Indane-amines as PD-L1 antagonists

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is Formula (IIb):

each of substitutents R 1a , R 1b , R 1c and R 1d is independently selected from the group consisting of H, halogen, —CN, —R c , —CO 2 R a , —CONR a R b , —C(O)R a , —OC(O)NR a R b , —NR b C(O)R a , —NR b C(O) 2 R c , —NR a —C(O)NR a R b , —NR a R b , —OR a , —O—X 1 —OR a , —O—X 1 —CO 2 R a , —O—X 1 —CONR a R b , —X 1 —OR a , —X 1 —NR a R b , —X 1 —CO 2 R a , —X 1 —CONR a R b , —SF 5 , and —S(O) 2 NR a R b , wherein each X 1 is a C 1-4 alkylene; each R a and R b is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O, and S, wherein the five or six-membered ring is optionally substituted with oxo;

each R c is independently selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, and C 1-8 haloalkyl; and optionally when two substituents are on adjacent carbon atoms of the benzene ring, they may combine to form a fused five, six or seven-membered carbocyclic or heterocyclic ring optionally substituted with from 1 to 3 substituents independently selected from halo, oxo, C 1-8 haloalkyl, and C 1-8 alkyl;

L is a linking group selected from the group consisting of:

wherein each of the subscripts q is independently 1, 2, 3, or 4, and L is optionally further substituted with one or two members selected from the group consisting of halogen, hydroxy, C 1-3 alkyl, —O—C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 haloalkyl, and —CO 2 H;

Z is selected from the group consisting of azetidinyl, pyrollidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, guanidinyl, quinuclidine, and 8-azabicyclo[3.2.1]octane, each of which is optionally substituted with from 1 to 3 groups independently selected from halogen, hydroxy, C 1-3 alkyl, —NH 2 , —NHC 1-3 alkyl, —N(C 1-3 alkyl) 2 , —O—C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 haloalkyl, and —CO 2 H;

or

Z is selected from the group consisting of —CO 2 R z1 and —NR z1 R z2 ; wherein R z1 is selected from the group consisting of H, C 1-8 alkyl, C 1-8 haloalkyl, and C 1-8 hydroxyalkyl; and R z2 is selected from —C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkyl-COOH, C 1-8 alkyl-OH, C 1-8 alkyl-CONH 2 , C 1-8 alkyl-SO 2 NH 2 , C 1-8 alkyl-PO 3 H 2 , C 1-8 alkyl-C(O)NHOH, —C(O)—C 1-8 alkyl-OH, —C(O)—C 1-8 alkyl-COOH, C 3-10 cycloalkyl, —C 3-10 cycloalkyl-COOH, —C 3-10 cycloalkyl-OH, C 4-8 heterocyclyl, —C 4-8 heterocyclyl-COOH, —C 4-8 heterocyclyl-OH, —C 1-8 alkyl-C 4-8 heterocyclyl, —C 1-8 alkyl-C 3-10 cycloalkyl, C 5-10 heteroaryl, and —C 1-8 alkyl-C 5-10 heteroaryl;

each R 2a , R 2b , and R 2c is independently selected from the group consisting of H, halogen, —CN, —R d , —CO 2 R e , —CONR e R f , —OC(O)NR e R f , —NR f C(O)R e , —NR f C(O) 2 R d , —NR e —C(O)NR e R f , —NR e R f , —OR e , —X 2 —OR e , —X 2 —NR e R f , —X 2 —CO 2 R e , —SF 5 , and —S(O) 2 NR e R f , wherein each X 2 is a C 1-4 alkylene; each R e and R f is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O, and S, and optionally substituted with oxo; and each R d is independently selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, and C 1-8 haloalkyl;

R 3 is selected from the group consisting of —NR g R h and C 4-12 heterocyclyl, wherein the C 4-12 heterocyclyl is optionally substituted with 1 to 6 R 3a ;

