Heterocyclic Compounds as Immunomodulators

Abstract

To provide pharmaceuticals comprising useful in treating, preventing or ameliorating diseases or disorders such as cancer or infections.SOLUTION: The present disclosure provides pharmaceuticals for use in treating a disease or disorder associated with inhibition of PD-1 / PD-L1 interaction in combination with one or more additional therapeutic agents, the pharmaceuticals containing a compound represented by the formula (I') in the figure or a pharmaceutically acceptable salt or stereoisomer thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 650,821, filed March 30, 2018, and U.S. Provisional Application No. 62 / 687,964, filed June 21, 2018, each of which is incorporated by reference in its entirety.

[0002] This application relates to pharma- ceutically active compounds. The disclosure provides compounds as well as compositions and methods of use thereof. The compounds modulate PD-1 / PD-L1 protein / protein interactions and are useful in the treatment of a variety of diseases, including infectious diseases and cancer. BACKGROUND OF THEINVENTION

[0003] The immune system plays a key role in controlling and eradicating diseases such as cancer. However, cancer cells often develop strategies to evade or suppress the immune system to support their growth. One such mechanism is to alter the expression of costimulatory and co-inhibitory molecules expressed in immune cells (Postow et al, J. Clinical Oncology 2015, 1-9). Blocking the signaling of inhibitory immune checkpoints such as PD-1 has proven to be a promising and effective treatment.

[0004] Programmed cell death-1 (PD-1), also known as CD279, is a cell surface receptor expressed on activated T cells, natural killer T cells, B cells, and macrophages (Greenwald et al, Annu. Rev. Immunol 2005, 23:515-548; Okazaki and Honjo, Trends Immunol 2006, (4):195-201). It functions as an intrinsic negative feedback mechanism to prevent T cell activation, which in turn reduces autoimmunity and promotes self-tolerance. In addition, PD-1 is also known to play an important role in suppressing antigen-specific T cell responses in diseases such as cancer and viral infections (Sharpe et al, Nat Immunol 2007 8, 239-245; Postow et al, J. Clinical Oncol 2015, 1-9).

[0005] The structure of PD-1 consists of an extracellular immunoglobulin variable-like domain followed by a transmembrane region and an intracellular domain (Parry et al, Mol Cell Biol 2005, 9543-9553). The intracellular domain contains two phosphorylation sites located at an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switch motif, suggesting that PD-1 negatively regulates T cell receptor-mediated signals. PD-1 has two ligands, PD-L1 and PD-L2 (Parry et al, Mol Cell Biol 2005, 9543-9553; Latchman et al, Nat Immunol 2001, 2, 261-268), which differ in their expression patterns. PD-L1 protein is upregulated in macrophages and dendritic cells in response to lipopolysaccharide and GM-CSF treatment, and in T cells and B cells by T cell receptor and B cell receptor signaling. PD-L1 is also highly expressed by almost all tumor cells, and expression is further increased after IFN-γ treatment (Iwai et al, PNAS 2002, 99(19):12293-7; Blank et al, Cancer Res 2004, 64(3):1140-5). Indeed, tumor PD-L1 expression status has been shown to be prognostic in multiple tumor types (Wang et al, Eur J Surg Oncol 2015; Huang et al, Oncol Rep 2015; Sabatier et al, Oncotarget 2015, 6(7):5449-5464). In contrast, PD-L2 expression is more restricted and is mainly expressed by dendritic cells (Nakae et al, J Immunol 2006, 177:566-73). Ligation of PD-1 with its ligands PD-L1 and PD-L2 on T cells results in signals that inhibit IL-2 and IFN-γ production, as well as cell proliferation induced by T cell receptor activation (Carter et al, Eur J Immunol 2002, 32(3):634-43; Freeman et al, J Exp Med 2000, 192(7):1027-34).This mechanism involves recruitment of SHP-2 or SHP-1 phosphatases that inhibit T cell receptor signaling, such as Syk and Lck phosphorylation (Sharpe et al, Nat Immunol 2007, 8, 239-245). Activation of the PD-1 signaling axis also attenuates activation of the NF-κB and AP1 pathways, as well as phosphorylation of the PKC-θ activation loop, which is required for cytokine production, such as IL-2, IFN-γ, and TNF (Sharpe et al, Nat Immunol 2007, 8, 239-245; Carter et al, Eur J Immunol 2002, 32(3):634-43; Freeman et al, J Exp Med 2000, 192(7):1027-34).

[0006] Several lines of evidence from preclinical animal studies indicate that PD-1 and its ligands negatively regulate immune responses. PD-1-deficient mice have been shown to develop lupus-like glomerulonephritis and dilated cardiomyopathy (Nishimura et al, Immunity 1999, 11:141-151; Nishimura et al, Science 2001, 291:319-322). Using the LCMV model of chronic infection, PD-1 / PD-L1 interactions have been shown to inhibit the activation, expansion, and acquisition of effector functions of virus-specific CD8 T cells (Barber et al, Nature 2006, 439, 682-7). Taken together, these data support the development of therapeutic approaches that block PD-1-mediated inhibitory signaling cascades to augment or "rescue" T cell responses. Thus, new compounds that block PD-1 / PD-L1 protein / protein interactions are needed. Summary of the Invention

[0007] The present disclosure relates in particular to a compound of formula (I'): [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof, wherein the constituent variables are defined herein.

[0008] The present disclosure also relates to a compound of formula (I): [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof, wherein the constituent variables are defined herein.

[0009] The present disclosure further provides pharmaceutical compositions comprising a compound disclosed herein, or a pharma- ceutically acceptable salt or stereoisomer thereof, and one or more pharma- ceutically acceptable excipients or carriers.

[0010] The disclosure further provides a method of inhibiting PD-1 / PD-L1 interaction, the method comprising administering to a patient a compound disclosed herein, or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0011] The disclosure further provides a method of treating a disease or disorder associated with inhibition of PD-1 / PD-L1 interaction, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0012] The present disclosure further provides a method of enhancing, stimulating, and / or increasing an immune response in a patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0013] I. Compound The present disclosure relates in particular to a compound of formula (I'): [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof, wherein Ring A is azetidinyl, pyrrolidinyl, or piperidinyl; X 1 is CH or N, R 1 is methyl or halo, R 2 is C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl-C 1-2 Alkyl-, OH, NH2, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl) 2, 4- to 6-membered heterocycloalkyl, or 4- to 6-membered heterocycloalkyl-C 1-2 alkyl-, 4- to 6-membered heterocycloalkyl and 4- to 6-membered heterocycloalkyl-C 1-2 Each alkyl- has one or two heteroatoms as ring members selected from O and N, and R 2 C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl-C 1-2 Alkyl-, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, 4- to 6-membered heterocycloalkyl, and 4- to 6-membered heterocycloalkyl-C 1-2 each alkyl- is optionally substituted with 1 or 2 substituents independently selected from halo, CN, and OH; R 3 is selected from (R)-3-hydroxy-3-methylpyrrolidin-1-yl, (S)-3-hydroxy-3-methylpyrrolidin-1-yl, (R)-3-hydroxypyrrolidin-1-yl, (S)-3-hydroxypyrrolidin-1-yl, (R)-2-hydroxy-2-methyl-ethylamino, (S)-2-hydroxy-2-methyl-ethylamino, (R)-2-hydroxy-1-methyl-ethylamino, and (S)-2-hydroxy-1-methyl-ethylamino; R 4 is H or C 1-3 is alkyl, R 5 is C(O)OH, C(O)N(CH3)2, C(O)NH(CH3), or C(O)NH(CH2)2C(O)OH.

[0014] In some embodiments, the compound of formula (I): [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof, wherein: Ring A is azetidinyl, pyrrolidinyl, or piperidinyl; X 1 is CH or N, R 1 is methyl or halo, R 2 is C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl-C 1-2 Alkyl-, OH, NH2, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl) 2, 4- to 6-membered heterocycloalkyl, or 4- to 6-membered heterocycloalkyl-C 1-2 alkyl-, 4- to 6-membered heterocycloalkyl and 4- to 6-membered heterocycloalkyl-C 1-2 Each alkyl- has one or two heteroatoms as ring members selected from O and N, and R 2 C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl-C 1-2 Alkyl-, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, 4- to 6-membered heterocycloalkyl, and 4- to 6-membered heterocycloalkyl-C 1-2each alkyl- is optionally substituted with 1 or 2 substituents independently selected from halo, CN, and OH; R 3 is selected from (R)-3-hydroxy-3-methylpyrrolidin-1-yl, (S)-3-hydroxy-3-methylpyrrolidin-1-yl, (R)-3-hydroxypyrrolidin-1-yl, (S)-3-hydroxypyrrolidin-1-yl, (R)-2-hydroxy-2-methyl-ethylamino, (S)-2-hydroxy-2-methyl-ethylamino, (R)-2-hydroxy-1-methyl-ethylamino, and (S)-2-hydroxy-1-methyl-ethylamino; R 4 is H or C 1-3 It is an alkyl.

[0015] In some embodiments, Ring A is pyrrolidinyl. In some embodiments, Ring A is piperidinyl. In other embodiments, Ring A is piperidinyl.

[0016] In some embodiments, the moiety [ka] is selected from 4-carboxypiperidin-1-yl, 3-carboxypyrrolidin-1-yl, 3-methyl-3-carboxypyrrolidin-1-yl, 4-(N,N-dimethylaminocarbonyl)piperidin-1-yl, 4-(N-methylaminocarbonyl)piperidin-1-yl, and 4-(2-carboxyethylaminocarbonyl)piperidin-1-yl, where the wavy line indicates the point of attachment to the remainder of the molecule.

[0017] In some embodiments, the moiety [ka] is selected from 4-carboxypiperidin-1-yl, 3-carboxypyrrolidin-1-yl, and 3-methyl-3-carboxypyrrolidin-1-yl, and the wavy line indicates the point of attachment to the remainder of the molecule.

[0018] In some embodiments, the moiety [ka] is 4-carboxypiperidin-1-yl, and the wavy line indicates the point of attachment to the rest of the molecule.

[0019] In some embodiments, the moiety [ka] is 3-carboxypyrrolidin-1-yl, with the wavy line indicating the point of attachment to the remainder of the molecule. In some embodiments, 3-carboxypyrrolidin-1-yl is (R)-3-carboxypyrrolidin-1-yl. In some embodiments, 3-carboxypyrrolidin-1-yl is (S)-3-carboxypyrrolidin-1-yl.

[0020] In some embodiments, the moiety [ka] is selected from 4-(N,N-dimethylaminocarbonyl)piperidin-1-yl, 4-(N-methylaminocarbonyl)piperidin-1-yl, and 4-(2-carboxyethylaminocarbonyl)piperidin-1-yl, where the wavy line indicates the point of attachment to the remainder of the molecule.

[0021] In some embodiments, the moiety [ka] is 3-methyl-3-carboxypyrrolidin-1-yl, with the wavy line indicating the point of attachment to the remainder of the molecule. In some embodiments, 3-methyl-3-carboxypyrrolidin-1-yl is (R)-3-methyl-3-carboxypyrrolidin-1-yl. In some embodiments, 3-methyl-3-carboxypyrrolidin-1-yl is (S)-3-methyl-3-carboxypyrrolidin-1-yl.

[0022] In some embodiments, the moiety [ka] is selected from 4-carboxypiperidin-1-yl, (R)-3-carboxypyrrolidin-1-yl, (S)-3-carboxypyrrolidin-1-yl, (R)-3-methyl-3-carboxypyrrolidin-1-yl, and (S)-3-methyl-3-carboxypyrrolidin-1-yl, where the wavy line indicates the point of attachment to the remainder of the molecule.

[0023] In some embodiments, X 1 is N. In some embodiments, X 1 is CH.

[0024] In some embodiments, R 1 is CH3 or Cl. In some embodiments, R 1 is CH3. In some embodiments, R 1 , is halo (e.g., F, Cl, or Br). In some embodiments, R 1 is Cl.

[0025] In some embodiments, R 2 is C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl-C 1-2 Alkyl-, OH, NH2, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl), 1-azetidinyl, azetidin-1-ylmethyl, 1-pyrrolidinyl, pyrrolidin-1-ylmethyl, 1-piperidinyl, or piperidin-1-ylmethyl; R 2 C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl-C 1-2 Alkyl, -NH-C1-4 Alkyl, -N(C 1-4 Alkyl), 1-azetidinyl, azetidin-1-ylmethyl, 1-pyrrolidinyl, pyrrolidin-1-ylmethyl, 1-piperidinyl, and piperidin-1-ylmethyl are each optionally substituted with 1 or 2 substituents independently selected from halo, CN, and OH.

[0026] In some embodiments, R 2 is C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, OH, NH2, -NH-C 1-4 Alkyl, or -N(C 1-4 alkyl)2, and R 2 C 1-4 Alkyl, C 1-4 Alkoxy, -NH-C 1-4 Alkyl, and -N(C 1-4 Each alkyl)2 is optionally substituted with 1 or 2 substituents independently selected from halo, CN, and OH.

[0027] In some embodiments, R 2 is C 3-6 Cycloalkyl, C 3-6 Cycloalkyl-C 1-2 alkyl-, 1-azetidinyl, azetidin-1-ylmethyl, 1-pyrrolidinyl, pyrrolidin-1-ylmethyl, 1-piperidinyl, or piperidin-1-ylmethyl; R 2 C 3-6 Cycloalkyl, C 3-6 Cycloalkyl-C 1-2 Alkyl-, 1-azetidinyl, azetidin-1-ylmethyl, 1-pyrrolidinyl, pyrrolidin-1-ylmethyl, 1-piperidinyl, and piperidin-1-ylmethyl are each optionally substituted with 1 or 2 substituents independently selected from halo, CN, and OH.

[0028] In some embodiments, R 2is methyl, ethyl, isopropyl, methoxy, ethoxy, CF3, CHF2, CFH2, OCF3, OCHF2, OCH2F, cyclopropyl, cyclobutyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, OH, NH2, NHCH3, N(CH3)2, 1-azetidinyl, azetidin-1-ylmethyl, 1-pyrrolidinyl, pyrrolidin-1-ylmethyl, 1-piperidinyl, or piperidin-1-ylmethyl; R 2 wherein methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, NHCH3, N(CH3)2, 1-azetidinyl, azetidin-1-ylmethyl, 1-pyrrolidinyl, pyrrolidin-1-ylmethyl, 1-piperidinyl, and piperidin-1-ylmethyl are each optionally substituted with 1 or 2 substituents independently selected from F, Cl, Br, CN, and OH.

[0029] In some embodiments, R 2 is methyl, ethyl, isopropyl, methoxy, ethoxy, CF3, CHF2, CFH2, OCF3, OCHF2, OCH2F, OH, NH2, NHCH3, or N(CH3)2, and R 2 wherein methyl, ethyl, isopropyl, methoxy, ethoxy, NHCH3, and N(CH3)2 are each optionally substituted with 1 or 2 substituents independently selected from F, Cl, Br, CN, and OH.

[0030] In some embodiments, R 2 is cyclopropyl, cyclobutyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, 1-azetidinyl, azetidin-1-ylmethyl, 1-pyrrolidinyl, pyrrolidin-1-ylmethyl, 1-piperidinyl, or piperidin-1-ylmethyl; R 2wherein cyclopropyl, cyclobutyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, 1-azetidinyl, azetidin-1-ylmethyl, 1-pyrrolidinyl, pyrrolidin-1-ylmethyl, 1-piperidinyl, and piperidin-1-ylmethyl are each optionally substituted with 1 or 2 substituents independently selected from F, Cl, Br, CN, and OH.

[0031] In some embodiments, R 2 is CH3, CF3, CHF2, CH(CH3)2, NH2, cyclopropyl, or CH2OH.

[0032] In some embodiments, R 2 is C 1-4 Alkyl or C 1-4 haloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from F, Cl, Br, CN, and OH.

[0033] In some embodiments, R 2 is C 1-4 Alkyl or C 1-4 In some embodiments, R 2 is CH, CF, CHF, or CH(CH). In some embodiments, R 2 is CH3 and CH(CH3)2 etc. 1-4 In some embodiments, R 2 is CH3. In some embodiments, R 2 is CH(CH). In some embodiments, R 2 C such as CF3, CHF2, and CH2F 1-4 In some embodiments, R 2 C such as CF3 and CHF2 1-4 In some embodiments, R 2 is CF3. In some embodiments, R 2 is CHF2. In some embodiments, R2 is CH2F.

[0034] In some embodiments, R 2 is NH2, NHCH3, or N(CH3)2, and R 2 Each of NHCH and N(CH) is independently substituted with 1 or 2 substituents selected from F, Cl, Br, CN, and OH. 2 is NH2.

[0035] In some embodiments, R 2 is cyclopropyl, cyclobutyl, or cyclohexyl; R 2 Each of the cyclopropyl, cyclobutyl, and cyclohexyl in R is optionally substituted with 1 or 2 substituents independently selected from F, Cl, Br, CN, and OH. In some embodiments, R 2 is cyclopropyl optionally substituted with 1 or 2 substituents independently selected from F, Cl, Br, CN, and OH. In some embodiments, R 2 is cyclopropyl.

[0036] In some embodiments, R 3 is (R)-3-hydroxy-3-methylpyrrolidin-1-yl or (S)-3-hydroxy-3-methylpyrrolidin-1-yl. In some embodiments, R 3 is (R)-3-hydroxypyrrolidin-1-yl or (S)-3-hydroxypyrrolidin-1-yl. In some embodiments, R 3 is (R)-2-hydroxy-2-methyl-ethylamino or (S)-2-hydroxy-2-methyl-ethylamino. In some embodiments, R 3 is (R)-2-hydroxy-1-methyl-ethylamino or (S)-2-hydroxy-1-methyl-ethylamino.

[0037] In some embodiments, R 4is H or CH. In some embodiments, R 4 is H. In some embodiments, R 4 is C such as CH3 1-3 It is an alkyl.

[0038] In some embodiments, the compounds provided herein are compounds of formula II: [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof, and R 2 , R 3 , R 4 and ring A are as described herein.

