M-1).

EXAMPLE 2-19 N- Acid. { 4-r 4 -hydroxy-3- (1-phenyl- (1 R) -ethylcarbamoyl) -phenoxy] -3,5-dimethylphenyl} -oxamic Calculated MS: 448.5 Found: 447.3 (M-1).

EXAMPLE 2-20 N- acid. { 4- [3-cyclopropyl-methyl-carbamoyl) -4-hydroxy-phenoxy] -3,5-dimethyl-dimethyl-pentyl} -oxamic Calculated MS: 398.4 Found: 397.3 (M-1).

EXAMPLE 2-21 N- acid. { 4- [3- (c8clobutyl-methyl-carbamoyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -oxamic Calculated MS: 412.5 Found: 411.3 (M-1).

EXAMPLE 2-22 N- acid. { 4- [4-hydroxy-3- (1-isopropyl-2-methyl-propylcarbamoyl) -phenoxy] -3,5- d -methyl-phenyl ..}. -oxamic Calculated MS: 442.5 Found: 441.3 (M-1).

EXAMPLE 2-23 N- Acid. { 4- [3- (cyclopentyl-methyl-carbamoyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -oxamic Calculated MS: 426.5 Found: 425.3 (M-1).

EXAMPLE 2-24 N- acid. { 4- [3- (Cyclohexyl-methyl-carbamoyl) -4-hydroxy-phenoxy] -3,5-dinnethyl-phenyl} -oxamic Calculated MS: 440.5 Found: 439.3 (M-1).

EXAMPLE 2-25 Ethyl ester of N- acid. { 3-Chloro-4- [4-hydroxy-3- (3-methyl-3-phenyl-piperidine-1-carbonyl) -phenoxy] -5-methyl-phenyl} -oxamic Calculated MS: 551.0 Found: 549.2 (M-1).

EXAMPLE 2-26 Ethyl ester of N- acid. { 4- [3- (azepane-1-carbonyl) -4-hydroxy-phenoxy] -3-chloro-5-methyl-phenyl} -oxamic Calculated MS: 475.0 Found: 473.3 (M-1).

EXAMPLE 2-27 Ethyl ester of N- acid. { 3-Chloro-4- [3- (3,3-dimethyl-piperidine-1-carbonyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -oxamic Calculated MS: 489.0 Found: 487.3 (M-1).

EXAMPLE 2-28 Ethyl ester of N- acid. { 3-chloro-4-. { 4-hydroxy-3 - [(thiophen-2-ylmethyl) -carbamoyl] -phenoxy} -5-methyl-phenyl} -oxamic Calculated MS: 489.0 Found: 487.2 (M-1).

EXAMPLE 2-29 Ethyl ester of N- acid. { 3-Chloro-4- [3- (2,3-dichloro-benzylcarbamoyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -oxamic Calculated MS: 551.8 Found: 549.1 (M-1).

EXAMPLE 2-30 Ethyl ester of N- acid. { 3-Chloro-4- (3-cyclopropylcarbamoyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -oxamic acid Calculated MS: 432.9 Found: 431.2 (M-1).

EXAMPLE 2-31 N- (3-Chloro-4-f3- (2,3-dihydro-indole-1-carbonyl) -4-hydroxy-phenoxy] -methyl-phenyl} -oxamic acid ethyl ester Calculated MS: 494.9 Found: 492.2 (M-1).

EXAMPLE 2-32 Ethyl ester of N- acid. { 3-chloro-4- [3- (3,4-dihydro-2H-quinoline-1-carbonyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -oxamic Calculated MS: 509.0 Found: 507.2 (M-1).

EXAMPLE 2-33 Ethyl ester of N- acid. { 3-chloro-4- [3- (3,4-dihydro-1H-isoquinoline-2-carbonyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -oxamic Calculated MS: 509.0 Found: 507.3 (M-1). 14 EXAMPLE 2-34 Ethyl ester of N- acid. { 3-Chloro-4- [4-hydroxy-3- (indan-1-ylcarbamoyl) -phenoxy] -5-methyl-phenyl} -oxamic Calculated MS: 509.0 Found: 507.3 (M-1).

EXAMPLE 2-35 N- acid ethyl ester. { 3-Chloro-4- [4-hydroxy-3- (indan-5-ylcarbamoyl) -phenoxy] -5-methyl-phenyl} -oxamic Calculated MS: 509.0 Found: 507.2 (M-1).

EXAMPLE 2-36 Ethyl ester of N- acid. { 4- [3- (bicyclo- [2.2.1] -hept-2-ylcarbamoyl) -4-hydroxy-phenoxy] -3-chloro-5-methyl-phenyl} -oxamic Calculated MS: 487.0 Found: 485.1 (M-1).

EXAMPLE 2-37 N- acid ethyl ester. { 3-Chloro-4- [3- (cyclohexylmethyl-carbamoyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -oxamic Calculated MS: 489.0 Found: 487.3 (M-1).

EXAMPLE 2-38 Ethyl ester of N- acid. { 3-Chloro-4-f3- (1-cyclohexyl- (1R) -ethylcarbamoyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -oxamic Calculated MS: 503.0 Found: 501.3 (M-1).

EXAMPLE 2-39 Ethyl ester of N- acid. { 3-Chloro-4- [3- (1-cyclohexyl- (1S) -ethylcarbamoyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -oxamic Calculated MS: 503.0 Found: 501.4 (M-1).

EXAMPLE 2-40 Ethyl ester of N- acid. { 3-chloro-4- [4-hydroxy-3- (p -peridine-1-carbonyl) -phenoxy] -5-methyl-phenyl} -oxamic Calculated MS: 460.9 Found: 459.3 (M-1).

EXAMPLE 2-41 Ethyl ester of N- acid. { 4- [3- (Azocan-1-carbonyl) -4-hydroxy-phenoxy] -3-chloro-5-methyl-phenyl} -oxamic Calculated MS: 489.0 Found: 487.3 (M-1).

EXAMPLE 2-42 N- [3-Chloro-4- (3-cyclohexylcarbamoyl-4-hydroxy-phenoxy] -5-methyl-phenyl] -oxamic acid ethyl ester Calculated MS: 475.0 Found: 473.3 (M-1).

EXAMPLE 2-43 N- acid ethyl ester. { 3-Chloro-4- [4-hydroxy-3-M-phenyl- (1R) -ethylcarbamoyl-phenoxy] -5-methyl-phenyl} -oxámíco Calculated MS: 497.0 Found: 495.2 (M-1).

EXAMPLE 2-44 Ethyl ester of N- acid. { 3-Chloro-4- (4-hydroxy-3-propylcarbamoyl-phenoxy) -5-methyl-phenyl} -oxamic Calculated MS: 434.9 Found: 433.2 (M-1).

EXAMPLE 2-45 N- [4- (3-Butylcarbamoyl-4-hydroxy-phenoxy) -3-chloro-5-methyl-phenyl] -oxamic acid ethyl ester Calculated MS: 448.9 Found: 447.3 (M-1).

EXAMPLE 2-46 N- [3-Chloro-4- (4-hydroxy-3-pentylcarbamoyl-phenoxy] -5-methyl-phenyl] -oxamic acid ethyl ester Calculated MS: 462.9 Found: 461.2 (M-1).

EXAMPLE 2-47 N- [3-Chloro-4- (3-hexylcarbamoyl-4-hydroxy-phenoxy] -5-methyl-phenyl] -oxamic acid ethyl ester Calculated MS: 477.0 Found: 475.2 (M-1).

EXAMPLE 2-48 Ethyl ester of N- acid. { 3-Chloro-4- [3- (1,1-dimethyl-propylcarbamoyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -oxamic Calculated MS: 462.9 Found: 461.2 (M-1).

EXAMPLE 2-49 'N- (3-Chloro-4- (3-diisopropylcarbamoyl-4-hydroxy-phenoxy) -5-methyl-phenyl) -oxamic acid ethyl ester Calculated MS: 477.0 Found: 475.3 (M-1).

EXAMPLE 2-50 Ethyl ester of N- acid. { 3-Chloro-4- [3- (2,2-dimethyl-propylcarbamoyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -oxámíco Calculated MS: 462.9 Found: 461.2 (M-1).

EXAMPLE 2-51 Ethyl ester of N- acid. { 3-Chloro-4- [3- (1,2-dimethyl-propylcarbamoyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -oxamic Calculated EM: 462.9. Found: 461.2 (M-1).

EXAMPLE 2-52 Ethyl ester of N- acid. { 3-Chloro-4- [4-hydroxy-3- (1-phenyl- (1S) -ethylcarbamoyl) -phenoxy] -5-methyl-phenyl} -oxamic Calculated MS: 497.0. Found: 495.3 (M-1) EXAMPLE 2-53 Ethyl ester of N- acid. { 3-Chloro-4- [3- (ethyl-methyl-carbamoyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -oxamic Calculated MS: 434.9. Found: 433.3 (M-1).

EXAMPLE 2-54 Ethyl ester of N- acid. { 3-Chloro-4- [4-hydroxy-3- (methyl-propyl-carbamoyl) -phenoxy] -5-methyl-phenyl} -oxamic Calculated MS: 448.9. Found: 447.2 (M-1).

EXAMPLE 2-55 Ethyl ester of N- acid. { 3-chloro-4- [3- (ethyl-isopropyl-carbamoyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -oxamic Calculated MS: 462.2. Found: 461.2 (M-1).

EXAMPLE 2-56 N- acid ethyl ester. { 3-chloro-4- [3- (cyclobutyl-methyl-carbamoyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -oxamic Calculated MS: 460.9. Found: 459.3 (M-1).

EXAMPLE 2-57 N- Acid. { 4- [3- (azepane-1-carbonyl) -4-hydroxy-phenoxy] -3-chloro-5-methyl-phenyl} - oxmic Calculated MS: 446.9. Found: 445.3 (M-1).

EXAMPLE 2-58 N- Acid. { 3-Chloro-4-f3- (1-cyclohexyl- (1S) -ethylcarbamoyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} oxmic Calculated MS: 475.0. Found: 473.2 (M-1).

EXAMPLE 2-59 N- Acid. { 3-chloro-4- [3- (cyclobutyl-methyl-carbamoyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} oxmic Calculated MS: 432.9. Found: 431.3 (M-1).

EXAMPLE 2-60 Ethyl ester of N- acid. { 4- [3- (Cyclo [2.2.1] -hept-2-ylcarbamoyl) -4-hydroxy-phenoxy] -3,5-dichloro-phenyl] -oxamic Calculated MS: 507.4. Found: 505.0 (M-1).

EXAMPLE 2-61 Ethyl ester of N- acid. { 4- [3- (bicyclo [2.2.1] -hept-2-ylcarbamoyl) -4-hydroxy-phenoxy] -3,5-dichloro-phenyl] -oxamic Calculated MS: 507.4. Found: 505.1 (M-1).

EXAMPLE 2-62 N- (3,5-Dichloro-4-. {4-hydroxy-3 - [(thiophen-2-ylmethyl) -carbamoyl] -phenoxy} -phenyl) -oxamic acid ethyl ester Calculated MS: 509.4. Found: 507.1 (M-1).

EXAMPLE 2-63 N- acid ethyl ester. { 3.5-dichloro-4- [3- (2-chloro-benzylcarbamoyl) -4-hydroxy-phenoxy] -phenyl} -oxamic Calculated MS: 537.8. Found: 535.0 (M-1).

EXAMPLE 2-64 Ethyl ester of N- acid. { 3.5-dichloro-4-r4-hydroxy-3- (3-methyl-3-phenyl-piperidine-1-carbonyl) -phenoxy] -phenyl} -oxamic Calculated MS: 571.5. Found: 569.2 (M-1).

EXAMPLE 2-65 Ethyl ester of N- acid. { 3.5-dichloro-4- [3- (3,4-dihydro-1H, isoquinoline-2-carbonyl) -4-hydroxy-phenoxy] -phenyl} -oxamic Calculated MS: 529.4. Found: 527.2 (M-1).

EXAMPLE 2-66 Ethyl ester of N- acid. { 3.5-dichloro-4- [4-hydroxy-3- (indan-1-ylcarbamoyl) -phenoxy] -phenyl} -oxamic Calculated MS: 529.4. Found: 527.2 (M-1).

