Malonamic acids and derivatives thereof as thyroid receptor ligands

• US 20010051657A1
• Filed: 03/28/2001
• Published: 12/13/2001
• Est. Priority Date: 03/31/2000
• Status: Active Grant

• Current Assignee: Pfizer Inc., Pfizer Products Incorporated (Pfizer Inc.)
• Original Assignee: Pfizer Inc., Pfizer Products Incorporated (Pfizer Inc.)
• Inventors: Aspnes, Gary E., Estep, Kimberly G., Chiang, Yuan-Ching P.
• Granted Patent: US 6,664,291 B2
• Time in Patent Office: Days
• US Class Current: 514/562
• CPC Class Codes: C07C 233/25 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 235/16 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 235/80 having carbon atoms of carboxamide groups and keto groups bound to the same carbon atom, e.g. acetoacetamides
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/04 with a four-membered ring
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2601/18 with a ring being at least seven-membered
• CPC Class Codes: C07C 311/29 having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 317/22 with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07D 209/46 with an oxygen atom in position 1

Abstract

The present invention relates to novel thyroid receptor ligands and, more particularly, relates to malonamic acids and derivatives thereof of Formula 1, which are useful in the treatment of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorders, thyroid disease, hypothyroidism, thyroid cancer and related disorders and diseases such as diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesteremia, depression, osteoporosis and hair loss. The present invention also provides methods, pharmaceutical compositions and kits for treating such diseases and disorders.

Claims

1. A compound of Formula I

2. A compound of

claim 1

wherein W is O;

R⁰ is hydrogen;

R¹ is located at the 5-position and R² is located at the 3-position; and

R¹ and R² are each independently hydrogen, —

(C₁-C₆)alkyl, halogen or CN.

3. A compound of

claim 2

wherein R³ is hydrogen, —

(C₁-C₄)alkyl or halogen;

R⁴ is (a) —

(C₁-C₁₀)alkyl substituted with zero to three substituents independently selected from F, hydroxy, oxo, aryl, heteroaryl, —

(C₃-C₈)cycloalkyl, or heterocycloalkyl, (b) —

(C₃-C₈)cycloalkyl, (c) heterocycloalkyl, (d) —

C(O)R^c, (e) —

OR^b, (f) NR^aC(O)R^d, (g) —

NR^aC(O)NR^cR^d or (h) —

NR^aS(O)₂R^d;

or R³ and R⁴ are taken together along with the carbon atoms to which they are attached to form a carbocyclic ring of formula —

(CH₂)_i—

or a heterocyclic ring of formula —

(CH₂)_k—

Q—

(CH₂)_i—

wherein Q is —

O—

, —

S—

or —

NR^e—

;

i is 3, 4, 5 or 6;

k is 0, 1, 2, 3, 4 or 5; and

I is 0, 1, 2, 3, 4 or 5; and

wherein the carbocyclic ring and the heterocyclic ring are each substituted with zero to four substituents independently selected from (a) —

(C₁-C₄)alkyl, (b) —

OR^b, (c) oxo, (d) —

CN, (e) phenyl or (f) —

NR^aR^g;

provided that when the substituent R⁴ is —

(C₁C₁₀)alkyl substituted with zero to three substituents, the oxo group is substituted on a carbon atom other than the C₁ carbon atom in —

(C₁-C₁₀)alkyl.

4. A compound of

claim 3

wherein R⁵ is —

OH, —

OC(O)R^f or —

F;

R^f is-(C₁-C₁₀)alkyl substituted with zero to three substituents independently selected from Group VI;

R⁶ is hydrogen, halogen or-(C₁-C₄)alkyl;

R⁷ is hydrogen or methyl; and

R⁸ and R⁹ are each independently hydrogen, —

(C₁-C₆)alkyl or halogen.

5. A compound of

claim 4

wherein R⁴ is —

(C₀-C₂)alkyl-(C₃-C₆)cycloalkyl, —

(C₁-C₁₀)alkyl, or —

(C₀-C₂)alkyl-aryl; and

R¹⁰ is —

C(O)OH, —

C(O)OCH₃ or —

C(O)OCH₂CH₃.

6. A compound of

claim 5

wherein R¹ is CH₃;

R² is CH₃;

R³ is hydrogen;

R⁴ is —

CH₂-phenyl-4-F;

R⁵ is —

OH;

R⁶, R⁷, R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH.

7. A compound of

claim 4

wherein R⁴ is —

CH(OH)-aryl, —

CH(OH)-heteroaryl, —

CH(OH)—

(CO—

C₂)alkyl-(C₃-C₈)cycloalkyl or —

CH(OH)—

(CO—

C₂)alkyl-heterocycloalkyl; and

R¹⁰ is —

C(O)OH, —

C(O)OCH₃ or-C(O)OCH₂CH₃.