[0039] In some embodiments, the compounds provided herein are compounds of formula III: [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof, and R 2 , R 3 and ring A are as described herein.

[0040] In some embodiments, the compounds provided herein are compounds of formula IV: [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof, and R 2 , R 3 , R 4 and ring A are as described herein.

[0041] In some embodiments, the compounds provided herein are compounds of formula V: [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof, and R 2 , R3 and ring A are as described herein.

[0042] In some embodiments, the compound is selected from: 1-((7-cyano-2-(3'-(7-((3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid; 1-((7-cyano-2-(3'-(7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid; 1-((7-cyano-2-(3'-(7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid; 1-((7-cyano-2-(3'-(7-((1-hydroxypropan-2-ylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid; 1-((7-cyano-2-(3'-(7-((2-hydroxypropylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid; 1-((7-cyano-2-(3'-(7-((-3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid; 1-((7-cyano-2-(3'-(7-((-3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid; 1-((7-cyano-2-(3'-(7-((-3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid; 1-((7-cyano-2-(3'-(7-((-1-hydroxypropan-2-ylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid; 1-((7-cyano-2-(3'-(7-((-2-hydroxypropylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid; 1-((7-cyano-2-(3'-(7-((-3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid; 1-((7-cyano-2-(3'-(7-((-3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid; 1-((7-cyano-2-(3'-(7-((-3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid; 1-((7-cyano-2-(3'-(7-((-1-hydroxypropan-2-ylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid; 1-((7-cyano-2-(3'-(7-((-2-hydroxypropylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid; 1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid; 1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid; 1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid; 1-((7-cyano-2-(3'-(7-((3-hydroxypyrrolidin-1-yl)methyl)-2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid; 1-((7-cyano-2-(3'-(7-((-3-hydroxypyrrolidin-1-yl)methyl)-2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid; and 1-((7-cyano-2-(3'-(7-((-3-hydroxypyrrolidin-1-yl)methyl)-2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid, or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0043] In some embodiments, the compound is selected from: 1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid; 1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid; 1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-4-methylpiperidine-4-carboxylic acid; 1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-N,N-dimethylpiperidine-4-carboxamide; 1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-N-methylpiperidine-4-carboxamide; 3-(1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxamido)propanoic acid; 1-((7-cyano-2-(3'-(2-cyclopropyl-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid; 1-((2-(3'-(2-amino-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid; 1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid; 1-((7-cyano-2-(3'-(2-(hydroxymethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid; 1-((7-cyano-2-(3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-6-methyl-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid; and 1-((7-cyano-2-(3'-(6-(difluoromethyl)-3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid, or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0044] In some embodiments, the compound is selected from the examples provided herein.

[0045] It is further understood that certain features of the invention that are described in the context of separate embodiments for clarity can also be provided in combination in a single embodiment (although it is intended that these embodiments be combined as if described in multiple dependent forms). Conversely, various features of the invention that are described in the context of a single embodiment for brevity can also be provided separately or in any suitable subcombination. Thus, it is contemplated that the features described in the embodiments of the compound of formula (I) can be combined in any suitable combination.

[0046] At various places in the present specification, certain features of compounds are disclosed in groups or ranges. It is specifically intended that such disclosure include each and every individual subcombination of the members of such groups and ranges. For example, "C 1-6 The term "alkyl" is specifically intended to individually (without limitation) disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0047] The term "n-membered", where n is an integer, typically refers to the number of ring-forming atoms in a moiety where n is the number of ring-forming atoms. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0048] At various places in the specification, variables defining divalent linking groups may be described. Specifically, each linking substituent is intended to include both the forward and backward forms of the linking substituent. For example, -NR(CR'R'') n -NR(CR'R'') n -and-(CR'R'') nIt is intended that both NR- and NR- are included and each form is disclosed separately. If a structure requires a linking group, the Markush variable listed in the group is understood to be the linking group. For example, if a structure requires a linking group and the Markush group definition for the variable lists "alkyl" or "aryl", it is understood that "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

[0049] The term "substituted" means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group. The term "substituted" refers to any level of substitution where such substitution is permitted, e.g., mono-, di-, tri-, tetra-, or penta-substitution, unless otherwise noted. Substituents are independently selected, and substitution may be at any chemically accessible position. It should be understood that substitution at a given atom is limited by valence. It should be understood that substitution at a given atom results in a chemically stable molecule. The phrase "optionally substituted" means unsubstituted or substituted. The term "substituted" means that a hydrogen atom has been removed and replaced by a substituent. A single monovalent substituent, e.g., oxo, can replace two hydrogen atoms.

[0050] "C n-m " denotes a range inclusive of the endpoints, where n and m are integers and indicate the number of carbons. Examples include 1-4 , C 1-6 etc.

[0051] The term "alkyl," used alone or in combination with other terms, refers to a saturated hydrocarbon group which may be straight-chained or branched. n-mThe term "alkyl" refers to an alkyl group having n to m carbon atoms. An alkyl group formally corresponds to an alkane with one C-H bond replaced at the point of attachment of the alkyl group to the remainder of the compound. In some embodiments, an alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; and higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like.

[0052] The term "alkenyl," used alone or in combination with other terms, refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more double carbon-carbon bonds. An alkenyl group formally corresponds to an alkene in which one C-H bond is replaced at the point of attachment of the alkenyl group to the remainder of the compound. n-m The term "alkenyl" refers to an alkenyl group having n to m carbons. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0053] The term "alkynyl," used alone or in combination with other terms, refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more triple carbon-carbon bonds. An alkynyl group formally corresponds to an alkyne in which one C-H bond is replaced at the point of attachment of the alkyl group to the remainder of the compound. n-m The term "alkynyl" refers to an alkynyl group having n to m carbons. Examples of alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0054] The term "alkylene," used alone or in combination with other terms, refers to a divalent alkyl linking group. An alkylene group formally corresponds to an alkane in which two C-H bonds are replaced at the points of attachment of the alkylene group to the remainder of the compound. n-m The term "alkylene" refers to an alkylene group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, 2-methyl-propane-1,3-diyl, and the like.

[0055] The term "alkoxy", used alone or in combination with other terms, refers to a radical of the formula -O-alkyl, wherein the alkyl radical is as defined above. n-m The term "alkoxy" refers to an alkoxy group, where the alkyl group has n to m carbons. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0056] The term "amino" refers to a group of the formula -NH2.

[0057] The term "carbamyl" refers to a group of formula -C(O)NH2.

[0058] The term "carbonyl," used alone or in combination with other terms, refers to a -C(=O)- group, which can also be written as C(O).

[0059] The term "cyano" or "nitrile" refers to a group of formula -C≡N, which may also be written as -CN.

[0060] The term "halo" or "halogen," used alone or in combination with other terms, refers to fluoro, chloro, bromo, and iodo. In some embodiments, "halo" refers to a halogen atom selected from F, Cl, or Br. In some embodiments, the halo group is F.

[0061] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are replaced with a halogen atom. n-m The term "haloalkyl" refers to a C alkyl group having n to m carbon atoms and at least 1 to a maximum of {2(n to m)+1} halogen atoms. n-m In some embodiments, the halogen atom is a fluoro atom. In some embodiments, the haloalkyl group has 1-6 or 1-4 carbon atoms. Examples of haloalkyl groups include CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, and the like. In some embodiments, the haloalkyl group is a fluoroalkyl group.

[0062] The term "haloalkoxy", used alone or in combination with other terms, refers to a radical of the formula -O-haloalkyl, wherein the haloalkyl radical is as defined above. n-m The term "haloalkoxy" refers to a haloalkoxy group, where the haloalkyl group has n to m carbons. Examples of haloalkoxy groups include trifluoromethoxy, and the like. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0063] The term "oxo" refers to an oxygen atom as a divalent substituent that forms a carbonyl group when attached to a carbon, or a sulfoxide or sulfone group, or an N-oxide group when attached to a heteroatom. In some embodiments, heterocyclic groups may be optionally substituted with one or two oxo (=O) substituents.

[0064] The term "sulfide" refers to a sulfur atom as a divalent substituent which, when attached to carbon, forms a thiocarbonyl group (C=S).

[0065] The term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings having aromatic character (i.e., having (4n+2) delocalized π (pi) electrons, where n is an integer).

[0066] The term "aryl," used alone or in combination with other terms, refers to an aromatic hydrocarbon group that can be monocyclic or polycyclic (e.g., having two fused rings). n-m The term "aryl" refers to an aryl group having n to m ring carbon atoms. Aryl groups include, for example, phenyl, naphthyl, indanyl, indenyl, and the like. In some embodiments, an aryl group has from 6 to about 10 carbon atoms. In some embodiments, an aryl group has 6 carbon atoms. In some embodiments, an aryl group has 10 carbon atoms. In some embodiments, an aryl group is phenyl. In some embodiments, an aryl group is naphthyl.

[0067] As used herein, the term "heteroatom" is meant to include boron, phosphorus, sulfur, oxygen, and nitrogen.

[0068] The term "heteroaryl" or "heteroaromatic", used alone or in combination with other terms, refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from boron, phosphorus, sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any ring-forming N in the heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl has 5-14 ring atoms, including carbon atoms, and 1, 2, 3, or 4 heteroatom ring members, independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl has 5-14, or 5-10 ring atoms, including carbon atoms, and 1, 2, 3, or 4 heteroatom ring members, independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl has 5-6 ring atoms, and heteroatom ring members, independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl ring. In other embodiments, the heteroaryl is an 8-, 9-, or 10-membered fused bicyclic heteroaryl ring. Examples of heteroaryl groups include, but are not limited to, pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl, quinolinyl, isoquinolinyl, naphthyridinyl (including 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3-, and 2,6-naphthyridine), indolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, and the like.

[0069] A 5-membered heteroaryl ring is a heteroaryl group having 5 ring atoms, where one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 5-membered heteroaryls include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

[0070] A 6-membered heteroaryl ring is a heteroaryl group having 6 ring atoms, in which one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 6-membered heteroaryls include pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

[0071] The term "cycloalkyl," used alone or in combination with other terms, refers to non-aromatic hydrocarbon ring systems (monocyclic, bicyclic, or polycyclic) including cyclized alkyl and alkenyl groups. n-m The term "cycloalkyl" refers to a cycloalkyl having n to m ring carbon atoms. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring carbons (C 3-14 In some embodiments, the cycloalkyl group has 3 to 14 ring members, 3 to 10 ring members, 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is C 3-6It is a monocyclic cycloalkyl group. The ring-forming carbon atoms of the cycloalkyl group can be optionally oxidized to form an oxo or sulfido group. The cycloalkyl group also includes cycloalkylidene. In some embodiments, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The definition of cycloalkyl also includes moieties having one or more aromatic rings fused (i.e., having a common bond) to the cycloalkyl ring, such as, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, etc. Cycloalkyl groups containing fused aromatic rings can be bonded through any ring-forming atom, including the ring-forming atoms of the fused aromatic ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, etc. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0072] The term "heterocycloalkyl," used alone or in combination with other terms, refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, has at least one heteroatom ring member independently selected from boron, nitrogen, sulfur, oxygen, and phosphorus, and has 4 to 14 ring members, 4 to 10 ring members, 4 to 7 ring members, or 4 to 6 ring members. The term "heterocycloalkyl" includes monocyclic 4-, 5-, 6-, and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can include monocyclic or bicyclic or polycyclic (e.g., having 2 or 3 fused or bridged rings) ring systems or spirocycles. In some embodiments, heterocycloalkyl groups are monocyclic groups having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group may be optionally oxidized to form oxo or sulfido groups or other oxidized linkages (e.g., C(O), S(O), C(S) or S(O), N-oxide, etc.), or the nitrogen atom may be quaternized. The heterocycloalkyl group may be bonded through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0-3 double bonds. In some embodiments, the heterocycloalkyl group contains 0-2 double bonds. The definition of heterocycloalkyl also includes moieties that have one or more aromatic rings fused (i.e., having a bond in common) to the heterocycloalkyl ring, such as, for example, benzo or thienyl derivatives such as piperidine, morpholine, azepines, etc. Heterocycloalkyl groups that contain fused aromatic rings may be bonded through any ring-forming atom, including the ring-forming atoms of the fused aromatic ring.Examples of heterocycloalkyl groups include azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, morpholino, 3-oxa-9-azaspiro[5.5]undecanyl, 1-oxa-8-azaspiro[4.5]decanyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, and thiomorpholino.

[0073] In certain places, definitions or embodiments refer to certain rings (e.g., azetidine ring, pyridine ring, etc.). Unless otherwise specified, these rings can be bonded to any ring member, provided that the valence of the atom is not exceeded. For example, the azetidine ring can be bonded at any position of the ring, while the azetidin-3-yl ring is bonded at the 3-position.

[0074] The compounds described herein may be asymmetric (e.g., have one or more stereocenters). Unless otherwise specified, all stereoisomers, such as enantiomers and diastereomers, are intended. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like may also exist in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.

[0075] The resolution of racemic mixtures of compounds can be carried out by any of a number of methods known in the art. One method includes fractional recrystallization using chiral resolving acids that are optically active salt-forming organic acids. Suitable resolving agents for fractional recrystallization are optically active acids such as, for example, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or the D- and L-forms of various optically active camphorsulfonic acids, such as β-camphorsulfonic acid. Other suitable resolving agents for fractional crystallization include stereoisomerically pure forms (e.g., S- and R-forms, or diastereomerically pure forms) of α-methylbenzylamine, 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0076] Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by one skilled in the art.

[0077] In some embodiments, the compounds of the invention have the (R) configuration. In other embodiments, the compounds have the (S) configuration. In compounds with two or more chiral centers, unless otherwise specified, each of the chiral centers in the compound may independently be (R) or (S).

[0078] The compounds of the present invention also include tautomeric forms. Tautomeric forms are obtained by the exchange of a single bond with an adjacent double bond, accompanied by the concomitant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position of a heterocyclic ring system, such as 1H-imidazole and 3H-imidazole, 1H-1,2,4-triazole, 2H-1,2,4-triazole, and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically fixed in one form by appropriate substitution.

[0079] The compounds of the present invention may also include all isotopes of atoms occurring in intermediates or final compounds. Isotopes include atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the present invention may be replaced or substituted with an isotope of the atom at natural or non-natural abundance. In some embodiments, the compounds include at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of the present disclosure may be replaced or substituted with deuterium. In some embodiments, the compounds include two or more deuterium atoms. In some embodiments, the compounds include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. Synthetic methods for including isotopes in organic compounds are known in the art.

[0080] The term "compound" as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. The term is also meant to refer to compounds of the invention regardless of how they are prepared, for example, by synthesis, by a biological process (e.g., metabolic or enzymatic transformation), or a combination thereof.

[0081] All compounds and their pharma- ceutically acceptable salts may be found together with other substances such as water and solvents (e.g., hydrates and solvates) or may be isolated. When in the solid state, the compounds and their salts described herein may occur in various forms, for example, in the form of solvates, including hydrates. The compounds may be in any solid state form, such as polymorphs or solvates, so unless otherwise specified, references to compounds and their salts herein should be understood to include any solid state form of the compounds.

[0082] In some embodiments, the compound of the present invention or its salt is substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compound of the present invention. Substantial separation can include a composition that includes at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compound of the present invention or its salt.

[0083] The phrase "pharmacologically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0084] As used herein, the expressions "ambient temperature" and "room temperature" are understood in the art and generally refer to a temperature approaching the temperature of the room in which the reaction is carried out, e.g., a temperature of about 20° C. to about 30° C., e.g., the reaction temperature.

[0085] The present invention also includes pharma- ceutically acceptable salts of the compounds described herein. The term "pharma- ceutically acceptable salts" refers to derivatives of the disclosed compounds, where the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharma- ceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharma- ceutically acceptable salts of the present invention include non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharma- ceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or in a mixture of the two. In general, non-aqueous media such as ether, ethyl acetate, alcohol (e.g., methanol, ethanol, isopropanol, or butanol) or acetonitrile (MeCN) are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17, pp. 171-175, 1997. th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19, and Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). In some embodiments, the compounds described herein include N-oxide forms.

[0086] II.Synthesis The compounds of the invention, including their salts, may be prepared using known organic synthesis techniques, or may be synthesised according to any of a number of possible synthetic routes.

[0087] The reaction for preparing the compound of the present invention can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is carried out, which can range from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of two or more solvents. Depending on the specific reaction step, a suitable solvent for a specific reaction step can be selected by those skilled in the art.

[0088] Preparation of the compounds of the invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one of ordinary skill in the art. The chemistry of protecting groups can be found, for example, in Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6 th Ed. (Wiley, 2007), Peturssion et al., "Protective Groups in Carbohydrate Chemistry," J. Chem. Educ., 1997, 74(11), 1297, and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006).

[0089] The reaction can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g. 1 H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatography, such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).

[0090] III. Use of the Compounds The compounds of the present disclosure can inhibit the activity of PD-1 / PD-L1 protein / protein interaction and are therefore useful for treating diseases and disorders associated with the activity of PD-1, as well as diseases and disorders associated with PD-L1, including its interaction with other proteins such as PD-1 and B7-1 (CD80). In certain embodiments, the compounds of the present disclosure, or pharma- ceutically acceptable salts or stereoisomers thereof, are useful for therapeutic administration to enhance, stimulate, and / or increase immunity to cancer, chronic infections, or sepsis, including enhancing responses to vaccinations. In some embodiments, the present disclosure provides methods of inhibiting PD-1 / PD-L1 protein / protein interaction. The methods include administering to an individual or patient a compound of Formula (I) or any of the formulas described herein, or any of the claims and described herein, or a pharma-ceutically acceptable salt or stereoisomer thereof. The compounds of the present disclosure can be used alone, in combination with other drugs or therapies, or as adjuvants or neoadjuvants for the treatment of diseases or disorders, including cancer or infectious diseases. For the uses described herein, any of the disclosed compounds may be used, including any of the embodiments thereof.