EXAMPLE 2-67 N- (4. {3-R (benzof1.3) -dioxol-5-ylmethyl) -carbamoyl] -4-hydroxy-phenoxy} -3,5-dichloro-phenyl ethyl ester -oxamic Calculated MS: 547.4. Found: 545.2 (M-1).

EXAMPLE 2-68 Ethyl ester of N- acid. { 4- [3- (azepane-1-carbonyl) -4-hydroxy-phenoxy] -3,5-dichloro-phenyl} -oxamic Calculated MS: 495.4. Found: 493.3 (M-1).

EXAMPLE 2-69 N- acid ethyl ester. { 3.5-dichloro-4- [4-hydroxy-3- (4-methyl-piperidine-1-carbonyl) -phenoxy] -phenyl} -oxámíco Calculated MS: 495.4. Found: 493.2 (M-1).

EXAMPLE 2-70 Ethyl ester of N- acid. { 3.5-dichloro-4-f3-.4-fluoro-phenylcarbamoyl) -4-hydroxy-phenoxy] -phenyl} oxmic Calculated MS: 507.3. Found: 505.1 (M-1).

EXAMPLE 2-71 N- acid ethyl ester. { 3.5-dichloro-4- [3- (cyclohexylmethyl-carbamoyl) -4-hydroxy-phenoxy] -phenyl} -oxamic Calculated MS: 509.4. Found: 507.2 (M-1).

EXAMPLE 2-72 N- acid ethyl ester. { 3.5-dichloro-4- [3- (1-cyclohexyl- (1R) -ethylcarbamoyl) -4-hydroxy-phenoxy] -phenyl} -oxamic Calculated MS: 523.4. Found: 521.2 (M-1).

EXAMPLE 2-73 N- acid ethyl ester. { 3.5-dichloro-4- [3- (1-cyclohexyl-.1S) -eti Icarbamoyl) -4-hydroxy-phenoxy] -phenyl} -oxamic Calculated MS: 523.4. Found: 521.2 (M-1).

EXAMPLE 2-74 N- acid ethyl ester. { 3.5-dichloro-4- [4-hydroxy-3- (piperidinyl-1-carbonyl) -phenoxy] -phenyl} -oxamic Calculated MS: 481.3. Found: 481.2 (M-1).

EXAMPLE 2-75 N- acid ethyl ester. { 3.5-dichloro-4- [4-hydroxy-3- (3-methyl-piperidin-1-carbonyl) -phenoxy] -phenyl} -oxamic Calculated MS: 495.3. Found: 493.1 (M-1). 54 EXAMPLE 2-76 N- acid ethyl ester. { 4- [3- (b-phenyl-3-ylcarbamoyl) -4-hydroxy-phenoxy] -3,5-dichloro-phenyl} -oxamic Calculated MS: 565.4. Found: 563.2 (M-1).

EXAMPLE 2-77 N- [3,5-Dichloro-4- (3-cyclopropylcarbamoyl-4-hydroxy-phenoxy) -phenyl] -oxamic acid ethyl ester Calculated MS: 453.3. Found: 453.2 (M-1).

EXAMPLE 2-78 N- acid ethyl ester. { 3.5-dichloro-4- [3- (2,3-dichloro-benzylcarbamoyl) -4-hydroxy-phenoxy] phenyl} -oxamic Calculated MS: 572.2. Found: 571.0 (M-1).

EXAMPLE 2-79 N- [3,5-Dichloro-4- (3-cyclobutylcarbamoyl-4-hydroxy-phenoxy) -phenyl] -oxamic acid ethyl ester Calculated MS: 467.3. Found: 465.2 (M-1).

EXAMPLE 2-80 N- [3,5-Dichloro-4- (3-cyclopentylcarbamoyl-4-hydroxy-phenoxy) -phenyl] -oxamic acid ethyl ester Calculated MS: 481.3. Found: 479.2 (M-1).

EXAMPLE 2-81 N- (3,5-Dichloro-4-. {4-hydroxyl-3-f (naphthalen-1-ylmethyl) -carbamoyl] -phenoxy} -phenyl) -oxamic acid ethyl ester Calculated MS: 533.4. Found: 551.1 (M-1).

EXAMPLE 2-82 Ethyl ester of N- acid. { 3.5-dichloro-4- [3- (4-fluoro-benzylcarbamoyl) -4-hydroxy-phenoxy] -phenyl} -oxamic Calculated MS: 521.3. Found: 519.2 (M-1).

EXAMPLE 2-83 Ethyl ester of N- acid. { 4- [3- (Azocan-1-carbonyl) -4-hydroxy-phenoxy] -3,5-dichlorophenyl} -oxamic Calculated MS: 509.4. Found: 507.2 (M-1).

EXAMPLE 2-84 Ethyl ester of N- acid. { 3.5-dichloro-4- [4-hydroxy-3- (1,2,3,4-tetrahydro-naphthalen-1-ylcarbamoyl) -phenoxy] phenyl} -oxamic Calculated MS: 543.4. Found: 541.2 (M-1).

EXAMPLE 2-85 Ethyl ester of N- acid. { 3.5-dichloro-4- [4-hydroxy-3- (1-isopropyl-2-methyl-propylcarbamoyl) -phenoxy] -phenyl} -oxamic Calculated MS: 511.4. Found: 509.2 (M-1).

EXAMPLE 2-86 Ethyl ester of N- acid. { 3.5-dichloro-4- [4-hydroxy-3- (6-methoxy-3,4-dihydro-2H-quinoline-1-carbonyl) -phenoxy] -phenyl} -oxamic Calculated MS: 559.4. Found: 556.4 (M-1).

EXAMPLE 2-87 N- acid ethyl ester. { 3.5-dichloro-4- [4-hydroxy-3- (6-methyl-3,4-dihydro-2H-quinoline-1-carbonyl) -phenoxy] -phenyl} -oxamic Calculated MS: 543.4. Found: 541.1 EXAMPLE 2-88 Ethyl ester of N- acid. { 3.5-dichloro-4-hydroxy-3- (4-isopropyl-benzylcarbamoyl) -phenoxy] -phenyl} -oxamic Calculated MS: 545.4. Found: 545.0 (M-1).

EXAMPLE 2-89 N- acid ethyl ester. { 3.5-dichloro-4- [3- (4-chloro-benzylcarbamoyl) -4-hydroxy-phenoxy] -phenyl} -oxamic Calculated MS: 537.8. Found: 535.0 (M-1).

EXAMPLE 2-90 N- acid ethyl ester. { 3.5-dichloro-4- [4-hydroxy-3 - ((1R) -indan-1-ylcarbamoyl) -phenoxy] phenyl} -oxamic Calculated MS: 529.4. Found: 527.1 (M-1).

EXAMPLE 2-91 N- acid ethyl ester. { 3.5-dichloro-4- [4-hydroxy-3 - ((1S) -indan-1-ylcarbamoyl) -phenoxy] phenyl} -oxamic Calculated MS: 529.4. Found: 527.1 (M-1).

EXAMPLE 2-92 N- acid ethyl ester. { 3.5-dichloro-4- [4-hydroxy-3- (1-phenyl- (1R) -ethylcarbamoyl) -phenoxy] phenyl} -oxamic Calculated MS: 517.4. Found: 514.8 (M-1).

EXAMPLE 2-93 N- acid ethyl ester. { 3.5-dichloro-4- [4-hydroxy-3- (1-naphthalen-1-yl- (1S) -ethylcarbamoyl) -phenoxy] -phenyl} -oxamic Calculated MS: 567.4. Found: 564.8 (M-1).

EXAMPLE 2-94 N- acid ethyl ester. { 3.5-dichloro-4- [3- (3,4-difluoro-benzylcarbamoyl) -4-hydroxy-phenoxy] -phenyl} -oxamic Calculated MS: 539.3. Found: 536.7 (M-1).

EXAMPLE 2-95 Ethyl ester of N- acid. { 3.5-dichloro-4- [3- (3-chloro-4-fluoro-benzylcarbamoyl) -4-hydroxy-phenoxy] -phenyl} -oxamic Calculated MS: 555.8. Found: 555.1 (M-1).

EXAMPLE 2-96 Ethyl ester of N- acid. { 3.5-dichloro-4- [3- (2-chloro-4-fluoro-benzylcarbamoyl) -4-hydroxy-phenoxy] -phenyl} -oxamic Calculated MS: 555.8. Found: 553.0 (M-1).

EXAMPLE 2-97 N- acid ethyl ester. { 3.5-dichloro-4- [4-hydroxy-3- (1-naphthalen-2-yl- (1 R) -ethylcarbamoyl) -phenoxy] -phenyl} -oxamic Calculated MS: 564.4. Found: 565.1 (M-1).

EXAMPLE 2-98 Ethyl ester of N- acid. { 3.5-dichloro-4- [3- (2,4-dichloro-benzylcarbamoyl) -4-hydroxy-phenoxy] phenyl} -oxamic Calculated MS: 572.2. Found: 572.9 (M + 1).

EXAMPLE 2-99 N- acid ethyl ester. { 3.5-dichloro-4- [3- (3,4-dichloro-benzylcarbamoyl) -4-hydroxy-phenoxy] phenyl} -oxamic Calculated MS: 572.2. Found: 571.1 (M-1).

EXAMPLE 2-100 N- acid ethyl ester. { 3.5-dichloro-4- [3- (4-chloro-3-trifluoromethyl-benzylcarbamoyl) -4-hydroxy-phenoxy] phenyl} -oxamic Calculated MS: 605.8. Found: 606.9 (M + 1).

EXAMPLE 2-101 N- acid ethyl ester. { 3.5-dichloro-4- [3- (4-chloro-2-fluorobenzylcarbamoyl) -4-hydroxy-phenoxy] -phenyl} -oxamic Calculated MS: 555.8. Found: 553.1 (M-1).

EXAMPLE 2-102 Ethyl ester of N- acid. { 4- [3- (4-tert-Butyl-benzylcarbamoyl) -4-hydroxy-phenoxy] -3,5-dichloro-phenyl} -oxamic Calculated MS: 559.5. Found: 557.2 (M-1).

EXAMPLE 2-103 N-f3.5-dichloro-4- (3-cyclohexylcarbamoyl-4-hydroxy-phenoxy) -phenyl] -oxamic acid ethyl ester MS Calculated: 495.4. Found: 493.2 (M-1).

EXAMPLE 2-104 '' N- [3,5-Dichloro-4- (4-hydroxy-3-isopropylcarbamoyl-, 10-phenoxy) -phenyl-oxamic acid ethyl ester Calculated MS: 455.3. Found: 453.1 (M-1).

EXAMPLE 2-105 N- acid ethyl ester. { 3.5-dichloro-4- [4-hydroxy-3- (isopropyl-methyl-carbamoyl) -phenoxy] -phenyl} oxmic Calculated MS: 469.3. 20 Found: 467.2 (M-1).

EXAMPLE 2-106 Ethyl ester of N- acid. { 3.5-dichloro-4-f3-cyclopropylmethylcarbamoyl) -4-hydroxy-phenoxy] phenyl} -oxamic Calculated MS: 467.3. Found: 465.2 (M-1).

EXAMPLE 2-107 N- Acid. { 3.5-dichloro-4- [3- (4-fluoro-benzylcarbamoyl) -4-hydroxy-phenoxy] phenyl} -oxamic Calculated MS: 493.3. Found: 491.1 (M-1).

EXAMPLE 2-108 N- [3,5-Dichloro-4- (3-dimethylcarbamoyl-4-hydroxy-phenoxy) -phenyl] -oxamic acid Calculated MS: 413.2. Found: 413.2 (M-1).

EXAMPLE 2-109 N- [3,5-dichloro-4- [4-hydroxy-3- (1-isopropyl-2-methyl-propylaminocarbonyl) -phenoxy] -phenyl acid} -oxamic Calculated MS: 483.4. Found: 481.2 (M-1).