8. A compound of

claim 7

selected from the group consisting of:

a compound wherein R¹ is CH₃;

R² is CH₃;

R³ is hydrogen;

R⁴ is —

CH(OH)-phenyl-4-F;

R⁵ is —

OH;

R⁶, R⁷, R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is CH₃;

R² is CH₃;

R³ is hydrogen;

R⁴ is —

CH(OH)-phenyl-4-F;

R⁵ is —

OH;

R⁶, R⁷, R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OCH₃;

a compound wherein R¹ is CH₃;

R² is CH₃;

R³ is hydrogen;

R⁴ is —

CH(OH)—

CH₂-cyclopentyl;

R⁵ is —

OH;

R⁶, R⁷, R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is CH₃;

R² is CH₃;

R³ is hydrogen;

R⁴ is —

CH(OH)—

CH₂-cyclobutyl;

R⁵ is —

OH;

R⁶, R⁷, R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl;

R² is CH₃;

R³ is hydrogen;

R⁴ is —

CH(OH)-phenyl-4-F;

R⁵ is —

OH;

R⁶, R⁷, R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl;

R² is CH₃;

R³ is hydrogen;

R⁴ is —

CH(OH)-cyclopentyl;

R⁵ is —

OH;

R⁶, R⁷, R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH; and

a compound wherein R¹ is Cl;

R² is CH₃;

R³ is hydrogen;

R⁴ is —

CH(OH)-cyclobutyl;

R⁵ is —

OH;

R⁶, R⁷, R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH.

9. A compound of

claim 4

wherein R⁴ is —

C(O)-aryl, —

C(O)-heteroaryl, —

C(O)—

(C₀-C₂)alkyl-(C₃-C₈)cycloalkyl or —

C(O)—

(C₀-C₂)alkyl-heterocycloalkyl; and

R¹⁰ is —

C(O)OH, —

C(O)OCH₃ or —

C(O)OCH₂CH₃.

10. A compound of

claim 9

selected from the group consisting of:

a compound wherein R¹ is CH₃;

R² is CH₃;

R³ is hydrogen;

R⁴ is —

C(O)-phenyl-4-F;

R⁵ is —

OH;

R⁶, R⁷, R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is CH₃;

R² is CH₃;

R³ is hydrogen;

R⁴ is —

C(O)-phenyl-4-F;

R⁵ is —

OH;

R⁶, R⁷, R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OCH₃;

a compound wherein R¹ is CH₃;

R² is CH₃;

R³ is hydrogen;

R⁴ is —

C(O)—

CH₂-cyclopentyl;

R⁵ is —

OH;

R^6, R⁷, R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is CH₃;

R² is CH₃;

R³ is hydrogen;

R⁴ is —

C(O)—

CH₂-cyclobutyl;

R⁵ is —

OH;

R⁶, R⁷, R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl;

R² is CH₃;

R³ is hydrogen;

R⁴ is —

C(O)-cyclobutyl;

R⁵ is —

OH;

R⁶, R⁷, R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl;

R² is CH₃;

R³ is hydrogen;

R⁴ is —

C(O)-cyclopentyl;

R⁵ is —

OH;

R⁶, R⁷, R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH; and

a compound wherein R¹ is Cl;

R² is CH₃;

R³ is hydrogen;

R⁴ is —

C(O)-phenyl-4-F;

R⁵ is —

OH;

R⁶, R⁷, R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH.

11. A compound of

claim 3

wherein R³ and R⁴ are taken together along with the carbon atoms to which they are attached to form a carbocyclic ring of formula —

(CH₂)_i—

or a heterocyclic ring of formula —

(CH₂)_k—

Q—

(CH₂)i—

wherein Q is —

O—

, —

S—

, or —

NR^e—

;

i is 3, 4, 5or6;

k is 0, 1, 2, 3, 4or 5; and

I is 0, 1, 2, 3, 4 or 5; and

wherein the carbocyclic ring and the heterocyclic ring are each substituted with zero to four substituents independently selected from (a) —

(C₁-C₄)alkyl, (b) —

OR^b, (c) oxo, (d) —

CN, (e) phenyl or (f) —

NR^aR^g.

12. A compound of

claim 11

wherein R³ and R⁴ are taken together along with the carbon atoms to which they are attached to form a carbocyclic ring of formula —

(CH₂)_i—

wherein i is 3 and the carbocyclic ring is optionally substituted with zero to three substituents independently selected from the group consisting of oxo and methyl;

or a heterocyclic ring of formula —

(CH₂)_k—

Q—

(CH₂₁—

wherein Q is —

NR^a, R^a is hydrogen or-(C₁-C₆)alkyl; and

k is 1;

I is 1; and

the heterocyclic ring is optionally substituted with one or two substituents independently selected from the group consisting of oxo and methyl.