[0091] The compounds of the present disclosure inhibit PD-1 / PD-L1 protein / protein interaction, resulting in blockade of the PD-1 pathway. Blockade of PD-1 can enhance immune responses to cancer cells and infectious diseases in mammals, including humans. In some embodiments, the present disclosure provides for the treatment of an individual or patient in vivo using a compound of formula (I) or a salt or stereoisomer thereof, such that the growth of a cancerous tumor is inhibited. A compound of formula (I) or any of the formulas described herein, or any of the compounds described in any of the claims and described herein, or a salt or stereoisomer thereof, can be used to inhibit the growth of a cancerous tumor. Alternatively, a compound of formula (I) or any of the formulas described herein, or any of the compounds described in any of the claims and described herein, or a salt or stereoisomer thereof, can be used in combination with other agents or standard cancer treatments, as described below. In one embodiment, the present disclosure provides a method of inhibiting the growth of tumor cells in vitro. The method includes contacting tumor cells in vitro with a compound of formula (I) or any of the formulas described herein, or any of the compounds described in any of the claims and described herein, or a salt or stereoisomer thereof. In another embodiment, the present disclosure provides a method of inhibiting tumor cell growth in an individual or patient. The method includes administering to an individual or patient in need thereof a therapeutically effective amount of a compound of formula (I) or any of the formulas described herein, or any of the compounds described in any of the claims and described herein, or a salt or stereoisomer thereof.

[0092] In some embodiments, methods for treating cancer are provided herein. The methods include administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or any of the formulas described herein, any of the compounds described in the claims and described herein, or a salt thereof. Examples of cancers include cancers whose growth can be inhibited using the compounds of the present disclosure, and cancers that are typically responsive to immunotherapy.

[0093] In some embodiments, the disclosure provides a method of enhancing, stimulating, and / or increasing an immune response in a patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or any of the formulae described herein, a compound or composition as described in any of the claims and described herein, or a salt thereof.

[0094] Examples of cancers treatable using the compounds of the present disclosure include, but are not limited to, bone cancer, splenic cancer, skin cancer, head and neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, colorectal cancer, anal cancer, gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, carcinoma of the endometrium, endometrial cancer, and uterine cancer. Cancers of the present disclosure include cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, childhood solid tumors, lymphocytic lymphoma, bladder cancer, kidney or urethral cancer, renal pelvis cancer, central nervous system neoplasms (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers including asbestos-induced cancers, and combinations of such cancers. The compounds of the present disclosure are also useful for the treatment of metastatic cancers, particularly metastatic cancers that express PD-L1.

[0095] In some embodiments, cancers treatable by the compounds of the present disclosure include melanoma (e.g., metastatic malignant melanoma, cutaneous melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone refractory prostate adenocarcinoma), breast cancer (e.g., invasive breast cancer), colon cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), head and neck squamous cell carcinoma (e.g., squamous cell carcinoma of the head and neck), urothelial carcinoma (e.g., bladder cancer, non-muscle invasive bladder cancer (NMIBC)), and microsatellite instability-high cancer (MSI-HSC). highAdditionally, the present disclosure includes refractory or recurrent malignancies whose growth may be inhibited using the compounds of the present disclosure.

[0096] In some embodiments, cancers treatable using the compounds of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), hematological cancers (e.g., leukemias such as lymphoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and relapsed follicular), Hodgkin's lymphoma, or multiple myeloma), and combinations of such cancers.

[0097] In some embodiments, cancers treatable using the compounds of the present disclosure include, but are not limited to, cholangiocarcinoma, bile duct cancer, biliary tract cancer, triple-negative breast cancer, rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellular carcinoma, Ewing's sarcoma, brain cancer, brain tumor, astrocytoma, neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma, epithelioid sarcoma, eye cancer, fallopian tube cancer, gastrointestinal cancer, gastrointestinal stromal tumor, hairy cell leukemia, intestinal cancer, pancreatic islet cell cancer, oral cancer, mouth cancer, throat cancer, laryngeal cancer, lip cancer, mesothelioma, cervical cancer, nasal cavity cancer, ocular cancer, ocular melanoma, pelvic cancer, rectal cancer, renal cell carcinoma, salivary gland cancer, paranasal sinus cancer, spinal cancer, tongue cancer, tubular cancer, urethral cancer, and ureteral cancer.

[0098] In some embodiments, compounds of the present disclosure can be used to treat sickle cell disease and sickle cell anemia.

[0099] In some embodiments, diseases and indications treatable using compounds of the present disclosure include, but are not limited to, hematological cancers, sarcomas, lung cancer, gastrointestinal cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, and skin cancer.

[0100] Exemplary hematological cancers include lymphomas and leukemias, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and relapsed follicular), Hodgkin's lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET)), myelodysplastic syndromes (MDS), T-cell acute lymphoblastic leukemia (T-ALL), and multiple myeloma (MM).

[0101] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, and teratoma.

[0102] Exemplary lung cancers include non-small cell lung cancer (NSCLC) (e.g., squamous cell NSCLC), small cell lung carcinoma, bronchogenic carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchial) carcinoma, bronchial adenoma, chondroitin hamartoma, and mesothelioma.

[0103] Exemplary gastrointestinal cancers include esophageal cancer (carcinoma, squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma, adenocarcinoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIPoma), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer (colorectal adenocarcinoma).

[0104] Exemplary genitourinary tract cancers include kidney cancer (adenocarcinoma, Wilms' tumor, [nephroblastoma]), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), and testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma). In some embodiments, the cancer is a urological system cancer (e.g., papillary renal carcinoma, testicular germ cell carcinoma, chromophobe renal cell carcinoma, clear cell renal carcinoma, or prostate adenocarcinoma).

[0105] Exemplary liver cancers include hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0106] Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign cartilage tumor, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor.

[0107] Exemplary nervous system cancers include cancer of the skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cord (neurofibroma, meningioma, glioma, non-epithelial malignant tumors), as well as neuroblastoma and Lhermitte-Dacros disease.

[0108] Exemplary gynecologic cancers include cancer of the uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovary (ovarian carcinoma (serous cystadenocarcinoma, serous adenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma), and fallopian tubes (epithelial carcinoma).

[0109] Exemplary skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma (e.g., cutaneous squamous cell carcinoma), Kaposi's sarcoma, lenticular dysplastic nevus, lipoma, hemangioma, dermatofibroma, and keloid. In some embodiments, diseases and indications treatable using the compounds of the present disclosure include, but are not limited to, sickle cell disease (e.g., sickle cell anemia), triple-negative breast cancer (TNBC), myelodysplastic syndrome, testicular cancer, bile duct cancer, esophageal cancer, and urothelial cancer.

[0110] Blocking the PD-1 pathway with the compounds of the present disclosure can also be used to treat infectious diseases, such as viral, bacterial, fungal, and parasitic infections. The present disclosure provides a method for treating an infectious disease, such as a viral infection. The method includes administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or any of the formulas described herein, any of the compounds described in the claims and described herein, or salts thereof. Examples of viruses that cause infectious diseases treatable by the methods of the present disclosure include, but are not limited to, human immunodeficiency virus, human papilloma virus, influenza, hepatitis A, B, C, or D virus, adenovirus, pox virus, herpes simplex virus, human cytomegalovirus, severe acute respiratory syndrome virus, Ebola virus, and measles virus. In some embodiments, viruses causing infectious diseases treatable by the methods of the present disclosure include, but are not limited to, hepatitis (types A, B, or C), herpes viruses (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein-Barr virus), adenovirus, influenza virus, flavivirus, echovirus, rhinovirus, coxsackievirus, cornovirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papilloma virus, infectious virus, poliovirus, rabies virus, JC virus, tuberculosis, and arboviral encephalitis virus.

[0111] The present disclosure provides a method for treating a bacterial infection. The method includes administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or any of the formulas described herein, any of the claims and described herein, or a salt thereof. Non-limiting examples of infectious diseases treatable by the methods of the present disclosure include chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci, and conococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme disease bacteria.

[0112] The present disclosure provides a method of treating a fungal infection. The method includes administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or any of the formulas described herein, any of the claims and described herein, or a salt thereof. Non-limiting examples of pathogenic fungi causing infections treatable by the methods of the present disclosure include Candida (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis, and Histoplasma capsulatum.

[0113] The present disclosure provides a method of treating a parasitic infection. The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or any of the formulas described herein, any of the claims and described herein, or a salt thereof. Non-limiting examples of pathogenic parasites causing infections treatable by the methods of the present disclosure include Entamoeba histolytica, Balantidium coli, Naegleria fowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus brasiliensis.

[0114] The present disclosure provides a method for treating a neurodegenerative disease or disorder. The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or any of the formulas described herein, any of the compounds described herein in any of the claims, or a salt thereof. Non-limiting examples of neurodegenerative diseases or disorders include Alzheimer's disease, Parkinson's disease, Huntington's disease, prion disease, motor neuron disease, spinocerebellar ataxia, and spinal muscular atrophy.

[0115] It is believed that compounds of formula (I), or any of its embodiments, may have promising biopharmaceutical properties, such as satisfactory pharmacological and toxicological profiles, metabolic and pharmacokinetic properties, solubility, and permeability. It will be understood that the determination of suitable biopharmaceutical properties, for example, the determination of inhibition of a particular target or channel to determine cytotoxicity or potential toxicity in cells, is within the knowledge of one of ordinary skill in the art.

[0116] The terms "individual" or "patient", used interchangeably, refer to a mammal, preferably any animal, including a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, most preferably a human.

[0117] The phrase "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, physician, or other clinician.

[0118] As used herein, the term "treat" or "treatment" refers to (1) inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in an individual experiencing or exhibiting the pathology or symptomology of the disease, condition, or disorder (i.e., halting further development of the pathology and / or symptomology), and (2) ameliorating a disease, e.g., ameliorating a disease, condition, or disorder in an individual experiencing or exhibiting the pathology or symptomology of the disease, condition, or disorder (i.e., reversing the pathology and / or symptomology), e.g., reducing the severity of the disease.

[0119] In some embodiments, the compounds of the invention may be useful in preventing or reducing the risk of developing any of the diseases referred to herein, for example, in preventing or reducing the risk of developing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder but has not yet experienced or exhibited the pathology or symptomology of the disease.

[0120] Combination therapy Cancer cell growth and survival can be affected by the dysfunction of multiple biological pathways. Therefore, it may be useful to combine inhibitors of different mechanisms, such as enzyme inhibitors, signal transduction inhibitors, chromatin dynamics inhibitors, or immune response regulators, to treat such conditions. Targeting two or more signal transduction pathways (or two or more biological molecules involved in a given signal transduction pathway) can reduce the possibility of drug resistance occurring in cell populations or reduce the toxicity of treatment.

[0121] The compounds of the present disclosure may be used in combination with one or more other therapies for the treatment of diseases such as cancer or infectious diseases. Examples of diseases and indications treatable with combination therapy include those described herein. Examples of cancer include solid tumors and non-solid tumors such as liquid tumors, blood cancers, etc. Examples of infectious diseases include viral infections, bacterial infections, fungal infections, or parasitic infections. For example, the compounds of the present disclosure may be combined with inhibitors of one or more of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, BCL2, CDK, TGF-βR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IDH2, IGF-1R, IR-R, PDGFαR, PDGFβR, PI3K (alpha, beta, gamma, delta, and multiple or selective) , CSF1R, KIT, FLK-II, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, PARP, Ron, Sea, TRKA, TRKB, TRKC, TAM kinases (Axl, Mer, Tyro3), FLT3, VEGFR / Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK, and B-Raf. In some embodiments, the compounds of the present disclosure can be combined with one or more of the following inhibitors for the treatment of cancer or infectious diseases. Non-limiting examples of inhibitors that may be combined with the compounds of the present disclosure for the treatment of cancer and infectious diseases include FGFR inhibitors (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., pemigatinib (INCY54828), INCB62079), JAK inhibitors (JAK1 and / or JAK2, e.g., ruxolitinib, baricitinib, or itacitinib (INCB39110)), IDO inhibitors (e.g., epacadostat, NLG919, or BMS-986205, MK7162), LSD1 inhibitors (e.g., INCB59872 and INCB60003), TDO inhibitors, PI3K-delta inhibitors (e.g.,palsaclisib (INCB50465) and INCB50797), PI3K-gamma inhibitors such as PI3K-gamma selective inhibitors, Pim inhibitors (e.g., INCB53914), EGFR inhibitors (also known as ErB-1 or HER-1; e.g., erlotinib, gefitinib, vandetanib, osimertinib, cetuximab, necitumumab, or panitumumab), VEGFR inhibitors or pathway blockers (e.g., bevacizumab, basizumab, pazopanib, sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib, axitinib, vandetanib, ramucirumab, lenvatinib, ziv-aflibercept), PARP inhibitors (e.g., olaparib, rucaparib, veliparib, talazoparib, or niraparib), CSF1R inhibitors, TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer), adenosine receptor antagonists (e.g., A2a / A2b receptor antagonists), HPK1 inhibitors, chemokine receptor inhibitors (e.g., CCR2 or CCR5 inhibitors), SHP1 / 2 phosphatase inhibitors, histone deacetylase inhibitors (HDACs) such as HDAC8 inhibitors, angiogenesis inhibitors, interleukin receptor inhibitors, bromo and extra-terminal family member inhibitors (e.g., bromodomain inhibitors or BET inhibitors, e.g., INCB54329 and INCB57643), arginase inhibitors (INCB001158), PARP inhibitors (such as rucaparib or olaparib), sitravatinib, B-Raf inhibitor-MEK inhibitor combinations (such as encorafenib and binimetinib, dabrafenib and trametinib, or cobimetinib and vemurafenib), and adenosine receptor antagonists, or combinations thereof.

[0122] In some embodiments, compounds of the present disclosure can be combined with a TLR7 agonist (eg, imiquimod).

[0123] The compounds of the present disclosure can further be used in combination with other methods of treating cancer, for example, by chemotherapy, radiation therapy, tumor targeting therapy, adjuvant therapy, immunotherapy, or surgery. Examples of immunotherapy include cytokine therapy (e.g., interferon, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccines, monoclonal antibodies, bispecific or multispecific antibodies, antibody-drug conjugates, adoptive T cell transfer, Toll receptor agonists, STING agonists, RIG-I agonists, oncolytic virus therapy, and immunomodulatory small molecules, including thalidomide or JAK1 / 2 inhibitors, PI3Kδ inhibitors, etc. The compounds can be administered in combination with one or more anti-cancer agents, such as chemotherapeutic agents. Examples of chemotherapeutic agents include abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, intravenous busulfan, oral busulfan, calcitinib, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanol. lopionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alpha 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen,Mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib , streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate.

[0124] Other anti-cancer agent(s) include antibody therapeutics such as trastuzumab (Herceptin), antibodies against costimulatory molecules such as CTLA-4 (e.g., ipilimumab), 4-1BB (e.g., urelumab, utomilumab), antibodies against PD-1 and PD-L1, or antibodies against cytokines (IL-10, TGF-β, etc.). Examples of PD-1 and / or PD-L1 antibodies that may be combined with the compounds of the present disclosure for the treatment of cancer or infectious diseases such as viral, bacterial, fungal, and parasitic infections include, but are not limited to, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, and SHR-1210.

[0125] The compounds of the present disclosure may be used in combination with one or more immune checkpoint inhibitors for the treatment of diseases such as cancer or infectious diseases. Exemplary immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CBL-B, CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, TIGIT, CD112R, VISTA, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA. In some embodiments, the compounds provided herein may be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors, and TGFR beta inhibitors.

[0126] In some embodiments, the inhibitor of an immune checkpoint molecule is an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0127] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-1, such as an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is pembrolizumab.

[0128] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-L1, such as an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

[0129] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab.

[0130] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of LAG3, such as an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385.

[0131] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of TIM3, such as an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

[0132] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of GITR, such as an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, or MEDI1873.

[0133] In some embodiments, the inhibitor of immune checkpoint molecule is an inhibitor of OX40, such as an anti-OX40 antibody or an OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562, MOXR-0916, PF-04518600, GSK3174998, or BMS-986178. In some embodiments, the OX40L fusion protein is MEDI6383.

[0134] The compounds of the present disclosure may further be used in combination with one or more anti-inflammatory agents, steroids, immunosuppressants, or therapeutic antibodies.

[0135] A compound of formula (I) or any of the formulae described herein, any of the claims and described herein, or a salt thereof, can be combined with another immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines. Non-limiting examples of tumor vaccines that can be used include peptides of melanoma antigens, such as peptides of gp100, MAGE antigens, Trp-2, MARTI, and / or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.

[0136] Compounds of formula (I) or any of the formulas described herein, compounds described in any of the claims and described herein, or salts thereof, can be used in combination with vaccination protocols for the treatment of cancer. In some embodiments, tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines include proteins from viruses implicated in human cancers, such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's herpes sarcoma virus (KHSV). In some embodiments, compounds of the present disclosure can be used in combination with tumor-specific antigens, such as heat shock proteins isolated from the tumor tissue itself. In some embodiments, compounds of formula (I) or any of the formulas described herein, compounds described in any of the claims and described herein, or salts thereof can be combined with dendritic cell immunity to activate a strong anti-tumor response.

[0137] The compounds of the present disclosure can be used in combination with bispecific macrocyclic peptides that target Fe alpha or Fe gamma receptor expressing effector cells to tumor cells. The compounds of the present disclosure can also be combined with macrocyclic peptides that activate the host's immune responsiveness.

[0138] The compounds of the present disclosure can be used in combination with bone marrow transplantation for the treatment of various tumors of hematopoietic origin.

[0139] The compounds of formula (I) or any of the formulas described herein, any of the compounds described in the claims and described herein, or salts thereof, can be used in combination with vaccines to stimulate immune responses against pathogens, toxins, and self-antigens. Examples of pathogens for which this therapeutic approach may be particularly useful include those for which there is currently no effective vaccine, or for which traditional vaccines are not fully effective. These include, but are not limited to, HIV, Hepatitis (types A, B, and C), influenza, herpes, Giardia, Malaria, Leishmania, Staphylococcus aureus, and Pseudomonas Aeruginosa.

