ARYL GPR120 RECEPTOR AGONISTS AND USES THEREOF

US 20100216827A1
Filed: 10/20/2009
Published: 08/26/2010
Est. Priority Date: 10/21/2008
Status: Abandoned Application

First Claim

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1. A compound of Formula (A) or a pharmaceutically acceptable salt thereof, wherein:

represents a 5-10 membered monocyclic or bicyclic aryl group, a 5-10 membered monocyclic or bicyclic heteroaryl group, a 5-10 membered monocyclic or bicyclic cycloalkyl group, a 5-10 membered monocyclic or bicyclic heterocycloalkyl group, or a 8-10 membered bicyclic group wherein an aryl or a 5-6 membered heteroaryl ring is fused to a 5-6 membered cycloalkyl or heterocycloalkyl ring;

E¹, E²and E³are independently selected from the group consisting of C, N and S;

E⁴is selected from the group consisting of C and N;

X is selected from the group consisting of —

CH₂—

, —

C(O)— and

—

C(O)CH₂—

;

Y is selected from the group consisting of —

CH₂—

, —

NH— and

—

O—

;

Z is selected from the group consisting of a —

(CR⁴R⁵)_n—

, —

S—

, —

C(O)— and

—

CR⁴═

CR⁵—

;

V is selected from the group consisting of a bond, —

(CR⁴R⁵)_n—

, —

CR⁴═

CR⁵—

, and —

O—

CR⁴R⁵—

;

W is selected from the group consisting of H, C_1-6alkyl and substituted C_1-6alkyl;

R¹is independently selected from the group consisting of halo, C_1-6alkyl, substituted C_1-6alkyl, C_3-7cycloalkyl, substituted C_3-7cycloalkyl, C_2-6alkenyl, substituted C_2-6alkenyl, C_2-6alkynyl, substituted C_2-6alkynyl, CN, —

OR^a, —

NR^aR^b, —

C(O)R^a, —

C(O)OR^a, —

NR^aC(O)R^b, —

S(O)R^aand —

S(O)₂R^a;

R²is independently selected from the group consisting of halo, C_1-6alkyl, substituted C_1-6alkyl, C_3-7cycloalkyl, substituted C_3-7cycloalkyl, C_2-6alkenyl, substituted C_2-6alkenyl, C_2-6alkynyl, substituted C_2-6alkynyl, aryloxy, -substituted aryloxy, CN, —

OR^a, —

NR^aR^b, —

C(O)R^a, —

C(O)OR^a, —

C(O)NR^aR^b, —

NR^aC(O)R^b, —

S(O)R^aand —

S(O)₂R^a;

each of R^aand R^bis independently selected from the group consisting of H, C_1-6alkyl, substituted C_1-6alkyl, C_3-7cycloalkyl, C_2-6alkenyl and C_2-6alkynyl;

R⁴is independently selected from the group consisting of H, halo, C_1-6alkyl, substituted C_1-6alkyl, C_1-6alkoxy and substituted C_1-6alkoxy;

R⁵is independently selected from the group consisting of H, halo, C_1-6alkyl, substituted C_1-6alkyl and C_1-6alkoxy;

R⁶is selected from the group consisting of halo, C_1-6alkyl, substituted C_1-6alkyl, C_1-6alkoxy, substituted C_1-6alkoxy, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

optionally R⁴and R⁵cyclize to form a C_3-7saturated ring or a spiro C_3-7cycloalkyl group;

the subscript b is 0, 1, 2, 3 or 4;

the subscript g is 0, 1 or 2; and

the subscript n is independently 1, 2 or 3.

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Abstract

Aryl GPR120 agonists are provided. These compounds are useful for the treatment of metabolic diseases, including Type II diabetes and diseases associated with poor glycemic control.

Citations

27 Claims

1. A compound of Formula (A) or a pharmaceutically acceptable salt thereof, wherein:
- represents a 5-10 membered monocyclic or bicyclic aryl group, a 5-10 membered monocyclic or bicyclic heteroaryl group, a 5-10 membered monocyclic or bicyclic cycloalkyl group, a 5-10 membered monocyclic or bicyclic heterocycloalkyl group, or a 8-10 membered bicyclic group wherein an aryl or a 5-6 membered heteroaryl ring is fused to a 5-6 membered cycloalkyl or heterocycloalkyl ring;
  
  E¹, E²and E³are independently selected from the group consisting of C, N and S;
  
  E⁴is selected from the group consisting of C and N;
  
  X is selected from the group consisting of —
  
  CH₂—
  
  , —
  
  C(O)— and
  
  —
  
  C(O)CH₂—
  
  ;
  