13. A compound of

claim 12

wherein R¹ and R² are each independently —

CH₃ or —

Cl;

R³ is hydrogen;

R⁵ is —

OH;

R⁶, R⁷, R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH, —

C(O)OCH₃ or —

C(O)OCH₂CH₃.

14. A compound of

claim 13

selected from the group consisting of:

a compound wherein R¹ is CH₃, R² is CH₃, R³ and R⁴ are taken together along with the carbon atoms to which they are attached to form an indanyl, and R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl, R² is CH₃, R³ and R⁴ are taken together along with the carbon atoms to which they are attached to form an indanyl, and R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl, R² is CH₃, R³ and R⁴ are taken together along with the carbon atoms to which they are attached to form a 2-methyl-1-oxo-2,3-dihydro-1H-isoindolyl, and R¹⁰ is —

C(O)OH;

a compound wherein R¹ is CH₃, R² is CH₃, R³ and R⁴ are taken together along with the carbon atoms to which they are attached to form a 2-methyl-1-oxo-2,3-dihydro-1H-isoindolyl, and R¹⁰ is —

C(O)OH;

a compound wherein R¹ is CH₃, R² is CH₃, R³ and R⁴ are taken together along with the carbon atoms to which they are attached to form a 2-methyl-1-oxo-indanyl, and R¹⁰ is —

C(O)OH; and

a compound wherein R¹ is CH₃, R² is CH₃, R³ and R⁴ are taken together along with the carbon atoms to which they are attached to form a 2,2-dimethyl-1-oxo-indanyl, and R¹⁰ is —

C(O)OH.

36. A method of treating a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorder, thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesteremia, depression, osteoporosis and hair loss, in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug, as defined in

claim 1

.

37. A method of

claim 36

wherein the condition is obesity.

38. A method of

claim 36

wherein the condition is diabetes.

39. A pharmaceutical composition comprising a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug, as defined in

claim 1

.

46. A method of treating a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorder, thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesteremia, depression, osteoporosis and hair loss, comprising:

administering to a patient having or at risk of having a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorder, thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesteremia, depression, osteoporosis and hair loss, a therapeutically effective amount of

1) a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug, as defined in

claim 1

; and

2) an additional compound useful for treating a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorder, thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesteremia, depression, osteoporosis and hair loss.

47. A method of

claim 46

wherein the condition is obesity.

48. A method of

claim 47

wherein the additional compound is a lipase inhibitor.

49. A method of

claim 48

wherein the lipase inhibitor is selected from the group consisting of lipstatin, tetrahydrolipstatin (orlistat), FL-386, WAY-121898, Bay-N-3176, valilactone, esterastin, ebelactone A, ebelactone B and RHC 80267, stereoisomers thereof, and pharmaceutically acceptable salts of said compounds and stereoisomers.

50. A method of

claim 47

wherein the additional compound is an anorectic agent.

51. A method of

claim 50

wherein the anorectic agent is selected from the group consisting of phentermine, sibutramine, fenfluramine, dexfenfluramine and bromocriptine.

52. A kit for treating a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorder, thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesteremia, depression, osteoporosis and hair loss, the kit comprising:

a) a first pharmaceutical composition comprising a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug, as defined in

claim 1

;

b) a second pharmaceutical composition comprising an additional compound useful for treating a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorder, thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesteremia, depression, osteoporosis and hair loss; and

c) a container.

53. A pharmaceutical composition comprising a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug, as defined in

claim 1

;

and an additional compound useful to treat a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorder, thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesteremia, depression, osteoporosis and hair loss.

54. A composition of

claim 53

wherein the condition is obesity.

55. A composition of

claim 54

wherein the additional compound is a lipase inhibitor.

56. A composition of

claim 55

wherein the lipase inhibitor is selected from the group consisting of lipstatin, tetrahydrolipstatin (orlistat), FL-386, WAY-121898, Bay-N-3176, valilactone, esterastin, ebelactone A, ebelactone B and RHC 80267, stereoisomers thereof, and pharmaceutically acceptable salts of said compounds and stereoisomers.

57. A composition of

claim 54

wherein the additional compound is an anorectic agent.

58. A composition of

claim 57

wherein the anorectic agent is selected from the group consisting of phentermine, sibutramine, fenfluramine, dexfenfluramine and bromocriptine.