[0140] Viruses causing infectious diseases treatable by the methods of the present disclosure include, but are not limited to, human papillomavirus, influenza, hepatitis A, B, C or D virus, adenovirus, poxvirus, herpes simplex virus, human cytomegalovirus, severe acute respiratory syndrome virus, Ebola virus, measles virus, herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein-Barr virus), flavivirus, echovirus, rhinovirus, coxsackievirus, cornovirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, infectious virus, poliovirus, rabies virus, JC virus, and arboviral encephalitis virus.

[0141] Pathogenic bacteria causing infections treatable by the methods of the present disclosure include, but are not limited to, chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme burgdorferi.

[0142] Pathogenic fungi causing infections treatable by the methods of the present disclosure include, but are not limited to, Candida (e.g., albicans, krusei, glabrata, tropicalis), Cryptococcus neoformans, Aspergillus (e.g., fumigatus, niger), Genus Mucorales (e.g., mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis, and Histoplasma capsulatum.

[0143] Pathogenic parasites causing infections treatable by the methods of the present disclosure include, but are not limited to, Entamoeba histolytica, Balantidium coli, Naegleria fowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus brasiliensis.

[0144] When two or more pharmaceutical agents are administered to a patient, they may be administered simultaneously, separately, sequentially, or in combination (eg, in the case of three or more agents).

[0145] IV. Formulation, Dosage Forms, and Administration When used as a medicament, the compounds of the present disclosure may be administered in the form of a pharmaceutical composition. Thus, the present disclosure provides a composition comprising a compound of formula (I) or any of the formulas described herein, any of the compounds described in any of the claims and described herein, or a pharma- ceutically acceptable salt thereof, or any of the embodiments thereof, and at least one pharma- ceutically acceptable carrier or excipient. These compositions may be prepared by methods well known in the pharmaceutical art, and may be administered by various routes depending on whether local or systemic treatment is indicated and the area to be treated. Administration may be topical (including transdermal, epithelial, ocular, and mucous membranes, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection or infusion, or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose or, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous bases, powder bases, or oil bases, thickeners, and the like, may be necessary or desirable.

[0146] The present invention also includes pharmaceutical compositions that contain the disclosed compound or its pharma- ceutically acceptable salt as an active ingredient in combination with one or more pharma- ceutically acceptable carriers or excipients. In some embodiments, the compositions are suitable for topical administration. In making the compositions of the present invention, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed in such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When an excipient functions as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, carrier, or medium for the active ingredient. Thus, the composition can be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), for example, ointment containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders.

[0147] When preparing formulation, active compound can be ground to provide suitable particle size before being combined with other components.If active compound is substantially insoluble, it can be ground to a particle size of less than 200 mesh.If active compound is substantially water-soluble, its particle size can be adjusted by grinding to, for example, about 40 mesh to provide substantially uniform distribution in formulation.

[0148] The compounds of the present invention can be milled using known milling procedures, such as wet milling, to obtain a particle size suitable for tableting and other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the present invention can be prepared by processes known in the art, see, for example, WO2002 / 000196.

[0149] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose.In addition, the formulation may contain lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl and propylhydroxybenzoates, sweeteners, and flavoring agents.The composition of the present invention may be formulated to provide quick, sustained, or delayed release of active ingredient after administration to patient by using procedures known in the art.

[0150] In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose (SMCC) and at least one compound described herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, the silicified microcrystalline cellulose comprises about 98% microcrystalline cellulose and about 2% silicon dioxide w / w.

[0151] In some embodiments, the composition is a sustained release composition comprising at least one compound described herein, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable carrier or excipient. In some embodiments, the composition comprises at least one compound described herein, or a pharma- ceutically acceptable salt thereof, and at least one component selected from microcrystalline cellulose, lactose monohydrate, hydroxypropyl methylcellulose, and polyethylene oxide. In some embodiments, the composition comprises at least one compound described herein, or a pharma- ceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate, and hydroxypropyl methylcellulose. In some embodiments, the composition comprises at least one compound described herein, or a pharma- ceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate, and polyethylene oxide. In some embodiments, the composition further comprises magnesium stearate or silicon dioxide. In some embodiments, the microcrystalline cellulose is Avicel PH102™. In some embodiments, the lactose monohydrate is Fast-flo 316™. In some embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and / or hydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LV™). In some embodiments, the polyethylene oxide is polyethylene oxide WSR 1105 (e.g., Polyox WSR 1105™).

[0152] In some embodiments, the compositions are produced using a wet granulation process. In some embodiments, the compositions are produced using a dry granulation process.

[0153] The compositions may be formulated in unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually from about 100 mg to about 500 mg, of the active ingredient. In some embodiments, each dosage contains about 10 mg of the active ingredient. In some embodiments, each dosage contains about 50 mg of the active ingredient. In some embodiments, each dosage contains about 25 mg of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of the active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0154] The components used to formulate pharmaceutical compositions are of high purity and substantially free of potentially harmful contaminants (e.g., at least national food grade, generally at least analytical grade, and more typically at least pharmaceutical grade). Particularly for human consumption, the compositions are preferably manufactured or formulated in accordance with Good Manufacturing Practice provisions as defined in applicable regulations of the U.S. Food and Drug Administration. For example, suitable formulations may be sterile and / or substantially isotonic, and / or in full compliance with all U.S. Food and Drug Administration Good Manufacturing Practice provisions.

[0155] The active compounds can be effective over a wide dosage range and are generally administered in a therapeutically effective amount. However, it will be understood that the amount of compound actually administered will usually be determined by the physician according to the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0156] The therapeutic dosage of the compounds of the invention may vary according to, for example, the particular application for which the treatment is being administered, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compound of the invention in a pharmaceutical composition may vary depending on several factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compounds of the invention may be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health of the particular patient, the relative biological effectiveness of the selected compound, the excipient formulation, and its route of administration. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0157] To prepare solid compositions such as tablets, the primary active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogenous mixture of the compound of the present invention. When these preformulation compositions are referred to as homogenous, the active ingredient is typically dispersed evenly throughout the composition, so that the composition can be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above, containing, for example, about 0.1 to about 1000 mg of the active ingredient of the present invention.

[0158] The tablets or pills of the present invention are coated or otherwise compounded to provide a dosage form that provides the advantage of long-term action. For example, the tablets or pills can include an inner dosage component and an outer dosage component, the outer dosage component being in the form of an envelope for the inner dosage component. These two components can be separated by an enteric layer, which functions to resist disintegration in the stomach and allows the inner component to reach the duodenum intact or to be delayed-released. A variety of materials can be used for such enteric layers or coatings, including some polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0159] Liquid forms into which the compounds and compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0160] Compositions for inhalation or insufflation include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharma- ceutically acceptable excipients as described above. In some embodiments, the compositions are administered by oral or nasal respiratory routes for local or systemic effect. Compositions may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask, obturator, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0161] Topical formulations may include one or more conventional carriers. In some embodiments, ointments may include water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, and the like. The carrier composition of creams may be based on water in combination with glycerol and one or more other components, for example, glycerol monostearate, PEG-glycerol monostearate, and cetylstearyl alcohol. Gels may be formulated using isopropyl alcohol and water, suitably in combination with other components, for example, glycerol, hydroxyethylcellulose, and the like. In some embodiments, topical formulations include at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5% by weight of the compound of the present invention. Topical formulations may be suitably packaged, for example, in 100 g tubes, optionally associated with indications for the treatment of a selected indication, for example, psoriasis or other skin conditions.

[0162] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of administration, such as prophylaxis or treatment, the condition of the patient, the mode of administration, etc. In therapeutic applications, the compositions may be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the disease state being treated, as well as the judgment of the attending physician based on factors such as the severity of the disease, the age, weight, and general condition of the patient.

[0163] The compositions administered to patients may be in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. Aqueous solutions may be packaged for use as is or lyophilized, and the lyophilized preparations are combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations will typically be 3-11, more preferably 5-9, and most preferably 7-8. It will be understood that the use of certain of the aforementioned excipients, carriers, or stabilizers will result in the formulation of pharmaceutical salts.

[0164] The therapeutic dosage of the compounds of the invention may vary according to, for example, the particular application for which the treatment is being given, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compound of the invention in a pharmaceutical composition may vary depending on several factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compounds of the invention may be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health of the particular patient, the relative biological effectiveness of the compound selected, the excipient formulation, and its route of administration. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0165] V. Labeled Compounds and Assay Methods The compounds of the present disclosure may further be useful in investigating biological processes in normal and abnormal tissues. Accordingly, another aspect of the present invention relates to labeled compounds of the present invention (radiolabeled, fluorescently labeled, etc.) that are useful in imaging techniques as well as in assays for localizing and quantifying PD-1 or PD-L1 proteins in tissue samples, including humans, both in vitro and in vivo, and identifying PD-L1 ligands by inhibitory binding of the labeled compounds. Thus, the present invention includes PD-1 / PD-L1 binding assays comprising such labeled compounds.

[0166] The present invention further includes the isotopically substituted compounds of the present disclosure. An "isotopically substituted" compound is a compound of the present invention in which one or more atoms are replaced or substituted by an atom having the same atomic number but a different atomic mass or mass number, for example, an atomic mass or mass number that is different from the atomic mass or mass number typically found in nature (i.e., occurring in nature). It is understood that a "radiolabeled" compound is a compound that incorporates at least one isotope (e.g., a radionuclide) that is radioactive. Suitable radionuclides that can be incorporated into the compounds of the present invention include, but are not limited to, 3 H (written as T for tritium), 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, and 131 I. The radionuclide that is incorporated into the present radiolabeled compounds will depend on the particular application of that radiolabeled compound. For example, in in vitro PD-L1 protein labeling and competition assays: 3 H, 14 C. 82 Br, 125 I, 131 I, 35 Compounds incorporating S are generally the most useful. For radioimaging applications, 11 C. 18 F, 125 I, 123 I, 124 I, 131 I, 75 Br, 76 Br, or 77 Br is most useful.

[0167] In some embodiments, the radionuclide is 3 H, 14 C. 125 I, 35 S, and 82 Br. Synthetic methods for incorporating radioisotopes into organic compounds are known in the art.

[0168] Specifically, the labeled compounds of the present invention can be used in screening assays to identify and / or evaluate compounds. For example, a labeled newly synthesized or identified compound (i.e., a test compound) can be evaluated for its ability to bind to PD-L1 protein by monitoring its concentration change upon contact with PD-L1 protein through tracking of the label. For example, a (labeled) test compound can be evaluated for its ability to reduce the binding of another compound known to bind to PD-L1 protein (i.e., a standard compound). Thus, the ability of a test compound to compete with a standard compound for binding to PD-L1 protein is directly correlated to its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and the test compound is not labeled. Thus, the concentration of the labeled standard compound is monitored to evaluate the competition between the standard compound and the test compound, and thus the relative binding affinity of the test compound is ascertained.

[0169] VI. Kit The present disclosure also includes pharmaceutical kits useful for treating or preventing a disease or disorder associated with activity of PD-L1, including PD-1 and its interaction with other proteins such as B7-1 (CD80), e.g., cancer or infectious disease, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), or any of its any embodiments. Such kits may further include one or more of a variety of conventional pharmaceutical kit components, such as, for example, a container containing one or more pharma- ceutically acceptable carriers, additional containers, etc., as would be readily apparent to one of skill in the art. Instructions, either as an insert or as a label, indicating the amounts of components to be administered, dosing guidelines, and / or guidelines for mixing the components may also be included in the kit.

[0170] The following abbreviations may be used herein: aq. (aqueous); br (broad); d (doublet); dd (doublet of doublets); DCM (dichloromethane); DMF (N,N-dimethylformamide); Et (ethyl); EtOAc (ethyl acetate); g (gram(s); h (hour(s); HPLC (high performance liquid chromatography); Hz (hertz); J (coupling constant); LCMS (liquid chromatography-mass spectrometry); m (multiplet); M (molar); MS (mass spectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); m g (milligram(s); min. (minute(s); mL (milliliter(s); mmol (millimole(s); nM (nanomole); NMR (nuclear magnetic resonance spectroscopy); Ph (phenyl); rt (room temperature); s (singlet); t (triplet or tertiary); TBS (tert-butyldimethylsilyl); tert (tertiary); tt (triplet of triplets); TFA (trifluoroacetic acid); THF (tetrahydrofuran); μg (microgram(s); μL (microliter(s); μM (micromole); wt% (weight percent).

[0171] The present invention will be described in more detail by specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any manner. Those skilled in the art will readily recognize various non-critical parameters that can be changed or modified to produce essentially the same results. The compounds of the examples have been found to inhibit the activity of PD-1 / PD-L1 protein / protein interaction by at least one assay described herein. EXAMPLES

[0172] The experimental procedures for the compounds of the present invention are provided below. Open access preparative LCMS purification of some of the prepared compounds was performed on a Waters mass fractionation system. The basic instrument setup, protocols, and control software for the operation of these systems are described in detail in the literature. See, for example, Blom, "Two-Pump At Column Dilution Configuration for Preparative LC-MS", K. Blom, J. Combi. Chem., 2002, 4, 295-301; Blom et al., "Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification", J. Combi. Chem., 2003, 5, 670-83; and Blom et al., "Preparative LC-MS Purification: Improved Compound Specific Method Optimization", J. Combi. Chem., 2004, 6, 874-883.

[0173] Example 1 (R)-1-((7-cyano-2-(3'-(7-((3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid [ka]

[0174] Step 1: Methyl 3-chloro-4-hydroxy-5-nitrobenzoate [ka] To a solution of methyl 3-chloro-4-hydroxybenzoate (Alfa Aesar, #A512389: 10.0 g, 53.6 mmol) in acetic acid (20.0 mL), a mixture of acetic acid (20.0 mL) and nitric acid (4.72 mL, 112 mmol) was added dropwise at 0° C. The ice bath was then removed and the thick mixture was stirred at room temperature for 2 h. An equal volume of water was then added to the reaction suspension at 0° C. The mixture was filtered and washed with cold water. A yellow solid was obtained as the desired product without further purification. C8H7ClNO5 (M+H) + LC-MS calculated for: m / z = 232.0; found 232.0.

[0175] Step 2: Methyl 3-amino-5-chloro-4-hydroxybenzoate [ka] Methyl 3-chloro-4-hydroxy-5-nitrobenzoate (2.08 g, 8.98 mmol) was hydrogenated under ambient pressure of hydrogen using palladium on carbon (10 wt%, 0.57 g, 0.539 mmol) in ethyl acetate (15 mL). The resulting suspension was filtered through a pad of Celite, washed with EtOAc, and the solvent was removed under reduced pressure to give the crude product, which was purified by column chromatography (eluted with MeOH / DCM 0%-10%). C8H9ClNO3 (M+H) + LC-MS calculated for: m / z = 202.0; found 202.0.

[0176] Step 3: Methyl 2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazole-5-carboxylate [ka] A mixture of methyl 3-amino-5-chloro-4-hydroxybenzoate (1.04 g, 5.16 mmol), 3-bromo-2-methylbenzaldehyde (AstaTech, #52940: 0.98 g, 4.92 mmol) in EtOH (25 ml) was placed in a vial and stirred at room temperature for 1 h. The mixture was then concentrated. The residue was redissolved in methylene chloride (25 mL) and dichlorodicyanoquinone (1.12 g, 4.92 mmol) was added. The mixture was stirred at room temperature for 30 min. The reaction was diluted with methylene chloride and washed with aqueous Na2S2O3 and NaHCO3 solutions. The organic phase was dried over MgSO4, filtered, and the filtrate was concentrated. The crude residue was used directly without further purification. C 16 H 12 BrClNO3(M+H) + LC-MS calculated for: m / z = 380.0; found 379.9.

[0177] Step 4: (2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazol-5-yl)methanol [ka] To a solution of methyl 2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazole-5-carboxylate (395.0 mg, 1.04 mmol) in DCM (10.0 ml) was added diisobutylaluminum hydride in DCM (1.0 M, 2.08 ml, 2.08 mmol) dropwise at -78 °C. The mixture was slowly warmed to 0 °C. The mixture was quenched with EtOAc and DCM, followed by aqueous Rochelle's salt. The mixture was vigorously stirred at room temperature for 1 h. The organic phase was separated and dried over MgSO4, then filtered through a short pad of Celite to remove solids. The filtrate was concentrated and purified by column chromatography (eluted with MeOH / DCM, 0-5%). C 15 H 12 BrClNO2(M+H) + LC-MS calculated for: m / z = 352.0; found 352.0.

[0178] Step 5: (7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methanol [ka] A mixture of (2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazol-5-yl)methanol (113 mg, 0.322 mmol), bis(pinacolato)diboron (98 mg, 0.386 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (26.3 mg, 0.032 mmol), and anhydrous potassium acetate (79 mg, 0.804 mmol) in 1,4-dioxane (3.5 mL) was purged with nitrogen and stirred at 110° C. for 2 h. The crude was diluted with DCM and then filtered through Celite. The filtrate was concentrated. The residue was purified by flash chromatography (eluted with EtOAc / hexanes, 0-40%). 21 H 24 BrClNO4(M+H) + LC-MS calculated for: m / z = 400.2; found 400.2.

[0179] Step 6: 5-(hydroxymethyl)-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazole-7-carbonitrile [ka] A stirred mixture of (7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methanol (1.08 g, 2.63 mmol), zinc cyanide (0.253 g, 2.11 mmol), and methanesulfonato(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.171 g, 0.211 mmol) in THF (5.27 ml) and water (5.27 ml) was degassed at room temperature and backfilled with N2 three times. It was heated at 90°C overnight. The reaction mixture was diluted with THF while hot. It was cooled to room temperature and filtered to remove insoluble solids. The filtrate was concentrated in vacuo. Acetonitrile was then added. The resulting slurry was filtered and washed with acetonitrile. The solid was collected and used directly in the next step without further purification. 22 H 24 BN2O4(M+H) + LC-MS calculated for: m / z = 391.2; found 391.2.

