Malonamic acids and derivatives thereof as thyroid receptor ligands

• US 6,664,291 B2
• Filed: 03/28/2001
• Issued: 12/16/2003
• Est. Priority Date: 03/31/2000
• Status: Expired due to Term

• Current Assignee: Pfizer Inc., Pfizer Products Incorporated (Pfizer Inc.)
• Original Assignee: Pfizer Inc.
• Inventors: Aspnes, Gary E., Estep, Kimberly G., Chiang, Yuan-Ching P.
• Primary Examiner(s): Richter, Johann
• Assistant Examiner(s): Zucker, Paul A.
• Application Number:
  US09/819,283
• Publication Number:
  US 20010051657A1
• Time in Patent Office: 993 Days
• Field of Search: 560/36, 560/44, 560/11, 560/45, 562/441, 562/444, 562/436, 562/457, 514/563, 514/533
• US Class Current: 514/533
• 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 I, 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

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

wherein

W is —

O—

;

R⁰ is hydrogen;

R¹ and R² are each independently hydrogen, —

(C₁-C₆)alkyl, halogen or CN;

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

R³ is hydrogen, —

(C¹-C₄)alkyl or halogen;

R⁴ is (a) —

(C₁-C₁₀)alkyl substituted with zero to three substituents dependently 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)₁—

wherein Q is —

O—

, —

S—

or —

NR_a—

;

i is 3, 4, 5 or 6;

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

l 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^RR⁸;

provided that when the substituent R⁴ is —

(C₁-C₁₀)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;

R⁵ is (a) —

OH, (b) —

O(C₁-C₆)alkyl, (c) —

OC(O)R^f, (d) F, or (e) —

C(O)OR^c;

or R⁴ and R⁵ are taken together along with the carbon atoms to which they are attached to form a heterocyclic ring selected from the group consisting of —

CR^c═

CR^a—

NH—

, —

N═

CR^a—

NH, —

CR^o═

CR^a—

O—

, —

CR^c═

CR^a—

NH— and

—

CR^a═

CR^a—

CR^a═

N—

;

R⁶ is (a) hydrogen, (b) halogen, (c) —

(C₁-C₈)alkyl, (d) —

CF₃, (e) —

OCF₃, (f) —

O(C₁-C₈)alkyl, or (g) —

CN;

R⁷ is (a) hydrogen or (b) —

(C₁-C₆)alkyl;

R⁸ and R⁹ are each independently (a) hydrogen, (b) —

(C₁-C₆)alkyl, (c) aryl, or (d) halogen;

R¹⁰ is (a) —

(C₀-C₁)alkyl-C(O)OH, (b) —

(C₀-C₁)alkyl-C(O)OR^f, (c) —

(C₀-C₁)alkyl —

C(O)NR^cR^d, or (d) —

(C₀-C₁)alkyl-OH;

R^a for each occurrence is independently (a) hydrogen or (b) —

(C₁-C₆)alkyl substituted with zero or one —

(C₃-C₆)cycloalkyl or methoxy;

R^b for each occurrence is independently (a) hydrogen, (b) —

(C₁-C₁₂)alkyl substituted with zero to three substituents independently selected from Group V, (c) aryl, (d) heteroaryl, (e) —

(C₃-C₁₀) cycloalkyl, (f) heterocycloalkyl, (g) —

C(O)NR^cR^d, or (h) —

C(O)R^f;

R^c and R^d for each occurrence are each independently (a) hydrogen, (b) —

(C₁-C₁₂)alkyl substituted with zero to three substituents independently selected from Group VI, (c) —

(C₂-C₁₂)alkenyl, (d) —

(C₂-C₁₂)alkynyl, (e) aryl, (f) heteroaryl, (g) —

(C₃-C₁₀)cycloalkyl or (h) heterocycloalkyl;

or R^c and R^d are taken together along with the atom(s) to which they are attached to form a 3-10 membered heterocyclic ring which may optionally contain a second heterogroup selected from —

O—

, —

NR^e—

or —

S—

; and

wherein the heterocyclic ring is 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^b;

R^e for each occurrence is (a) hydrogen, (b) —

CN, (c) —

(C₁-C₁₀)alkyl substituted with zero to three substitutents independently selected from Group V, (d) —

(C₂-C₁₀)alkenyl, (e) —

(C₂-C₁₀) alkoxy, (f) —

(C₃-C₁₀)cycloalkyl, (g) aryl, (h) heteroaryl, (i) —

C(O)R^f, (j) —

C(O)OR^f, (k) —

C(O)NR^aR^f or (l) —

S(O)₂R^f;

R^f for each occurrence is independently (a) —

(C₁-C₁₀)alkyl substituted with zero to three substituents independently selected from the Group VI, (b) —

(C₂-C₁₀)alkenyl, (c) —

(C₂-C₁₀)alkynyl, (d) —

(C₃-C₁₀)cycloalkyl, (e) aryl, (f) heteroaryl or (g) heterocycloalkyl;

R⁸ for each occurrence is independently (a) hydrogen, (b) —

(C₁-C₆)alkyl, (c) —

(C₂-C₆)alkenyl, (d) aryl, (e) —

C(O)R^f, (f) —

C(O)OR^f, (g) —

C(O)NR^aR^f, (h) —

S(O)₂R^f or (i) —

(C₃-C₈)cycloalkyl;

R^b is (a) —

(C₁-C₆)alkyl substituted with zero or one substituent selected from the group consisting of (1) —

(C₃-C₆)cycloalkyl, (2) heterocycloalkyl and (3) phenyl substituted with zero or one substituent selected from the group consisting of (i) —

(C₁-C₄)alkyl, (ii) halogen, (iii) —

CF₃ and (iv) —

OCF₃;

(b) phenyl substituted with zero to two substituents independently selected from the group consisting or (1) —

(C₁-C₄)alkyl, (2) halogen, (3) —

CF₃, and (4) —

OCF₃;

(c) —

(C₃-C₆)cycloalkyl or (d) heterocycloalkcyl;

Group V is (a) halogen, (b) —

CF₃, (c) —

OCF₃, (d) —

OH, (e) -oxo, (f) —

(C₁-C₆)alkoxy, (g) —

CN, (h) aryl, (i) heteroaryl, (j) —

(C₃-C₁₀)cycloalkyl, (k) heterocycloalkyl, (l) —

SR^f, (m) —

S(O)R^f, (n) —

S(O)₂R^f, (o) —

S(O)₂NR^aR^f (p) —

NR^aR^g or (q) —

C(O)NR^aR^f;

Group VI is (a) halogen, (b) hydroxy, (c) oxo, (d) —

(C₁-C₆)alkoxy, (e) aryl, (f) heteroaryl, (g) —

(C₃-C₈)cycloalkyl, (h) heterocycloalkyl, (i) —

CN, or (j) —

OCF₃;

aryl for each occurrence is independently phenyl or naphthyl substituted with zero to four substituents independently selected from (a) halogen, (b) —

(C₁-C₆)alkyl, (c) —

CN, (d) —

SR^f, (e) —

S(O)R^f, (f) —

S(O)₂R^f, (g) —

(C₃-C₆)cycloalkyl, (h) —

S(O)₂NR^aR^f, (i) —

NR^aR^g, (j) —

C(O)NR^aR^f, (k) —

OR^b, (l)-perfluoro-(C₁-C₄)alkyl, or (m) —

COOR^f;

provided that when the substituent(s) on aryl are —

SR^f, —

S(O)R^f, —

S(O)²R^f, —

S(O)₂NR^aR^f, —

NR^aR^g, —

C(O)NR^aR^f, —

OR^b, or —

COOR^f, the substituents R^b, R^f and R^g are other than aryl or heteroaryl;

heteroaryl for each occurrence is independently a 5-, 6-, 7-, 8-, 9- or 10-membered monocyclic or bicyclic ring having from 1 to 3 heteroatoms selected from O, N or S;

wherein in the bicyclic ring, a monocyclic heteroaryl ring is fused to a benzene ring or to another heteroaryl ring; and

having zero to three substituents independently selected from (a) halogen, (b) —

(C₁-C₄)alkyl, (c) —

CF₃, (d) —

OR^b, (e) —

NR^aR^g, or (f) —

CO₂R^f;

provided that when the substituent(s) on heteroaryl are —

OR^b, —

NR^aR^g or —

CO₂R^f, the substituents R^b, R^f and R^g are other than aryl or heteroaryl;

heterocycloalkyl for each occurrence is independently a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered monocyclic or bicyclic cycloalkyl ring having from 1 to 3 heteroatoms selected from O, NR^c or S; and

having 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.

2. A compound of claim 1 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.

3. A compound of claim 2 wherein R⁴ is —

(C₀-C₂)alkyl-(C₃-C₆)cycloalky, —

(C₁-C₁₀)alkyl, or —

(C₀-C₂)alkyl-aryl; and

R¹⁰ is —

C(O)OH, —

C(O)OCH₃ or —

C(O)OCH₂CH₃.

4. A compound of claim 3 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.

5. A compound of claim 2 wherein R⁴ is —

CH(OH)-aryl, —

CH(OH)-heteroaryl, —

CH(OH)—

(C₀-C₂)alkyl-(C₃-C₈)cycloalkyl or —

CH(OH)—

(C₀-C₂)alkyl-heterocycloalkyl; and

R¹⁰ is —

C(O)OH, —

C(O)OCH₃ or —

C(O)OCH₂CH₃.

6. A compound of claim 5 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.

7. A compound of claim 2 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.

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 —

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;

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)—

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.

9. A compound of claim 1 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^c—

;

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.

10. A compound of claim 9 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.

11. A compound of claim 10 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.

17. A method of treating obesity 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.

18. 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.

19. A method of treating obesity comprising:

administering to a patient who is obese or is at risk of becoming obese 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 obesity.

20. A method of claim 19 wherein the additional compound is a lipase inhibitor.

21. A method of claim 20, wherein the lipase inhibitor is selected from the group consisting of lipstatin, tetrahydrolipstatin, 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.

22. A method of claim 19 wherein the additional compound is an anorectic agent.

23. A method of claim 22 wherein the anorectic agent is selected from the group consisting of phentermine, sibutramine, fenfluramine, dexfenfluramine and bromocriptine.

24. A kit for treating obesity, 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 obesity; and

c) a container.

25. 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 obesity.

26. A composition of claim 25 wherein the additional compound is a lipase inhibitor.

27. A composition of claim 26 wherein the lipase inhibitor is selected from the group consisting of lipstatin, tetrahydrolipstatin , FL-386, WAY-21898Bay-N-3176, valilactone, esterastin, ebelactone A, ebelactone B and RHC 80267, stereoisomers thereof, and pharmaceutically acceptable salts of said compounds and stereoisomers.

28. A composition of claim 25 wherein the additional compound is an anorectic agent.

29. A composition of claim 28 wherein the anorectic agent is selected from the group consisting of phentermine, sibutramine, fenfluramine, dexfenfluramine and bromocriptine.

13. 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;

wherein R¹ and R² are each independently —

CH₃ or —

Cl;

R⁴ is —

SO₂—

CH₂-cyclopropyl, —

SO₂—

CH₂-cyclobutyl, —

SO₂—

CH₂-cyclopentyl, —

SO₂—

CH₂-cyclohexyl, —

SO₂-cyclpentyl or —

SO₂-cyclohexyl;

;

R⁸ and R⁹ are each independently hydrogen or methyl; and

R¹⁰ is —

C(O)OH, —

C(O)OCH₃ or —

C(O)OCH₂CH₃.

12. 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.

14. A compound of claim 13 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, 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 methyl 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-cyclobutyl, 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-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 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 —

SO₂CH₂-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-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, R⁸ 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, R² is CH₃, R⁴ is —

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

C(O)OH.

15. A compound of claim 13 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.

16. A method of treating obesity, 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 13.

30. N-[3-chloro-4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-malonamic acid, or a pharmaceutically acceptable salt thereof.