15. A compound of formula A

16. A compound of

claim 15

selected from the group consisting of:

a compound wherein R¹ is Cl;

R² is Cl;

R⁴ is —

SO₂—

NH-cyclopropyl;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl;

R² is Cl;

R⁴ is —

SO₂—

NH-cyclobutyl;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl;

R² is CH₃;

R⁴ is —

SO₂—

NH-cyclobutyl;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is CH₃, R² is CH₃, R⁴ is —

SO₂—

NH-cyclobutyl;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is CH₃, R² is CH₃, R⁴ is —

SO₂—

NH-cyclopropyl;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl;

R² is CH₃;

R⁴ is —

SO₂—

NH-cyclopropyl;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl;

R² is Cl;

R⁴ is —

SO₂—

NH—

CH(CH₃)₂;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl;

R² is Cl;

R⁴ is —

SO₂—

NH-(CH₂)₃—

CH₃;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl;

R² is Cl;

R⁴ is —

SO₂—

NH-(CH₂)₆—

CH₃;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl;

R² is Cl;

R⁴ is —

SO₂—

NH-(4-fluoro-phenyl);

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is CH₃, R² is CH₃, R⁴ is —

SO₂—

NH-cyclohexyl;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH; and

a compound wherein R¹ is Cl, R² is Cl, R⁴ is —

SO₂—

NH-cyclohexyl;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH.

17. A compound of

claim 15

selected from the group consisting of:

N-[3,5-dichloro-4-(3-cyclopropylsulfamoyl-4-hydroxy-phenoxy)-phenyl]-malonamic acid;

N-[3,5-dichloro-4-(3-cyclobutylsulfamoyl-4-hydroxy-phenoxy)-phenyl]-malonamic acid;

N-[3-chloro-4-(3-cyclobutylsulfamoyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-malonamic acid;

N-[4-(3-cyclobutylsulfamoyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid; and

N-[4-(3-cyclopropylsulfamoyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid.

18. A method of treating a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorder, thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesteremia, depression, osteoporosis and hair loss, in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of Formula A, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug, as defined in

claim 15

.

19. A compound of formula A

20. A compound of

claim 19

selected from the group consisting of:

a compound wherein R¹ is CH₃;

R² is CH₃;

R⁴ is —

C(O)N(CH₃)-cyclobutyl;

R³ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is CH₃;

R² is CH₃;

R⁴ is —

C(O)N(CH₃)-cyclobutyl;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OCH₃;

a compound wherein R¹ is Cl;

R² is CH₃;

R⁴ is —

C(O)N(CH₃)-cyclobutyl;

R⁸ and R⁹ are each hydrogen; and

R¹ is —

C(O)OH;

a compound wherein R¹ is Cl;

R² is CH₃;

R⁴ is —

C(O)NH—

CH(CH(CH₃)₂)₂;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl;

R² is Cl;

R⁴ is —

C(O)NH—

CH(CH(CH₃)₂)₂;

R³ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl;

R² is Cl;

R⁴ is —

C(O)NH—

CH(CH₃)-cyclohexyl;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is CH₃;

R² is CH₃;

R⁴is —

C(O)N(CH₃)-cyclopentyl;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is CH₃;

R² is CH₃;

R⁴is —

C(O)N(CH₃)—

CH(CH₃)₂, R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl;

R² is Cl;

R⁴ is —

C(O)NH-(4-fluoro-phenyl);

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl;

R² is Cl;

R⁴ is —

C(O)NH—

CH₂-cyclohexyl;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl;

R² is Cl;

R⁴ is —

C(O)N(CH₃)—

CH₂-cyclohexyl;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl;

R² is Cl;

R⁴ is —

C(O)N(CH₃)-cyclohexyl;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl;

R² is Cl;

R⁴ is —

C(O)N(CH₃)-cyclopentyl;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl;

R² is Cl;

R⁴ is —

C(O)N(CH₃)-cycloheptyl;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl;

R² is Cl;

R⁴ is —

C(O)N(CH₃)—

CH(CH(CH₃)₂)₂;

R⁸ and R⁹ are each hydrogen; and

Rt°

is —

C(O)OH; and

a compound wherein R¹ is Cl;

R² is Cl;

R⁴ is —

C(O)N(CH₃)—

CH(CH₃)-cyclohexyl;

R³ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH.

21. A compound of

claim 19

selected from the group consisting of:

N-{4-[3-(cyclobutyl-methyl-carbamoyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-malonamic acid;

N-{3-chloro-4-[4-hydroxy-3-(1-isopropyl-2-methyl-propylcarbamoyl)-phenoxy]-5-methyl-phenyl}-malonamic acid; and

N-{3,5-dichloro-4-[3-((1S)-cyclohexyl-ethylcarbamoyl)-4-hydroxy-phenoxy]-phenyl}-malonamic acid.

22. A method of treating a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorder, thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesteremia, depression, osteoporosis and hair loss, in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of Formula A, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug, as defined in

claim 19

.