[0180] Step 7: 5-Formyl-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazole-7-carbonitrile [ka] To a solution of 5-(hydroxymethyl)-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazole-7-carbonitrile (1.51 g, 3.68 mmol) in DCM (16.4 mL) and DMF (2.0 ml) was added Dess-Martin periodinane (2.49 g, 5.70 mmol). The mixture was stirred at room temperature for 3 h. The crude mixture was quenched with saturated Na2S2O3 and saturated NaHCO3. The mixture was extracted three times with DCM. The organic phases were combined, dried and filtered. The filtrate was concentrated. Diethyl ether was added to the residue to form a slurry which was filtered to give the desired aldehyde. C 22 H 22 BN2O4(M+H) + LCMS calculated for: m / z=389.2; found 389.2.

[0181] Step 8: 7-Bromo-N-(3-chloro-2-methylphenyl)-2-methylpyrido[3,2-d]pyrimidin-4-amine [ka] To a mixture of 7-bromo-2-methylpyrido[3,2-d]pyrimidin-4-ol (Combi-Blocks, Catalog #ST-6117: 175 mg, 0.729 mmol), benzyltriethylammonium chloride (332 mg, 1.46 mmol), and N,N-diethylaniline (174 μl, 1.09 mmol) in acetonitrile (3.6 ml) was added phosphoryl chloride (408 μl, 4.37 mmol). The mixture was stirred at 90° C. for 2 hours. The reaction was then cooled to room temperature. The volatiles were removed under reduced pressure. The residue was used directly.

[0182] To the above residue in 2-propanol (3.6 ml) was added 3-chloro-2-methylaniline (113 mg, 0.800 mmol) and methanesulfonic acid (47.2 μl, 0.727 mmol). The mixture was stirred at 80° C. for 2 h. The reaction was then cooled to room temperature. The mixture was carefully quenched with aqueous NaHCO3 and extracted with DCM. The combined DCM solution was dried over MgSO4 and filtered. The filtrate was concentrated. The residue was purified by flash chromatography (0-70% EtOAc / Hexanes). 15 H 13 BrClNO4(M+H) + LC-MS calculated for: m / z = 363.0; found 363.0.

[0183] Step 9: N-(3-chloro-2-methylphenyl)-2-methyl-7-vinylpyrido[3,2-d]pyrimidin-4-amine [ka] A mixture of 7-bromo-N-(3-chloro-2-methylphenyl)-2-methylpyrido[3,2-d]pyrimidin-4-amine (250 mg, 0.687 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (159 mg, 1.03 mmol), tetrakis(triphenylphosphine)palladium(0) (79 mg, 0.069 mmol), and potassium phosphate (365 mg, 1.72 mmol) in tert-butanol (3.4 ml) and water (3.4 ml) was purged with N2 and sealed. The resulting mixture was stirred at 100° C. for 3 hours. The reaction mixture was cooled and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was used directly in the next step without further purification. C 17 H 16 ClNO(M+H) + LC-MS calculated for: m / z = 311.2; found 311.2.

[0184] Step 10: 4-(3-chloro-2-methylphenylamino)-2-methylpyrido[3,2-d]pyrimidine-7-carbaldehyde [ka] A vial was charged with N-(3-chloro-2-methylphenyl)-2-methyl-7-vinylpyrido[3,2-d]pyrimidin-4-amine (214 mg, 0.689 mmol), THF (5.5 ml), a stir bar, and water (1.4 ml). To this solution was added sodium periodate (736 mg, 3.44 mmol), followed by osmium tetroxide (4% w / w in water, 270 μl, 0.034 mmol). After stirring at room temperature for 1 h, the reaction was quenched with a saturated aqueous solution of sodium thiosulfate. The mixture was then extracted with DCM, and the combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was used directly in the next step without further purification. C 16 H 14 ClNO(M+H) + LC-MS calculated for: m / z = 313.1; found 313.1.

[0185] Step 11: (R)-1-((4-(3-chloro-2-methylphenylamino)-2-methylpyrido[3,2-d]pyrimidin-7-yl)methyl)pyrrolidin-3-ol [ka] A mixture of 4-((3-chloro-2-methylphenyl)amino)-2-methylpyrido[3,2-d]pyrimidine-7-carbaldehyde (215 mg, 0.687 mmol) and (R)-pyrrolidin-3-ol (71.9 mg, 0.825 mmol) in DCM (4.6 ml) was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (219 mg, 1.03 mmol) was then added. The mixture was further stirred at room temperature for 1 h. The reaction was quenched with aqueous NH4OH and extracted with DCM. The organic phases were combined and dried over MgSO4. After filtration, the DCM solution was concentrated and the residue was purified by flash chromatography (0-12% MeOH / DCM) to give the desired product. C 20 H 23 ClNO(M+H) + LC-MS calculated for: m / z = 384.2; found 384.2.

[0186] Step 12: (R)-5-formyl-2-(3'-(7-((3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile [ka] (R)-1-((4-((3-chloro-2-methylphenyl)amino)-2-methylpyrido[3,2-d]pyrimidin-7-yl)methyl)pyrrolidin-3-ol (229 mg, 0.597 mmol), 5-formyl-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxa A mixture of sazol-7-carbonitrile (Step 7: 255 mg, 0.657 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (47.0 mg, 0.060 mmol), and potassium phosphate (317 mg, 1.493 mmol) was purged with N2 and then sealed. The reaction was stirred at 100 °C for 2 h. The reaction was cooled to room temperature. The reaction mixture was diluted with DCM and H2O. The layers were separated. The aqueous layer was extracted three times with DCM. The organic layer was dried over MgSO4, filtered, and concentrated to give a crude residue that was used directly in the next step without further purification. C 36 H 32 N7O3(M+H) + LC-MS calculated for: m / z = 610.3; found 610.4.

[0187] Step 13: (R)-1-((7-cyano-2-(3'-(7-((3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid A mixture of (R)-5-formyl-2-(3'-((7-((3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile (16 mg, 0.026 mmol) and tert-butyl piperidine-4-carboxylate (9.7 mg, 0.052 mmol) in DCM (500 μL) was stirred at room temperature for 2 h. Sodium triacetoxyborohydride (16.7 mg, 0.079 mmol) was then added. The mixture was further stirred at room temperature for 1 h. The reaction was treated with trifluoroacetic acid (404 μL, 5.25 mmol) and stirred at room temperature for 30 min. After evaporation of the volatiles, the residue was diluted with MeOH and then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired TFA salt. 42 H 43 N8O4(M+H) + LC-MS calculated for: m / z = 723.3; found 723.3. 1 H NMR (500 MHz, DMSO) δ 9.08 (s, 1H), 8.38 (d,J = 9.5 Hz, 2H), 8.19 (d, J = 7.1 Hz, 1H), 8.10 (s, 1H), 7.65 - 7.55 (m, 2H), 7.48 (d, J = 6.8 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 7.18 (d, J = 7.5 Hz, 1H), 4.72 (s, 2H), 4.59 - 4.41 (m, 3H), 3.76 - 3.20 (m, 6H), 3.09 - 2.90 (m, 2H), 2.56 (s, 3H), 2.49 (s, 3H), 2.48 (s, 1H), 2.39 - 2.25 (m, 1H), 2.14 - 2.02 (m, 2H), 1.96 (s, 3H), 1.96 - 1.86 (m, 1H), 1.80 - 1.68 (m, 2H).

[0188] Example 2 (R)-1-((7-cyano-2-(3'-(7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid [ka]

[0189] Step 1: (R)-1-((4-(3-chloro-2-methylphenylamino)-2-methylpyrido[3,2-d]pyrimidin-7-yl)methyl)-3-methylpyrrolidin-3-ol [ka] This compound was prepared using a procedure similar to that described for Example 1, step 11, using (R)-3-methylpyrrolidin-3-ol instead of (R)-pyrrolidin-3-ol. 21 H 25 ClNO(M+H) + LC-MS calculated for: m / z = 398.2; found 398.2.

[0190] Step 2: (R)-5-formyl-2-(3'-(7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile [ka] This compound was prepared using a procedure similar to that described for Example 1, step 12, using (R)-1-((4-(3-chloro-2-methylphenylamino)-2-methylpyrido[3,2-d]pyrimidin-7-yl)methyl)-3-methylpyrrolidin-3-ol (step 1) instead of (R)-1-((4-(3-chloro-2-methylphenylamino)-2-methylpyrido[3,2-d]pyrimidin-7-yl)methyl)pyrrolidin-3-ol. 37 H 34 N7O3(M+H) + LC-MS calculated for: m / z = 624.3; found 624.3.

[0191] Step 3: (R)-1-((7-cyano-2-(3'-(7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid This compound was prepared using a procedure similar to that described for Example 1, step 13, using (R)-5-formyl-2-(3'-(7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile (step 2) instead of (R)-5-formyl-2-(3'-(7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile. The reaction mixture was evaporated, the residue was diluted with MeOH, and then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. C 43 H 45 N8O4(M+H) + LC-MS calculated for: m / z = 737.4; found 737.4.

[0192] Example 3 (S)-1-((7-cyano-2-(3'-(7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid [ka]

[0193] Step 1: (S)-1-((4-(3-chloro-2-methylphenylamino)-2-methylpyrido[3,2-d]pyrimidin-7-yl)methyl)-3-methylpyrrolidin-3-ol [ka] This compound was prepared using a procedure similar to that described for Example 1, step 11, using (S)-3-methylpyrrolidin-3-ol instead of (R)-pyrrolidin-3-ol. 21 H 25 ClNO(M+H) + LC-MS calculated for: m / z = 398.2; found 398.2.

[0194] Step 2: (S)-5-formyl-2-(3'-(7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile [ka] This compound was prepared using a procedure similar to that described for Example 1, step 12, using (S)-1-((4-(3-chloro-2-methylphenylamino)-2-methylpyrido[3,2-d]pyrimidin-7-yl)methyl)-3-methylpyrrolidin-3-ol (step 1) instead of (R)-1-((4-(3-chloro-2-methylphenylamino)-2-methylpyrido[3,2-d]pyrimidin-7-yl)methyl)pyrrolidin-3-ol. 37 H 34 N7O3(M+H) + LC-MS calculated for: m / z = 624.3; found 624.3.

[0195] Step 3: (S)-1-((7-cyano-2-(3'-(7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid This compound was prepared using a procedure similar to that described for Example 1, step 13, using (S)-5-formyl-2-(3'-(7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile (step 2) instead of (R)-5-formyl-2-(3'-(7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile. The reaction mixture was evaporated, and the residue was diluted with MeOH, then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. C 43 H 45 N8O4(M+H) + LC-MS calculated for: m / z = 737.4; found 737.4.

[0196] Example 4 (S)-1-((7-cyano-2-(3'-(7-((1-hydroxypropan-2-ylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid [ka]

[0197] Step 1: (S)-2-((4-(3-chloro-2-methylphenylamino)-2-methylpyrido[3,2-d]pyrimidin-7-yl)methylamino)propan-1-ol [ka] This compound was prepared using a procedure similar to that described for Example 1, step 11, using (S)-2-aminopropan-1-ol instead of (R)-pyrrolidin-3-ol. 19 H 23 ClNO(M+H) + LC-MS calculated for: m / z = 372.2; found 372.2.

[0198] Step 2: (S)-5-formyl-2-(3'-(7-((1-hydroxypropan-2-ylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile [ka] This compound was prepared using a procedure similar to that described for Example 1, step 12, using (S)-2-((4-(3-chloro-2-methylphenylamino)-2-methylpyrido[3,2-d]pyrimidin-7-yl)methylamino)propan-1-ol (step 1) instead of (R)-1-((4-(3-chloro-2-methylphenylamino)-2-methylpyrido[3,2-d]pyrimidin-7-yl)methyl)pyrrolidin-3-ol. 35 H 32 N7O3(M+H) + LC-MS calculated for: m / z = 598.3; found 598.3.

[0199] Step 3: (S)-1-((7-cyano-2-(3'-(7-((1-hydroxypropan-2-ylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid This compound was prepared using a procedure similar to that described for Example 1, step 13, using (S)-5-formyl-2-(3'-(7-((1-hydroxypropan-2-ylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile (step 2) instead of (R)-5-formyl-2-(3'-(7-((3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile. The reaction mixture was evaporated, and the residue was diluted with MeOH, then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. C 41 H 43 N8O4(M+H) + LC-MS calculated for: m / z = 711.3; found 711.3.

[0200] Example 5 (S)-1-((7-cyano-2-(3'-(7-((2-hydroxypropylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid [ka]

[0201] Step 1: (S)-1-((4-(3-chloro-2-methylphenylamino)-2-methylpyrido[3,2-d]pyrimidin-7-yl)methylamino)propan-2-ol [ka] This compound was prepared using a procedure similar to that described for Example 1, step 11, using (S)-1-aminopropan-2-ol instead of (R)-pyrrolidin-3-ol. 19 H 23 ClNO(M+H) + LC-MS calculated for: m / z = 372.2; found 372.2.

[0202] Step 2: (S)-5-formyl-2-(3'-(7-((2-hydroxypropylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile [ka] This compound was prepared using a procedure similar to that described for Example 1, step 12, using (S)-1-((4-(3-chloro-2-methylphenylamino)-2-methylpyrido[3,2-d]pyrimidin-7-yl)methylamino)propan-2-ol (step 1) instead of (R)-1-((4-(3-chloro-2-methylphenylamino)-2-methylpyrido[3,2-d]pyrimidin-7-yl)methyl)pyrrolidin-3-ol.35 H 32 N7O3(M+H) + LC-MS calculated for: m / z = 598.3; found 598.3.

[0203] Step 3: (S)-1-((7-cyano-2-(3'-(7-((2-hydroxypropylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid This compound was prepared using a procedure similar to that described for Example 1, step 13, using (S)-5-formyl-2-(3'-(7-((2-hydroxypropylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile (step 2) instead of (R)-5-formyl-2-(3'-(7-((3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile. The reaction mixture was evaporated and the residue was diluted with MeOH, then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. C 41 H 43 N8O4(M+H) + LC-MS calculated for: m / z = 711.3; found 711.3.

[0204] Example 6 (R)-1-((7-cyano-2-(3'-(7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid [ka] A mixture of (R)-5-formyl-2-(3'-((7-((3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile (Example 1, Step 12: 16 mg, 0.026 mmol), (R)-pyrrolidine-3-carboxylic acid (6.0 mg, 0.052 mmol), and triethylamine (7.3 μL, 0.052 mmol) in DCM (500 μL) was stirred at room temperature for 2 h. Sodium triacetoxyborohydride (16.69 mg, 0.079 mmol) was then added. The mixture was further stirred at room temperature for 1 h. The reaction mixture was diluted in MeOH and then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. 41 H 41 N8O4(M+H) + LC-MS calculated for: m / z = 709.3; found 709.3.

[0205] Example 7 (R)-1-((7-cyano-2-(3'-(7-(((R)-3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid [ka] This compound was prepared using a procedure similar to that described for Example 6, using (R)-5-formyl-2-(3'-(7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile (Example 2, step 2) instead of (R)-5-formyl-2-(3'-((7-((3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile. The reaction mixture was evaporated, and the residue was diluted with MeOH, then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. C 42 H 43 N8O4(M+H) + LC-MS calculated for: m / z = 723.3; found 723.3.

[0206] Example 8 (R)-1-((7-cyano-2-(3'-(7-(((S)-3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid [ka] This compound was prepared using a procedure similar to that described for Example 6, using (S)-5-formyl-2-(3'-(7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile (Example 3, step 2) instead of (R)-5-formyl-2-(3'-((7-((3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile. The reaction mixture was evaporated, and the residue was diluted with MeOH, then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. C 42 H 43 N8O4(M+H) + LC-MS calculated for: m / z = 723.3; found 723.3.

[0207] Example 9 (R)-1-((7-cyano-2-(3'-(7-(((S)-1-hydroxypropan-2-ylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid [ka] This compound was prepared using a procedure similar to that described for Example 6, using (S)-5-formyl-2-(3'-(7-((1-hydroxypropan-2-ylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile (Example 4, step 2) instead of (R)-5-formyl-2-(3'-((7-((3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile. The reaction mixture was evaporated, and the residue was diluted with MeOH, then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. C 40 H 41 N8O4(M+H) + LC-MS calculated for: m / z = 697.3; found 697.3.

[0208] Example 10 (R)-1-((7-cyano-2-(3'-(7-(((S)-2-hydroxypropylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid [ka] This compound was prepared using a procedure similar to that described for Example 6, using (S)-5-formyl-2-(3'-(7-((2-hydroxypropylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile (Example 5, step 2) instead of (R)-5-formyl-2-(3'-((7-((3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile. The reaction mixture was evaporated, and the residue was diluted with MeOH, then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. C 40 H 41 N8O4(M+H) + LC-MS calculated for: m / z = 697.3; found 697.3.

