Bicyclic carboxamides and methods of use thereof

1. A method for the treatment of an EP4-mediated cancer in a patient comprising administering to the patient a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers, isotopic variant, or prodrug thereof:

wherein:

X 1 is N;

X 3 is CR 3 ;

X 4 is CR 4 ;

X 5 is CR 5 ;

L 1 is —CR b 2 —;

Ring A is aryl;

R 1 is aryl optionally substituted with one, two, or three R y ;

each R y is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, halogen, —OR 8 , —NR 8 R 9 , —CN, —C(O)R 11 , —C(O)NR 8 R 9 , —NR 8 C(O)R 11 , —NR 8 C(O)OR 9 , —NR 10 C(O)NR 8 R 9 , —OC(O)NR 8 R 9 , —S(O) 2 R 11 , —S(O)R 11 , —SR 8 , —S(O) 2 NR 8 R 9 , —S(O)NR 8 R 9 , —NR 8 S(O)R 11 , —NR 8 S(O) 2 R 11 , or —NR 10 S(O) 2 NR 8 R 9 ; wherein the alkyl is optionally substituted with —OR 8 or —NR 8 R 9 and wherein the cycloalkyl and heterocyclyl are optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl;

each R x is independently halogen, methyl, C 1 haloalkyl, or —CN;

R 2 , R 3 , R 4 , and R 5 are each independently hydrogen, alkyl, halogen, —OR, —NR 8 R 9 , —SR 8 , —S(O)R 11 , —S(O) 2 R 11 , —CN, cycloalkyl, or haloalkyl;

R 6 is hydrogen, alkyl, or haloalkyl;

R 7 is hydrogen, halogen, alkyl, alkoxy, haloalkoxy, hydroxyl, or haloalkyl;

each R 8 and each R 9 are independently hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl; or

R 8 and R 9 , together with the atom or atoms to which they are attached, form a heterocyclyl optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl;

each R 10 is independently hydrogen or alkyl;

each R 11 is independently alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl;

Y 1 and Y 2 are each independently a bond or —(CR a 2 ) n —, provided that Y 1 and Y 2 are not both a bond;

Z 1 and Z 2 are each —CR a 2 —;

L 2 is —(CR c 2 ) m —;

G is —C(O)OR 12 , —C(O)NHOH, —SO 3 H, —SO 2 NH 2 , —SO 2 NHR d , —SO 2 NHC(O)R d , —NHC(O)NHSO 2 R d , -1H-tetrazolyl, —P(O)(OH) 2 , -1,2,4-oxadiazol-5(4H)-one, -tetrazol-5(4H)-one, or —C(O)NHSO 2 R d ;

R 12 is selected from H, C 1 -C 6 alkyl, aryl, aralkyl, CH(R 13 )OC(═O)R 14 , CH(R 13 )OC(═O)OR 14 and a (5-alkyl-2-oxo-1,3-dioxolen-4-yl)methyl group having the following formula:

wherein R c is C 1 -C 6 alkyl;

R 13 is hydrogen or C 1 -C 6 alkyl;

R 14 is C 1 -C 6 alkyl or C 3 -C 6 -cycloalkyl;

each R a is independently hydrogen, alkyl, halogen, or haloalkyl;

each R b is independently hydrogen, alkyl or haloalkyl, or two R b s, together with the carbon atom to which they are attached, form a cycloalkyl or a heterocyclyl;

each R c is independently hydrogen or halogen;

R d is alkyl, haloalkyl, cycloalkyl, aryl, or heteroaryl;

m is 0, 1, or 2;

each n is independently 1, 2, or 3;

p is 1; and

q is 0, 1, or 2.

2. The method of claim 1 , wherein:

R 2 , R 3 , R 4 , and R 5 are each independently hydrogen, alkyl, halogen, —OR 8 , —CN, cycloalkyl, or haloalkyl; each R b is independently hydrogen, deuterium, optionally deuterated alkyl or haloalkyl, or two R b s, together with the carbon atom to which they are attached, form optionally deuterated cycloalkyl; and

each R 8 is independently hydrogen, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl.