each R 3a is independently selected from the group consisting of

halogen, —CN, —R i , —CO 2 R j , —CONR j R k , —CONHC 1-6 alkyl-OH, —C(O)R j , —OC(O)NR j R k , —NR j C(O)R k , —NR j C(O) 2 R k , —CONHOH, —PO 3 H 2 , —NR j —X 3 —C(O) 2 R k , —NR j C(O)NR j R k , —NR j R k , —OR j , —S(O) 2 NR j R k , —O—X 3 —OR j , —O—X 3 —NR j R k , —O—X 3 —CO 2 R j , —O—X 3 —CONR j R k , —X 3 —OR j , —X 3 —NR j R k , —X 3 —CO 2 R j , —X 3 —CONR j R k , —X 3 —CONHSO 2 R j , and SF 5 ; wherein X 3 is a C 1-6 alkylene and is optionally further substituted with OH, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl, or CO 2 H, wherein each R j and R k is independently selected from hydrogen, C 1-8 alkyl optionally substituted with 1 to 2 substituents selected from OH, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl, and CO 2 H, and C 1-8 haloalkyl optionally substituted with 1 to 2 substituents selected from OH, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl, or CO 2 H, or when attached to the same nitrogen atom R j and R k can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O, and S, and optionally substituted with oxo; and each R i is independently selected from the group consisting of —OH, C 1-8 alkyl, C 2-8 alkenyl, and C 1-8 haloalkyl, each of which may be optionally substituted with OH, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl, or CO 2 H;

R g is selected from the group consisting of H, C 1-8 haloalkyl, and C 1-8 alkyl;

R h is selected from —C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkyl-CO 2 R j , C 1-8 alkyl-CONR j R k , C 1-8 alkyl-CONHSO 2 R j , C 1-8 alkyl-SO 2 NR j R k , C 1-8 alkyl-PO 3 H 2 , C 1-8 alkyl-C(O)NHOH, C 1-8 alkyl-NR h1 R h2 , —C(O)R j , C 3-10 cycloalkyl, —C 3-10 cycloalkyl-COOR j , —C 3-10 cycloalkyl-OR j , C 4-8 heterocyclyl, —C 4-8 heterocyclyl-COOR j , —C 4-8 heterocyclyl-OR j , —C 1-8 alkyl-C 4-8 heterocyclyl, —C(═O)OC 1-8 alkyl-C 4-8 heterocyclyl, —C 1-8 alkyl-C 3-10 cycloalkyl, C 5-10 heteroaryl, —C 1-8 alkyl-C 5-10 heteroaryl, —C 1-8 alkyl-C 6-10 aryl, —C 1-8 alkyl-(C═O)—C 6-10 aryl, —CO 2 —C 1-8 alkyl-O 2 C—C 1-8 alkyl, —C 1-8 alkyl-NH(C═O)—C 2-8 alkenyl, —C 1-8 alkyl-NH(C═O)—C 1-8 alkyl, —C 1-8 alkyl-NH(C═O)—C 2-8 alkynyl, —C 1-8 alkyl-(C═O)—NH—C 1-8 alkyl-COOR j , and —C 1-8 alkyl-(C═O)—NH—C 1-8 alkyl-OR j optionally substituted with CO 2 H; or

R h combined with the N to which it is attached is a mono-, di- or tri-peptide comprising 1-3 natural amino acids and 0-2 non-natural amino acids, wherein

the non-natural amino acids have an alpha carbon substituent selected from the group consisting of C 2-4 hydroxyalkyl, C 1-3 alkyl-guanidinyl, and C 1-4 alkyl-heteroaryl,

the alpha carbon of each natural or non-natural amino acid is optionally further substituted with a methyl group, and

the terminal moiety of the mono-, di-, or tri-peptide is selected from the group consisting of C(O)OH, C(O)O—C 1-6 alkyl, and PO 3 H 2 , wherein

R h1 and R h2 are each independently selected from the group consisting of H, C 1-6 alkyl, and C 1-4 hydroxyalkyl;

the C 1-8 alkyl portions of R h are optionally further substituted with from 1 to 3 substituents independently selected from OH, COOH, SO 2 NH 2 , CONH 2 , C(O)NHOH, COO—C 1-8 alkyl, PO 3 H 2 , and C 5-6 heteroaryl optionally substituted with 1 to 2 C 1-3 alkyl substituents,

the C 5-10 heteroaryl and the C 6-10 aryl portions of R h are optionally substituted with 1 to 3 substituents independently selected from OH, B(OH) 2 , COOH, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl, C 1-4 alkyl, C 1-4 alkyl-OH, C 1-4 alkyl-SO 2 NH 2 , C 1-4 alkyl CONH 2 , C 1-4 alkyl-C(O)NHOH, C 1-4 alkyl-PO 3 H 2 , C 1-4 alkyl-COOH, and phenyl, and

the C 4-8 heterocyclyl and C 3-10 cycloalkyl portions of R h are optionally substituted with 1 to 4 R w substituents;

each R w substituent is independently selected from C 1-4 alkyl, C 1-4 alkyl-OH, C 1-4 alkyl-COOH, C 1-4 alkyl-SO 2 NH 2 , C 1-4 alkyl CONH 2 , C 1-4 alkyl-C(O)NHOH, C 1-4 alkyl-PO 3 H, OH, COO—C 1-8 alkyl, COOH, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , and oxo;