23. A compound of formula A

24. A compound of

claim 23

selected from the group consisting of:

a compound wherein R¹ is Cl, R² is CH₃, R⁴ is —

SO₂—

CH₂-cyclobutyl, R⁸ is hydrogen, R⁹ is hydrogen and R¹⁰ is —

C(O)OCH₃;

a compound wherein R¹ is Cl, R² is CH₃, R⁴ is —

SO₂—

CH₂-cyclobutyl, R³ is hydrogen, R⁹ is hydrogen and R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl, R² is CH₃, R⁴ is —

SO₂—

CH₂-cyclobutyl, R⁸ is hydrogen, R⁹ is methyl and R¹⁰ is —

C(O)OH;

a compound wherein R¹ is CH₃, R² is Cl, R⁴ is —

SO₂—

CH₂-cyclobutyl, R³ is hydrogen, R⁹ is hydrogen and R¹⁰ is —

C(O)OH;

a compound wherein R¹ is CH₃, R² is H, R⁴ is —

SO₂—

CH₂-cyclobutyl, R⁸ is hydrogen, R⁹ is hydrogen and R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl, R² is CH₃, R⁴ is —

SO₂—

CH₂-cyclobutyl, R⁸ is hydrogen, R⁹ is hydrogen and R¹⁰ is —

C(O)OCH₂CH₃;

a compound wherein R¹ is Cl, R² is CH₃, R⁴ is —

SO₂—

CH₂-cyclopropyl, R⁸ is hydrogen, R⁹ is hydrogen and R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl, R² is Cl, R⁴ is —

SO₂—

CH₂-cyclopropyl, R⁸ is hydrogen, R⁹ is hydrogen and R¹⁰ is —

C(O)OH;

a compound wherein R¹ is CH₃, R² is CH₃, R⁴ is —

SO₂—

CH₂-cyclobutyl, R⁸ is hydrogen, R⁹ is hydrogen and R¹⁰ is —

C(O)OCH₂CH₃;

a compound wherein R¹ is CH₃, R² is CH₃, R⁴ is —

SO₂—

CH₂-cyclobutyl, R⁸ is hydrogen, R⁹ is hydrogen and R¹⁰ is —

C(O)OCH₃;

a compound wherein R¹ is CH₃, R² is CH₃, R⁴ is —

SO₂—

CH₂-cyclobutyl, R⁸ is hydrogen, R⁹ is hydrogen and R¹⁰ is —

C(O)OH;

a compound wherein R¹ is CH₃, R² is CH₃, R⁴ is —

SO₂—

CH₂-cyclobutyl, R⁸ is hydrogen, R⁹ is methyl and R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl, R² is Cl, R⁴ is —

SO₂—

CH₂-cyclobutyl, R⁸ is hydrogen, R⁹ is hydrogen and R¹⁰ is —

C(O)OH;

a compound wherein R¹ is CH₃, R² is CH₃, R⁴ is —

SO₂—

CH₂-cyclopentyl, R⁸ is hydrogen, R⁹ is hydrogen and R¹⁰ is —

C(O)OH;

a compound wherein R¹ is CH₃, R² is CH₃, R⁴ is —

SO₂—

CH₂-cyclobutyl, R⁸ is methyl, R⁹ is hydrogen and R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl, R² is CH₃, R⁴ is —

SO₂—

CH₂-cyclohexyl, R⁸ is hydrogen, R⁹ is hydrogen and R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl, R² is CH₃, R⁴ is —

SO₂—

CH₂-cyclobutyl, R⁸ is methyl, R⁹ is hydrogen and R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl, R² is CH₃, R⁴ is —

SO₂—

CH₂-cyclopentyl, R⁸ is hydrogen, R⁹ is hydrogen and R¹⁰ is —

C(O)OH;

a compound wherein R¹ is CH₃, R² is CH₃, R⁴ is —

SO₂—

CH₂-cyclohexyl, R³ is hydrogen, R⁹ is hydrogen and R¹⁰ is —

C(O)OH;

a compound wherein R¹ is CH₃, R² is CH₃, R⁴ is —

SO₂-cyclopentyl, R⁸ is hydrogen, R⁹ is hydrogen and R¹⁰ is —

C(O)OH; and

a compound wherein R¹ is Cl, R is CH₃, R⁴ is —

SO₂-cyclopentyl, R⁸ is hydrogen, R⁹ is hydrogen and R¹⁰ is —

C(O)OH.