EXAMPLE 3 Ethyl ester of N- acid. { 3.5-dichloro-4- [4-hydroxy-3- (indan-1-ylaminomethyl) -phenoxy] -phenyl} -oxamic Step AA a solution of 2 ', 6'-dichloro-4-methoxy-4'-nitrophenyl ether (10 g, 31.8 mmol) in chloroform (200 ml) at 0 ° C was added dropwise boron tribromide (1 N in CH2Cl2, 63.7 ml, 63.7 mmol). After stirring at RT for 3 h, the reaction was quenched with H20 (200 mL). The mixture was stirred at RT for 1 h and the phases were separated. The aqueous phase was extracted with chloroform (2 x 150 ml). The combined organic phases were washed with H2O (1 x 200 ml). Saturated aqueous NaHC03 (1 x 200 ml), brine (1 x 200 ml), dried over Na2SO4, filtered and concentrated to yield a brown solid. The crude product was used in the next step without further purification. NMR (400 MHz, CD3OD) d 8.28 (s, 2H), 6.67-6.70 (m, 2H), 6.61-6.64 (m, 2H).

Calculated MS: 299.0 Found: 298.2 (M-1).

Step B: To a solution of 2 ', 6'-dichloro-4-hydroxy-4'-n-diphenyl ether (9.5 g, 32 mmoles) in a mixture of EtOAc (50 ml) and MeOH (150 ml) were added 0.48 g of 10% Pd / C. The mixture was hydrogenated at 275.79 kPa of pressure at RT for 5 h. The solution was filtered through Celite® and concentrated to give a brown solid. NMR (400 MHz, CD3OD) d 6.71 (s, 2H), 6.66-6.68 (m, 2H), 6.59-6.61 (m, 2H). Calculated MS: 269.0 Found: 268.2 (M-1).

Step C A mixture of 2 ', 6-dichloro-4-hydroxy-4'-aminodiphenyl ether (8.6 g, 31.8 mmol) and diethyl oxalate (69.8 g, 47.8 mmol) was stirred at 140 ° C for 2 h giving a brown solution. The excess diethyl oxalate was removed under reduced pressure and the resulting brown oily solid was triturated with a mixture of CH2Cl2 / hexane (1/9, 200 ml) for 1 hour. The solid was collected by filtration, washed with CH2Cl2 / hexane and dried in vacuo to give a tan solid. The product was used in the next step without further purification.

NMR (400 MHz, CDCl 3) d 7.68 (s, 2H), 6.59-6.61 (m, 2H), 6.53-6.55 (m, 2H), 4.25-4.30 (q, 2H), 1.27-1.31 (t, 3H) . Calculated EM: 369.0. Found: 367.5 (M-1).

Step D A mixture of N- [3-ethyl] ethyl ester, 5-dichloro-4- (4-hydroxy-phenoxy) -phenyl] -oxamic acid (500 mg, 1.35 mmol), TFA (5.0 mL) and hexamethylenetetramine (284 mg, 2.03 mmol) was stirred at 75 ° C for 1 h. hour giving a brownish-red solution. The solution was cooled to RT. The TFA was removed under reduced pressure and 20 ml of H2O was added to the residual brown oil. After stirring for 20 minutes at RT, the mixture was extracted with EtOAc (2 x 20 ml). The aqueous phase was basified with saturated aqueous NaHC 3 3 and extracted with more EtOAc (2 x 20 ml). The combined EtOAc extracts were washed with saturated aqueous NaHCO3 (2 x 30 ml), H20 (50 ml), 1 N HCl (2 x 50 ml) and brine (50 ml), dried over Na2SO4, filtered and concentrated giving a solid brown. The crude product was purified by flash chromatography to yield a white solid. NMR (400 MHz, CDCl 3) d 10.72 (s, 1H), 9.77 (s, 1 H), 8.90 (s, 1H), 7.71 (s, 2H), 7.14-7.17 (dd, 1H), 6.96-6.98 ( d, 1H), 6.89-6.60 (d, 1H), 4.42-4.47 (q, 2H), 1.23-1.27 (t, 3H). Calculated MS: 397.0. Found: 395.7 (M-1) Step EA a mixture of N- [3,5-dichloro-4- (3-formyl-4-hydroxy-phenoxy) -phenyl] -oxamic acid ethyl ester (30 mg, 0.08 mmol ) and aminoindane (10 mg, 0.08 mmol) in dichloroethane (1.0 ml), sodium triacetoxyborohydride (22.4 mg, 0.11 mmol) and acetic acid (4.5 mg, 0.08 mmol) were added in single portions. After stirring at RT for 3 hours, the solution became clear and yellow. The solution was quenched with saturated aqueous NaHCOs (5 mL) and extracted with Et20 (3 x 10 mL). The combined extracts were dried over Na 2 SO 4, filtered and concentrated to give the crude product as a yellow glass. The crude product was purified by preparative TLC (5% Et20 in CH2Cl2) to afford the title compound as an off-white solid. NMR (400 MHz, CDCl 3) d 8.94 (s, 1H), 7.74 (s, 2H), 7.36-7.37 (d, 1H), 7.19-7.25 (m, 4H), 6.75-6.77 (d, 1 H), 6.61-6.64 (dd, 1 H), 6.54-6.55 (d, 1H), 4.40-4.46 (q, 2H), 4.30-4.33 (t, 1 H), 4.05-4.08 (d, 1H), 3.95-3.98 (d, 1H), 2. 98-3.06 (m, 1H), 2.81-2.88 (m, 1H), 2.42-2.51 (m, 1H), 1.88-1.96 (m, 1H), 1. 41-1.45 (t, 3H). Calculated MS: 514.20. Found 513.1 (M-1). Using the appropriate starting materials, examples 3-1 a 3-54 were prepared in a manner analogous to that described in example 3.

EXAMPLE 3-1 Ethyl ester of N- acid. { 4- [3- (2,3-dihydro-indol-1-ylmethyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -oxamic Calculated MS: 460.5. Found: 459.3 (M-1).

EXAMPLE 3-2 Ethyl ester of N- acid. { 4- [3- (3,3-dimethyl-piperidin-1-ylmethyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -oxamic Calculated MS: 454.6. Found: 453.3 (M-1).

EXAMPLE 3-3 Ethyl ester of N- acid. { 4- [4-hydroxy-3- (3-methyl-3-phenyl-piperidin-1-ylmethyl) -phenoxy] -3,5-dimethyl-phenyl} -oxamic Calculated MS: 516.6 Found: 515.3 (M-1).

EXAMPLE 3-4 Ethyl ester of N- acid. { 4- [3- (3,4-dihydro-1H-isoquinolin-2-ylmethyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenol} -oxamic Calculated MS: 474.6. Found: 473.3 (M-1).

EXAMPLE 3-5 N- (4- {3 - [(4-Fluoro-benzylamino) -methyl] -4-hydroxy-phenoxy} -3,5-dimethyl-phenyl) -oxamic acid ethyl ester Calculated MS: 466.5 Found: 465.2 (M-1).

EXAMPLE 3-6 N- (4. {3 - [(4-Chloro-benzylamino) -methyl] -4-hydroxy-phenoxy] -3,5-dimethy-phenyl) -oxamic acid ethyl ester Calculated MS: 483.0. Found: 481.3 (M-1).

EXAMPLE 3-7 N- (4. {4-Hydroxy-3 - [(4-isopropyl-benzylamino) -methyl-phenoxy} -3,5-dimethyl-phenylamino) -acetic acid ethyl ester Calculated MS: 490.6. Found: 489.2 (M-1).

EXAMPLE 3-8 Ethyl ester of N-f4- (3-azepan-1-ylmethyl-4-hydroxy-phenoxy) -3,5-dimethyl-phene ..}. -oxamic Calculated MS: 440.5. Found: 439.3 (M-1).

EXAMPLE 3-9 N-4- (3. {F (benzof1.3) dioxol-5-ylmethyl) -amino] -methyl] - 4-hydroxy-phenoxy) -3,5-dimethyl-ethyl acid ethyl ester phenyl] -oxamic Calculated MS: 492.5. Found: 491.3 (M-1).

EXAMPLE 3-10 N- (4-. {4-Hydroxy-3 - [(1.2.3.4-tetrahydro-naphthalen-1-ylamino) -methyl] -phenoxy} -3.5-dimethyl-phenyl ethyl ester .}. -oxamic Calculated MS: 488.6. Found: 487.4 (M-1).

EXAMPLE 3-11 N- [4- (3-Dimethylaminomethyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid ethyl ester Calculated MS: 386.5. Found: 385.3 (M-1).

EXAMPLE 3-12 N- (4-. {4-Hydroxy-3 - [(methyl-propyl-amino) methyl] -phenoxy] -3,5-dimethyl-phenyl] -oxamic acid ethyl ester Calculated MS: 414.9. Found: 413.4 (M-1).

EXAMPLE 3-13 N- [4- (3-Cyclopropylaminomethyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid ethyl ester Calculated MS: 398.5. Found: 397.4 (M-1).

EXAMPLE 3-14 N- [4- (4-Hydroxy-3-morpholin-4-ylmethyl-phenoxy) -3,5-dimethyl-phenyl-oxamic acid ethyl ester Calculated MS: 428.5. Found: 427.3 (M-1).

EXAMPLE 3-15 N- (4- {4-hydroxy-3 - [(isopropyl-methyl-amino) -methyl] -phenoxy} -3,5-dimethyl-phenyl) -oxamic acid ethyl ester Calculated MS: 414.5. Found: 413.5 (M-1).

EXAMPLE 3-16 Ethyl ester of N- acid. { 4- [4-hydroxy-3- (isopropylamino-methyl) -phenoxy] -3,5-dimethyl-phene ..}. -oxamic Calculated MS: 400.5. Found: 399.4 (M-1).

EXAMPLE 3-17 N- [4- (3-Cyclobutylaminomethyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl-oxamic acid ethyl ester Calculated MS: 412.5. Found: 411.4 (M-1).

EXAMPLE 3-18 N- [4- (3-Cyclopentylaminomethyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid ethyl ester Calculated MS: 426.5. Found: 425.4 (M-1).

EXAMPLE 3-19 Methyl ester of N- acid. { 3-Chloro-4- [3- (3,3-dimethyl-piperidin-1-ylmethyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -oxamic Calculated EM: 461.0. Found: 461.1 (M + 1).

EXAMPLE 3-20 N-methyl acid ester. { 3-Chloro-4- [3- (2,3-dihydro-indol-1-ylmethyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -oxamic Calculated EM: 467.0. Found: 467.2 (M + 1).

EXAMPLE 3-21 N- (3-chloro-4-. {3 - [(4-fluoro-benzylamino) methyl] -4-hydroxy-phenoxy] -5-methyl-phenyl ethyl ester ) -oxamic Calculated MS: 486.9. Found: 485.2 (M-1).

EXAMPLE 3-22 Ethyl ester of N- acid. { 3-Chloro-4- [4-hydroxy-3- (3-methyl-3-phenyl-piperidin-1-ylmethyl) -phenoxy] -5-methyl-phenyl} -oxamic Calculated MS: 537.1. Found: 535.2 (M-1).

EXAMPLE 3-23 Ethyl ester of N- (3-chloro-4-. {3- [4-chloro-benzylamino) -methyl] -4-hydroxy-phenoxy acid} -5-methyl-phenyl} -oxamic Calculated MS: 503.4. Found: 501.1 (M-1).

EXAMPLE 3-24 N- (3-chloro-4-. {4-hydroxy-3 - ([(4-isopropyl-benzylamino) -methyl] -phenoxy] -5-methyl-phenyl) -oxamic acid ethyl ester Calculated MS: 511.2. Found: 509.2 (M-1).

EXAMPLE 3-25 Ethyl ester of N- acid. { 3-chloro-4- [34-dihydro-1H-isoquinolin-2-ylmethyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -oxamic Calculated MS: 495.0. Found: 493.2 (M-1).

EXAMPLE 3-26 N- [4- (3-Azepan-1-ylmethyl-4-hydroxy-phenoxy) -3-chloro-5-methyl-phenyl] -oxamic acid ethyl ester Calculated EM: 461.0. Found: 459.2 (M-1).

EXAMPLE 3-27 Ethyl ester of N-f4- (3- {f (benzo [1.3] dioxol-5-ylmethyl) amino] -methyl} - 4-hydroxy-phenoxy) -3-chloro-5- methyl-phenyl] -oxamic Calculated MS: 513.0. Found: 511.2 (M-1).