R 4 is selected from the group consisting of O—C 1-8 alkyl, O—C 1-8 haloalkyl, C 6-10 aryl, C 5-10 heteroaryl, —O—C 1-4 alkyl-C 4-7 heterocycloalkyl, —O—C 1-4 alkyl-C 6-10 aryl, and —O—C 1-4 alkyl-C 5-10 heteroaryl, each of which is optionally substituted with 1 to 5 R 4a ;

each R 4a is independently selected from the group consisting of halogen, —CN, —R m , —CO 2 R n , —CONR n R p , —C(O)R n , —OC(O)NR n R p , —NR n C(O)R p , —NR n C(O) 2 R m , —NR n —C(O)NR n R p , —NR n R p , —OR n , —O—X 4 —OR n , —O—X 4 —NR n R p , —O—X 4 —CO 2 R n , —O—X 4 —CONR n R p , —X 4 —OR n , —X 4 —NR n R p , —X 4 —CO 2 R n , —X 4 —CONR n R p , —SF 5 , —S(O) 2 R n R p , —S(O) 2 NR n R p , C 3-7 cycloalkyl, and C 4-7 heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl rings are optionally substituted with 1 to 5 R t , wherein each R t is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, —CO 2 R n , —CONR n R p , —C(O)R n , —OC(O)NR n R p , —NR n C(O)R p , —NR n C(O) 2 R m , —NR n —C(O)NR n R p , —NR n R p , —OR n , —O—X 4 —OR n , —O—X 4 —NR n R p , —O—X 4 —CO 2 R n , —O—X 4 —CONR n R p , —X 4 —OR n , —X 4 —NR n R p , —X 4 —CO 2 R n , —X 4 —CONR n R p , —SF 5 , and —S(O) 2 NR n R p ;

wherein each X 4 is a C 1-6 alkylene; each R n and R p is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O, and S, and optionally substituted with oxo; each R m is independently selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, and C 1-8 haloalkyl; and optionally when two R 4a substituents are on adjacent atoms, they are combined to form a fused five or six-membered carbocyclic or heterocyclic ring optionally substituted with oxo;

the subscript n is 0, 1, 2, or 3;

each R 5 is independently selected from the group consisting of halogen, —CN, —R q , —CO 2 R r , —CONR r R s , —C(O)R r , —OC(O)NR r R s , —NR r C(O)R s , —NR r C(O) 2 R q , —NR r —C(O)NR r R s , —NR r R s , —OR r , —O—X 5 —OR r , —O—X 5 —NR r R s , —O—X 5 —CO 2 R r , —O—X 5 —CONR r R s , —X 5 —OR r , —X 5 —NR r R s , —X 5 —CO 2 R r , —X 5 —CONR r R s , —SF 5 , and —S(O) 2 NR r R s , wherein each X 5 is a C 1-4 alkylene; each R r and R s is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O, and S, and optionally substituted with oxo; and each R q is independently selected from the group consisting of C 1-8 alkyl and C 1-8 haloalkyl;

R 6a is selected from the group consisting of H, C 1-4 alkyl, and C 1-4 haloalkyl;

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

each R 6b is independently selected from the group consisting of F, C 1-4 alkyl, O—R u , C 1-4 haloalkyl, and NR u R v , wherein each R u and R v is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O, and S, and optionally substituted with oxo.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the formula (Ia)

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the formula (Ib)

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the group Z-L- is selected from the group consisting of:

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

the group Z-L- is selected from the group consisting of:

and

each of R 2a , R 2b , and R 2c is independently selected from the group consisting of hydrogen, halogen, CN, C 1-4 alkyl, and C 1-4 haloalkyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

the group Z-L- is selected from the group consisting of:

and

each of R 2a , R 2b , and R 2c is independently selected from the group consisting of hydrogen, halogen, CN, C 1-4 alkyl, and C 1-4 haloalkyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each of R 2a , R 2b , and R 2c is independently selected from the group consisting of hydrogen, halogen, CN, C 1-4 alkyl, and C 1-4 haloalkyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is —NR g R h .