25. A compound of

claim 23

selected from the group consisting of:

N-[3-chloro-4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-malonamic acid;

N-[3-chloro-4-(3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-malonamic acid;

N-[3,5-dichloro-4-(3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy)-phenyl]-malonamic acid;

N-[4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid;

N-[3,5-dichloro-4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-phenyl]-malonamic acid;

N-[4-(3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid;

N-[4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-2-methyl-malonamic acid;

N-[3-chloro-4-(3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-malonamic acid;

N-[3-chloro-4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-2-methyl-malonamic acid;

N-[3-chloro-4-(3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-malonamic acid;

N-[4-(3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid;

N-[3-chloro-4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-malonamic acid methyl ester;

N-[3-chloro-4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-malonamic acid ethyl ester;

N-[4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid ethyl ester;

N-[4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid methyl ester;

N-[3-chloro-4-(3-cyclopentanesulfonyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-malonamic acid; and

N-[4-(3-cyclopentanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid.

26. A method of treating a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorder, thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesteremia, depression, osteoporosis and hair loss, in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of Formula A, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug, as defined in

claim 23

.

27. A compound selected from the group consisting of:

N-{4-[3-(cyclobutyl-methyl-carbamoyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-malonamic acid;

N-{3-chloro-4-[4-hydroxy-3-(1-isopropyl-2-methyl-propylcarbamoyl)-phenoxy]-5-methyl-phenyl}-malonamic acid;

N-{3,5-dichloro-4-[3-((1 S)-cyclohexyl-ethylcarbamoyl)-4-hydroxy-phenoxy]-phenyl}-malonamic acid;

N-[3,5-dichloro-4-(3-cyclopropylsulfamoyl-4-hydroxy-phenoxy)-phenyl]-malonamic acid;

N-[3,5-dichloro-4-(3-cyclobutylsulfamoyl-4-hydroxy-phenoxy)-phenyl]-malonamic acid;

N-[3-chloro-4-(3-cyclobutylsulfamoyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-malonamic acid;

N-[4-(3-cyclobutylsulfamoyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid;

N-[4-(3-cyclopropylsulfamoyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid;

N-[3-chloro-4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-malonamic acid;

N-[3-chloro-4-(3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-malonamic acid;

N-[3,5-dichloro-4-(3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy)-phenyl]-malonamic acid;

N-[4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid;

N-[3,5-dichloro-4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-phenyl]-malonamic acid;

N-[4-(3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid;

N-[4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-2-methyl-malonamic acid;

N-[3-chloro-4-(3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-malonamic acid;

N-[3-chloro-4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-2-methyl-malonamic acid;

N-[3-chloro-4-(3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-malonamic acid;

N-[4-(3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid;

N-{4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-malonamic acid;

N-{3-chloro-4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-5-methyl-phenyl}-malonamic acid;

N-{4-[3-(4-fluoro-benzoyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-malonamic acid;

N-[4-(3-cyclopentylacetyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid;

N-(4-{3-[(4-fluoro-phenyl)-hydroxy-methyl]-4-hydroxy-phenoxy}-3,5-dimethyl-phenyl)-malonamic acid;

N-{4-[3-(2-cyclopentyl-1-hydroxy-ethyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-malonamic acid;

N-[3-chloro-4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-malonamic acid methyl ester;

N-[3-chloro-4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-malonamic acid ethyl ester;

N-[4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid ethyl ester;

N-[4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid methyl ester;

N-[3-chloro-4-(3-cyclopentanesulfonyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-malonamic acid;

N-[4-(3-cyclopentanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid;

N-{3-chloro-4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-5-methyl-phenyl}-malonamic acid;

N-{3-chloro-4-[3-(4-fluoro-benzenesulfonyl)4-hydroxy-phenoxy]-5-methyl-phenyl}-malonamic acid methyl ester;

N-{3,5-dichloro-4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-phenyl}-malonamic acid methyl ester;

N-{3,5-dichloro-4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-phenyl}-malonamic acid ethyl ester;

N-{4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-2-methyl-malonamic acid methyl ester;

N-{4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-2-methyl-malonamic acid;

N-{3-chloro-4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-5-methyl-phenyl}-2-methyl-malonamic acid methyl ester;

N-{3-chloro-4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-5-methyl-phenyl}-2-methyl-malonamic acid;

N-{3,5-dichloro-4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-phenyl}-2-methyl-malonamic acid methyl ester; and

N-{3,5-dichloro-4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-phenyl}-2-methyl-malonamic acid;

or an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug.

28. A method of treating a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorder, thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesteremia, depression, osteoporosis and hair loss, in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of

claim 27

, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug.

29. A method of

claim 28

wherein the condition is obesity.

30. A method of

claim 28

wherein the condition is diabetes.

31. A method of

claim 29

which further comprises administering an anorectic agent.

32. A method of

claim 31

wherein the anorectic agent is selected from the group consisting of phentermine, sibutramine, fenfluramine, dexfenfluramine and bromocriptine.

33. A method of

claim 29

which further comprises administering a lipase inhibitor.