EXAMPLE 3-28 Ethyl ester of N- (3-chloro-4-. {4-hydroxy-3 - [(1.2.3.4-tetrahydro-naphthalen-1-ylamino) -methyl] -phenoxy} -5 -methyl-phenyl) -oxamic Calculated MS: 509.0. Found: 507.3 (M-1).

EXAMPLE 3-29 N- [3-Chloro-4- (3-dimethylaminomethyl-4-hydroxy-phenoxy] -5-methyl-phenyl) -oxamic acid ethyl ester Calculated MS: 406.9. Found: 405.3 (M-1).

EXAMPLE 3-30 N- (3-Chloro-4- (4-hydroxy-3 - [(methyl-propyl-amino) -methyl] -phenoxy} -5-methyl-phenyl) -oxamic acid ethyl ester Calculated MS: 434.9. Found: 433.3 (M-1).

EXAMPLE 3-31 N- [3-Chloro-4- (3-cyclopropylaminomethyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -oxamic acid ethyl ester Calculated MS: 418.9. Found: 417.3 (M-1).

EXAMPLE 3-32 Methyl ester of N- acid. { 3.5-dichloro-4- [3- (2,3-dihydro-indol-1-ylmethyl-4-hydroxy-phenoxy] -phenyl} -oxamic acid Calculated MS: 487.3. Found: 487.2 (M + 1).

EXAMPLE 3-33 Methyl ester of N. acid. 3.5-dichloro-4- [3- (3,3-dimethyl-piperidin-1-ylmethyl) -4-hydroxy-phenoxy] -phenyl} -oxamic Calculated MS: 481.4. Found: 481.2 (M + 1) EXAMPLE 3-34 Methyl ester of N- acid. { 3,5-dichloro-4- [4-hydroxy-3- (indan-1-laminomethyl) -phenoxy] -phenyl} -oxamic Calculated MS: 501.4. Found: 499.1 (M-1).

EXAMPLE 3-35 Methyl ester of N. acid. 3.5-dichloro-4- [3- (3,4-dihydro-1H-isoquinolin-2-ylmethyl) -4-hydroxy-phenoxy] -phenyl} -oxamic Calculated MS: 501.4. Found: 501.1 (M + 1).

EXAMPLE 3-36 N- [4- (3-azepan-1-ylmethyl-4-hydroxy-phenoxy) -3,5-dichloro-phenyl] -oxamic acid methyl ester Calculated MS: 467.4. Found: 465.1 (M-1).

EXAMPLE 3-37 N- (3,5-Dichloro-4-. {3-f (1-cyclohexyl- (1ff) -ethylamino) -methyl] -4-hydroxy-phenoxy} -phenyl acid ethyl ester - oxmic Calculated MS: 509.4. Found: 507.2 (M-1).

EXAMPLE 3-38 Ethyl ester of N- acid. { 4- [3- (bicyclof2.2.1.] Hept-2-ylaminomethyl) -4- hydroxy-phenoxy] -3,5-dichloro-phenyl} -oxamic Calculated MS: 493.4. Found: 491.2 (M-1).

EXAMPLE 3-39 Ethyl ester of N- acid. { 3.5-dichloro-4- [4-hydroxy-3- (3-methyl-3-phenyl-piperidin-1-ylmethyl) -phenoxy] -phenyl} -oxamic Calculated MS: 557.5. Found: 555.1 (M-1).

EXAMPLE 3-40 'N- (3,5-Dichloro-4-. {3 - [(4-fluoro-benzylamino) -methyl] -4-hydroxy-phenoxy] -phenyl) -oxamic acid ethyl ester Calculated MS: 507.35. Found: 505.0 (M-1).

EXAMPLE 3-41 N- (3,5-Dichloro-4-. {4-hydroxy-3 - [(1-phenyl- (1-phenyl) -ethylamino) -methyl] -phenoxy} -phenyl acid) ethyl ester - oxmic Calculated MS: 503.4. Found: 501.0 (M-1).

EXAMPLE 3-42 N- (3,5-Dichloro-4-. {4-hydroxy-3 - [(1-phenyl- (1S) -ethylamino) -methyl] -phenoxy} -phenyl acid) ethyl ester - oxmic Calculated MS: 503.4. Found: 501.0 (M-1).

EXAMPLE 3-43 N-f3.5-dichloro-4- (4-hydroxy-3. {[[(Naphthalen-1-ylmethyl) -amino] -methyl] -phenoxy) -phenyl acid ethyl ester] -oxamic Calculated MS: 539.4. Found: 536.7 (M-1).

EXAMPLE 3-44 Ethyl ester of N-f3.5-dichloro-4- acid. { 4-hydroxy-3 - [(1-naphthalen-1-yl- (1jR) -ethylamino) -methyl] -phenoxy} phenyl) -oxamic Calculated MS: 553.5. Found: 550.8 (M-1).

EXAMPLE 3-45 N- (3,5-Dichloro-4-. {4-hydroxy-3 - [(1.2.3.4-tetrahydro-naphthalen-1-ylamino) -methyl] -phenoxy} -phenyl acid ethyl ester ) -oxamic Calculated MS: 529.4. Found: 526.8 (M-1).

EXAMPLE 3-46 N- [3,5-Dichloro-4- (3-cyclohexyllaminomethyl-4-hydroxy-phenoxy) -phenyl] -oxamic acid ethyl ester Calculated MS: 481.4. Found: 478.8 (M-1).

EXAMPLE 3-47 N- [3,5-Dichloro-4- (3-cyclopentylaminomethyl-4-hydroxy-phenoxy) -phenyl] -oxamic acid ethyl ester Calculated MS: 467.4. Found: 465.1 (M-1).

EXAMPLE 3-48 N- [4- (3. {[[Benzo [1.3] dioxol-5-ylmethyl) -amino] -methyl acid ethyl ester} - 4-hydroxy-phenoxy) -3,5-dichloro-phenyl] -oxamic Calculated MS: 533.4. Found: 531.0 (M-1).

EXAMPLE 3-49 N- (3,5-Dichloro-4-. {3-f (4-chloro-benzylamino) -methyl] -4-hydroxy-phenoxy} -phenyl) - ethyl ester - oxmic Calculated MS: 523.8. Found: 521.1 (M-1).

EXAMPLE 3-50 N- (3,5-Dichloro-. {4-hydroxy-3 - [(4-isopropyl-benzylamino) -methyl] -phenoxy} -phenyl) -oxamic acid ethyl ester Calculated MS: 531.4. Found: 529.2 (M-1).

EXAMPLE 3-51 N- [3,5-Dichloro-4- (4-hydroxy-3-methylaminomethyl-phenoxy) -phenyl] -oxamic acid ethyl ester Calculated MS: 413.3. Found: 411.2 (M-1).

EXAMPLE 3-52 N- [3,5-Dichloro-4- (3-cyclopropylaminomethyl-4-hydroxy-phenoxy-phenyl] -oxamic acid ethyl ester Calculated MS: 439.3. Found: 437.3 (M-1).

EXAMPLE 3-53 N- [3,5-Dichloro-4- (4-hydroxy-3-morpholin-4-ylmethyl-phenoxy) -phenyl] -oxamic acid ethyl ester Calculated MS: 469.3. Found: 467.3 (M-1).

EXAMPLE 3-54 N- [3,5-Dichloro-4- (3-cyclobutylaminomethyl-4-hydroxy-phenoxy) -phenyl] -oxamic acid ethyl ester Calculated MS: 453.3. Found: 451.3 (M-1).

EXAMPLE 4 N-. { 4- [4-hydroxy-3- (isopropylmethylcarbamoyl) -phenoxy] -3,5-dimethyl-phenol} - oxamide A solution of ethyl ester of N- acid. { 4- [4-hydroxy-3- (isopropylmethanolcarbamoyl) -phenoxy] -3,5-dimethyl-phenyl} -oxamic (7.1 mg, 0.017 mmol) in 1 ml of EtOH in the presence of magnesium sulfate (10 mg) at 0 ° C was bubbled in NH3 gas for 10 minutes. The solution was allowed to warm to RT. After stirring at RT for 0.5 h, the solution was diluted with 2 mL of CH2Cl2 and filtered. The filtrate was concentrated to give the title compound as a white solid. Calculated MS: 399.5. Found: 398.4 (M-1). Using the appropriate starting materials, Examples 4-1 to 4-10 were prepared in a manner analogous to that described in Example 4.

EXAMPLE 4-1 N-. { 4- [4-Hydroxy-3- (1-isopropyl-2-methyl-propylcarbamoyl) -phenoxy] -3,5-dimethyl-phenyl} oxamide Calculated MS: 441.5. Found: 440.5 (M-1).

EXAMPLE 4-2 N- [3,5-Dichloro-4- (3-cyclohexylcarbamoyl-4-hydroxy-phenoxy) -phenyl] -oxamide Calculated MS: 465.1. Found: 464.2 (M-1).

EXAMPLE 4-3 N-. { 3-Chloro-4- [4-hydroxy-3- (morpholine-4-sulfonyl) -phenoxy] -5-methyl-phenyl} oxamide Calculated MS: 469.1. Found: 468.2 (M-1).

EXAMPLE 4-4 N- [4- (3-Benzenesulfonyl-4-hydroxy-phenoxy) -3,5-dichloro-phenyl] -oxamide calculated EM: 480.0. Found: 479.2 (M-1).

EXAMPLE 4-5 N-. { 3-Chloro-4- [3- (cyclobutylmethylcarbamoyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} oxamide Calculated MS: 431.1. Found: 430.3 (M-1).

EXAMPLE 4-6 N-. { 3-Chloro-4- [3- (cyclopropylmethyl-amino-sulfonyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -oxamide Calculated MS: 453.1. Found: 452.3 (M-1).

EXAMPLE 4-7 N-. { 3-Chloro-4- [4-hydroxy-3- (methylpropylsulfamoyl) -phenoxy] -5-methyl-phenyl} - oxamide Calculated MS: 455.1. Found: 545.2 (M-1).

EXAMPLE 4-8 N-. { 4-f4-Hydroxy-3- (pyrrolidine-1-carbonyl) -phenoxp-3,5-dimethyl-phenyl-oxamide Calculated MS: 397.4. Found: 396.3 (M-1).

EXAMPLE 4-9 N - [- 3-Chloro-4- (3-cyclopropylsulfamoyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -oxamide Calculated MS: 439.1. Found: 438.2 (M-1).

EXAMPLE 4-10 N-. { 4- [3-Cyclobutyl-methyl-carbamoyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} - oxamide Calculated MS: 411.5. Found: 410.3 (M-1).

EXAMPLE 5 Ethyl ester of N- acid. { 3.5-dichloro-4- [3- (4-chloro-benzenesulfonyl) -4-hydroxy-phenoxy] -phenyl} -oxamic Step A A mixture of 2 ', 6'-dichloro-4-methoxy-4'-nitrophenyl ether (250 mg, 0.80 mmol), p-chlorobenzenesulfonic acid (90%, 290 mg, 1.4 mmol) and Eaton's reagent it was stirred at 80 ° C for 5 hours and cooled to RT. The reaction mixture is quenched by dropwise addition in 30 ml of ice water. A white precipitate formed. The precipitate was collected by filtration and taken up in CH 2 Cl 2, dried and concentrated. The product was purified by preparative TLC (25% EtOAc in Hex). NMR (400 MHz, CDCl 3) d 8.29-8.30 (s, 2H), 7.83-7.86 (d, 2H), 7.53-7.54 (d, 1H), 7.42-7.46 (d, 2H), 7.04-7.07 (dd, 1 H), 6.82-6.87 (d, 1 H), 3.73 (s, 3H). Calculated MS: 486.9. Found: 486.0 (M-1).

Step B The title compound of this example 5 can be prepared from the product of step A by demethylation, hydrogenation and oxamate formation according to procedures analogous to those described in the present description and known methods.

NMR (400 Mhz 'CDCIs) d 8.95 (s, 1H), 8.68 (s broad, 1H), 7.80- -82 (d, 2H), 7.76 (s, 2H), 7.49-7.51 (d, 2H), 7.06 (d, 1 H), 7.00-7.02 (dd, 1 H), .93-6.95 (d, 1 H), 4.43 (q, 2H), 1.44 (t, 3H). Calculated MS: 543.0. Found: 542.1 (M-1). Using the appropriate starting materials, Examples 5-1 to -12 were prepared in a manner analogous to that described in Example 5.