[0209] Example 11 (R)-1-((7-cyano-2-(3'-(7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid [ka] A mixture of (R)-5-formyl-2-(3'-((7-((3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile (Example 1, step 12: 16 mg, 0.026 mmol), (R)-3-methylpyrrolidine-3-carboxylic acid (6.8 mg, 0.052 mmol), and triethylamine (7.3 μL, 0.052 mmol) in DCM (500 μL) was stirred at room temperature for 2 h. Sodium triacetoxyborohydride (16.7 mg, 0.079 mmol) was then added. The mixture was further stirred at room temperature for 1 h. The reaction mixture was diluted in MeOH and then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. 42 H 43 N8O4(M+H) + LC-MS described for: m / z=723.3; measured value 723.3. 1H NMR (600 MHz, DMSO) δ 9.87 (s, 1H), 8.77 (d, J = 1.7 Hz, 1H), 8.15 (d, J = 7.3 Hz, 1H), 8.10 (s, 1H), 7.95 (s, 1H), 7.90 - 7.81 (m, 2H), 7.55 (t, J = 7.7 Hz, 1H), 7.44 (d, J = 6.9 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.06 (d, J = 7.3 Hz, 1H), 4.21 (dt, J = 6.3, 3.6 Hz, 1H), 3.87 - 3.80 (m, 1H), 3.79 - 3.72 (m, 2H), 3.72 - 3.66 (m, 1H), 2.92 (d, J = 9.1 Hz, 1H), 2.71 (dd, J = 9.6, 6.1 Hz, 1H), 2.65 (q, J = 8.0 Hz, 1H), 2.62 - 2.54 (m, 2H), 2.48 - 2.46 (m, 6H), 2.46 - 2.43 (m, 1H), 2.38 (dd, J = 9.6, 3.5 Hz, 1H), 2.33 - 2.26 (m, 2H), 2.05 - 1.99 (m, 1H), 1.98 (s, 3H), 1.60 - 1.50 (m, 2H), 1.24 (s, 3H).

[0210] Example 12 (R)-1-((7-cyano-2-(3'-(7-(((R)-3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid [ka] This compound was prepared using a procedure similar to that described for Example 11, using (R)-5-formyl-2-(3'-(7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile (Example 2, step 2) instead of (R)-5-formyl-2-(3'-((7-((3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile. The reaction mixture was evaporated, the residue was diluted with MeOH, and then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. C 43 H 45 N8O4(M+H) + LC-MS calculated for: m / z = 737.4; found 737.4.

[0211] Example 13 (R)-1-((7-cyano-2-(3'-(7-(((S)-3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid [ka] This compound was prepared using a procedure similar to that described for Example 11, using (S)-5-formyl-2-(3'-(7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile (Example 3, step 2) instead of (R)-5-formyl-2-(3'-((7-((3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile. The reaction mixture was evaporated, and the residue was diluted with MeOH, then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. C 43 H 45 N8O4(M+H) + LC-MS calculated for: m / z = 737.4; found 737.4.

[0212] Example 14 (R)-1-((7-cyano-2-(3'-(7-(((S)-1-hydroxypropan-2-ylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid [ka] This compound was prepared using a procedure similar to that described for Example 11, using (S)-5-formyl-2-(3'-(7-((1-hydroxypropan-2-ylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile (Example 4, step 2) instead of (R)-5-formyl-2-(3'-((7-((3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile. The reaction mixture was evaporated, the residue was diluted with MeOH, and then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. C 41 H 43 N8O4(M+H) + LC-MS calculated for: m / z = 711.3; found 711.3.

[0213] Example 15 (R)-1-((7-cyano-2-(3'-(7-(((S)-2-hydroxypropylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid [ka] This compound was prepared using a procedure similar to that described for Example 11, using (S)-5-formyl-2-(3'-(7-((2-hydroxypropylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile (Example 5, step 2) instead of (R)-5-formyl-2-(3'-((7-((3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile. The reaction mixture was evaporated, and the residue was diluted with MeOH, then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. C 41 H 43 N8O4(M+H) + LC-MS calculated for: m / z = 711.3; found 711.3.

[0214] Example 16 (R)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid [ka]

[0215] Step 1: 7-Bromo-2-(difluoromethyl)-4H-pyrido[3,2-d][1,3]oxazin-4-one [ka] A mixture of 3-amino-5-bromopicolinic acid (PharmBlock, Catalog #PB0554: 645 mg, 2.97 mmol) and 2,2-difluoroacetic anhydride (4.14 g, 23.8 mmol) was stirred at 60° C. for 3 h. After cooling to room temperature, the volatiles were removed by rotary evaporation and high vacuum pump. The residue was used directly in the next step. C8H4BrF2N2O2 (M+H) + LC-MS calculated for: m / z = 276.9; found 277.0.

[0216] Step 2: 7-Bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidin-4-ol [ka] A mixture of 7-bromo-2-(difluoromethyl)-4H-pyrido[3,2-d][1,3]oxazin-4-one (801 mg, 2.89 mmol) and aqueous ammonium hydroxide (8.0 ml, 28%) in a thick-walled glass tube was sealed and stirred at 85° C. for 2 h. After cooling to room temperature, the solution was then evaporated and the residue was rediluted with CH3CN and toluene. The suspension was evaporated again and the residue was used in the next step without further purification. C8H5BrF2N3O (M+H) + LC-MS calculated for: m / z = 276.0; found 276.0.

[0217] Step 3: 7-Bromo-N-(3-chloro-2-methylphenyl)-2-(difluoromethyl)pyrido[3,2-d]pyrimidin-4-amine [ka] To a mixture of 7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidin-4-ol (crude product from step 2: 750 mg, 2.72 mmol), benzyltriethylammonium chloride (1238 mg, 5.43 mmol), and N,N-diethylaniline (648 μl, 4.08 mmol) in acetonitrile (13.6 ml) was added phosphoryl chloride (1.52 ml, 16.3 mmol). The mixture was stirred at 75° C. for 2 hours. The reaction was then cooled to room temperature. Volatiles were removed under reduced pressure.

[0218] To a solution of 3-chloro-2-methylaniline (409 mg, 2.89 mmol) and 7-bromo-4-chloro-2-(difluoromethyl)pyrido[3,2-d]pyrimidine (residue from above) in 2-propanol (14.4 ml) was added methanesulfonic acid (188 μl, 2.89 mmol). The mixture was stirred at 80° C. for 2 h. The reaction was then cooled to room temperature. The mixture was carefully quenched with aqueous NaHCO3. The precipitate was filtered, washed with water and air-dried. The solid was used directly in the next step. C 15 H 11 BrClF2N4(M+H) + LC-MS calculated for: m / z = 399.0; found 399.0.

[0219] Step 4: N-(3-chloro-2-methylphenyl)-2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidin-4-amine [ka] A mixture of 7-bromo-N-(3-chloro-2-methylphenyl)-2-(difluoromethyl)pyrido[3,2-d]pyrimidin-4-amine (841 mg, 2.10 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (537 μl, 3.16 mmol), tetrakis(triphenylphosphine)palladium(0) (243 mg, 0.21 mmol), and potassium phosphate (1117 mg, 5.26 mmol) in tert-butanol (7.0 ml) and water (7.0 ml) was purged with N2 and then stirred at 100 °C for 3 h. The reaction was cooled to room temperature. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated to give the crude residue, which was purified by flash chromatography (0-30% EtOAc / DCM). C 17 H 14 ClF2N4(M+H) + LC-MS calculated for: m / z = 347.1; found 347.1.

[0220] Step 5: 4-(3-chloro-2-methylphenylamino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-7-carbaldehyde [ka] A vial was charged with N-(3-chloro-2-methylphenyl)-2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidin-4-amine (195 mg, 0.562 mmol), THF (4.5 ml), a stir bar, and water (1.1 ml). To this solution was added sodium periodate (601 mg, 2.81 mmol), followed by osmium tetroxide (4% w / w in water, 221 μl, 0.028 mmol). After stirring at room temperature for 1 h, the reaction was quenched with a saturated aqueous solution of sodium thiosulfate. The mixture was then extracted with DCM, and the combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was used directly in the next step without further purification. C 16 H 12LC-MS calculated for ClF2N4O(M+H)+: m / z = 349.1; found 349.1.

[0221] Step 6: (R)-1-((4-(3-chloro-2-methylphenylamino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidin-7-yl)methyl)pyrrolidin-3-ol [ka] A mixture of 4-((3-chloro-2-methylphenyl)amino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-7-carbaldehyde (101 mg, 0.290 mmol) and (R)-pyrrolidin-3-ol (30.3 mg, 0.348 mmol) in DCM (1931 μl) was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (92 mg, 0.434 mmol) was then added. The mixture was further stirred at room temperature for 1 h. The reaction was quenched with aqueous NH4OH and extracted with DCM. The organic phases were combined and dried over MgSO4. After filtration, the DCM solution was concentrated to a residue that was purified by flash chromatography (0-12% MeOH / DCM). C 20 H 21 ClF2NO(M+H) + LC-MS calculated for: m / z = 420.1; found 420.2.

[0222] Step 7: (R)-2-(3'-(2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile [ka] (R)-1-((4-((3-chloro-2-methylphenyl)amino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidin-7-yl)methyl)pyrrolidin-3-ol (34.4 mg, 0.082 mmol), 5-formyl-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo in water (140 μl) and 1,4-dioxane (690 μl). A mixture of [d]oxazole-7-carbonitrile (Example 1, Step 7: 35 mg, 0.090 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (6.5 mg, 8.2 μmol), and potassium phosphate (43.5 mg, 0.205 mmol) was purged with N2 and sealed. The reaction was stirred at 100 °C for 2 h. The reaction was cooled to room temperature. The reaction mixture was diluted with DCM and H2O. The layers were separated. The aqueous layer was extracted three times with DCM. The organic layer was dried over MgSO4, filtered, and concentrated to give a crude residue that was used directly in the next step without further purification. C 36 H 30 F2N7O3(M+H) + LC-MS calculated for: m / z = 646.2; found 646.3.

[0223] Step 8: (R)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid A mixture of (R)-2-(3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile (9.5 mg, 0.015 mmol) and tert-butyl piperidine-4-carboxylate (5.45 mg, 0.029 mmol) was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (9.36 mg, 0.044 mmol) was then added. The mixture was stirred at room temperature for 1 hour. Trifluoroacetic acid (300 μL) was then added to the mixture and stirred for 30 minutes. The volatiles were evaporated and the residue was diluted with MeOH and then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. 42 H 41 F2N8O4(M+H) + LC-MS calculated for: m / z = 759.3; found 759.6. 1 H NMR (500 MHz, DMSO) δ 10.63 (s, 1H), 9.13 (s, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.39 (d, J = 1.6 Hz, 1H), 8.19 (dd, J = 7.9, 1.5 Hz, 1H), 8.11 (d, J = 2.1 Hz, 1H), 7.64 (dd, J = 8.1, 1.3 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.49 (dd, J = 7.5, 1.5 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.16 (dd, J = 7.6, 1.3 Hz, 1H), 6.74 (t, J = 54.5 Hz, 1H), 4.85 - 4.65 (m, 2H), 4.58 - 4.40 (m, 3H), 3.74 - 3.00 (m, 8H), 2.78 - 2.54 (m, 1H), 2.50 (s, 3H), 2.32 - 1.91 (m, 5H), 1.95 (s, 3H), 1.79 - 1.67 (m, 1H).

[0224] Example 17 (R)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid [ka] This compound was prepared using a procedure similar to that described for Example 6, using (R)-2-(3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile (Example 16, step 7) instead of (R)-5-formyl-2-(3'-((7-((3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile. The reaction mixture was evaporated and the residue was diluted with MeOH and then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. 41 H 39 F2N8O4(M+H) + LC-MS calculated for: m / z = 745.3; found 745.3.

[0225] Example 18 (R)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid [ka] This compound was prepared using a procedure similar to that described for Example 11, using (R)-2-(3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile (Example 16, step 7) instead of (R)-5-formyl-2-(3'-((7-((3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile. The reaction mixture was evaporated and the residue was diluted with MeOH and then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. 42 H 41 F2N8O4(M+H) + LC-MS calculated for: m / z = 759.3; found 759.6.

[0226] Example 19 (R)-1-((7-cyano-2-(3'-(7-((3-hydroxypyrrolidin-1-yl)methyl)-2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid [ka]

[0227] Step 1: (R)-5-formyl-2-(3'-(7-((3-hydroxypyrrolidin-1-yl)methyl)-2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile [ka] This compound was prepared using a similar procedure (steps 1-7) as described for Example 16, except that in step 1, trifluoroacetic anhydride was used instead of 2,2-difluoroacetic anhydride. 36 H 29 F3N7O3(M+H) + LC-MS calculated for: m / z = 664.2; found 664.2.

[0228] Step 2: (R)-1-((7-cyano-2-(3'-(7-((3-hydroxypyrrolidin-1-yl)methyl)-2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid This compound was prepared using a procedure similar to that described for Example 1, step 13, using (R)-5-formyl-2-(3'-(7-((3-hydroxypyrrolidin-1-yl)methyl)-2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile (step 1) instead of (R)-5-formyl-2-(3'-(7-((3-hydroxypyrrolidin-1-yl)methyl)-2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile. The reaction mixture was evaporated, the residue was diluted with MeOH, and then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. C 42 H 40 F3N8O4(M+H) + LC-MS calculated for: m / z = 777.3; found 777.3.

[0229] Example 20 (R)-1-((7-cyano-2-(3'-(7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid [ka] This compound was prepared using a procedure similar to that described for Example 6, using (R)-5-formyl-2-(3'-(7-((3-hydroxypyrrolidin-1-yl)methyl)-2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile (Example 19, step 1) instead of (R)-5-formyl-2-(3'-(7-((3-hydroxypyrrolidin-1-yl)methyl)-2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile. The reaction mixture was evaporated, the residue was diluted with MeOH, and then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. C 41 H 38 F3N8O4(M+H) + LC-MS calculated for: m / z = 763.3; found 763.3.

[0230] Example 21 (R)-1-((7-cyano-2-(3'-(7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid [ka] This compound was prepared using a procedure similar to that described for Example 11, using (R)-5-formyl-2-(3'-(7-((3-hydroxypyrrolidin-1-yl)methyl)-2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile (Example 19, step 1) instead of (R)-5-formyl-2-(3'-(7-((3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile. The reaction mixture was evaporated, the residue was diluted with MeOH, and then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. C 42 H 40 F3N8O4(M+H) + LC-MS calculated for: m / z = 777.3; found 777.3.

[0231] Example 22 (S)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid [ka] This compound was prepared using a procedure similar to that described for Example 6, using (S)-pyrrolidine-3-carboxylic acid instead of (R)-pyrrolidine-3-carboxylic acid, and (R)-2-(3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile (Example 16, step 7) instead of (R)-5-formyl-2-(3'-((7-((3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile. The reaction mixture was evaporated and the residue was diluted with MeOH and then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. 41 H 39 F2N8O4(M+H) + LC-MS calculated for: m / z = 745.3; found 745.3.

[0232] Example 23 (S)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid [ka] This compound was prepared using a procedure similar to that described for Example 6, using (S)-3-methylpyrrolidine-3-carboxylic acid instead of (R)-pyrrolidine-3-carboxylic acid, and (R)-2-(3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile (Example 16, step 7) instead of (R)-5-formyl-2-(3'-((7-((3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile. The reaction mixture was evaporated and the residue was diluted with MeOH and then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. 42 H 41 F2N8O4(M+H) + LC-MS calculated for: m / z = 759.3; found 759.3.

[0233] Example 24 (R)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-4-methylpiperidine-4-carboxylic acid [ka] This compound was prepared using a similar procedure as described for Example 16, except that in step 8, tert-butyl 4-methylpiperidine-4-carboxylate was used instead of tert-butyl piperidine-4-carboxylate. The reaction mixture was evaporated and the residue was diluted with MeOH, then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt.43 H 43 F2N8O4(M+H) + LC-MS calculated for: m / z = 773.3; found 773.3.

[0234] Example 25 (R)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-N,N-dimethylpiperidine-4-carboxamide [ka] To a solution of (R)-1-((7-cyano-2-(3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid (Example 16: 7.0 mg, 9.22 μmol), dimethylamine (2.0 M in methanol, 0.014 ml), and N,N-diisopropylethylamine (5 μl, 0.028 mmol) in DMF (0.3 ml) was added HATU (7.0 mg, 0.018 mmol). After stirring at room temperature for 2 h, the reaction mixture was diluted with MeOH and then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. C 44 H 46 F2N9O3(M+H) + LC-MS calculated for: m / z = 786.4; found 786.4.

[0235] Example 26 (R)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-N-methylpiperidine-4-carboxamide [ka] This compound was prepared using a similar procedure as described for Example 25, using a methylamine solution instead of a dimethylamine solution. The reaction mixture was diluted with MeOH and purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. 43 H 44 F2N9O3(M+H) + LC-MS calculated for: m / z = 772.4; found 772.3.

[0236] Example 27 (R)-3-(1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxamido)propanoic acid [ka] This compound was prepared using a similar procedure as described for Example 25, using tert-butyl 3-aminopropanoate instead of dimethylamine solution. After amide bond formation, the reaction mixture was treated with trifluoroacetic acid (0.5 mL) and stirred at room temperature for 1 h. The reaction mixture was then concentrated, redissolved in MeOH, and then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. 45 H 46 F2N9O5(M+H) + LC-MS calculated for: m / z = 830.4; found 830.3.

[0237] Example 28 (R)-1-((7-cyano-2-(3'-(2-cyclopropyl-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid [ka]

[0238] Step 1: (R)-2-(3'-(2-cyclopropyl-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile [ka] This compound was prepared using a similar procedure (steps 1-7) as described for Example 16, using cyclopropanecarboxylic anhydride instead of 2,2-difluoroacetic anhydride in step 1. 38 H 34 N7O3(M+H) + LC-MS calculated for: m / z = 636.3; found 636.4.

[0239] Step 2: (R)-1-((7-cyano-2-(3'-(2-cyclopropyl-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid This compound was prepared using a procedure similar to that described for Example 6, using (R)-2-(3'-(2-cyclopropyl-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile (step 1) instead of (R)-5-formyl-2-(3'-(7-((3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile. The reaction mixture was evaporated, and the residue was diluted with MeOH, then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. C 43 H 43 N8O4(M+H) + LC-MS calculated for: m / z = 735.3; found 735.3.