34. A method of

claim 33

wherein the lipase inhibitor is selected from the group consisting of lipstatin, tetrahydrolipstatin (orlistat), FL-386, WAY-121898, Bay-N-3176, valilactone, esterastin, ebelactone A, ebelactone B and RHC 80267, stereoisomers thereof, and pharmaceutically acceptable salts of said compounds and stereoisomers.

35. A pharmaceutical composition comprising a compound of

claim 27

, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug.

59. A method of treating a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorder, thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesteremia, depression, osteoporosis and hair loss, comprising:

administering to a patient having or at risk of having a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorder, thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesteremia, depression, osteoporosis and hair loss, a therapeutically effective amount of

1) a compound of

claim 27

, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug; and

2) an additional compound useful for treating a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorder, thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesteremia, depression, osteoporosis and hair loss.

60. A method of

claim 59

wherein the condition is obesity.

61. A method of

claim 60

wherein the additional compound is a lipase inhibitor.

62. A method of

claim 61

wherein the lipase inhibitor is selected from the group consisting of lipstatin, tetrahydrolipstatin (orlistat), FL-386, WAY-121898, Bay-N-3176, valilactone, esterastin, ebelactone A, ebelactone B and RHC 80267, stereoisomers thereof, and pharmaceutically acceptable salts of said compounds and stereoisomers.

63. A method of

claim 60

wherein the additional compound is an anorectic agent.

64. A method of

claim 63

wherein the anorectic agent is selected from the group consisting of phentermine, sibutramine, fenfluramine, dexfenfluramine and bromocriptine.

65. A kit for treating a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorder, thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesteremia, depression, osteoporosis and hair loss, the kit comprising:

a) a first pharmaceutical composition comprising a compound of

claim 27

, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug;

b) a second pharmaceutical composition comprising an additional compound useful for treating a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorder, thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesteremia, depression, osteoporosis and hair loss; and

c) a container.

66. A pharmaceutical composition comprising a compound of

claim 27

, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug;

and an additional compound useful to treat a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorder, thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesteremia, depression, osteoporosis and hair loss.

67. A composition of

claim 66

wherein the condition is obesity.

68. A composition of

claim 67

wherein the additional compound is a lipase inhibitor.

69. A composition of

claim 68

wherein the lipase inhibitor is selected from the group consisting of lipstatin, tetrahydrolipstatin (orlistat), FL-386, WAY-121898, Bay-N-3176, valilactone, esterastin, ebelactone A, ebelactone B and RHC 80267, stereoisomers thereof, and pharmaceutically acceptable salts of said compounds and stereoisomers.

70. A composition of

claim 67

wherein the additional compound is an anorectic agent.

71. A composition of

claim 68

wherein the anorectic agent is selected from the group consisting of phentermine, sibutramine, fenfluramine, dexfenfluramine and bromocriptine.

40. A method of treating hair loss in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of

41. A method of

claim 40

which comprises administering a compound of Formula I wherein W is O;

R⁰ is hydrogen;

R¹ is located at the 5-position and R² is located at the 3-position; and

R¹ and R² are each independently hydrogen, —

(C₁-C₆)alkyl, halogen or CN.

42. A method of

claim 41

which comprises administering a compound of Formula I wherein R³ is hydrogen, —

(C₁-C₄)alkyl or halogen;

R⁴ is (a) —

(C₁-C₁₀)alkyl substituted with zero to three substituents independently selected from F, hydroxy, oxo, aryl, heteroaryl, —

(C₃-C₈)cycloalkyl, or heterocycloalkyl, (b) —

S(O)₂NR^cR^d, (c) —

C(O)NR^cR^d, (d) —

S(O)₂R^c, (e) —

(C₃-C₈)cycloalkyl, (f) heterocycloalkyl, (g) —

C(O)R^c, (h) OR^b, (i) SRr, (j) —

S(O)R^c, (k) —

NR^aC(O)R^d, (I) —

NR^aC(O)NR^cR^d or (m) —

NR^aS(O)₂R^d;

or R³ and R⁴ are taken together along with the carbon atoms to which they are attached to form a carbocyclic ring of formula —

(CH₂)_i—

or a heterocyclic ring of formula —

(CH₂)_k—

Q—

(CH₂₁—

wherein Q is —

O—

, —

S—

or —

NR^e—

;

i is 3, 4, 5 or 6;

k is 0, 1, 2, 3, 4 or 5; and

I is 0, 1, 2, 3, 4 or 5; and

wherein the carbocyclic ring and the heterocyclic ring are each substituted with zero to four substituents independently selected from (a) —

(C₁-C₄)alkyl, (b) —

OR^b, (c) oxo, (d) —

CN, (e) phenyl or (f) —

NR^aR^g;

provided that when the substituent R⁴ is —

(C₁C₁₀)alkyl substituted with zero to three substituents, the oxo group is substituted on a carbon atom other than the C₁ carbon atom in —

(C₁-C₁₀)alkyl.

