BICYCLIC CARBOXAMIDES AND METHODS OF USE THEREOF

1 .- 13 . (canceled)

14 . A method of treating cancer in a subject in need thereof, comprising: administering to the subject (i) a compound of Formula (1), 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; and (ii) a second therapy,

wherein;

X 1 is N;

X 3 is CR 3 ;

X 4 is CR 4 ,

X 5 is CR 5 ;

L 1 is —CR 2 b -;

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 2 , —NR 2 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(0) 2R 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 1 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 8 , —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 2 a ) n -, provided that Y 1 and Y 2 are not both a bond;

Z 1 and Z 2 are each —CR 2 a -;

L 2 is —(CR 2 c ) m -;

G is —C(O)OR 12 , —C(O)NHOH, —SO 3 H, —SO 2 NH 2 , —SO 2 NHR 4 , —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 e 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 Ros, 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.

15 . The method of claim 144 , 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'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.

16 . The method of claim 144 , 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 9 , —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, baloalkyl, 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; and

each R b is independently hydrogen or deuterium.

17 . The method of claim 16 , wherein the compound has a structure of the 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, isotopic variant, or prodrug thereof, wherein L 1 is —CR 2 b - and each RD is independently hydrogen or deuterium.

18 . The method of claim 16 , wherein the compound has a structure of the 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, isotopic variant, or prodrug thereof, wherein L 1 is —CR 2 b - and each RD is independently hydrogen or deuterium.

19 . The method of claim 14 , wherein Ring A is phenyl and R 1 is phenyl.

20 . The method of claim 19 , wherein R 7 is hydrogen or deuterium and wherein q is 0 or 1.

21 . The method of claim 14 , 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.

22 . The method of claim 14 , wherein the second therapy comprises a radiation therapy, an antibody, an antibody drug conjugate (ADC), an activator of stimulator of an interferon gene pathway, or a cytotoxic agent.

23 . The method of claim 14 , wherein the second therapy comprises an antibody against cytotoxic t-lymphocyte antigen 4 (anti-CTLA4), an antibody against programmed death-ligand 1 (anti-PD-L1), or antibody against programmed cell death protein 1 (anti-PD-1).

24 . The method of claim 14 , wherein the second therapy comprises a STING activator comprising ADET-S100, ADU-S100, or MK-1454.

25 . The method of claim 14 , wherein the second therapy comprise a hormone therapy, aromatase inhibitor, signaling inhibitor, anti-angiogenic agent, biologic response modifier, mammalian target of rapamycin (mTOR) inhibitor, or indoleamine 2,3-dioxygenase (IDO) inhibitor.

26 . The method of claim 14 , wherein the second therapy comprises cisplatin, dacarbazine, cyclophosphamide, chlorambucil, mechlorethamine, ifosfamide, melphalan, methotrexate, cytarabine, fludarabine, gemcitabine, 6-mercaptopurine, azathioprine, 5-fluorouracil, vincristine, vinblastine, vindesine, vinorelbine, paclitaxel, docetaxel, carboplatin, tamoxifen, oxaliplatin, bicalutamide, anastrozole, exemestane, letrozole, imatinib, gefitinib, erlotinib, sorafenib, pazopanib, sunitinib, interferon-alpha, tivozanib, axitinib, cediranib, camptothecin, amsacrine, etoposide, etoposide phosphate, teniposide, daunorubicin, epirubicin, idarubicin, sabarubicin, carubicin, valrubicin, aclarubicin, topotecan, doxorubicin, rapamycin, temsirolimus, everolimus, epacadostat, indoximod, BMS-986205, anthracycline, actinomycin, bleomycin, plicamycin, or mitomycin.

27 . The method of claim 14 , wherein the second therapy comprises nivolumab, pembrolizumab, trastuzumab, pertuzumab, inotuzumab, ozogamicin, trastuzumab emtansine, or bevacizumab.

28 . The method of claim 14 , wherein the second therapy is administered separately from the compound.

29 . The method of claim 14 , wherein the second therapy is co-administered with the compound.

30 . The method of claim 14 , wherein the cancer comprises an EP2-mediated cancer or EP4-mediated cancer.

31 . The method of claim 14 , wherein the cancer comprises brain cancer, bone cancer, sarcoma, head and neck cancer, retinoblastoma, thyroid cancer, leukemia, skin cancer, basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, oral cancer, esophageal cancer, stomach cancer, gastric cancer, bile duct cancer, intestinal cancer, colon cancer, bladder cancer, liver cancer, renal cancer, pancreatic cancer, ovarian cancer, endometrial cancer, cervical cancer, uterine cancer, ureteral cancer, lung cancer, breast cancer, or prostate cancer.

32 . The method of claim 14 , wherein the cancer comprises glioblastoma, medulloblastoma, colorectal cancer (CRC), acute myeloid leukemia, squamous cell carcinoma of the head and neck (SCCHN), melanoma, hepatocellular carcinoma, or renal cell carcinoma.

33 . The method of claim 14 , 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, isotopic variant, or prodrug thereof, and a pharmaceutically acceptable carrier.