[0240] Example 29 (R)-1-((2-(3'-(2-amino-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid [ka]

[0241] Step 1: N-(7-bromo-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-2-yl)acetamide [ka] A mixture of 3-amino-5-bromopicolinamide (1.88 g, 8.70 mmol) and carbamimidine chloride hydrochloride (1.30 g, 11.31 mmol) in sulfolane (5.44 ml) and dimethylsulfone (5.44 ml) was stirred in a sealed vial at 165° C. for 5 h. After cooling to room temperature, the reaction was carefully diluted with water to form a suspension. The precipitate was collected by filtration and washed with water. The solid was dried in air and used directly without further purification. A mixture of the above solid (685 mg, 2.84 mmol) and acetic anhydride (13.4 ml) was stirred at 115° C. for 8 h. After cooling to room temperature, the mixture was diluted with DCM and washed with water. The organic layer was dried over MgSO4, filtered and concentrated to give the crude material, which was used directly in the next step. C9H8BrN4O2 (M+H) + LC-MS calculated for: m / z = 283.0; found 283.0.

[0242] Step 2: 7-Bromo-N 4 -(3-chloro-2-methylphenyl)pyrido[3,2-d]pyrimidine-2,4-diamine [ka] To a mixture of N-(7-bromo-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-2-yl)acetamide (201 mg, 0.710 mmol), benzyltriethylammonium chloride (323 mg, 1.420 mmol), and N,N-diethylaniline (169 μl, 1.065 mmol) in acetonitrile (3.5 ml) was added POCl3 (397 μl, 4.26 mmol). The mixture was stirred at 75° C. for 2 hours. The reaction was then cooled to room temperature. The volatiles were removed under reduced pressure.

[0243] To a solution of 3-chloro-2-methylaniline (100 mg, 0.710 mmol) and N-(7-bromo-4-chloropyrido[3,2-d]pyrimidin-2-yl)acetamide (residue from above) in 2-propanol (3549 μl) was added methanesulfonic acid (46.1 μl, 0.710 mmol). The mixture was stirred at 80° C. for 2 h. The reaction was then cooled to room temperature. The mixture was carefully quenched with aqueous NaHCO3. The precipitate was filtered, washed with water and air-dried. The solid was used directly in the next step. C 14 H 12 BrClN5(M+H) + LC-MS calculated for: m / z = 364.0; found 364.0.

[0244] Step 3: (R)-1-((2-amino-4-(3-chloro-2-methylphenylamino)pyrido[3,2-d]pyrimidin-7-yl)methyl)pyrrolidin-3-ol [ka] In step 4, instead of 7-bromo-N-(3-chloro-2-methylphenyl)-2-(difluoromethyl)pyrido[3,2-d]pyrimidin-4-amine, 4 This compound was prepared using a procedure similar to that described for Example 16 (steps 4-6) using -(3-chloro-2-methylphenyl)pyrido[3,2-d]pyrimidine-2,4-diamine. 19 H 22 ClNO(M+H) + LC-MS calculated for: m / z = 385.2; found 385.2.

[0245] Step 4: tert-Butyl 1-((7-cyano-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylate [ka] A mixture of 5-formyl-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazole-7-carbonitrile (Example 1, step 7: 684 mg, 1.76 mmol) and tert-butyl piperidine-4-carboxylate (392 mg, 2.11 mmol) in DCM (7.0 ml) was stirred at room temperature for 2 h. Sodium triacetoxyborohydride (560 mg, 2.64 mmol) was added. The mixture was further stirred at room temperature for 1 h. The reaction was quenched with aqueous NH4OH and extracted with DCM. The organic phases were combined and dried over MgSO4. After filtration, the DCM solution was concentrated to a residue that was purified by flash chromatography (0-20% EtOAc / Hexanes). C 32 H 41 BN3O5(M+H) + LC-MS calculated for: m / z = 558.3; found 558.3.

[0246] Step 5: (R)-1-((2-(3'-(2-amino-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid (R)-1-((2-amino-4-((3-chloro-2-methylphenyl)amino)pyrido[3,2-d]pyrimidin-7-yl)methyl)pyrrolidin-3-ol (33.9 mg, 0.088 mmol), tert-butyl 1-((7-cyano-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxa) in water (150 μl) and 1,4-dioxane (750 μl). A mixture of chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (6.9 mg, 8.8 μmol), and potassium phosphate (46.7 mg, 0.22 mmol) was purged with N2 and then stirred at 100 °C for 3 h. The reaction was cooled to room temperature. The reaction mixture was diluted with DCM and H2O. The layers were separated. The aqueous layer was extracted three times with DCM. The organic layers were combined, dried over MgSO4, filtered, and concentrated to give the crude residue. The residue was dissolved in DCM (1 mL) and treated with trifluoroacetic acid (1.0 mL). After stirring at room temperature for 30 min, the reaction mixture was evaporated and the residue was diluted with MeOH and then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. 41 H 42 NO4(M+H) + LC-MS calculated for: m / z = 724.3; found 724.4.

[0247] Example 30 (R)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid [ka]

[0248] Step 1: (R)-1-((4-(3-chloro-2-methylphenylamino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidin-7-yl)methyl)-3-methylpyrrolidin-3-ol [ka] This compound was prepared using a procedure similar to that described for Example 16, step 6, using (R)-3-methylpyrrolidin-3-ol instead of (R)-pyrrolidin-3-ol. 21 H 23 ClF2NO(M+H) + LC-MS calculated for: m / z = 434.2; found 434.2.

[0249] Step 2: (R)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid This compound was prepared using a procedure similar to that described for Example 29, using (R)-1-((4-(3-chloro-2-methylphenylamino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidin-7-yl)methyl)-3-methylpyrrolidin-3-ol (Step 1) instead of (R)-1-((2-amino-4-(3-chloro-2-methylphenylamino)pyrido[3,2-d]pyrimidin-7-yl)methyl)pyrrolidin-3-ol in Step 5. The reaction mixture was evaporated and the residue was diluted with MeOH, then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. C 43 H 43 F2N8O4(M+H) + LC-MS calculated for: m / z = 773.3; found 773.3.

[0250] Example 31 (S)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid [ka] This compound was prepared using a procedure similar to that described for Example 30, using (S)-3-methylpyrrolidin-3-ol instead of (R)-3-methylpyrrolidin-3-ol. The reaction mixture was evaporated, and the residue was diluted with MeOH, then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. 43 H 43 F2N8O4(M+H) + LC-MS calculated for: m / z = 773.3; found 773.3.

[0251] Example 32 (R)-1-((7-cyano-2-(3'-(2-(hydroxymethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid [ka]

[0252] Step 1: 7-Bromo-2-(hydroxymethyl)pyrido[3,2-d]pyrimidin-4(3H)-one [ka] To a solution of 3-amino-5-bromopicolinamide (142 mg, 0.657 mmol) in THF was added 2-chloro-2-oxoethyl acetate (90 mg, 0.66 mmol) at 0° C. The mixture was stirred at room temperature until LCMS showed the reaction was complete. Water was then added slowly to the mixture. The precipitate was collected by filtration and washed with a small amount of water and CH3CN. After air drying, the solid was used directly.

[0253] A mixture of the above solid and ammonium hydroxide (aqueous, 28%, 1.7 ml, 12.04 mmol) in a thick glass tube was stirred at 85° C. for 2 h. After cooling to room temperature, the solution was evaporated and the residue was rediluted with CH3CN and toluene. The suspension was evaporated again and the residue was used in the next step without further purification. C8H7BrN3O2 (M+H) + LC-MS calculated for: m / z = 256.0; found 256.1.

[0254] Step 2: 7-Bromo-2-((tert-butyldimethylsilyloxy)methyl)pyrido[3,2-d]pyrimidin-4(3H)-one [ka] To a solution of 7-bromo-2-(hydroxymethyl)pyrido[3,2-d]pyrimidin-4(3H)-one (185 mg, 0.722 mmol) and imidazole (73.8 mg, 1.084 mmol) in DMF (4817 μl) was added tert-butyldimethylsilyl chloride (120 mg, 0.795 mmol). The mixture was stirred at room temperature for 2 h. The mixture was then concentrated and the residue was purified by flash chromatography (0-20% EtOAc / Hexanes) to give the desired product. 14 H 21 BrNOSi(M+H) + LC-MS calculated for: m / z = 370.1; found 370.1.

[0255] Step 3: 7-Bromo-2-((tert-butyldimethylsilyloxy)methyl)-N-(3-chloro-2-methylphenyl)pyrido[3,2-d]pyrimidin-4-amine [ka] To a mixture of 7-bromo-2-((tert-butyldimethylsilyloxy)methyl)pyrido[3,2-d]pyrimidin-4(3H)-one (201 mg, 0.54 mmol) and DIEA (190 μL, 1.09 mmol) in DCM (2.2 ml) was added methanesulfonyl chloride (85 μL, 1.09 mmol) at 0° C. The mixture was stirred at room temperature for 3 h. Then, 3-chloro-2-methylaniline (100 mg, 0.71 mmol) was added to the mixture and the corresponding mixture was further stirred at room temperature overnight. The mixture was diluted with DCM and then washed with water. The DCM solution was dried over MgSO4 and filtered. The filtrate was concentrated. The residue was purified by flash chromatography (0-40% EtOAc / Hexanes). 21 H 27 BrClN4OSi(M+H) + LC-MS calculated for: m / z = 493.1; found 493.1.

[0256] Step 4: (R)-1-((2-(3'-(2-((tert-butyldimethylsilyloxy)methyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid [ka] This compound was prepared using a similar procedure (steps 9-13) as described for Example 1, using 7-bromo-2-((tert-butyldimethylsilyloxy)methyl)-N-(3-chloro-2-methylphenyl)pyrido[3,2-d]pyrimidin-4-amine (step 3) instead of 7-bromo-N-(3-chloro-2-methylphenyl)-2-methylpyrido[3,2-d]pyrimidin-4-amine. Upon completion, the reaction solution was used directly in the next step. C 48 H 57 N8O5Si(M+H) + LC-MS calculated for: m / z = 853.4; found 853.4.

[0257] Step 5: (R)-1-((7-cyano-2-(3'-(2-(hydroxymethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid To the above reaction solution (Step 4), triethylamine trihydrofluoride (411 μl, 60 equiv.) was added at room temperature. The mixture was further stirred at this temperature for 1 h. The reaction mixture was then concentrated and the residue was diluted with MeOH and then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. 42 H 43 N8O5(M+H) + LC-MS calculated for: m / z = 739.3; found 739.5.

[0258] Example 33 (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-6-methyl-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid [ka]

[0259] Step 1: 5-Bromo-N-tert-butyl-3-(2-oxopropyl)picolinamide [ka] To a solution of diisopropylamine (3.42 ml, 24.0 mmol) in THF (10 mL) was added butyllithium (2.5 M in hexanes, 12.79 ml, 32.0 mmol) at -40°C under N2 atmosphere. The mixture was stirred at this temperature for 5 min. Then a solution of 5-bromo-N-(tert-butyl)-3-methylpicolinamide (2.71 g, 10.0 mmol) in THF (2 mL) was added. The reaction was stirred at -40°C for 30 min before being warmed to -10°C. The above mixture was then added to ethyl acetate (1.17 ml, 12.0 mmol) in THF (6 mL) at -40°C with stirring. After the addition, the reaction was further stirred and slowly warmed to -10°C. The reaction was then quenched by adding aqueous NH4Cl. The mixture was then extracted three times with DCM. The organic phases were combined, dried over MgSO4, and filtered. The filtrate was concentrated, and the residue was purified by flash chromatography using EtOAc / hexanes (0-25%) to give the desired product. 13 H 18 BrN2O2(M+H) + LC-MS calculated for: m / z = 313.1; found 313.1.

[0260] Step 2: 3-Bromo-6-methyl-1,7-naphthyridin-8-ol [ka] A mixture of 5-bromo-N-(tert-butyl)-3-(2-oxopropyl)picolinamide (716 mg, 2.29 mmol) and ammonium acetate (1762 mg, 22.86 mmol) in acetic acid (1.8 ml) was heated to 108° C. and stirred at this temperature for 12 hours. The reaction was cooled to room temperature. Water was added to form a precipitate. The suspension was filtered and the solid was collected and used directly. C9H8BrN2O(M+H) + LC-MS calculated for: m / z = 239.0; found 239.1.

[0261] Step 3: (R)-1-((8-(3-chloro-2-methylphenylamino)-6-methyl-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol [ka] This compound was prepared using a similar procedure (steps 3-6) as described for Example 16, using 3-bromo-6-methyl-1,7-naphthyridin-8-ol (step 2) instead of 7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidin-4-ol. 21 H 24 ClNO(M+H) + LC-MS calculated for: m / z = 383.2; found 383.3.

[0262] Step 4: (R)-5-formyl-2-(3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-6-methyl-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile [ka] This compound was prepared using a procedure similar to that described for Example 1, step 12, using (R)-1-((8-(3-chloro-2-methylphenylamino)-6-methyl-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol (step 3) instead of (R)-1-((4-(3-chloro-2-methylphenylamino)-2-methylpyrido[3,2-d]pyrimidin-7-yl)methyl)pyrrolidin-3-ol. 37 H 33 N6O3(M+H) + LC-MS calculated for: m / z = 609.3; found 609.4.

[0263] Step 5: (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-6-methyl-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid This compound was prepared using a procedure similar to that described for Example 6, using (R)-5-formyl-2-(3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-6-methyl-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile (step 4) instead of (R)-5-formyl-2-(3'-((7-((3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile. The reaction mixture was evaporated, and the residue was diluted with MeOH, then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. C 42 H 42 N7O4(M+H) + LC-MS calculated for: m / z = 708.3; found 708.3.

[0264] Example 34 (R)-1-((7-cyano-2-(3'-(6-(difluoromethyl)-3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid [ka]

[0265] Step 1: (R)-2-(3'-(6-(difluoromethyl)-3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile [ka] This compound was prepared using a similar procedure (steps 1-4) as described for Example 33, using methyl 2,2-difluoroacetate instead of ethyl acetate. 37 H 31 F2N6O3(M+H) + LC-MS calculated for: m / z = 645.2; found 645.2.

[0266] Step 2: (R)-1-((7-cyano-2-(3'-(6-(difluoromethyl)-3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid This compound was prepared using a procedure similar to that described for Example 11, using (R)-2-(3'-(6-(difluoromethyl)-3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile (step 1) instead of (R)-5-formyl-2-(3'-((7-((3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile. The reaction mixture was evaporated, and the residue was diluted with MeOH, then purified by preparative HPLC (pH=2, acetonitrile / water+TFA) to give the desired product as a TFA salt. C 43 H 42 F2N7O4(M+H) + LC-MS calculated for: m / z = 758.3; found 758.3.

[0267] Example A. Homogeneous Time-Resolved Fluorescence (HTRF) PD-1 / PD-L1 Binding Assay The assay was performed in a standard black 384-well polystyrene plate using a final volume of 20μL. The inhibitors were first serially diluted in DMSO and then added to the wells of the plate before the addition of the other reaction components. The final concentration of DMSO in the assay was 1%. The assay was performed at 25℃ in PBS buffer (pH 7.4) containing 0.05% Tween-20 and 0.1% BSA. Recombinant human PD-L1 protein (19–238) with a C-terminal His tag was purchased from AcroBiosystems (PD1-H5229). Recombinant human PD-1 protein (25–167) with a C-terminal Fc tag was also purchased from AcroBiosystems (PD1-H5257). PD-L1 and PD-1 proteins were diluted in assay buffer and 10μL was added to the plate wells. The plates were centrifuged and the proteins were pre-incubated with the inhibitors for 40 minutes. Following incubation, 10 μL of HTRF detection buffer supplemented with Europium cryptate-labeled anti-human IgG specific for Fc (PerkinElmer-AD0212) and anti-His antibody conjugated to SureLight®-allophycocyanin (APC, PerkinElmer-AD0059H) was added. After centrifugation, the plate was incubated for 60 min at 25° C. and read on a PHERAstar FS plate reader (665 nm / 620 nm ratio). Final concentrations in the assay were -3 nM PD1, 10 nM PD-L1, 1 nM Europium anti-human IgG, and 20 nM anti-His-allophycocyanin. IC was calculated by curve fitting of percent control activity against the logarithm of inhibitor concentration using GraphPad Prism 5.0 software. 50 The decision was made.

[0268] Example B. Src Homology Region 2 Domain-Containing Phosphatase (SHP) Assay U2OS / PD-L1 cells (DiscoveRx Corporation) were maintained in McCoy's 5A medium supplemented with 10% FBS, 0.25μg / ml puromycin. After removing the culture medium, the cell medium was replaced with assay medium (RPMI1640 medium with 1% FBS). U2OS / PD-L1 cells were then added to 384-well black clear bottom assay plates (CELLCOAT® tissue culture plates, Greiner Bio-One) at 5000 cells per well in 20μL assay medium. Test compounds were prepared by serial dilution in DMSO, and 125nL of compound was first transferred to 384 REMP plate wells (Thermofisher) by an ECHO liquid handler (Labcyte), followed by the addition of 27.5μL of assay medium. 5μL / well compound in assay medium was transferred to the cell plate with 0.05% DMSO at 0.25μM in the final assay. Jurkat-PD-1-SHP cells (DiscoveRx Corporation) were cultured in RPMI1640 medium supplemented with 10% FBS, 250 μg / ml hygromycin B, and 500 μg / ml G418. After replacing the culture medium with assay medium, 5,000 Jurkat-PD-1-SHP cells in 20 μL were dispensed into each well. The assay plate was incubated at 37°C and 5% CO2 for 2 h, after which 2.5 μL of PathHunter Reagent 1 (DiscoveRx Corporation) was added to each well. The assay plate was shaken at 350 rpm in the dark for 1 min, after which 10 μL of PathHunter Reagent 2 (DiscoveRx Corporation) was added. Chemiluminescence signals were recorded on a TopCount reader (Perkin Elmer) after 1 h of incubation at room temperature. Wells containing DMSO were used as positive controls, and wells without cells were used as negative controls. IC was calculated by fitting a curve of percent control activity against the logarithm of compound concentration using GraphPad Prism 6.0 software. 50 The decision was made.