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of:

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of:

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of:

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of:

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of:

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0.

15. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

16. A method of enhancing, stimulating, modulating and/or increasing the immune response in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

17. A method of inhibiting growth, proliferation, or metastasis of cancer cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

18. A method of treating a subject suffering from or susceptible to a disease or disorder, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein the disease or disorder is selected from the group consisting of melanoma, glioblastoma, esophagus tumor, nasopharyngeal carcinoma, uveal melanoma, lymphoma, lymphocytic lymphoma, primary CNS lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, prostate cancer, castration-resistant prostate cancer, chronic myelocytic leukemia, Kaposi's sarcoma fibrosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma, synovioma, meningioma, leiomyosarcoma, rhabdomyosarcoma, sarcoma of soft tissue, sarcoma, sepsis, biliary tumor, basal cell carcinoma, thymus neoplasm, cancer of the thyroid gland, cancer of the parathyroid gland, uterine cancer, cancer of the adrenal gland, liver infection, Merkel cell carcinoma, nerve tumor, follicle center lymphoma, colon cancer, Hodgkin's disease, non-Hodgkin's lymphoma, leukemia, chronic or acute leukemias, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, ovary tumor, myelodysplastic syndrome, cutaneous or intraocular malignant melanoma, renal cell carcinoma, small-cell lung cancer, lung cancer, mesothelioma, breast cancer, squamous non-small cell lung cancer (SCLC), non-squamous NSCLC, colorectal cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic carcinoma, pancreatic cancer, Pancreatic ductal adenocarcinoma, squamous cell carcinoma of the head and neck, cancer of the head or neck, gastrointestinal tract, stomach cancer, HIV, Hepatitis A, Hepatitis B, Hepatitis C, hepatitis D, herpes viruses, papillomaviruses, influenza, bone cancer, skin cancer, rectal cancer, cancer of the anal region, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the urethra, cancer of the penis, cancer of the bladder, cancer of the kidney, cancer of the ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, epidermoid cancer, abestosis, carcinoma, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchogenic carcinoma, renal cell carcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, wilm's tumor, pleomorphic adenoma, liver cell papilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma, and fibroma.

19. A compound selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

20. A method of treating a subject suffering from or susceptible to a disease or disorder, comprising administering to the subject a therapeutically effective amount of a compound of claim 19 , or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is selected from the group consisting of melanoma, glioblastoma, esophagus tumor, nasopharyngeal carcinoma, uveal melanoma, lymphoma, lymphocytic lymphoma, primary CNS lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, prostate cancer, castration-resistant prostate cancer, chronic myelocytic leukemia, Kaposi's sarcoma fibrosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma, synovioma, meningioma, leiomyosarcoma, rhabdomyosarcoma, sarcoma of soft tissue, sarcoma, sepsis, biliary tumor, basal cell carcinoma, thymus neoplasm, cancer of the thyroid gland, cancer of the parathyroid gland, uterine cancer, cancer of the adrenal gland, liver infection, Merkel cell carcinoma, nerve tumor, follicle center lymphoma, colon cancer, Hodgkin's disease, non-Hodgkin's lymphoma, leukemia, chronic or acute leukemias, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, ovary tumor, myelodysplastic syndrome, cutaneous or intraocular malignant melanoma, renal cell carcinoma, small-cell lung cancer, lung cancer, mesothelioma, breast cancer, squamous non-small cell lung cancer (SCLC), non-squamous NSCLC, colorectal cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic carcinoma, pancreatic cancer, Pancreatic ductal adenocarcinoma, squamous cell carcinoma of the head and neck, cancer of the head or neck, gastrointestinal tract, stomach cancer, HIV, Hepatitis A, Hepatitis B, Hepatitis C, hepatitis D, herpes viruses, papillomaviruses, influenza, bone cancer, skin cancer, rectal cancer, cancer of the anal region, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the urethra, cancer of the penis, cancer of the bladder, cancer of the kidney, cancer of the ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, epidermoid cancer, abestosis, carcinoma, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchogenic carcinoma, renal cell carcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, wilm's tumor, pleomorphic adenoma, liver cell papilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma, and fibroma.