METHODS OF TREATING CANCER WITH SMALL MOLECULE PD-L1 INHIBITORS
The present disclosure provides, inter alia, methods of treating cancer by administering an effective amount of a com-pound of Formula (I). In some embodiments, the cancer is a solid cancer. In some embodiments, the cancer is melanoma. In some aspects, the present disclosure provides methods of increasing the CD8+ T cell/CD4+ T cell ratio in a solid tumor microenvironment by administering an effective amount of a compound of Formula (I).
1 . A method of preventing and/or treating cancer in an individual in need thereof, said method comprising administering an effective amount of a small molecule programmed death ligand 1 (PD-L1) inhibitor.
2 . The method of claim 1 , wherein said small molecule PD-L1 inhibitor is a compound of Formula (I).
or a pharmaceutically acceptable salt thereof, or a prodrug or bioisostere thereof;
wherein:
each of R 1a , R 1b R 1c and R 1d is independently selected from the group consisting of H, halogen, CF 3 , CN, C 1-4 alkyl and —O—C 1-4 alkyl, wherein the C 1-4 alkyl and —O—C 1-4 alkyl are optionally further substituted with halogen, hydroxyl, methoxy or ethoxy;
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, piperazinyl, morpholinyl, pyridyl, pyrimidinyl, imidazolyl, guanidinyl, quinuclidine, 2-azaspiro[3.3]heptane and 8-azabicyclo[3.2.1]octane, each of which is optionally substituted with from 1 to 4 groups independently selected from halogen, CN, hydroxy, oxo, C 1-4 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, —OC(O)(C 1-4 alkyl), —CO 2 (C 1-4 alkyl) and —CO 2 H;
or
Z is selected from the group consisting of —CO 2 R a and —NR a R b ; wherein R a is selected from the group consisting of H, C 1-8 alkyl, C 1-8 haloalkyl and C 1-8 hydroxyalkyl; and R b is selected from H, —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 a 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 d , —NR e —C(O) 2 R d , —NR e —C(O)NR e R f , —NR e R f , —OR 3 , —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; 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, oxo, —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 1 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 —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 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 or 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 or S, and optionally substituted with oxo; each R′ 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-CONRJR j R k , and C 1-8 alkyl-CONHSO 2 R j , C 1-8 alkyl-SO 2 NR h1 R k , C 1-8 alkyl-SO 3 R j , C 1-8 alkyl-B(OH) 2 , 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)- 13 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 aminoacids 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 acids are 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 4 a;
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 —CO2R 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 or 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;
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 , —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 or S, and optionally substituted with oxo; each R q is independently selected from the group consisting of C 1-8 alkyl, and C 1-4 shaloalkyl;
R 6a is selected from the group consisting of H, C 1-4 alkyl and C 1-4 haloalkyl;
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, NR u R v , wherein each R u and R v is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 -ghaloalkyl, 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 or S, and optionally substituted with oxo.
3 . The method of claim 2 , wherein the small molecule PD-L1 inhibitors has the formula (Ia)
or a pharmaceutically acceptable salt thereof.
4 . The method of claim 2 , wherein the small molecule PD-L1 inhibitor has the formula (Ib)
or a pharmaceutically acceptable salt thereof.
5 . The method of claim 2 , wherein the PD-L1 inhibitor has the formula (Ia1) or (Ia2):
or a pharmaceutically acceptable salt thereof.
6 . The method of any one of claims 2 to 4 , 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.
7 . The method of any one of claims 2 to 4 , wherein R 3 is —NR g R h .
8 . The method of any one of claims 2 to 4 , wherein R 3 is C 4-12 heterocyclyl, wherein the C 4-12 heterocyclyl is optionally substituted with 1 to 6 R 3a .
9 . The method of claim 8 , wherein the C 4-12 heterocyclyl a C 7-11 spiroheterocyclyl and is optionally substituted with 1 to 6 R 3a
10 . The method of any one of claims 2 to 4 , wherein R 3 is selected from the group consisting of:
11 . The method of any one of claims 2 to 4 , wherein R 3 is selected from the group consisting of:
12 . The method of any one of claims 2 to 4 , wherein R 4 is selected from the group consisting of:
13 . The method of any one of claims 2 to 12 , wherein n is 0.
14 . The method of any one of claims 2 to 13 , wherein R 6a and R 6b are each independently selected from the group consisting of hydrogen, halogen, C 1-4 alkyl and C 1-4 haloalkyl.
15 . The method of any one of claims 2 to 13 , wherein the group Z-L- is selected from the group consisting of:
16 . The method of any one of claims 2 to 13 , wherein the group Z-L- is selected from the group consisting of:
17 . The method of any one of claims 2 to 13 , wherein R 4 is selected from the group consisting of:
18 . The method of any one of claims 2 to 4 , wherein R 2b and R 2c are both H and R 2a is selected from the group consisting of halogen, C 1-4 alkyl, C 2-4 alkenyl, C 1-3 haloalkyl, —CN, —OMe and OEt.
19 . The method of any one of claims 2 to 4 , wherein R 2b and R 2c are both H and R 2a is halogen.
20 . The method of any one of claims 2 to 4 , wherein R 2b and R 2c are both H and R 2a is Cl.
21 . The method of any one of claims 2 to 4 , wherein R 6a is H.
22 . The method of any one of claims 2 to 4 , wherein m is 0.