3. The method of claim 1 , wherein:

each R y is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, halogen, —OR 8 , —NR 8 R 9 , —CN, —C(O)R 11 , —C(O)NR 8 R 9 , —NR 8 C(O)R 11 , —NR 8 C(O)OR 9 , —NR 10 C(O)NR 8 R 9 , —OC(O)NR 8 R 9 , —S(O) 2 R 11 , —S(O)R 11 , —SR 8 , —S(O) 2 NR 8 R 9 , —NR 8 S(O) 2 R 11 , or —NR 10 S(O) 2 NR 8 R 9 wherein alkyl is optionally substituted with —OR 8 or —NR 8 R 9 and wherein cycloalkyl and heterocyclyl are optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl;

each R 8 and each R 9 are independently hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl; or

R 8 and R 9 , together with the atom or atoms to which they are attached, form a heterocyclyl optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl;

each R 10 is independently hydrogen or alkyl;

each R 11 is independently alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl; and

each R b is independently hydrogen or deuterium.

4. The method of claim 3 , wherein the compound is of Formula (II):

or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers, or prodrug thereof, wherein L 1 is —CR b 2 — and each R b is independently hydrogen or deuterium.

5. The method of claim 3 , wherein the compound is of Formula (IIc):

or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers, or prodrug thereof, wherein L 1 is —CR b 2 — and each R b is independently hydrogen or deuterium.

6. The method of claim 5 wherein:

R 3 , R 4 , and R 5 are each independently hydrogen, alkyl, halogen, —OR 8 , —NR 8 R 9 , —S(O)R 11 , —S(O) 2 R 11 , —CN, cycloalkyl, or haloalkyl; and

each R 8 and each R 9 are independently hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl; or

R 8 and R 9 , together with the atom or atoms to which they are attached, form a heterocyclyl optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl; and

each R 11 is independently alkyl, deuterated alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl.

7. The method of claim 6 , wherein:

one of R 3 , R 4 , and R 5 is alkyl, halogen, —OR 8 , —NR 8 R 9 , —SR 8 , —S(O)R 11 , —S(O) 2 R 11 , —CN, cycloalkyl, or haloalkyl and the remainder of R 3 , R 4 , and R 5 , when present, are hydrogen.

8. The method of claim 7 , wherein:

one of R 3 or R 4 is halogen and the other of R 3 and R 4 , when present, is hydrogen and R 5 is hydrogen.

9. The method of claim 8 , wherein:

R 1 is aryl optionally deuterated and optionally substituted with one or two R y ;

each R y is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, halogen, —OR 8 , —NR 8 R 9 , —CN, —C(O)R 11 , —C(O)NR 8 R 9 , —NR 8 C(O)R 11 , —NR 8 C(O)OR 9 , —NR 10 C(O)NR 8 R 9 , —OC(O)NR 8 R 9 , —S(O) 2 R 11 , —S(O)R 11 , —SR 8 , —S(O) 2 NR 8 R 9 , —S(O)NR 8 R 9 , —NR 8 S(O)R 11 , —NR 8 S(O) 2 R 11 , or —NR 10 S(O) 2 NR 8 R 9 ; wherein alkyl is optionally substituted with —OR 8 or —NR 8 R 9 and wherein cycloalkyl and heterocyclyl are optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl;

each R 8 and each R 9 are independently hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl; or

R 8 and R 9 , together with the atom or atoms to which they are attached, form a heterocyclyl optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl;

each R 10 is independently hydrogen, deuterium, alkyl or deuterated alkyl; and

each R 11 is independently alkyl, deuterated alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, alkyl, and haloalkyl.

10. The method of claim 1 , wherein Ring A is phenyl and R 1 is phenyl.

11. The method of claim 10 , wherein R 7 is hydrogen or deuterium.

12. The method of claim 11 , wherein q is 0 or 1.

13. The method of claim 1 , wherein the compound is selected from:

or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers, isotopic variant, or prodrug thereof.

14. The method of claim 1 , further comprising administering a pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers, or prodrug thereof, and a pharmaceutically acceptable carrier.

15. The method of claim 1 , wherein said EP4-mediated cancer is selected from glioblastoma, bone cancer, head and neck cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, colon cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer and prostate cancer.

16. The method of claim 15 , wherein said EP4-mediated cancer is selected from colon cancer, bladder cancer, hepatocellular carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer.

17. The method of claim 1 , wherein said EN-mediated cancer selected from colorectal cancer (CRC), lung cancer, squamous cell carcinoma of the head and neck (SCCHN), bladder cancer, endometrial cancer, and gastric cancer.

18. The method of claim 1 , wherein said EP4-mediated cancer is colorectal cancer (CRC).