EXAMPLE 5-1 N- Acid. { 3.5-dichloro-4- [3- (4-chloro-benzenesulfonyl) -4-hydroxy-phenoxy] -phenyl} -oxamic Calculated MS: 514.9. Found: 513.0 (M-1).

EXAMPLE 5-2 N- acid. { 3-Chloro-4- [3- (4-chloro-benzenesulfonyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -oxamic Calculated MS: 495.0. Found: 494.1 (M-1).

EXAMPLE 5-3 N-. { 3-Chloro-4- [3- (4-chloro-benzenesulfonyl) -4-hydroxy-phenyl] -5-methyl-phenyl} - oxamide Calculated MS: 494.0. Found: 493.2 (M-1).

EXAMPLE 5-4 N- [4- (3-Benzenesulfonyl-4-hydroxy-phenoxy) -3,5-dichloro-phenyl] -oxamic acid ethyl ester Calculated MS: 509.0. Found: 508.2 (M-1).

EXAMPLE 5-5 N- [4- (3-Benzenesulfonyl-4-hydroxy-phenoxy) -3,5-dichloro-phenyl acid} - oxmic Calculated MS: 481.0. Found: 480.2 (M-1).

EXAMPLE 5-6 N-f4- (3-Benzenesulfonyl-4-hydroxy-phenoxy) -3,5-dichloro-phenyl] -oxamide Calculated MS: 480.0. Found: 479.2 (M-1).

EXAMPLE 5-7 Ethyl ester of N- acid. { 3.5-dichloro-4- [4-hydroxy-3- (naphthalene-1-sulfonyl) -phenoxy] -phenyl} -oxamic Calculated MS: 559.0. Found: 558.2 (M-1).

EXAMPLE 5-8 N- Acid. { 3.5-dichloro-4- [4-hydroxy-3- (naphthalene-1-sulfonyl) -phenoxy] -phenyl} - oxmic Calculated MS: 531.0. Found: 530.1 (M-1).

EXAMPLE 5-9 Ethyl ester of N- acid. { 3.5-dichloro-4- [4-hydroxy-3- (naphthalene-2-sulfonyl) -phenoxy] -phenyl} -oxamic Calculated MS: 559.0. Found: 558.2 (M-1).

EXAMPLE 5-10 N- Acid. { 3.5-dichloro-4- [4-hydroxy-3- (naphthalene-2-sulfonyl) -phenoxy] -phenyl} - oxmic Calculated MS: 559.0. Found: 558.2 (M-1).

EXAMPLE 5-11 N- acid. { 3.5-dichloro-4-f4-hydroxy-3- (toluene-4-sulfonyl) -phenoxy] -phenyl} - oxmic Calculated MS: 495.0. Found: 494.1 (M-1).

EXAMPLE 5-12 N-. { 3.5-dichloro-4- [4-hydroxy-3- (toluene-4-sulfonyl) -phenoxy] -phenyl} -oxamide Calculated MS: 494.0. Found: 493.0 (M-1).

EXAMPLE 6 N- [3,5-Dichloro-4- (3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -oxamic acid ethyl ester Step A After cooling with an ice bath, 2 ', 6'-dichloro-4-methoxy-4'-nitrophenyl ether (5 g, 16 mmol) was added portionwise to chlorosulfonic acid (14 g, 120 mmol). The resulting reddish brown solution was allowed to warm to RT and was stirred at RT for 1 hour. The reaction mixture was added dropwise in an ice bath (200 ml), extracted with EtOAc (3 x 200 ml), dried and concentrated to give a tan solid. The solid was added in portions to a solution of Na 2 SO 3 (6 g, 48 mmol) in H 2 O (12 ml). The solution was made basic by the addition of 32% aqueous NaOH and the pH was adjusted to 9.0. After stirring at 65 ° C for 2 hours and then at 25 ° C for 19 hours, the solution was acidified with 1 N HCl and a precipitate formed. The precipitate was collected by filtration, washed with water and dried to produce the product.

Calculated MS: 377.0. Found: 376.1 (M-1).

Step BA a solution of sodium ethoxide (0.29 mmol) in EtOH at RT, 2-methoxy-4- (2 ', 6'-dichloro-4'-nitro-phenoxy) -benzenesulfinic acid (100 mg, 0.26 mmol) was added , the product of stage A and cyclopropylmethyl bromide (143 mg, 1.1 mmol). The resulting mixture was stirred at reflux for 18 hours and cooled to RT. To the solution was added 1N HCl (5 ml), followed by extraction with EtOAc (3x10 ml). The combined extracts were dried and concentrated. The crude product was purified by preparative TLC (EtOAc: Hex, 1: 1) to give a solid. Calculated MS: 431.0. Found: 431.0 (M).

Step C The title compound of this example 6 can be prepared from the product of step B by demethylation, hydrogenation and oxamate formation according to procedures analogous to those described in example 1. NMR (400 MHz, CDCl 3) d 8.93 (s, 1H), 8.68 (s, 1H), 7.75 (s, 2H), 7.10-7.13 (m, 1H), 6.96-6.99 (m, 2H), 4.41 (q, 2H), 3.01 (d, 2H) ), 1.41 (t, 3H), 0.95-0.99 (m, 1H), 0.54-0.58 (m, 2H), 0.11-0.14 (m, 2H).

Calculated MS: 487.0. Found: 485.9 (M-1). Using the appropriate starting materials, examples 6-1 to -13 were prepared in a manner analogous to that described in example 6.

EXAMPLE 6-1 N-f4- [4-hydroxy-3-methanesulfonyl-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid Calculated MS: 379.1. Found: 378.2 (M-1).

EXAMPLE 6-2 N- acid. { 3.5-dichloro-4- [3-ethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -oxamic acid Calculated MS: 433.0. Found: 432.0 (M-1).

EXAMPLE 6-3 Ethyl ester of N- acid. { 3.5-dichloro-4- [4-hydroxy-3- (propane-2-sulfonyl) -phenoxy] -phenyl} -oxamic Calculated MS: 475.0. Found: 474.0 (M-1).

EXAMPLE 6-4 N-f3.5-dichloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -oxamic acid ethyl ester Calculated MS: 501.0. Found: 499.9 (M-1).

EXAMPLE 6-5 N- [3,5-Dichloro-4- (3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -oxamic acid ethyl ester Calculated MS: 529.1 Found: 528.0 (M-1).

EXAMPLE 6-6 N- [3,5-Dichloro-4- (3-cyclopentanesulfonyl-4-hydroxy-phenoxy) -phenyl] -oxamic acid ethyl ester Calculated MS: 501.0 Found: 499.9 (M-1) EXAMPLE 6-7 N- acid. { 4- [3-butane-1-sulfonyl) 4-hydroxy-phenoxy] -3,5-dichloro-phenyl} - oxmic Calculated EM: 461.0. • Found: 460.2 (M-1).

EXAMPLE 6-8 N- [3,5-Dichloro-4- (4-hydroxy-3-phenylmethanesulfonyl-phenoxy) -phenyl] -oxamic acid Calculated MS: 495.0. Found: 493.9 (M-1).

EXAMPLE 6-9 N- [3,5-Dichloro-4- (4-hydroxy-3- (propane-1-sulfonyl) -phenoxy] -phenyl} -oxamic acid Calculated MS: 447.0. Found: 446.0 (M-1).

EXAMPLE 6-10 N- acid. { 3.5-dichloro-4- [3- (4-fluoro-phenylmethanesulfonyl) -4-hydroxy-phenoxy] -phenyl] -oxamic Calculated MS: 513.0. Found: 512.0 (M-1).

EXAMPLE 6-11 N- [3,5-Dichloro-4- (3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -oxamic acid Calculated MS: 459.0. Found: 458.2 (M-1).

EXAMPLE 6-12 N- [3,5-Dichloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -oxamic acid Calculated MS: 473.0. Found: 472.2 (M-1).

EXAMPLE 6-13 N-f4- (3-Cyclopropylmethanesulfonyl-4-hydroxl-phenoxy) -3,5-d-methylphenyl-oxamic acid Calculated MS: 419.1. Found: 418.0 (M-1).

EXAMPLE 7 4- (3-phenoxy-4-methoxyphenoxy) -3,5-dimethylnitrobenzene Step AA: A cooled (0 ° C) stirred solution of 3-benzyloxy-4-methoxybenzaldehyde (10 g) in MeOH (100 ml) was added dropwise hydrogen peroxide (5.5 ml of 30% aqueous solution) . After warming to RT, concentrated sulfuric acid (1 ml) was added and the resulting solution was allowed to stir for 1.5 hours. The reaction mixture was partitioned between ethyl ether / saturated aqueous sodium bicarbonate, another organic layer was dried over sodium sulfate and concentrated in vacuo to yield an oil. Flash chromatography (20% ethyl acetate / hexanes) yielded 3-benzyloxy-4-methoxyphenol (5.8 g).

Step B To a solution of 3-benzyloxy-4-methoxyphenol (3 g) in DMSO (2 ml) was added potassium t-butoxide (1.6 g). After 30 minutes, 4-chloro-3,5-dimethyl-nitrobenzene (2 g) was added and the resulting solution was heated at 80 ° C for 2 hours. The reaction mixture was partitioned between ethyl acetate and 1 N aqueous NaOH and the organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo yielding 4- (3-benzyloxy-4-methoxyphenoxy) -3 , 5-dimethylnitrobenzene (1.9 g) as an orange solid.

Step C A solution of 4- (3-benzyloxy-4-methoxy-phenoxy) -3,5-dimethylnitrilebenzene (1.65 g), TFA (3.5 ml) and thioanisole (2.2 ml) were stirred for 4 hours. The reaction was partitioned between ethyl acetate and water, the organic layer was dried over sodium sulfate and concentrated in vacuo. Flash chromatography afforded 4- (3-hydroxy-4-methoxyphenoxy) -3,5-dimethyl-nitrobenzene (1.2 g) as a yellow oil.

Step D A solution of 4- (3-hydroxy-4-methoxyphenoxy) -3,5-dimethynitrobenzene (150 mg), phenylboronic acid (190 mg), copper acetate (II) (189 mg) and TEA (0.22 m) in dichloromethane (4 ml) was stirred for 6 hours.

The reaction was diluted in ethyl acetate, washed with 1 N hydrochloric acid, dried sodium sulfate, and concentrated in vacuo. The resulting oil was subjected to flash chromatography (10% DEE / petroleum ether) yielding 4- (3-phenoxy-4-methoxyphenoxy) -3,5-dimethyl-nitrobenzene (130 mg) as a colorless solid. Using the appropriate starting materials, examples 7-1 to 7-9 were prepared in a manner analogous to that described in example 7.

EXAMPLE 7-1 N- [3,5-Dichloro-4- (4-hydroxy-3-phenoxy-phenoxy) -phenyl-oxamic acid ethyl ester Found: 460 EXAMPLE 7-2 Ethyl ester of N- acid. { 3.5-dichloro-4- (3- (4-chloro-phenoxy) -4-hydroxy-phenoxy] -phenyl} -oxamic acid Found: 495 EXAMPLE 7-3 N- Acid. { 3.5-dichloro-4- [3- (4-chloro-phenoxy) -4-hydroxy-phenoxy] -phenyl} -oxamic Found: 467 EXAMPLE 7-4 N- Acid. { 3.5-dichloro-4- (4-hydroxy-3-phenoxy-phenoxy) -phenyl] -oxamic acid Found: 432 EXAMPLE 7-5 Ethyl ester of N- acid. { 3.5-dichloro-4- (3- (4-fluoro-phenoxy) -4-hydroxy-phenoxy] -phenyl} -oxamic acid Found: 478 EXAMPLE 7-6 Ethyl ester of N- acid. { 3.5-dichloro-4- (3- (4-fluoro-phenoxy) -4-hydroxy-phenoxy] -phenyl} -oxamic acid Found: 450 EXAMPLE 7-7 N- Acid. { 4- (3- (4-fluoro-phenoxy) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -oxamic Found: 410 EXAMPLE 7-8 N- [4- (4-Hydroxy-3-phenoxy-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid Found: 392 EXAMPLE 7-9 Acid N-. { 4- [3- (4-chloro-phenoxy) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -oxámíco Found: 426 EXAMPLE 8 2.2-Dimethyl-7-hydroxy-4-methoxyindane Step A To a cooled (0 ° C) stirred solution of 4,7-dimethoxyindan-1-one (1 g) in THF (20 ml) was added lithium hexamethyldisilazane (6.2 ml of a 1 M solution in THF). After 45 minutes, methyl iodide (0.4 ml) was added and the resulting mixture was allowed to stir at RT for 3 hours.

Step B After stirring at RT and after addition of the first equivalent of methyl iodide, the reaction mixture was again cooled to 0 ° C and an additional portion of lithium hexamethyldisilizone (6.2 ml) was added.

After 45 minutes, methyl iodide (0.4 ml) was added and the resulting mixture was allowed to stir at RT for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, the organic layer was dried over sodium sulfate and concentrated until a dark oil was obtained. Flash chromatography (hexanes: chloroform) yielded 2,2-dimethyl-4,7-dimethoxydandan-1-one (1.0 g) as a brown oil.

Step CA: a cooled (-78 ° C) stirred solution of 2,2-dimethyl-4,7-dimethoxy-indan-1-one (1 g) in dichloromethane (20 ml) was added boron trichloride (9 ml. a 1 M solution in dichloromethane) for a period of 5 minutes. The reaction was allowed to warm to RT, stirred for 3 hours and then cooled again to -78 ° C, quenched with ice, allowed to warm to RT and stirred for 1 hour. The reaction was extracted with dichloromethane, the organic layers were dried over sodium sulfate, concentrated in vacuo and subjected to flash chromatography yielding 2,2-dimethyl-7-hydroxy-4-methoxyindan-1-one (0.85 g). in the form of a chestnut oil.

Step D To a stirred solution of 2,2-dimethyl-7-hydroxy-4-methoxyindan-1-one (500 mg) and methanesulfonic acid (466 mg) in dichloromethane (12 ml) was added triethylsilane (564 mg). Every 0.5 hours during a 3-hour period, additional portions of methanesulfonic acid and triethylsilane were added. The reaction was partitioned between water and dichloromethane, the organic layer was dried over sodium sulfate, concentrated in vacuo and the resulting oil subjected to flash chromatography (1: 1 mixture of chloroform: hexanes) yielding 2,2-dimethyl-7-. hydroxy-4-methoxyindan (230 mg) as a colorless waxy solid. Using the appropriate starting materials, examples 8-1 to 8-8 were prepared using procedures analogous to those described in example 8 and by schemes K and L.

EXAMPLE 8-1 N-R 3 -chloro-4- (7-hydroxy-2,2-dimethyl-indan-4-yloxy) -5-methyl-phenyl-oxamic acid Melting point found: 226-229 ° C (dec.).

EXAMPLE 8-2 N-r4-, 7-hydroxy-indan-4-yloxy) -3,5-dimethyl-phenyl-oxamic acid MS found: 340.

EXAMPLE 8-3 N-R3-Chloro-4- (7-hydroxy-indan-4-yloxy) -5-methyl-phenyl-oxamic acid EM found: 360.

EXAMPLE 8-4 N-.4- (7-Hydroxy-indan-4-yloxy) -3,5-dimethyl-phenyryoxamic acid ethyl ester EM found: 368.

EXAMPLE 8-5 N-.4-.7-hydroxy-indan-4-yloxy!) -3,5-dimethyl-phenH-oxamide EM found: 339.

EXAMPLE 8-6 N-.3-Chloro-4-.7-hydroxy-indan-4-yloxy) -5-methyl-phen.p-oxamide EM found: 360.

EXAMPLE 8-7 N-R3-Chloro-4- (4-hydroxy-5.6.7.8-tetrahydro-naphthalen-1-yloxy) -5-methyl-phenyl-oxamic acid MS found: 374.

EXAMPLE 8-8 N-R3-Chloro-4- (4-hydroxy-5.6.7.8-tetrahydro-naphthalen-1-yloxy) -5-methyl-phenin-oxamide EM found: 373.

EXAMPLE 9 Ethyl ester of N- acid. { 3-Chloro-4- [3- (4-fluoro-phenoxymethyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -oxamic Step AA a cooled (-78 ° C) and stirred solution of 5- (2-chloro-6-methyl-4-nitro-phenoxy) -2-methoxy-benzaldehyde (10 g) in dichloromethane (300 ml) was added dropwise. drop boron tribromide (23.3 g). The reaction was allowed to warm to room temperature, stirred for 1.5 hours, ice was added to activate the reaction and was treated with ethyl acetate / water. The organic layer was dried over sodium sulfate, concentrated in vacuo and the resulting oil was filtered through a short pad of silica gel (eluting with chloroform), yielding 5- (2-chloro-6-methyl-4-nitro) -phenoxy) -2-hydroxy-benzaldehyde (8.65 g) as an off-white solid.

Step BA a cooled (0 ° C) stirred solution of 5- (2-chloro-6-methyl-4-nitro-phenoxy) -2-hydroxy-benzaldehyde (8.6 g) in DMF (130 ml), hydride was added Sodium (1.3 g of 60% sodium hydride in oil), the cooling bath was removed after 5 minutes and the thickened mixture was allowed to stir at RT for 45 minutes. Trimethylsiloxyethoxymethyl chloride (5.59 g) was added and stirring was continued for 16 hours. The reaction was quenched with saturated ammonium chloride in half, extracted with ethyl acetate, the combined organic layers were dried over sodium sulfate and concentrated in vacuo to yield a brown oil. Flash chromatography (10-20% ethyl acetate: hexanes) yielded 5- (2-chloro-6-methyl-4-nitro-phenoxy) -2- (2-trimethylsilanyl-ethoxymethoxy) -benzaldehyde (12.1 g) in form of a whitish solid.

Step CA a cooled (-78 ° C) and stirred solution of 5- (chloro-6-methyl-4-nitro-phenoxy) -2- (2-trimethylsilyl-ethoxymethoxy) -benzaldehyde (10 g ) in THF (200 ml) was added diisobutylaluminum hydride (46 ml of a 1 M solution in THF). After 30 minutes, 0.5 M potassium sodium tartrate (100 ml) was added and the resulting mixture was allowed to warm to RT. Extraction with ethyl acetate, drying over sodium sulfate and concentration in vacuo gave [5- (2-chloro-6-methyl-4-nitro-phenoxy) -2- (2-trimethylsilyl-ethoxymethoxy) -phenyl) ] -MeOH (10.6 g), which was used in step D without further purification.

Step: Give a solution of [5- (2-chloro-6-methyl-4-nitro-phenoxy) -2- (2-trimethylsilanyl-ethoxymethoxy) -phenyl] -MeOH (250 mg), triphenylphosphine (300 mg) and p-fluorophenol (95 mg) was added 1.1 '- (azodicarbonyl) dipiperidine (214 mg). After 18 hours, hexanes were added, the solids were filtered, washed with more portions of hexanes and the filtrate was concentrated in vacuo. The residue was subjected to flash chromatography (hexanes-2% ethyl acetate / hexanes) yielding. { 2- [4- (2-chloro-6-methyl-4-nitro-phenoxy) -2- (4-fluoro-phenoxymethyl) -phenoxymethoxy] -ethyl} -trimethylsilane (300 mg) in the form of an oil.

Stage E To a stirred solution of. { 2- [4- (2-Chloro-6-methyl-4-nitro-phenoxy) -2- (4-fluoro-phenoxymethyl) -phenoxymethoxy] -ethyl} -trimethylsilane (280 mg) in MeOH (2.5 ml) / THF (0.2 ml) was added 6% sulfuric acid in MeOH (2.5 ml) and the resulting solution was stirred for 1 hour. The reaction was quenched with 1 N aqueous sodium bicarbonate, extracted with ethyl acetate, the organic layer was dried over sodium sulfate and concentrated in vacuo. Flash chromatography (15% ethyl acetate hexanes) yielded 4- (2-chloro-6-methyl-4-nitro-phenoxy) -2- (4-fluorophen-oxymethyl) -phenol (170 mg) in the form of a yellow semi-solid.

Step FA a hot solution (at 100 ° C) of 4- (2-chloro-6-methyl-4-nitro-phenoxy) -2- (4-fluorophenoxymethyl) -phenol (100 mg) in glacial acetic acid (2.5 ml) Zinc powder (243 mg) was added and heating was continued for 30 minutes. The reaction mixture was cooled, diluted with ethyl acetate and filtered through Celite®. The filtrate was washed with 1 M aqueous sodium bicarbonate, dried over sodium sulfate, concentrated in vacuo and subjected to flash chromatography (30% ethyl acetate / hexanes) to yield 4- (4-amino-2-chloro-6). -methyl-phenoxy) -2- (4-fluoro-phenoxymethyl) -phenol (90 mg) as a tan solid.

Step G A solution of 4- (4-amino-2-chloro-6-methyl-phenoxy) -2- (4-fluoro-phenoxy-methyl) -phenol (90 mg) in diethyl oxylate (1 ml) was added. heated at 125 ° C for 18 hours. The resulting solution was subjected to flash chromatography (30% ethyl acetate / hexanes) producing N- acid ethyl ester. { 3-Chloro-4- [3- (4-fluoro-phenoxymethyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -oxamic (70 mg). Using the appropriate starting materials, Example 9-1 was prepared in a manner analogous to that described in Example 9.

EXAMPLE 9-1 N- [3-Chloro-4- (4-hydroxy-3-phenoxymethyl-phenoxy) -5-methyl-phenyl] -oxamic acid ethyl ester MS found: 454.

EXAMPLE 10 N- [3,5-dichloro-4- (1H-indol-5-yloxy) -phenyl] -oxamic acid ethyl ester Step A Potassium carbonate (0.71 g, 5.12 mmol) was added to a solution of 5-hydroxyindole (0.62 g, 4.66 mmol) and 3,5-dichloro-4-iodoitrobenzene (1.48 g, 4.66 mmol) in N-methylpyrrolidone 810 mL ). The resulting mixture was stirred at 125 ° C for 3 hours and cooled to RT. The mixture was poured into 1 N HCl (100 mL) and extracted with CH2Cl2 (3 x 25 mL). The combined organic extracts were washed with 1 N HCl (2 x 50 ml), H20 (3 x 100 ml) and brine (1 x 100 ml) and then dried and concentrated. The residue was purified by preparative TLC (35% CH2Cl2 in hexanes) to give a yellow solid. Calculated MS: 322. Found: 321.2 (M-1).

Step B The title compound of example 10 was prepared from the product of step A by means of hydrogenation and oxamate formation. Calculated MS: 392.0. Found: 391.2 (M-1). Using the appropriate starting materials, Examples 10-1 to 10-7 were prepared in a manner analogous to that described in Example 10.

EXAMPLE 10-1 N- [3,5-Dichloro-4- (1H-indol-5-yloxy) -phenyl] -oxamic acid ethyl ester Calculated MS: 392.0. Found: 391.2 (M-1).

EXAMPLE 10-2 N- [3,5-Dichloro-4- (1 H -indol-5-yloxy) -phenyl] -oxamic acid Calculated EM: 364.0. Found: 363.1 (M-1).

EXAMPLE 10-3 N- [3,5-Dichloro-4- (1H-indol-5-yloxy) -phenyl] -oxamic Calculated MS: 372.1. Found: 371.2 (M-1).

EXAMPLE 10-4 N- [3-Chloro-4- (1 H -indol-5-yloxy) -5-methyl-phenyl] -oxamic acid Calculated MS: 344.1. Found: 343.2 (M-1).

EXAMPLE 10-5 N- [3-Chloro-4- (1 H -indol-5-yloxy) -5-methyl-phenyl] -oxamide Calculated MS: 343.1. Found: 342.2 (M-1).

EXAMPLE 10-6 N- [3,5-Dichloro-4- (2-methyl-1H-indol-5-yloxy) -phenyl] -oxamic acid ethyl ester Calculated MS: 406.0. Found: 405.2 (M-1).

EXAMPLE 10-7 N- [3,5-Dichloro-4- (2-methyl-1H-indol-5-yloxy) -phenyl] -oxamic acid Calculated MS: 378.0. Found: 377.1 (M-1).

EXAMPLE 11 N- [3,5-Dichloro-4- (4-fluoro-3-methyl-phenoxy) -phenyl] -oxamic acid Step A: A mixture of 3-methyl-4-fluorophenol (99 mg, 0.79 mmol), potassium hydroxide (53 mg, 0.94 mmol), 4-iodo-3,5-dichloro-nitrobenzene (250 mg, 0.79 mmol) and sieves. Molecules of 4A (75 mg) in N-methylpyrrolidinone (3 ml) was stirred at 130 ° C for 2 hours. The reaction mixture was poured into ice-cold 1 N HCl (20 ml) and EtOAc (25 ml) was added. The EtOAc layer was separated and washed with 1 N HCl (3 x 25 ml) and brine (25 ml). The EtOAc solution was dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (hexanes: CH 2 Cl 2 = 7: 3) yielding 3,5-dichloro-4- (4-fluoro-3-methyl-phenoxy) -nitrobenzene (207 mg). Calculated MS: 315.0. Found: 315.0 (M).

Step B N- [3,5-Dichloro-4- (4-fluoro-3-methyl-phenoxy) -phenyl] -oxamic acid ethyl ester was prepared from 3,5-dichloro-4- (4-fluoro) -3-methyl-phenoxy) -nitrobenzene by hydrogenation and acylation. Calculated MS: 385.0. Found: 384.0 (M-1).

Step C N- [3,5-Dichloro-4- (4-fluoro-3-methyl-phenoxy) -phenyl] -oxamic acid was prepared from the ethyl ester of N- [3,5-dichloro-4-] (4-fluoro-3-methyl-phenoxy) -phenyl] -oxamic acid by means of hydrolysis. EM found: 357.0. Found: 356.2 (M-1). Using the appropriate starting materials, Examples 11-1 to 11-13 were prepared in a manner analogous to that described in Example 11.

EXAMPLE 11-1 N- [4- (4-Fluoro-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid Calculated MS: 303.1. Found: 302.2 (M-1).

EXAMPLE 11-2 N- [3,5-Dichloro-4- (4-fluoro-phenoxy) -phenyl] -oxamic acid ethyl ester Calculated MS: 371.0. Found: 369.9 (M-1).

EXAMPLE 11-3 N- [3,5-Dichloro-4- (3,4-difluoro-phenoxy) -phenyl] -oxamic acid ethyl ester Calculated MS: 389.0. Found: 387.9 (M-1).

EXAMPLE 11-4 N-f3.5-dichloro-4- (3-chloro-4-fluoro-phenoxy) -phene-oxamic acid ethyl ester Calculated MS: 405.0. Found: 403.9 (M-1).

EXAMPLE 11-5 N- [4- (3,4-Difluoro-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid Calculated MS: 321.1. Found: 320.1 (M-1).

EXAMPLE 11-6 N- [4- (3-Chloro-4-fluoro-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid Calculated MS: 337.1. Found: 335.9 (M-1).

EXAMPLE 11-7 N- [4- (4-Fluoro-3-methyl-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid Calculated MS: 317.7. Found: 316.1 (M-1).

EXAMPLE 11-8 N- [3,5-dichloro-4- (4-fluoro-phenoxy) -phenyl] -oxamic acid Calculated EM: 343.0. Found: 342.1 (M-1).

EXAMPLE 11-9 N- [3,5-Dichloro-4- (3,4-difluoro-phenoxy) -phenyl] -oxamic acid Calculated MS: 361.0. Found: 360.1 (M-1).

EXAMPLE 11-10 N- [3,5-Dichloro-4- (3-chloro-4-fluoro-phenoxy) -phenyl] -oxamic acid Calculated MS: 376.9. Found: 376.1 (M-1).

EXAMPLE 11-11 Ethyl ester of N- acid. { 4- [3- (Cyclobutyl-methyl-carbamoyl) -4-fluoro-phenoxy] -3,5-dimethyl-phenyl} -oxalámico Calculated MS: 442.2. Found: 441.1 (M-1).

EXAMPLE 11-12 N- acid. { 4- [3- (Cyclobutyl-methyl-carbamoyl) -4-fluoro-phenoxy] -3,5-dimethyl-phenyl} -oxalámico Calculated MS: 414.2. Found: 413.3 (M-1).

EXAMPLE 11-13 N- [4- (4-Fluoro-phenoxy) -3,5-d-methyl-phenyl] -oxamic acid ethyl ester Calculated MS: 331.1. Found: 330.2 (M-1).

Claims (28)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula (I) a prodrug thereof, a geometrical or optical isomer thereof or a pharmaceutically acceptable salt of said compound, said prodrug or said isomer, wherein: each of R1, R2 and R3 is independently hydrogen, halogen, C1 alkyl -6, trifluoromethyl, -CN, -OCF3 or -O- C1-6 alkyl. R 4 is hydrogen, C 1-12 alkyl optionally substituted with one to three substituents independently selected from the group Z, C 3-10 alkenyl, heterocycloalkyl, -S (0) 2 NR 9 R 1, -C (0) NR 9 R 10, - (C alkyl? .6) -NR9R10, -NR9C (0) R10, -NR9C (0) NR9R10, -NR9S (0) 2R10, - (alkyl d.6) -OR11, -OR11 or -S (0) aR12, with the proviso that, when R5 is not fluorine, R4 is -S (0) 2NR9R10, -C (0) NR9R10, - (C1.6 alkyl) -NR9R10, - NR9C (0) R10, -NR9C (0) NR9R10, - NR9S (0) 2R1 °, - (C6-alkyl) -OR11, -OR11 or -S (0) aR12; or R3 and R4 can be taken together to form a carbocyclic ring A of formula - (CH2) b- or a heterocyclic ring has been selected from the group consisting of -Q- (CH2) C and - (CH2) jQ- (CH2) k -, wherein Q is O, S or NR17, each of said carbocyclic A and heterocyclic A rings being optionally substituted independently by one or more substituents selected independently from C 1-4 alkyl, halide or oxo; R5 is fluorine, hydroxy, C1-4 alkoxy or OC (0) R9; or R4 and R5 can be taken together to form a heterocyclic ring B selected from the group consisting of -CR9 = CR10-NH, -N = CR9-NH-, -CR9 = CH-0- and CR9 = CH-S-; R6 is hydrogen, halogen, C -? - 4 alkyl or trifluoromethyl; R7 is hydrogen or C-? 6 alkyl; R8 is -OR9 or -NR19R20; R9 and R10, each time they appear, are independently (A) hydrogen, (B) C1-12 alkyl optionally substituted with one or more substituents independently selected from the group V, (C) C2-? 2 alkenyl, (D) C3-10 cycloalkyl optionally substituted with one or more substituents independently selected from C.sub.-β alkyl, C 2-5 alkynyl, C 3-10 cycloalkyl, -CN, -NR 13 R 14, oxo, -OR 18, -COOR 18 or aryl optionally substituted with X and Y, (E) aryl optionally substituted with X and Y, or (F) het optionally substituted with X and Y; or R9 and R10, each time they appear, can be taken together to form a heterocyclic ring C which optionally also contains a second hetero group selected from the group consisting of -O-, -NR13- and -S-, and further is optionally substituted with one or more substituents independently selected from alkyl d.15, oxo, -NR13R14, -OR18, -C (0) 2R18, -CN, -C (0) R9, aryl optionally substituted with X and Y, het optionally substituted with X and Y, C5-6 spirocycloalkyl and a carbocyclic ring B selected from the group consisting of carbocyclic rings of 5, 6, 7 or 8 members, partially and fully saturated, and unsaturated, including any bicyclic group in which said carbocyclic ring B is condensed with a carbocyclic ring C selected from the group consisting of carbocyclic rings of 5, 6, 7 or 8 partially and fully saturated, and unsaturated members; R11 is C? -? 2 alkyl optionally substituted with one or more substituents independently selected from the group V, C2? 2 alkenyl, C3-10 cycloalkyl. trifluoromethyl, difluoromethyl, monofluoromethyl, aryl optionally substituted by X and Y, het optionally substituted by X and Y, -C (0) NR9R10 or -C (0) R9; R12 is C? -? 2 alkyl optionally substituted with one or more substituents independently selected from the group V, C2-? 2 alkenyl, C3-? Cycloalkyl or > aryl optionally substituted with X and Y, or het optionally substituted with X and Y; R13 and R14, each time they appear, are independently hydrogen, C1-6 alkyl, C2-6 alkenyl, - (C1-6 alkyl) -C1-6 alkoxy, aryl optionally substituted with X and Y, het optionally substituted with X and Y, - (C 1-4 alkyl) -aryl optionally substituted with X and Y, - (C 1-4 alkyl) -heterocycle optionally substituted with X and Y, - (C 1-4 alkyl) -hydroxy, - (C 1-4 alkyl) 4) -poly-halo, (C1-4 alkyl) -CONR15R16 or C3-10 cycloalkyl. R15 and R16, each time they appear, are independently hydrogen, C-6 alkyl, C3-10 cycloalkyl or aryl optionally substituted with X and Y; R 17 is hydrogen, C 1 -C 6 alkyl, -COR 9 or -S0 2 R 9; R18 is hydrogen, C1-6 alkyl, C2-6 alkenyl > - (C 1-6 alkyl) -C 1-6 alkoxy, aryl optionally substituted with X and Y, het optionally substituted with X and Y, - (C 1-4 alkyl) -aryl optionally substituted with X and Y, - (C 1-4 alkyl) 4) -heterocycle optionally substituted with X and Y, - (C 1-4 alkyl) -hydroxy, - (C 1-4 alkyl) -halo, - (C 1-4 alkyl) -poly-halo, (C 1-4 alkyl) - CONR15R16, - (C1-4 alkyl) - (C1-4 alkoxy) or C3-10 cycloalkyl; 19 is hydrogen or C 1 -β alkyl; R 20 is hydrogen or C 1-6 alkyl; W is O, S (0) d, CH2 or NR9; the Z group is C2-6 alkenyl, C2-6 alkynyl, halogen, -CF3, -OCF3, hydroxy, oxo, -CN, aryl, heteroaryl, C3-10 cycloalkyl, heterocycloalkyl, -S (0) aR12, -S ( 0) 2NR9R10, -C (0) R9R10 and -NR9R10; the group V is halogen, -NR13R14, -OCF3, -OR9, oxo, trifluoromethyl, -CN, C3-10 cycloalkyl. aryl optionally substituted with X and Y, and het optionally substituted with X and Y; het each time it appears, is a heterocyclic ring D selected from the group consisting of heterocyclic rings of 4, 5, 6, 7 and 8 members partially and totally saturated, and unsaturated, containing one to four heteroatoms independently selected from the group composed of N, O and S, and including any bicyclic group in which said heterocyclic ring D is fused with a benzene ring or a heterocyclic ring E selected from the group consisting of heterocyclic rings of 4, 5, 6, 7 and 8 partially and fully saturated, and unsaturated, members containing one to four heteroatoms independently selected from the group consisting of N, O and S; X and Y, each time they appear, are independently (A) hydrogen, (B) halogen, (C) trifluoromethyl, (D) -OCF3, (E) -CN, (F) alkyl C.-6 optionally substituted with one or more substituents selected independently from the group consisting of halogen, -OCF3, -CF3 and phenyl, (G) C6-6 alkoxy, (H) aryl optionally substituted with one or more substituents independently from the group consisting of halogen, -OCF3, -CF3, C1-4alkyl and C1-4alkoxy, (I) -C (0) 2R13, (J) -C (0) NR13R14, (K) -C (0) R13, (L) NR13C (0) NR13R14 and (M) NR13C (0) R14; or X and Y, each time it appears in the same variable, can be taken together to form (a) a carbocyclic ring D of formula - (CH 2) e- or (b) a heterocyclic ring F selected from the group consisting of -0 (CH) fO-, (CH2) gNH- and -CH = CHNH-; each of a and d are independently 0, 1 or 2; b is 3, 4, 5, 6 or 7; each of c, f, g, j and k are independently 2, 3, 4, 5, or 6; and e is 3, 4, 5, 6 or 7.

2. A compound or pharmaceutically acceptable salt as defined in claim 1, wherein W is oxygen.

3. A compound or pharmaceutically acceptable salt as defined in claim 2, wherein R1 is located in the 3-position, R2 is located in the 5-position, R3 is located in the 2 'position, R4 is located in the position 3 ', R5 is located at the 4' position and R6 is located at the 5 'position.

4. A compound or pharmaceutically acceptable salt as defined in claim 3, wherein each of R1 and R2 is independently hydrogen, C1-6 alkyl, bromine or chlorine, R3 is hydrogen, R4 is -C (0) NR9R10, -S (O) 2NR9R10 or S (O) aR12, or R3 and R4 are taken together to form said carbocyclic ring A of formula - (CH2) - or said heterocyclic ring has selected from group consisting of -Q- (CH2) c- and - (CH2) j -Q- (CH2) k-, wherein Q is O, S or NR17, said carbocyclic A and heterocyclic rings A being optionally independently substituted with one or more substituents independently selected from C 1-4 alkyl, halide or oxo, R 5 is fluorine or hydroxy, R 8 is hydroxy, methoxy, ethoxy, isopropoxy, NH 2 or NH (CHs), and both R 6 and R 7 are hydrogen.

5. A compound or pharmaceutically acceptable salt as defined in claim 4, wherein each of R3 and R4 are taken together to form said carbocyclic ring A of formula - (CH2) b- optionally substituted with one or more substituents independently selected from C 1-4 alkyl, halide or oxo.

6. A compound or pharmaceutically acceptable salt as defined in claim 5, wherein each of R1 and R2 is independently methyl or chloro, R3 and R4 taken together form - (CH2) 3-, -CH2-C ( CH3) 2-CH2- or - (CH2) -, R5 is hydroxy and R8 is hydroxy or ethoxy.

7. A compound or pharmaceutically acceptable salt as defined in claim 4, wherein R4 is -C (0) NR9R10.

8. A compound or pharmaceutically acceptable salt as defined in claim 7, wherein each of R1 and R2 is independently methyl or chloro, R5 is hydroxy, R8 is hydroxy or ethoxy, R9 is methyl, ethyl, isopropyl, .-propyl, isobutyl, n-butyl, n-pentyl, n-hexyl, 4-fluorophenyl, -CH2-2-thienyl, cyclopropyl, -CH2-cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclohexyl, endo-2 -norbornyl, exo-2-norbornyl, (S) -1-phenylethyl, (R) -1-phenylethyl, -CH2-2-chlorophenyl, -CH2-4-chlorophenyl, -CH2-4-fluorophenyl, -CH2-3 -chloro-4-fluorophenyl, -CH2-2-chloro-4-florophenyl, -CH2-2- fluoro-4-chlorophenyl, -CH2-3,4-difluorophenyl, -CH2-4-isopropylphenyl, -CH2-2, 3-dichlorophenyl, -CH2-2,4-dichlorophenyl, -CH2-3,4-dichlorophenyl, -CH2-3-trifluoromethyl-4-chlorophenyl, 4-phenylphenyl, 3- (2,4-dimethyl) pentyl, (R) -1- (1 -naphthyl) ethyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, (R) -1- (2-naphthyl) ethyl, (R) -2- (1 -naphthyl) ethyl, -CH2- (1 -naphthyl), (R) -l-cyclohex ethyl, (S) -1-cyclohexylethyl, -CH2-3,4-methylenedioxyphenyl, -CH2-4-f-butylphenyl, -CH2-2.3-dichlorophenyl, 1-indanyl, (R) -1-indanyl , (S) -l-indanyl, 5-indanyl, 1- (1, 2,3,4-tetrahydronaphthyl) or (R) -1-cyclohexylethyl, and R10 is hydrogen, methyl or ethyl, or R9 and R10 are taken together with the nitrogen atom to which they are attached to form N (CH2) 7, N (CH2) 6, N (CH2) 5, N (CH2) 4, morpholine,

9. - A compound or pharmaceutically acceptable salt as defined in claim 4, wherein R 4 is -S (O) 2 NR 9 R 10.

10. A compound or pharmaceutically acceptable salt as defined in claim 9, wherein each of R1 and R2 is independently methyl or chloro, R8 is hydroxy, isopropoxy or ethoxy, R9 is hydrogen, isopropyl, -CH2-2 -thienyl, -CH2-cyclopropyl, cyclopropyl, - (CH2) 2OH, exo-2-norbornyl, methyl, ethyl, 4-fluorophenyl, cyclobutyl, cyclopentyl, cyclohexyl, n-propyl, n-butyl, n-pentyl, n- hexyl, n-octyl or n-decyl, and R10 is hydrogen or methyl, or R9 and R10 are taken together with the nitrogen atom to which they are attached to form N (CH2.4, N (CH2) s, morpholine or

11. - A compound or pharmaceutically acceptable salt as defined in claim 4, wherein R4 is -S (O) aR12.

12. A compound or pharmaceutically acceptable salt as defined in claim 11, wherein each of R1 and R2 are independently methyl or chloro, R8 is hydroxy or ethoxy, and R12 is 4-chlorophenyl, phenyl, 1-naphthyl , 2-naphthyl, CH2-cyclopropyl, isopropyl, CH2-cyclobutyl, CH2-cyclohexyl, cyclopentyl, CH2-4-fluorophenyl, 4-tolyl, methyl, ethyl, n-butyl, CH2-phenyl or n-propyl.

13. A pharmaceutically acceptable salt as defined in claim 6, said salt being a sodium salt or a potassium salt.

14. A pharmaceutically acceptable salt as defined in claim 8, said salt being a sodium salt or a potassium salt.

15. A pharmaceutically acceptable salt as defined in claim 10, said salt being a sodium salt or a potassium salt.

16. - A pharmaceutically acceptable salt as defined in claim 12, said salt being a sodium salt or a potassium salt.

17. A compound, prodrug, isomer or pharmaceutically acceptable salt as defined in claim 1, said compound being selected from the group consisting of: N- [3-chloro-4- (3-cyclopropylsulfamoyl-4-hydroxy) phenoxy) -5-methyl-phenyl] -oxamic acid, N- [4- (3-cyclopropylsulfamoyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid, N- acid. { 4- [3- (Cyclobutylmethyl-carbamoyl) -4-hydroxy-phenoxy] 3,5-dimethyl-phenyl] -oxamic acid, N- acid. { 3-Chloro-4- [3- (cyclobutyl-methyl-carbamoyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -oxamic, N- [4- (7-hydroxy-indan-4-yloxy) -3,5-dimethyl-phenyl] -oxamic acid, N- acid. { 3,5-dichloro-4- [3-cyclobutyl-methyl-carbamoyl) -4-hydroxy-phenoxy] -phenyl} -oxamic acid, N- [3,5-dichloro-4- (3-cyclopentanesulfonyl-4-hydroxy-phenoxy) -phenyl] -oxamic acid, N- [3,5-dichloro-4- (3-cyclopropylmethanesulfonyl-4]] -hydroxy-phenoxy) -phenyl] -oxamic acid, N- [3,5-dichloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl-oxamic acid, N- [4- (3-cyclopropylmethanesulfonyl]] 4-hydroxy-phenoxy) -3,5-dimethyl-phenyl-oxamic acid, N- [3-chloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -oxamic acid, N- [4- (3-Cyclobutyl-methanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid, N- [4- (3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy) - 3,5-dimethyl-phenyl] -oxamic acid, N- [3-chloro-4- (3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -oxamic acid, N- [3,5-] dichloro-4- (3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -oxamic acid, N- [4- (3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid, N- [3-chloro-4- (3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -oxamic acid, N- [3,5-dichloro] -4- (3-Cyclohexylmethanesulfonyl-4-hydroxy-phenoxy) -pheny] -oxamic acid, N- [3,5-dichloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] ) -phenyl] -oxamic acid, N- acid. { 4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl-oxamic acid, and N- acid. { 3-Chloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -oxamic

18. A pharmaceutically acceptable salt as defined in claim 17, said salt being a sodium salt or a potassium salt.

19. A compound or pharmaceutically acceptable salt as defined in claim 1, said compound being selected from the group consisting of: N- [3-chloro-4- (3-cyclopropylsulfamoyl-4-hydroxy-phenoxy) ethyl ester ) -5-methyl-phenyl] -oxamic acid, N- [4- (3-cyclopropylsulfamoyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid ethyl ester, ethyl N- acid ester. { 4- [3- (Cyclobutyl-methyl-carbamoyl) -4-hldroxy-phenoxy] -3,5-dimethyl-phenyl} -oxamic, ethyl ester of N- acid. { 3-Chloro-4- [3-cyclobutyl-methyl-carbamoyl) -4-hydroxy-phenoxy] -5-methyl-phenyl] -oxamic acid ethyl ester N- [4- (7-hydroxy-andan- 4-yloxy) -3,5-dimethyl-phenyl] -oxamic acid ethyl ester of N- [3,5-dichloro-4- [3-cyclobutyl-methyl-carbamoyl) -4-hydroxy-phenoxy] - phenyl] -oxamic acid, N- [3,5-dichloro-4- (3-cyclopentanesulfonyl-4-hydroxy-phenoxy) -phenyl] -oxamic acid ethyl ester, N- [3,5-] ethyl ester dichloro-4- (3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -oxamic acid ethyl ester N- [3,5-dichloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -oxamic; N- [4- (3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid ethyl ester, N- [3-chloro-4- (3-ethyl) ethyl ester -cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -oxamic acid, ethyl ester of N- [4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] - oxamic, N- [4- (3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -oxamic acid ethyl ester, N- [3-chloro-4- (3-ethyl) ethyl ester -cyclopentylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl-oxamic acid, N- [3,5-dichloro-4- (3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -oxamic acid ethyl ester, N- [4- (3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy) -3 ethyl ester, 5-dimethyl-phenyl] -oxamic acid, N- [3-chloro-4- (3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -oxamic acid ethyl ester, ester Ethyl N- [3,5-dichloro-4- (3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -oxamic acid ester, N- [3,5-dichloro-4- [3- ( 4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy) -phenyl] -oxamic acid, ethyl ester of N- acid. { 4- [3- (4-Fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl-oxamic acid, and ethyl ester of N- acid. { 3-Chloro-4- [3 - (- fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -oxamic

20. The use of a compound, prodrug, isomer or pharmaceutically acceptable salt as claimed in claim 1, for the manufacture of a medicament for the treatment of a condition selected from the group consisting of obesity, hyperlipidemia, glaucoma, heart arrhythmia, skin disorders, thyroid disease, hypothyroidism, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, depression and osteoporosis, in a mammal.

21. - The use as claimed in claim 20, wherein said condition is obesity.

22. The use as claimed in claim 20, wherein said medicament is also administered with an anorectic agent or a lipase inhibitor.

23. A pharmaceutical composition comprising a compound, prodrug, isomer or pharmaceutically acceptable salt as defined in claim 1, and a pharmaceutically acceptable carrier, diluent or excipient.

24.- A pharmaceutical composition for the treatment of a condition selected from the group consisting of obesity, hyperlipidemia, glaucoma, cardiac arrhythmia, skin disorders, thyroid disease, hypothyroidism, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, depression and osteoporosis, in a mammal, comprising a compound, prodrug, isomer or pharmaceutically acceptable salt as defined in claim 1, and a pharmaceutically acceptable carrier, diluent or excipient.

25. A composition as defined in claim 24, wherein said condition is obesity.

26. A pharmaceutical composition as defined in claim 24 which further includes an anorectic agent or a lipase inhibitor.

27. - A kit for the treatment of a condition selected from the group consisting of obesity, hyperlipidemia, glaucoma, cardiac arrhythmia, skin disorders, thyroid disease, hypothyroidism, diabetes mellitus, atherosclerosis, hypertension, heart disease, coronary heart disease, hypercholesterolemia, depression and osteoporosis, comprising: a first compound, said first compound being a compound, prodrug, isomer or pharmaceutically acceptable salt as defined in claim 1, and a pharmaceutically acceptable carrier, excipient or diluent, in a first unit dosage form; a second compound, said second compound being an anorectic agent or a lipase inhibitor, and a pharmaceutically acceptable carrier, excipient or diluent, in a second unit dosage form; and a container.

28. A kit as defined in claim 27 wherein said condition is obesity.