23 . The method of any one of claims 2 to 4 , wherein m is 1 and R 6b is selected from the group consisting of F, C 1-4 alkyl, O- 13 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.
24 . The method of any one of claims 2 to 4 , wherein m is 1 and R 6b is F.
25 . The method of claim 1 , wherein said small molecule PD-L1 inhibitor is a compound in Table 1.
26 . The method of claim 1 , wherein said small molecule PD-L1 inhibitor has the formula of Compound 1.004
or a pharmaceutically acceptable salt thereof.
27 . The method of claim 1 , wherein said small molecule PD-L1 inhibitor has the formula of Compound 1.041
or a pharmaceutically acceptable salt thereof.
28 . The method of claim 1 , wherein said small molecule PD-L1 inhibitor has the formula of Compound 1.227
or a pharmaceutically acceptable salt thereof.
29 . The method of claim 1 , wherein said small molecule PD-L1 inhibitor has the formula of Compound 1.347
or a pharmaceutically acceptable salt thereof.
30 . The method of any one of claims 1 - 29 , wherein said cancer is a solid tumor.
31 . The method of any one of claims 1 - 29 , wherein said cancer is melanoma.
32 . The method of any one of claims 1 to 31 , wherein said treatment provides tumor size reduction as compared to an individual who was not administered a PD-L1 inhibitor.
33 . The method of any one of claims 1 to 31 , wherein said treatment reduces tumor growth.
34 . The method of any one of claims 1 to 31 , wherein said treatment destroys the cancer.
35 . The method of any one of claims 1 to 34 , wherein said small molecule PD-L1 inhibitor is administered orally.
36 . A method of preventing and/or treating melanoma in an individual in need thereof, said method comprising administering an effective amount of a small molecule programmed death ligand 1 (PD-L1) inhibitor selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
37 . The method of claim 36 , wherein said small molecule PD-L1 inhibitor has the formula of Compound 1.004
or a pharmaceutically acceptable salt thereof.
38 . The method of claim 36 , wherein said small molecule PD-L1 inhibitor has the formula of Compound 1.041
or a pharmaceutically acceptable salt thereof.
39 . The method of claim 36 , wherein said small molecule PD-L1 inhibitor has the formula of Compound 1.227
or a pharmaceutically acceptable salt thereof.
40 . The method of claim 36 , wherein said small molecule PD-L1 inhibitor has the formula of Compound 1.347
or a pharmaceutically acceptable salt thereof.
41 . A method of increasing the CD8+ T cell/CD4+ T cell ratio in a solid tumor microenvironment, said method comprising administering an effective amount of a small molecule programmed death ligand 1 (PD-L1) inhibitor of Formula (I)
or a pharmaceutically acceptable salt thereof, or a prodrug or bioisostere thereof;
wherein:
each of R 1a , R 1b , R 1c and R 1d is independently selected from the group consisting of H, halogen, CF 3 , CN, C 1-4 alkyl and —O—C 1-4 alkyl, wherein the C 1-4 alkyl and —O—C 1-4 alkyl are optionally further substituted with halogen, hydroxyl, methoxy or ethoxy;
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, piperazinyl, morpholinyl, pyridyl, pyrimidinyl, imidazolyl, guanidinyl, quinuclidine, 2-azaspiro[3.3]heptane and 8-azabicyclo[3.2.1]octane, each of which is optionally substituted with from 1 to 4 groups independently selected from halogen, CN, hydroxy, oxo, C 1-4 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, —OC(O)(C 1-4 alkyl), —CO 2 (C 1-4 alkyl) and —CO 2 H;
or
Z is selected from the group consisting of —CO 2 R a and —NR a R b ; wherein R a is selected from the group consisting of H, C 1-8 alkyl, C 1-8 haloalkyl and C 1-8 hydroxyalkyl; and R b is selected from H, —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 —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; 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, oxo, —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 , —NRC(O)NR j R k , —NR j R k , —OR j , —S(O) 2 NR j R k , —O—X 3 —O 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, —X 3 —CONR j R k , −X 3 —CONHSO 2 R j and SF 5 ; wherein X 3 is 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 or 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 or S, and optionally substituted with oxo; each R i s 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 , and C 1-8 alkyl-CONHSO 2 R j , C 1-8 alkyl-SO 2 NR j R k , C 1-8 alkyl-SO 3 R j , C 1-8 alkyl-B(OH) 2 , 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 aminoacids 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 acids are 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 —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 —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 RP, —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 or S, and optionally substituted with oxo; each Rm 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;
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)N 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 , —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 or S, and optionally substituted with oxo; each Rq 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;
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, 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 or S, and optionally substituted with oxo..
42 . The method of claim 41 , wherein said small molecule PD-L1 inhibitor of Formula (I) has the formula of Compound 1.004
or a pharmaceutically acceptable salt thereof.
43 . The method of claim 41 , wherein said small molecule PD-L1 inhibitor of Formula (I) has the formula of Compound 1.041
or a pharmaceutically acceptable salt thereof.
44 . The method of claim 41 , wherein said small molecule PD-L1 inhibitor of Formula (I) has the formula of Compound 1.227
or a pharmaceutically acceptable salt thereof.
45 . The method of claim 41 , wherein said small molecule PD-L1 inhibitor of Formula (I) has the formula of Compound 1.347
or a pharmaceutically acceptable salt thereof.