  Y is selected from the group consisting of —
  
  CH₂—
  
  , —
  
  NH— and
  
  —
  
  O—
  
  ;
  
  Z is selected from the group consisting of a —
  
  (CR⁴R⁵)_n—
  
  , —
  
  S—
  
  , —
  
  C(O)— and
  
  —
  
  CR⁴═
  
  CR⁵—
  
  ;
  
  V is selected from the group consisting of a bond, —
  
  (CR⁴R⁵)_n—
  
  , —
  
  CR⁴═
  
  CR⁵—
  
  , and —
  
  O—
  
  CR⁴R⁵—
  
  ;
  
  W is selected from the group consisting of H, C_1-6alkyl and substituted C_1-6alkyl;
  
  R¹is independently selected from the group consisting of halo, C_1-6alkyl, substituted C_1-6alkyl, C_3-7cycloalkyl, substituted C_3-7cycloalkyl, C_2-6alkenyl, substituted C_2-6alkenyl, C_2-6alkynyl, substituted C_2-6alkynyl, CN, —
  
  OR^a, —
  
  NR^aR^b, —
  
  C(O)R^a, —
  
  C(O)OR^a, —
  
  NR^aC(O)R^b, —
  
  S(O)R^aand —
  
  S(O)₂R^a;
  
  R²is independently selected from the group consisting of halo, C_1-6alkyl, substituted C_1-6alkyl, C_3-7cycloalkyl, substituted C_3-7cycloalkyl, C_2-6alkenyl, substituted C_2-6alkenyl, C_2-6alkynyl, substituted C_2-6alkynyl, aryloxy, -substituted aryloxy, CN, —
  
  OR^a, —
  
  NR^aR^b, —
  
  C(O)R^a, —
  
  C(O)OR^a, —
  
  C(O)NR^aR^b, —
  
  NR^aC(O)R^b, —
  
  S(O)R^aand —
  
  S(O)₂R^a;
  
  each of R^aand R^bis independently selected from the group consisting of H, C_1-6alkyl, substituted C_1-6alkyl, C_3-7cycloalkyl, C_2-6alkenyl and C_2-6alkynyl;
  
  R⁴is independently selected from the group consisting of H, halo, C_1-6alkyl, substituted C_1-6alkyl, C_1-6alkoxy and substituted C_1-6alkoxy;
  
  R⁵is independently selected from the group consisting of H, halo, C_1-6alkyl, substituted C_1-6alkyl and C_1-6alkoxy;
  
  R⁶is selected from the group consisting of halo, C_1-6alkyl, substituted C_1-6alkyl, C_1-6alkoxy, substituted C_1-6alkoxy, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
  
  optionally R⁴and R⁵cyclize to form a C_3-7saturated ring or a spiro C_3-7cycloalkyl group;
  
  the subscript b is 0, 1, 2, 3 or 4;
  
  the subscript g is 0, 1 or 2; and
  
  the subscript n is independently 1, 2 or 3.
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 19, 20, 21, 22, 23, 24, 25, 26, 27)
- - 2. The compound of claim 1, wherein:
    - X is —
      
      CH₂—
      
      ;
      
      Y is —
      
      O—
      
      ;
      
      Z is —
      
      (CR⁴R⁵)_n; and
      
      V is a bond.
  - 3. The compound of claim 2, wherein Q is selected from the group consisting of
- 4. The compound of claim 1 of Formula (B) or a pharmaceutically acceptable salt thereof, wherein:
  - A¹, A², A³and A⁴are independently selected from the group consisting of C and N, with the proviso that only 0, 1 or 2 of A¹, A², A³and A⁴is N;
    
    J¹, J², J³, J⁴and J⁵are independently selected from the group consisting of N and C, with the proviso that only 0, 1 or 2 of J¹, J², J³, J⁴and J⁵is N;
    
    each R³is independently selected from the group consisting of halo, C_1-6alkyl, substituted C_1-6alkyl, C_3-7cycloalkyl, substituted C_3-7cycloalkyl, C_2-6alkenyl, substituted C_2-6alkenyl, C_2-6alkynyl, substituted C_2-6alkynyl, cyano, —
    
    OR^a, —
    
    NR^aR^b, —
    
    C(O)R^a, —
    
    C(O)OR^a, —
    
    C(O)NR^aR^b, —
    
    NR^aC(O)R^b, —
    
    SR^a, —
    
    S(O)R^aand —
    
    S(O)₂R^a;
    
    the subscript c is 0, 1, 2 or 3; and
    
    E¹, E², E³, E⁴, R¹, R², Z, V, R^a, R^b, subscript b and subscript g are as previously defined.
- 5. The compound of claim 4, wherein Z and V taken together are selected from the group consisting of
- 6. The compound of claim 5, wherein E¹and E²are both C;
  - and E³and E⁴are both N.
- 7. The compound of claim 6, wherein A¹, A², A³and A⁴are all C, and J¹, J², J³, J⁴and J⁵are all C.
- 8. The compound of claim 7, wherein the subscript g is 0 or 1;
  - the subscript c is 0 or 1; and
    
    the subscript b is 0, 1 or 2.
- 9. The compound of claim 8, wherein R¹is halo, C_1-3alkyl or CF₃;
  - g is 0 or g is 1 and R²is CH₃; and
    
    R³is C_1-4alkyl or halo.
- 19. A compound or a pharmaceutically acceptable salt thereof of claim 1 or 10 selected from3-(3,5-difluoro-4-((3-isopropyl-1-phenyl-1H-pyrazol-5-yl)methoxy)phenyl)propanoic acid (55);
  - ethyl 3-(3,5-difluoro-4-((4-phenyl-1,2,3-thiadiazol-5-yl)methoxy)phenyl)propanoate (57);
    
    3-(3,5-difluoro-4-((1-phenyl-1H-imidazol-5-yl)methoxy)phenyl)propanoic acid (59);
    
    2-(2-(4-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluoro-phenyl)cyclopropyl)acetic acid (62);
    
    3-(3,5-difluoro-4-((1-phenyl-1H-1,2,3-triazol-5-yl)methoxy)phenyl)propanoic acid (65);
    
    2-(2-(3,5-difluoro-4-((5-methyl-3-phenylisoxazol-4-yl)methoxy)phenyl)cyclopropyl)-acetic acid (67);
    
    3-(3,5-difluoro-4-((1-isobutyl-3-methyl-1H-pyrazol-5-yl)methoxy)phenyl)propanoic acid (68);
    
    2-(2-(3,5-difluoro-4-((1-isobutyl-3-methyl-1H-pyrazol-5-yl)methoxy)phenyl)-cyclopropyl)acetic acid (69);
    
    2-(3,5-Difluoro-4-((1-isobutyl-3-methyl-1H-pyrazol-5-yl)methoxy)phenyl)-cyclopropanecarboxylic acid (70);
    
    3-(3,5-difluoro-4-((5-phenyloxazol-4-yl)methoxy)phenyl)propanoic acid (71);
    
    3-(4-((1-benzyl-1H-imidazol-2-yl)methoxy)-3,5-difluorophenyl)propanoic acid (72);
    
    3-(3,5-difluoro-4-((5-methyl-2-phenylfuran-3-yl)methoxy)phenyl)propanoic acid (73);
    
    3-(3,5-difluoro-4-((1-methyl-5-phenyl-1H-pyrazol-4-yl)methoxy)phenyl)propanoic acid (74);
    
    3-(3,5-difluoro-4-((5-methyl-3-phenylisoxazol-4-yl)methoxy)phenyl)propanoic acid (75);
    
    3-(3,5-difluoro-4-((3-methyl-5-phenylisoxazol-4-yl)methoxy)phenyl)propanoic acid (76);
    
    2-(3,5-difluoro-4-((5-methyl-3-phenylisoxazol-4-yl)methoxy)phenyl)cyclopropanecarboxylic acid (77);
    
    2-(3,5-difluoro-4-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)phenyl)cyclopropanecarboxylic acid (78);
    
    3-(3,5-difluoro-4-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)phenyl)propanoic acid (79);
    
    3-(4-((3′
    
    ,5-dimethyl-3,5′
    
    -biisoxazol-4′
    
    -yl)methoxy)-3,5-difluorophenyl)propanoic acid (80);
    
    3-(4-((3-(1H-pyrrol-1-yl)thiophen-2-yl)methoxy)-3,5-difluorophenyl)propanoic acid (81);
    
    3-(3,5-difluoro-4-((3-(4-methoxyphenyl)-5-methylisoxazol-4-yl)methoxy)phenyl)propanoic acid (82);
    
    3-(4-((3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl)methoxy)-3,5-difluorophenyl)propanoic acid (83);
    
    3-(4-((3,5-dimethylisoxazol-4-yl)methoxy)-3,5-difluorophenyl)propanoic acid (84);
    
    3-(4-((3-(4-chlorophenyl)-5-methylisoxazol-4-yl)methoxy)-3,5-difluorophenyl)propanoic acid (85);
    
    3-(3,5-difluoro-4-((1-isopropyl-3-methyl-1H-pyrazol-5-yl)methoxy)phenyl)propanoic acid (86);
    
    3-(3,5-difluoro-4-(2-(5-methyl-3-phenylisoxazol-4-yl)-2-oxoethoxy)phenyl)propanoic acid (87);
    
    3-(4-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)butanoic acid (88);
    
    3-(3,5-difluoro-4-((5-phenylthiazol-4-yl)methoxy)phenyl)propanoic acid (89);
    
    2-(4-((4-phenyl-1,2,3-thiadiazol-5-yl)methoxy)phenylthio)acetic acid (90);
    
    3-(3,5-difluoro-4-((2-methyl-4-phenylthiazol-5-yl)methoxy)phenyl)propanoic acid (91);
    
    3-(3,5-difluoro-4-((4-(4-fluorophenyl)-1,2,3-thiadiazol-5-yl)methoxy)phenyl)propanoic acid (92);
    
    3-(4-((4-(3-chlorophenyl)-1,2,3-thiadiazol-5-yl)methoxy)-3,5-difluorophenyl)propanoic acid (93);
    
    2-(3,5-difluoro-4-((2-methyl-4-phenylthiazol-5-yl)methoxy)phenyl)cyclopropane carboxylic acid (94);
    
    2-(3,5-difluoro-4-((5-methyl-3-phenylisoxazol-4-yl)methoxy)benzyloxy)acetic acid (95);
    
    2-(4-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorobenzyloxy)acetic acid (96);
    
    3-(4-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)-2-methylpropanoic acid (97);
    
    3-(3,5-difluoro-4-((5-methyl-3-phenylisoxazol-4-yl)methoxy)phenyl)-2-methylpropanoic acid (98);
    
    3-(4-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)-2,2-dimethylpropanoic acid (99);
    
    2-(6-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid (100);
    
    2-(6-((5-methyl-3-phenylisoxazol-4-yl)methoxy)-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid (101);
    
    3-(4-((1-tert-butyl-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)propanoic acid (102);
    
    3-(3,5-difluoro-4-((2-methyl-4-phenylthiazol-5-yl)methoxy)phenyl)-2-methylpropanoic acid (103);
    
    (R)-3-(4-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)-2-methylpropanoic acid (104);
    
    (S)-3-(4-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)-2-methylpropanoic acid (105);
    
    4-(4-((3-methyl-1-phenyl-1H-pyrazol-5-yl)methoxy)phenyl)butanoic acid (106);
    
    3-(3,5-difluoro-4-((3-methyl-1-phenyl-1H-pyrazol-5-yl)methoxy)phenyl)propanoic acid (107);
    
    3-(3,5-difluoro-4-((1-(4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)phenyl) propanoic acid (108);
    
    3-(3,5-difluoro-4-((1-phenyl-1H-pyrazol-5-yl)methoxy)phenyl)propanoic acid (109);
    
    3-(3,5-difluoro-4-((1-(4-methoxyphenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)phenyl)propanoic acid (110);
    
    3-(4-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)propanoic acid (111);
    
    3-(3,5-difluoro-4-((1-(4-fluorophenyl)-4-methyl-1H-pyrazol-5-yl)methoxy)phenyl)propanoic acid (112);
    
    3-(4-((4-(4-chlorophenyl)-1,2,3-thiadiazol-5-yl)methoxy)-3,5-difluorophenyl)-2,2-difluoropropanoic acid (113);
    
    3-(4-((1-(3,4-difluorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)propanoic acid (114);
    
    3-(4-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)-2-fluoropropanoic acid (115);
    
    2-(4-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorobenzyl)cyclopropanecarboxylic acid (116);
    
    3-(4-((1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)propanoic acid (117);
    
    3-(4-((1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)-2,2-difluoropropanoic acid (118);
    
    2-(5-((5-methyl-3-phenylisoxazol-4-yl)methoxy)-2,3-dihydro-1H-inden-1-yl)acetic acid (119);
    
    2-(5-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-2,3-dihydro-1H-inden-1-yl)acetic acid (120);
    
    2-(5-((5-methyl-3-phenylisoxazol-4-yl)methoxy)-2,3-dihydro-1H-inden-1-yl)propanoic acid (121);
    
    2-(5-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-2,3-dihydro-1H-inden-1-yl)propanoic acid (122);
    
    3-(4-((4-(4-chlorophenyl)-1,2,3-thiadiazol-5-yl)methoxy)-3,5-difluorophenyl)propanoic acid (123);
    
    2-(3,5-difluoro-4-((4-phenyl-1,2,3-thiadiazol-5-yl)methoxy)phenyl)cyclopropane carboxylic acid (124);
    
    2-(3,5-difluoro-4-((3-methyl-1-phenyl-1H-pyrazol-5-yl)methoxy)phenyl)cyclopropane carboxylic acid (125);
    
    3-(3,5-difluoro-4-((1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methoxy)phenyl)propanoic acid (126);
    
    4-(4-((4-(4-chlorophenyl)-1,2,3-thiadiazol-5-yl)methoxy)phenyl)-4-oxobutanoic acid (128);
    
    (E)-4-(4-((4-(4-chlorophenyl)-1,2,3-thiadiazol-5-yl)methoxy)phenyl)-3-methylbut-2-enoic acid (130);
    
    (E)-5-(4-((4-(4-chlorophenyl)-1,2,3-thiadiazol-5-yl)methoxy)phenyl)-3-methylpent-2-enoic acid (131);
    
    5-(4-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)phenyl)-3-methyl pentanoic acid (132);
    
    4-(4-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)phenyl)-3-methylbutanoic acid (133);
    
    3-(4-((4-(3,4-difluorophenyl)-1,2,3-thiadiazol-5-yl)methoxy)-3,5-difluorophenyl)propanoic acid (134);
    
    3-(4-((1-(3,4-dichlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)propanoic acid (135);
    
    3-(4-((4-isopropoxy-2-methylthiazol-5-yl)methoxy)phenyl)propanoic acid (136);
    
    3-(3,5-difluoro-4-((1-(4-isopropylphenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)phenyl)-2-methylpropanoic acid (137);
    
    3-(3,5-difluoro-4-((3-methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)methoxy)phenyl)-2-methylpropanoic acid (138);
    
    3-(4-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3-(trifluoromethyl)phenyl)-2-methylpropanoic acid (139);
    
    3-(4-((1-(4-carbamoylphenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)-2-methylpropanoic acid (140);
    
    3-(4-((1-(4-cyanophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)-2-methylpropanoic acid (141);
    
    3-(4-((1-(2,3-dihydro-1H-inden-5-yl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)-2-methylpropanoic acid (142);
    
    3-(4-((1-(4-butylphenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)-2-methylpropanoic acid (143);
    
    3-(4-((1-(4-ethylphenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)-2-methylpropanoic acid (144);
    
    3-(3,5-difluoro-4-((3-methyl-1-p-tolyl-1H-pyrazol-5-yl)methoxy)phenyl)-2-methylpropanoic acid (145);
    
    3-(3,5-difluoro-4-((1-(3-isopropylphenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)phenyl)-2-methylpropanoic acid (146);
    
    3-(4-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)phenyl)-2-methylpropanoic acid (147);
    
    3-(4-((1-(3,4-dimethylphenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)-2-methylpropanoic acid (148);
    
    3-(4-((1-(3-chloro-4-methylphenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)-2-methylpropanoic acid (149);
    
    3-(4-((1-(3-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)-2-methylpropanoic acid (150);
    
    3-(4-((1-(4-ethylphenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3-fluorophenyl)-2-methylpropanoic acid (151);
    
    3-(3,5-difluoro-4-((1-phenyl-1H-pyrazol-5-yl)methoxy)phenyl)-2-methylpropanoic acid (152);
    
    3-(4-((1-(3,5-dimethylphenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)-2-methylpropanoic acid (153);
    
    3-(4-((1-(4-chlorophenyl)-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)-2-methylpropanoic acid (154);
    
    3-(4-((1-(4-chloro-3-methylphenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)-2-methylpropanoic acid (155);
    
    3-(4-((1-(4-ethylphenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3-methylphenyl)-2-methylpropanoic acid (156);
    
    3-(4-((1-(4-ethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)-2-methylpropanoic acid (157);
    
    3-(4-((1-(4-bromophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)-2-methylpropanoic acid (158);
    
    (R)-3-(4-((1-(4-ethylphenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)-2-methylpropanoic acid (159);
    
    (S)-3-(4-((1-(4-ethylphenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)-2-methylpropanoic acid (160);
    
    3-(4-((1-(4-ethylphenyl)-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)-2-methylpropanoic acid (161);
    
    3-(4-((1-(4-chlorophenyl)-3-ethyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)-2-methylpropanoic acid (162);
    
    3-(4-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)-2-ethoxypropanoic acid (163);
    
    3-(4-((1-(4-Chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-2-methoxyphenyl)-2-methylpropanoic acid (164);
    
    3-(4-((1-(4-Cyclohexylphenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)-2-methylpropanoic acid (165);
    
    3-(3,5-Difluoro-4-((3-methyl-1-(4-propylphenyl)-1H-pyrazol-5-yl)methoxy)phenyl)-2-methylpropanoic acid (166);
    
    2-(5-((1-(4-Chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-6-fluoro-2,3-dihydro-1H-inden-1-yl)acetic acid (167);
    
    2-(4-((1-(4-Chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)cyclopent-1-enecarboxylic acid (168);
    
    3-(4-((1-(4-Chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3-fluorophenyl)-2-methylpropanoic acid (169);
    
    3-(4-((1-(4-Chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3-methylphenyl)-2-methylpropanoic acid (170);
    
    3-(4-((1-(5-Chloropyrimidin-2-yl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)-2-methylpropanoic acid (171);
    
    3-(4-((1-(4-Chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)benzylidene)cyclobutanecarboxylic acid (172);
    
    3-(4-((1-(4-Chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3-methoxyphenyl)-2-methylpropanoic acid (173);
    
    3-(3,5-Dichloro-4-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)phenyl)-2-methylpropanoic acid (174);
    
    3-(3,5-Difluoro-4-((1-methyl-5-phenoxy-3-(trifluoromethyl)-1H-pyrazol-4-yl)methoxy)phenyl)-2-methylpropanoic acid (175);
    
    3-(4-((5-(4-Chlorophenoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methoxy)-3,5-difluorophenyl)-2-methylpropanoic Acid (176);
    
    3-(3,5-Difluoro-4-((5-methyl-2-phenylfuran-3-yl)methoxy)phenyl)-2-methylpropanoic acid (177);
    
    3-(4-((1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)-2-methylpropanoic acid (178);
    
    3-(4-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-2-ethylphenyl)propanoic acid (179);
    
    2-(5-((1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methoxy)-2,3-dihydro-1H-inden-1-yl)acetic acid (180);
    
    2-(5-((1-(2,3-dihydro-1H-inden-5-yl)-3-methyl-1H-pyrazol-5-yl)methoxy)-2,3-dihydro-1H-inden-1-yl)acetic acid (181);
    
    2-(5-((1-(4-ethylphenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-2,3-dihydro-1H-inden-1-yl)acetic acid (182);
    
    3-(3,5-difluoro-4-((3-methyl-1-phenyl-1H-pyrazol-5-yl)methoxy)phenyl)-2-methylpropanoic acid (183);
    
    2-(6-((1-(4-ethylphenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-1,2,3,4-tetrahydronaphthalen-1-yl)acetic acid (184);
    
    3-(3,5-difluoro-4((3-methyl-1-(pyridin-2-yl)-1H-pyrazol-5-yl)methoxy)phenyl)-2-methylpropanoic acid (185);
    
    3-(4-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)phenyl)-3-methylbutanoic acid (186);
    
    3-(4-((1-(4-ethylphenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)phenyl)-3-methylbutanoic acid (187);
    
    4-(4-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)phenyl)butanoic acid (188);
    
    4-(4-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)butanoic acid (189);
    
    4-(4-((1-(4-ethylphenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)phenyl)butanoic acid (190);
    
    4-(4-((1-(4-ethylphenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3,5-difluorophenyl)butanoic acid (191);
    
    4-(4-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)phenyl)-2-methylbutanoic acid (192);
    
    4-(4-((1-(4-ethylphenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)phenyl)-2-methylbutanoic acid (193);
    
    3-(4-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3-methoxyphenyl)propanoic acid (194);
    
    3-(4-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-3-fluoro-2-methylphenyl)propanoic acid (195);
    
    3-(4-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-2-ethyl-3-fluorophenyl)propanoic acid (196);
    
    3-(4-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-2,3-dimethylphenyl)propanoic acid (197);
    
    3-(4-((1-(4-chlorophenyl)-1H-pyrazol-5-yl)methoxy)-3-fluoro-2-methylphenyl)propanoic acid (198);
    
    3-(4-((1-(4-chlorophenyl)-1H-pyrazol-5-yl)methoxy)-2,3-dimethylphenyl)propanoic acid (199);
    
    3-(4-((3-(4-chlorophenyl)-5-methylisoxazol-4-yl)methoxy)-2,3-dimethylphenyl)propanoic acid (200);
    
    3-(4-((1-(4-ethylphenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-2,3-dimethylphenyl)propanoic acid (201);
    
    3-(4-((1-(4-ethylphenyl)-1H-pyrazol-5-yl)methoxy)-2,3-dimethylphenyl)propanoic acid (202);
    
    3-(4-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-5,6,7,8-tetrahydro naphthalen-1-yl)propanoic acid (203); and
    
    3-(7-((1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)propanoic acid (207).
- 20. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
- 21. A method of treating a disease or condition selected from the group consisting of Type I diabetes, Type II diabetes and metabolic syndrome, said method comprising administering to a mammal in need of such treatment an effective amount of a compound of claim 1.
- 22. The method of claim 21, wherein said disease is Type II diabetes.
- 23. A method of stimulating insulin production, said method comprising administering an effective amount of a compound of claim 1 to a mammal in need of such treatment.
- 24. The method of claim 23, wherein said mammal is a human.
- 25. A method of lowering blood glucose in a mammal, said method comprising administering an effective amount of a compound of claim 1 to a mammal in need of such treatment.
- 26. The method of claim 25, wherein said mammal is a human.
- 27. A method of modulating GPR120 activity in a cell, said method comprising contacting said cell with an effective amount of a compound of claim 1.

10. A compound of Formula (C) or a pharmaceutically acceptable salt thereof, wherein:
- represents a 5-10 membered monocyclic or bicyclic aryl group, a 5-10 membered monocyclic or bicyclic heteroaryl group, a 5-10 membered monocyclic or bicyclic cycloalkyl group, a 5-10 membered monocyclic or bicyclic heterocycloalkyl group, or a 8-10 membered bicyclic group wherein an aryl or a 5-6 membered heteroaryl ring is fused to a 5-6 membered cycloalkyl or heterocycloalkyl ring;
  
  E¹, E²and E³are independently selected from the group consisting of C, N and O;
  
  X is selected from the group consisting of —
  
  CH₂— and
  
  —
  
  C(O)CH₂—
  
  ;
  
  Y is selected from the group consisting of —
  
  CH₂— and
  
  —
  
  O—
  
  ;
  
  Z is selected from the group consisting of —
  
  (CR⁴R⁵)_n—
  
  , —
  
  S—
  
  , —
  
  C(O)—
  
  , and —
  
  CR⁴═
  
  CR⁵—
  
  ;
  
  V is selected from the group consisting of a bond, —
  
  (CR⁴R⁵)_n—
  
  , —
  
  CR⁴═
  
  CR⁵—
  
  , and —
  
  O—
  
  CR⁴R⁵—
  
  ;
  
  W is selected from the group consisting of H, C_1-6alkyl and substituted C_1-6alkyl;
  
  R¹is independently selected from the group consisting of halo, C_1-6alkyl, substituted C_1-6alkyl, C_3-7cycloalkyl, substituted C_3-7cycloalkyl, C_2-6alkenyl, substituted C_2-6alkenyl, C_2-6alkynyl, substituted C_2-6alkynyl, CN, —
  
  OR^a, —
  
  NR^aR^b, —
  
  C(O)R^a, —
  
  C(O)OR^a, —
  
  NR^aC(O)R^b, —
  
  SR^a, —
  
  S(O)R^aand —
  
  S(O)₂R^a;
  
  R²is independently selected from the group consisting of halo, C_1-6alkyl, substituted C_1-6alkyl, C_3-7cycloalkyl, substituted C_3-7cycloalkyl, C_2-6alkenyl, substituted C_2-6alkenyl, C_2-6alkynyl, substituted C_2-6alkynyl, aryloxy, -substituted aryloxy, CN, —
  
  OR^a, —
  
  NR^aR^b, —
  
  C(O)R^a, —
  
  C(O)OR^a, —
  
  C(O)NR^aR^b, —
  
  NR^aC(O)R^b, —
  
  SR^a, —
  
  S(O)R^aand —
  
  S(O)₂R^a;
  
  each of R^aand R^bis independently selected from the group consisting of H, C_1-6alkyl, substituted C_1-6alkyl, C_3-7cycloalkyl, C_2-6alkenyl and C_2-6alkynyl;
  
  R⁴is independently selected from the group consisting of H, halo, C_1-6alkyl, substituted C_1-6alkyl, C_1-6alkoxy and substituted C_1-6alkoxy;
  
  R⁵is independently selected from the group consisting of H, halo, C_1-6alkyl, substituted C_1-6alkyl and C_1-6alkoxy;
  
  optionally R⁴and R⁵cyclize to form a C_3-7saturated ring or a spiro C_3-7cycloalkyl group;
  
  R⁶is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl;
  
  the subscript b is 0, 1, 2, 3 or 4;
  
  the subscript g is 0, 1, 2 or 3 and;
  
  the subscript n is independently 0, 1 or 2;
  
  with the proviso that the compound is not methyl 3-(4-((3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl)methoxy)phenyl)propanoate, 3-(4-((3-(2-chloro-6-methylphenyl)-5-isopropylisoxazol-4-yl)methoxy)phenyl)propanoic acid, 3-(4-((3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl)methoxy)phenyl)propanoic acid, ethyl 3-(4-((4-(3-chlorophenyl)-2-(trifluoromethyl)furan-3-yl)methoxy)-2-methylphenyl)propanoate and 3-(3-fluoro-5-methyl-4-((3-methyl-5-phenylisoxazol-4-yl)methoxy)phenyl)propanoic acid.
- View Dependent Claims (11, 12, 13, 14, 15, 16, 17, 18)
- - 11. The compound of claim 10, wherein:
    - X is —
      
      CH₂—
      
      ;
      
      Y is —
      
      O—
      
      ;
      
      Z is —
      
      (CR⁴R⁵)_n; and
      
      V is a bond.
  - 12. The compound of claim 11, wherein Q is selected from the group consisting of
- 13. The compound of claim 10 of Formula (D) or a pharmaceutically acceptable salt thereof, wherein:
  - A¹, A², A³and A⁴are independently selected from the group consisting of C and N, with the proviso that only 0, 1 or 2 of A¹, A², A³and A⁴is N;
    
    J¹, J², J³, J⁴and J⁵are independently selected from the group consisting of N and C, with the proviso that only 0, 1 or 2 of J¹, J², J³, J⁴and J⁵is N;
    
    each R³is independently selected from the group consisting of halo, C_1-6alkyl, substituted C_1-6alkyl, C_3-7cycloalkyl, substituted C_3-7cycloalkyl, C_2-6alkenyl, substituted C_2-6alkenyl, C_2-6alkynyl, substituted C_2-6alkynyl, cyano, —
    
    OR^a, —
    
    NR^aR^b, —
    
    C(O)R^a, —
    
    C(O)OR^a, —
    
    C(O)NR^aR^b, —
    
    NR^aC(O)R^b, —
    
    SR^a, —
    
    S(O)R^aand —
    
    S(O)₂R^a;
    
    the subscript c is 0, 1, 2 or 3; and
    
    E¹, E², E³, R¹, R², Z, V, R^a, R^b, subscript b and subscript g are as previously defined.
- 14. The compound of claim 13, wherein Z and V taken together are selected from the group consisting of
- 15. The compound of claim 14, wherein E¹is C and one of E²and E³is N and the other of E²and E³is O or N.
- 16. The compound of claim 15, wherein A¹, A², A³and A⁴are all C, and J¹, J², J³, J⁴and J⁵are all C.
- 17. The compound of claim 16, wherein the subscript g is 0 or 1;
  - the subscript c is 0 or 1 and the subscript b is 0, 1 or 2.
- 18. The compound of claim 17, wherein R¹is halo, C_1-3alkyl or CF₃;
  - g is 0 or g is 1 and R²is CH₃; and
    
    R³is C_1-4alkyl or halo.

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Current Assignee
CymaBay Therapeutics Inc. (Gilead Sciences Inc.)
Original Assignee
Metabolex Inc (Gilead Sciences Inc.)
Inventors
Shi, Dong Fang, Novack, Aaron, Pham, Phuongly, Chen, Xin, Song, Jiangao, Zhao, Zuchun, Ma, Jingyuan, Rabbat, Christopher J., Nashashibi, Imad, Choi, Yun-Jung

Application Number

US12/582,610
Publication Number

US 20100216827A1
Time in Patent Office

Days
Field of Search
US Class Current

514/275
CPC Class Codes

A61P 3/00   Drugs for disorders of the ...

A61P 3/06   Antihyperlipidemics

A61P 3/10   for hyperglycaemia, e.g. an...

A61P 5/50   for increasing or potentiat...

C07D 231/12   with only hydrogen atoms, h...

C07D 233/64   with substituted hydrocarbo...

C07D 249/06   with aryl radicals directly...

C07D 261/08   with only hydrogen atoms, h...

C07D 263/32   with only hydrogen atoms, h...

C07D 277/24   Radicals substituted by oxy...

C07D 285/06   1,2,3-Thiadiazoles; Hydroge...

C07D 307/42   Singly bound oxygen atoms

C07D 333/16   by oxygen atoms

C07D 409/04   directly linked by a ring-m...

ARYL GPR120 RECEPTOR AGONISTS AND USES THEREOF

First Claim

4 Assignments

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Abstract

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27 Claims

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ARYL GPR120 RECEPTOR AGONISTS AND USES THEREOF

First Claim

4 Assignments

Subscription Required

Subscription Required

0 Petitions

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Accused Products

Subscription Required

Abstract

Citations

27 Claims

Specification

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Solutions

Use Cases

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