43. A method of

claim 42

which comprises administering a compound of Formula I wherein R⁵ is —

OH, —

OC(O)R_f or —

F; and

R^f is —

(C₁-C₁₀)alkyl substituted with zero to three substituents independently selected from Group VI;

R⁶ is hydrogen, halogen or —

(C₁-C₄)alkyl;

R⁷ is hydrogen or methyl; and

R⁸ and R⁹ are each independently hydrogen, —

(C₁-C₆)alkyl or halogen.

44. A method of

claim 43

which comprises administering a compound of Formula I wherein R⁴ is (a) —

(C₁-C₁₀)alkyl substituted with zero to three substituents independently selected from F, hydroxy, oxo, aryl, heteroaryl, —

(C₃-C₈)cycloalkyl, or heterocycloalkyl, (b) —

S(O)₂NR^cR^d, (c) —

C(O)NR^cR^d, (d)—

S(O)₂R^c, (e) —

(C₃-C₈)cycloalkyl, (f) heterocycloalkyl or (g) —

C(O)R^c; and

R¹⁰ is —

C(O)OH, —

C(O)OCH₃ or —

C(O)OCH₂CH₃ or a pharmaceutically acceptable salt or prodrug thereof.

45. A method of

claim 44

which comprises administering a compound selected from the group consisting of:

N-{4-[3-(cyclobutyl-methyl-carbamoyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-malonamic acid;

N-{3-chloro-4-[4-hydroxy-3-( 1-isopropyl-2-methyl-propylcarbamoyl)-phenoxy]-5-methyl-phenyl}-malonamic acid;

N-{3,5-dichloro-4-[3-((1 S)-cyclohexyl-ethylcarbamoyl)-4-hydroxy-phenoxy]-phenyl}-malonamic acid;

N-[3,5-dichloro-4-(3-cyclopropylsulfamoyl-4-hydroxy-phenoxy)-phenyl]-malonamic acid;

N-[3,5-dichloro-4-(3-cyclobutylsulfamoyl-4-hydroxy-phenoxy)-phenyl]-malonamic acid;

N-[3-chloro-4-(3-cyclobutylsulfamoyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-malonamic acid;

N-[4-(3-cyclobutylsulfamoyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid;

N-[4-(3-cyclopropylsulfamoyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid;

N-[3-chloro-4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-malonamic acid;

N-[3-chloro-4-(3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-malonamic acid;

N-[3,5-dichloro-4-(3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy)-phenyl]-malonamic acid;

N-[4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid;

N-[3,5-dichloro-4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-phenyl]-malonamic acid;

N-[4-(3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid;

N-[4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-2-methyl-malonamic acid;

N-[3-chloro-4-(3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-malonamic acid;

N-[3-chloro-4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-2-methyl-malonamic acid;

N-[3-chloro-4-(3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-malonamic acid;

N-[4-(3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid;

N-{4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-malonamic acid;

N-{3-chloro-4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-5-methyl-phenyl}-malonamic acid;

N-{4-[3-(4-fluoro-benzoyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-malonamic acid;

N-[4-(3-cyclopentylacetyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid;

N-(4-{3-[(4-fluoro-phenyl)-hydroxy-methyl]-4-hydroxy-phenoxy}-3,5-dimethyl-phenyl)-malonamic acid;

N-{4-[3-(2-cyclopentyl-1-hydroxy-ethyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-malonamic acid;

N-[3-chloro-4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-malonamic acid methyl ester;

N-[3-chloro-4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-malonamic acid ethyl ester;

N-[4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid ethyl ester;

N-[4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid methyl ester;

N-[3-chloro-4-(3-cyclopentanesulfonyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-malonamic acid;

N-[4-(3-cyclopentanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid;

N-{3-chloro-4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-5-methyl-phenyl}-malonamic acid;

N-{3-chloro-4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-5-methyl-phenyl}-malonamic acid methyl ester;

N-{3,5-dichloro-4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-phenyl}-malonamic acid methyl ester;

N-{3,5-dichloro-4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-phenyl}-malonamic acid ethyl ester;

N-{4-[3-(4-fluoro-benzenesulfonyl)4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-2-methyl-malonamic acid methyl ester;

N-{4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-2-methyl-malonamic acid;

N-{3-chloro-4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-5-methyl-phenyl}-2-methyl-malonamic acid methyl ester;

N-{3-chloro-4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-5-methyl-phenyl}-2-methyl-malonamic acid;

N-{3,5-dichloro-4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-phenyl}-2-methyl-malonamic acid methyl ester; and

N-{3,5-dichloro-4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-phenyl}-2-methyl-malonamic acid;

N-{4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-malonamic acid; and

N-{4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-malonamic acid methyl ester;

or an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug.