Heterocyclic compounds useful in the treatment of disease

1. A compound wherein the compound has the structure of Formula I,

or a pharmaceutically acceptable salt or prodrug thereof,

wherein R A is —CO 2 H, —CO 2 R B , —CN, tetrazolyl, —C(═O)NH 2 , —C(═O)NHR B , —C(═O)NHSO 2 R B or —C(═O)NHCH 2 CH 2 SO 3 H or a carboxylic acid isostere selected from the group consisting of;

and wherein R B is —H or —C 1 -C 4 alkyl, or has the structure of one of:

L 1 is absent or substituted or unsubstituted C 1 -C 6 alkylene, substituted or unsubstituted C 3 -C 6 cycloalkylene, substituted or unsubstituted C 1 -C 6 fluoroalkylene, substituted or unsubstituted C 1 -C 6 heteroalkylene;

L 2 is absent;

Ring B has the structure of:

and is substituted or unsubstituted arylene, or substitured or unsubstituted heteroarylene, where when Ring B is substituted then Ring B is substituted with 1, 2, or 3 independently selected R H ,

wherein A 1 , A 2 and A 3 are independently N or C;

Ring A is a 5 membered heteroarene selected from one of:

wherein the dashed line indicates the point of attachment of Ring A to Ring B,

wherein R C is —CN, —F, —Cl, —Br, —I, —OC 1 -C 4 alkyl or C 1 -C 4 fluoroalkyl;

R D is —N(R F )—C(═O)XCH(R G )—CY, —N(R F )C(═O)XC(R G ) 2 —CY; —N(R F )C(═O)X—CY, —C(═O)N(R F )CH(R G )X—CY, or —C(═O)—N(R F )C(R G ) 2 X—CY, wherein X is absent, —O—, —NH—or —CH 2 —;

R E is —H, —C 1 -C 4 alkyl or —C 1 -C 4 fluoroalkyl;

R F is —H or C 1 -C 4 alkyl;

R G is independently selected from R E , or one R G is C 1 -C 4 alkyl and is taken together with CY and the carbon atom to which R G and CY are attached to define a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle, and the other R G , when present, is as defined for R E ;

CY is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein when CY is substituted then CY is substituted with 1, 2 , or 3 independently selected R H ;

wherein each R H is independently selected from —H, halogen, —CN, —NO 2 , —OH, —OR J , —SR J , —S(═O)R J , —S(═O) 2 R J , —N(R J )S(═O) 2 R J , —S(═O) 2 N(R L ) 2 , —C(═O)R J , OC(═O)R J , —C(═O)OR J , —OC(═O)OR J , —N(R L ) 2 , —C(═O)N(R L ) 2 , —OC(═O)N(R L ) 2 , —N(R J )C(═O)N(R L ) 2 , —N(R J )C(═O)R J , —N(R J )C(═O)OR J , C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, C 1 -C 4 alkoxy, and C 1 -C 4 heteroalkyl,

wherein each R J is independently substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C 1 -C 4 alkylene-(substituted or unsubstituted C 3 -C 6 cycloalkyl), —C 1 -C 4 alkylene-(substituted or unsubstituted heterocycloalkyl), —C 1 -C 4 alkylene- (substituted or unsubstituted aryl), or —C 1 -C 4 alkylene-(substituted or unsubstituted heteroaryl);

wherein each R L is independently —H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C 1 -C 4 alkylene-(substituted or unsubstituted cycloalkyl), —C 1 -C 4 alkylene-(substituted or unsubstituted heterocycloalkyl), —C 1 -C 4 alkylene(substituted or unsubstituted aryl), or —C 1 -C 4 alkylene-(substituted or unsubstituted heteroaryl),

or when R H is —S(═O) 2 N(R L ) 2 , —N(R L ) 2 , —C(═O)N(R L ) 2 , —OC(═O)N(R L ) 2 or N(R J )C(═O)N(R L ) 2 , each R L is independently —H or C 1 -C 6 alkyl, or the R L groups independently are C 1 -C 6 alkyl which are taken together with the N atom to which they are attached to define a substituted or unsubstituted heterocycle; and

Ring C is substituted or unsubstituted C 3 -C 10 cycloalkylene, substituted or unsubstituted C 2 -C 10 heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, where when ring C is substituted then ring C is substituted with 1, 2, or 3 independently selected R H , wherein R H is as previously defined.

2. The compound of claim 1 , wherein R D is —N(R F )—C(═O)XCH(R G )—CY, —N(R F )C(═O)XC(R G ) 2 —CY, —N(R F )C(═O)X—CY, wherein each R G is independently —H or C 1 -C 4 alkyl.

3. The compound of claim 2 , wherein Ring A has the structure:

wherein Ring B is substituted or unsubstituted arylene, and Ring C is substituted or unsubstituted arylene or is substituted or unsubstituted C 3 -C 10 cycloalkylene.

4. The compound of claim 2 wherein

L 1 is C 1 -C 6 alkylene, substituted or unsubstituted C 3 -C 6 cycloalkylene, or substituted or unsubstituted C 1 -C 6 heteroalkylene.

5. The compound of claim 2 , wherein L 1 is absent, a substituted or unsubstituted substituted C 1 -C 4 alkylene, or a substituted or unsubstituted C 3 cycloalkylene.

6. The compound of claim 2 , wherein L 1 is —CH 2 —,

or —C(CH 3 ) 2 —.

7. The compound of claim 6 , wherein R C is —F or —CF 3 , and R D is —N(R F )C(═O)XCH(R G )—CY.

8. The compound of claim 7 , wherein —X— is —NH— or —O—, and wherein R G and each R F , independently selected, are —H or —CH 3 .

9. The compound of claim 8 , wherein R G is —CH 3 , in the R or S configuration, and CY is substituted or unsubstituted phenyl or substituted or unsubstituted heteroaryl.

10. The compound of claim 9 , wherein R F is −H, X is −O−, and R D has the structure of:

11. The compound of claim 9 , wherein −R F is −H, X is −O−, and R G is in the R configuration.

12. The compound of claim 1 or 2 , wherein Ring C is substituted and unsubstituted arylene, where when Ring C is substituted, then Ring C is substituted with one R H .

13. The compound of claim 12 ,

wherein A 1 is C, A 2 is C or N, and A 3 is C, and when Ring B is substituted, then ring B is substituted with one R H ,

wherein R H is −H, halogen, −CH 3 , or −CF 3 ;

Ring A is a 5 membered heteroarene having the structure of

wherein R D is N(R F )C(═O)XCH(R G ) −CY, wherein

X is −O−,

R G is −H or −CH 3 , and

CY is phenyl substituted with one R H ;

R A is —CO 2 H or —CO 2 R B ; and

L 1 is −CH 2 − or

14. The compound of claim 2 , wherein the compound is selected from: 2-[4-[4-[5-[1-(2-chlorophenyl)ethoxycarbonylamino]-4-cyano-pyrazol-1-yl]phenyl]phenyl]acetic acid, (R)-1-(4′-{5-[1-(2-Chloro-phenyl)-ethoxycarbonylamino]-4-fluoro-pyrazol-1-yl}-3-fluoro-biphenyl-4-yl)-cyclopropanecarboxylic acid, (R)-1-(4′-{5-[1-(2-Chloro-phenyl)-ethoxycarbonylamino]-4-fluro-pyrazol-1yl}-2-fluoro-biphenyl-4-yl)-cyclopropanecarboxylic acid, (R)-1-(2-Chloro-4′-{5-[1-(2-chloro-phenyl)-ethoxycarbonylamino]-4-fluoro- pyrazol-1-yl}-biohenyl-4yl)-cyclopropanecarboxylic acid, (R)-1(4′-{5-[1-(2-Chloro-phenyl)-ethoxycarbonylamino]-4-fluoro-pyrazol-1-yl}-2-methyl-biphenyl-4-yl)-cyclopropanecarboxylic acid, (R)-1-(4′-{5-[1-(2Chloro-phenyl)-ethoxycarbonylamino]-4-fluoro-pyrazol-1-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid, (R)-1-{4′-[5-(1-Phenyl-ethoxycarbonylamino)-4-trifluoromethyl-pyrazol-1-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid, (R)-1-{2-Fluoro-4′-[5-(1-phenyl-ethoxycarbonylamino)-4-trifluoromethyl-pyrazol-1-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid, 2-[4-[4-[4-cyano-5-(1phenylethoxycarbonylamino)pyrazol-1yl]phenyl]phenyl]acetic acid, 1-[4-[4-[4-cyano-5-(1-phenylethoxycarbonylamino)pyrazol-1-yl]phenyl]phenyl]cyclopropanecarboxylic acid, 1-[4-[4-[5-[1-(2-chlorophenyl)ethoxycarbonylamino]-4-cyano-pyrazol-1-yl]phenyl]phenyl]cyclopropanecarboxylic acid, 2-[4-[4-[4-cyano-5-(1-phenylethoxycarbonylamino)pyrazol-1-yl]phenyl]phenyl]-2-methyl-propanoic acid, 2-[4-[4-[5-[1-(2-chlorophenyl)ethoxycarbonylamino]-4-cyano-pyrazol-1-yl]phenyl]phenyl]-2-methyl-propanoic acid, 1-{4′-[4-Fluoro-5-(1phenylethoxycarbonylamino)-1H-pyrazol-1-yl]-4-biphenylyl}cyclopropanecarboxlic acid, 1-(4′-{5-[1-(o-Chloropheny)ethoxycarbonylamino]-4-fluoro-1H-pyrazol-1yl}-4-biphenyly)cyclopropanecarboxlic acid, 1-{3-Fluoro-4′-[4-fluoro-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-yl]-4-biphenylyl}cyclopropanecarboxylic acid, 1-(4′-{5-[1-(o-Chlorophenyl)ethoxycarbonylamino]-4-fluoro-1H-pyrazol-1-yl}-3fluoro-4-biphenylyl)cyclopropanecarboxylic acid, 1-{2-Fluoro-4′-[4-fluoro-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-yl]-4-biphenylyl}cyclopropanecarboxylic acid, 1-(4′-{5-[1-(o-Chlorophenyl)ethoxycarbonylamino]-4-flouro-1H-pyrazol-1yl}-2-flouro-4-biphenylyl)cyclopropanecarboxylic acid, 1-(2-Chloro-4′-{5-[1-(o-chlorophenyl)ethoxycarbonylamino]-4-fluoro-1H-pyrazol-1-yl}-4-biphenylyl)cyclopropanecarboxylic acid, 1-(4-{p-[4-Fluoro-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1yl]phenyl}tolyl)cyclopropanecarboxylic acid, 1-[4-(p-{5-[1-(o-Chloropheny)ethoxycarbonylamino]-4-flouro-1H-pyrazol-1-yl}phenyl)tolyl]cyclopropanecarboxylic acid, 1-(p-{5-[4-Flouro-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-yl]-2-pyridyl}phenyl)cyclopropanecarboxylic acid, 1-[p-(5-{5-[1-(o-Chlorophenyl)ethoxycarbonylamino]-4-flouro-1H-pyrazol-1-yl}-2-pyridyl)phenyl]cyclopropanecarboxylic acid, 1(2-Fluoro-4-{5-[4-fluoro-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-yl]-2-pyridyl}phenyl)cyclopropanecarboxylic acid, 1-[4-(5-{5-[1-(o-Chlorophenyl)ethoxycarbonylamino]-4-fluoro-1H-pyrazol-1yl}-2-pyridyl)-2-fluorophenyl]cyclopropanecarboxylic acid, 1-(3-Fluoro-5-{5-[4-fluoro-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-yl]-2-pyridyl}phenyl)cyclopropanecarboxylic acid, 1-[4-(5-{5-[1-(o-Chlorophenyl)ethoxycarbonylamino]-4-fluoro-1H-pyrazol-1-yl}-2-pyridyl)-3-fluorophenyl]cyclopropanecarboxylic acid, 1-(p-{5-[4-Cyano-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-yl]-2pyridyl}phenyl)cyclopropanecarboxylic acid, 1-[p-(5-{5-[1-(o-Chlorophenyl)ethoxycarbonylamino]-4-cyano-1H-pyrazol-1yl}-2-pyridyl)phenyl]cyclopropanecarboxylic acid, 1-(4-{5-[4-Cyano-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-yl]-2-pyridyl}-2-fluorophenyl)cyclopropanecarboxylic acid, 1-[4-(5-{5-[1-(o-Chlorophenyl)ethoxycarbonylamino]-4-cyano-1H-pyrazol-1-yl}-2-pyridyl)-2-fluorophenyl]cyclopropanecarboxylic acid, 1-(4-{5-[4-Cyano-5-(1-phenylethoxycarbonylamino)-1H-pyrazol-1-yl]-2-pyridyl}-3-fluorophenyl)cyclopropanecarboxylic acid, and 1-[4-(5-{5-[1-(o-Chlorophenyl)ethoxycarbonylamino]-4-cyano-1H-pyrazol-1-yl}-2-pyridyl)-3-fluorophenyl]cyclopropanecarboxylic acid.

15. The compound of claim 14 , wherein the compound is 2-[4-[4-[5-[1-(2-chlorophenyl)ethoxycarbonylamino]-4-cyano-pyrazol-1-yl]phenyl]phenyl]acetic acid, (R)-1-(4′-{5-[1-(2-Chloro-phenyl)-ethoxycarbonylamino]-4-fluoro-pyrazol-1-yl}-3-fluoro-biphenyl-4-yl)-cyclopropanecarboxylic acid, (R)-1-(4′-{5-[1-(2-Chloro-phenyl)-ethoxycarbonylamino]-4-fluoro-pyrazol-1-yl}-2-fluoro-biphenyl-4-yl)cyclopropanecarboxylic acid, (R)-1-(2Chloro-4′-{5-[1-(2-chloro-phenyl)-ethoxycarbonylamino]-4-fluoro-pyrazol-1-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid, (R)-1-(4′-{5-[1-(2-Chloro-phenyl-ethoxycarbonylamino]-4-fluoro-pyrazol-1-yl}-2-methyl-biphenyl-4-yl)-cyclopropanecaroxylic acid, (R)-1-(4′-{5-[1-(2-Chloro-phenyl)-ethoxycarbonylamino]-4-fluoro-pyrazol-1-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid, (R)-1-{4′-[5-(1-Phenyl-ethoxycarbonylamino)-4-trifluoromethyl-pyrazol-1-yl]-biphenyl-4yl}-cyclopropanecarboxylic acid, or (R)-1-{2-Fluoro-4′-[5-(1-phenyl-ethoxycarbonylamino)-4-trifluoromethyl-pyrazol-1yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid.

16. The compound of claim 14 , wherein the compound is (R)-1-(4′-{5-[1-(2-Chloro-phenyl)-ethoxycarbonylamino]-4-fluoro-pyrazol-1-yl}-2-fluoro-biphenyl-4-yl)-cyclopropanecarboxylic acid.

17. The compound of claim 1 for preparation of medicament for treating a lysophosphatidic acid-dependent disease or condition.

18. A medicament for treating a subject with a lysophosphatidic acid-dependent disease or condition, the medicament comprising the compound of claim 1 .

19. The compound of claim 5 , wherein L 1 is cyclopropyl-di-yl.