[0269] Example C. Nuclear Factor of Activated T Cells (NFAT) Assay PD-L1 aAPC / CHO-K1 cells (Promega) were maintained in F-12 medium supplemented with 10% FBS, 200μg / ml hygromycin B, 250μg / ml geneticin (G418). Jurkat-PD-1-NFAT effector cells (Promega) were cultured in RPMI 1640 medium supplemented with 10% FBS, 100μg / ml hygromycin B, 500μg / ml G418. The culture medium of PD-L1 aAPC / CHO-K1 cells was first replaced with assay medium (RPMI1640 medium containing 1% FBS). PD-L1 aAPC / CHO-K1 cells were then added to white 384-well white clear bottom assay plates (CELLCOAT® tissue culture plates, Greiner Bio-One) at 8000 cells per well in 10μL assay medium. Test compounds were prepared by serial dilution in DMSO, and 0.8 μL of test compound in DMSO was first transferred to 384 REMP plate wells (Thermofisher) by PlateMate Plus (Thermofisher), followed by the addition of 50 μL of plating medium. 5 μL of compound in assay medium was transferred to cells at 2 μM with 0.4% DMSO in the final assay. After removing the culture medium, 10,000 Jurkat-PD-1-NFAT effector cells in 5 μL of assay medium were dispensed into each well. The assay plate was incubated at 37° C., 5% CO2 for 24 hours. The assay plate was equilibrated at room temperature for 15 minutes, after which 20 μL / well of Bio-Glo™ reagent (Promega) was added. After 8 minutes of incubation at room temperature, luminescence was read on a Pherastar microplate reader (BMG Labtech). Fold induction (FOI) was calculated based on the ratio of normalized luminescence to DMSO wells in each assay plate. Maximum percentage induction was reported based on the ratio between the highest FOI of each compound and the maximum FOI of the control compound in each assay plate. Wells containing DMSO were used as negative controls and wells containing the control compound with the highest FOI were used as positive controls.EC50 determinations were made by curve fitting percent control activity versus the logarithm of compound concentration using GraphPad Prism 6.0 software.

[0270] Example D. PD-L1 Whole Blood Internalization Assay To determine PD-L1 internalization in human whole blood, normal human blood (Biological Specialty Corp, Colmar. PA) was incubated in a 96-well "2 ml assay block" (Corning, Corning NY) with or without a range of test compounds and 1 ng / ml human interferon gamma (R&D Systems Inc., Minn. MN) for 18-20 hours at 37°C. Blood was then stained for PD-L1 (MIH1, eBioscience; or BD Biosciences, San Jose, CA), CD14 (Life Technologies, Carlsbad, CA) for 30 minutes in the dark at room temperature. Whole blood / red blood cells were lysed / fixed (lysis buffer, BD Biosciences) for 5 minutes at 37°C in the dark, then centrifuged at 1600 RPM for 5 minutes. Cells were resuspended in staining buffer (BD Bioscience, San Jose, CA) and transferred to a 96-well round-bottom plate (Corning). Cells were gated on CD14+ (BD Biosciences) and PD-L1 expression was determined by mean fluorescence intensity (MFI) (BD LSRFortessa™ X-20). IC was calculated by fitting a curve of percent inhibition of compound against the logarithm of compound concentration using GraphPad Prism 7.0 software. 50 The decision was made.

[0271] Example E. In vivo pharmacokinetics in rats, monkeys, and dogs For in vivo pharmacokinetic experiments, test compounds were administered intravenously or via oral gavage to male Sprague-Dawley rats, male beagle dogs, or male and female cynomolgus monkeys. For IV administration, test compounds were administered at 0.5-1 mg / kg using a formulation of 10% dimethylacetamide (DMAC) in acidified saline via IV bolus for rats and 5- or 10-minute IV infusion for dogs and monkeys, respectively. For oral administration, test compounds were administered at 1.0-3.0 mg / kg using 5% DMAC in 0.5% methylcellulose in citrate buffer (pH 3.5). Blood samples were collected pre-dose and at various time points up to 24 hours post-dose. All blood samples were collected using EDTA as an anticoagulant and centrifuged to obtain plasma samples. Plasma concentrations of test compounds are determined by LC-MS methods. Measured plasma concentrations are used to calculate PK parameters by standard non-compartmental methods using the Phoenix® WinNonlin software program (version 7.0, Pharsight Corporation).

[0272] In rats and monkeys, cassette administration of up to six test compounds was performed to obtain preliminary PK parameters.

[0273] Example F. Results As exemplified in Examples 1-34, compounds of the present disclosure were evaluated in each of the HTRF PD-1 / PD-L1 binding assay (Example A), SHP assay (Example B), NFAT assay (Example C), and whole blood internalization assay (Example D). The cutoffs for the range of values ​​observed in each of the assays are shown. The results obtained for the compounds tested are shown in Table 1. [Table 1] [Table 2]

[0274] In addition to those described herein, various modifications of the present invention will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application, including but not limited to all patents, patent applications, and publications, is hereby incorporated by reference in its entirety. The present application also includes the following aspects. [Aspect 1] A compound of formula (I'), [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof, wherein: Ring A is azetidinyl, pyrrolidinyl, or piperidinyl; X 1 is CH or N, R 1 is methyl or halo; R 2 But, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl-C 1-2 Alkyl-, OH, NH 2 , -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl) 2 , 4- to 6-membered heterocycloalkyl, or 4- to 6-membered heterocycloalkyl-C 1-2 alkyl-, and the 4- to 6-membered heterocycloalkyl and 4- to 6-membered heterocycloalkyl-C 1-2 Each alkyl- has one or two heteroatoms as ring members selected from O and N, and the R 2 C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl-C 1-2 Alkyl-, -NH-C 1-4 Alkyl, -N(C1-4 Alkyl) 2 , 4- to 6-membered heterocycloalkyl, and 4- to 6-membered heterocycloalkyl-C 1-2 each alkyl- is optionally substituted with 1 or 2 substituents independently selected from halo, CN, and OH; R 3 is selected from (R)-3-hydroxy-3-methylpyrrolidin-1-yl, (S)-3-hydroxy-3-methylpyrrolidin-1-yl, (R)-3-hydroxypyrrolidin-1-yl, (S)-3-hydroxypyrrolidin-1-yl, (R)-2-hydroxy-2-methyl-ethylamino, (S)-2-hydroxy-2-methyl-ethylamino, (R)-2-hydroxy-1-methyl-ethylamino, and (S)-2-hydroxy-1-methyl-ethylamino; R 4 But H or C 1-3 is alkyl, R 5 C(O)OH, C(O)N(CH 3 ) 2 , C(O)NH(CH 3 ), or C(O)NH(CH 2 ) 2 The compound of formula (I') or a pharma- ceutically acceptable salt or stereoisomer thereof, wherein: C(O)OH. [Aspect 2] A compound of formula (I),

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Claims

1. 1. A medicament for use in the treatment of a disease or disorder associated with inhibition of PD-1 / PD-L1 interaction in combination with one or more additional therapeutic agents, comprising a compound of formula (I'): 【Chemistry 1】 [In the formula, Ring A is azetidinyl, pyrrolidinyl, or piperidinyl; X １ is N, R １ is methyl or halo, R ２ is C １－４ Alkyl, C １－４ Alkoxy, C １－４ Haloalkyl, C １－４ Haloalkoxy, C ３－６ Cycloalkyl, C ３－６ Cycloalkyl-C １－２ Alkyl-, OH, NH ２ , -NH-C １－４ Alkyl, -N(C １－４ Alkyl) ２ , 4- to 6-membered heterocycloalkyl, or 4- to 6-membered heterocycloalkyl-C １－２ alkyl-, wherein the 4- to 6-membered heterocycloalkyl and 4- to 6-membered heterocycloalkyl-C １－２ Each alkyl- has one or two heteroatoms as ring members selected from O and N, ２ C １－４ Alkyl, C １－４ Alkoxy, C ３－６ Cycloalkyl, C ３－６ Cycloalkyl-C １－２ Alkyl-, -NH-C １－４ Alkyl, -N(C １－４ Alkyl) ２ , 4- to 6-membered heterocycloalkyl, and 4- to 6-membered heterocycloalkyl-C １－２ each alkyl- is optionally substituted with 1 or 2 substituents independently selected from halo, CN, and OH; R ３ is selected from (R)-3-hydroxy-3-methylpyrrolidin-1-yl, (S)-3-hydroxy-3-methylpyrrolidin-1-yl, (R)-3-hydroxypyrrolidin-1-yl, (S)-3-hydroxypyrrolidin-1-yl, (R)-2-hydroxy-2-methyl-ethylamino, (S)-2-hydroxy-2-methyl-ethylamino, (R)-2-hydroxy-1-methyl-ethylamino, and (S)-2-hydroxy-1-methyl-ethylamino; R ４ is H or C １－３ is alkyl, R ５ are C(O)OH, C(O)N(CH ３ ) ２ ,C(O)NH(CH ３ ), or C(O)NH(CH ２ ) ２ C(O)OH. or a pharma- ceutically acceptable salt or stereoisomer thereof.

2. A medicament for use in the treatment of a disease or disorder associated with inhibition of PD-1 / PD-L1 interaction in combination with one or more additional therapeutic agents, comprising a compound of formula (I): 【Chemistry 2】 [In the formula, Ring A is azetidinyl, pyrrolidinyl, or piperidinyl; X １ is N, R １ is methyl or halo, R ２ is C １－４ Alkyl, C １－４ Alkoxy, C １－４ Haloalkyl, C １－４ Haloalkoxy, C ３－６ Cycloalkyl, C ３－６ Cycloalkyl-C １－２ Alkyl-, OH, NH ２ , -NH-C １－４ Alkyl, -N(C １－４ Alkyl) ２ , 4- to 6-membered heterocycloalkyl, or 4- to 6-membered heterocycloalkyl-C １－２ alkyl-, wherein the 4- to 6-membered heterocycloalkyl and 4- to 6-membered heterocycloalkyl-C １－２ Each alkyl- has one or two heteroatoms as ring members selected from O and N, ２ C １－４ Alkyl, C １－４ Alkoxy, C ３－６ Cycloalkyl, C ３－６ Cycloalkyl-C １－２ Alkyl-, -NH-C １－４ Alkyl, -N(C １－４ Alkyl) ２ , 4- to 6-membered heterocycloalkyl, and 4- to 6-membered heterocycloalkyl-C １－２ each alkyl- is optionally substituted with 1 or 2 substituents independently selected from halo, CN, and OH; R ３ is selected from (R)-3-hydroxy-3-methylpyrrolidin-1-yl, (S)-3-hydroxy-3-methylpyrrolidin-1-yl, (R)-3-hydroxypyrrolidin-1-yl, (S)-3-hydroxypyrrolidin-1-yl, (R)-2-hydroxy-2-methyl-ethylamino, (S)-2-hydroxy-2-methyl-ethylamino, (R)-2-hydroxy-1-methyl-ethylamino, and (S)-2-hydroxy-1-methyl-ethylamino; R ４ is H or C １－３ is alkyl] or a pharma- ceutically acceptable salt or stereoisomer thereof.

3. The pharmaceutical composition according to claim 1 or 2, wherein ring A is pyrrolidinyl.

4. The pharmaceutical composition according to claim 1 or 2, wherein ring A is piperidinyl. 【Request 5】 【Chemical 3】 2. The medicament of claim 1, wherein is selected from 4-carboxypiperidin-1-yl, 3-carboxypyrrolidin-1-yl, 3-methyl-3-carboxypyrrolidin-1-yl, 4-(N,N-dimethylaminocarbonyl)piperidin-1-yl, 4-(N-methylaminocarbonyl)piperidin-1-yl, and 4-(2-carboxyethylaminocarbonyl)piperidin-1-yl, and the wavy line indicates the point of attachment to the remainder of the molecule.

6. R ５ is C(O)OH; 【Chemistry 4】 3. The pharmaceutical of claim 1 or 2, wherein is selected from 4-carboxypiperidin-1-yl, 3-carboxypyrrolidin-1-yl, and 3-methyl-3-carboxypyrrolidin-1-yl, and the wavy line indicates the point of attachment to the remainder of the molecule.

7. R ５ is C(O)OH; 【Chemistry 5】 is selected from 4-carboxypiperidin-1-yl, (R)-3-carboxypyrrolidin-1-yl, (S)-3-carboxypyrrolidin-1-yl, (R)-3-methyl-3-carboxypyrrolidin-1-yl, and (S)-3-methyl-3-carboxypyrrolidin-1-yl, and the wavy line indicates the point of attachment to the remainder of the molecule.

8. R １ But, CH ３ The pharmaceutical agent according to any one of claims 1 to 7, wherein said compound is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, or 8.

9. R １ But, CH ３ The pharmaceutical composition according to any one of claims 1 to 7,

10. R ２ But, C １－４ Alkyl, C １－４ Alkoxy, C １－４ Haloalkyl, C １－４ Haloalkoxy, C ３－６ Cycloalkyl, C ３－６ Cycloalkyl-C １－２ Alkyl-, OH, NH ２ , -NH-C １－４ Alkyl, -N(C １－４ Alkyl) ２ , 1-azetidinyl, azetidin-1-ylmethyl, 1-pyrrolidinyl, pyrrolidin-1-ylmethyl, 1-piperidinyl, or piperidin-1-ylmethyl, wherein R ２ C １－４ Alkyl, C １－４ Alkoxy, C ３－６ Cycloalkyl, C ３－６ Cycloalkyl-C １－２ Alkyl, -NH-C １－４ Alkyl, -N(C １－４ Alkyl) ２ 10. The pharmaceutical of any one of claims 1 to 9, wherein 1-azetidinyl, azetidin-1-ylmethyl, 1-pyrrolidinyl, pyrrolidin-1-ylmethyl, 1-piperidinyl, and piperidin-1-ylmethyl are each independently optionally substituted with 1 or 2 substituents selected from halo, CN, and OH.

11. R ２ Methyl, ethyl, isopropyl, methoxy, ethoxy, CF ３ , C.H.F. ２ , C.F.H. ２ , O.C.F. ３ , O.C.H.F. ２ , O.C.H. ２ F, cyclopropyl, cyclobutyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, OH, NH ２ , N.H.H. ３ , N(CH ３ ) ２ , 1-azetidinyl, azetidin-1-ylmethyl, 1-pyrrolidinyl, pyrrolidin-1-ylmethyl, 1-piperidinyl, or piperidin-1-ylmethyl, wherein R ２ Methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, NHCH ３ , N(CH ３ ) ２ 11. The pharmaceutical composition of claim 10, wherein 1-azetidinyl, azetidin-1-ylmethyl, 1-pyrrolidinyl, pyrrolidin-1-ylmethyl, 1-piperidinyl, and piperidin-1-ylmethyl are each independently optionally substituted with 1 or 2 substituents selected from F, Cl, Br, CN, and OH.

12. R ２ But, C １－４ Alkyl or C １－４ The medicament of any one of claims 1 to 9, which is a haloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from F, Cl, Br, CN, and OH.

13. R ２ But, C １－４ Alkyl or C １－４ The pharmaceutical agent according to any one of claims 1 to 9, which is haloalkyl.

14. R ２ But, CH ３ , C.F. ３ , C.H.F. ２ , CH(CH ３ ) ２ , N.H. ２ , cyclopropyl, or CH ２ The pharmaceutical agent according to any one of claims 1 to 9, which is OH.

15. R ２ But, CH ３ , C.F. ３ , C.H.F. ２ , or CH(CH ３ ) ２ The pharmaceutical composition according to any one of claims 1 to 9,

16. R ２ But, CH ３ The pharmaceutical composition according to any one of claims 1 to 9,

17. R ２ But, CF ３ or CHF ２ The pharmaceutical composition according to any one of claims 1 to 9,

18. R ２ But CH (CH ３ ) ２ The pharmaceutical composition according to any one of claims 1 to 9,

19. R ２ But NH ２ The pharmaceutical composition according to any one of claims 1 to 9,

20. R ２ The pharmaceutical agent according to any one of claims 1 to 9, wherein is cyclopropyl.

21. R ２ But, CH ２ The pharmaceutical agent according to any one of claims 1 to 9, which is OH.

22. R ３ The pharmaceutical agent according to any one of claims 1 to 21, wherein is (R)-3-hydroxy-3-methylpyrrolidin-1-yl or (S)-3-hydroxy-3-methylpyrrolidin-1-yl.

23. R ３ The pharmaceutical agent according to any one of claims 1 to 21, wherein is (R)-3-hydroxypyrrolidin-1-yl or (S)-3-hydroxypyrrolidin-1-yl.

24. R ３ The pharmaceutical agent according to any one of claims 1 to 21, wherein is (R)-2-hydroxy-2-methyl-ethylamino or (S)-2-hydroxy-2-methyl-ethylamino.

25. R ３ The pharmaceutical agent according to any one of claims 1 to 21, wherein is (R)-2-hydroxy-1-methyl-ethylamino or (S)-2-hydroxy-1-methyl-ethylamino.

26. R ４ is H or CH ３ The pharmaceutical composition according to any one of claims 1 to 25,

27. R ４ The pharmaceutical agent according to any one of claims 1 to 25, wherein is H.

28. R ４ But, CH ３ The pharmaceutical composition according to any one of claims 1 to 25,

29. The compound has the formula II: 【Chemistry 6】 The pharmaceutical composition according to claim 1, which is represented by the following formula (I): or a pharma- ceutically acceptable salt or stereoisomer thereof.

30. The compound has the formula III: 【Chemistry 7】 The pharmaceutical composition according to claim 1, which is represented by the following formula (I): or a pharma- ceutically acceptable salt or stereoisomer thereof.

31. The compound is (R)-1-((7-cyano-2-(3'-(7-((3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid; (R)-1-((7-cyano-2-(3'-(7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid; (S)-1-((7-cyano-2-(3'-(7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid; (S)-1-((7-cyano-2-(3'-(7-((1-hydroxypropan-2-ylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid; (S)-1-((7-cyano-2-(3'-(7-((2-hydroxypropylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid; (R)-1-((7-cyano-2-(3'-(7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid; (R)-1-((7-cyano-2-(3'-(7-(((R)-3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid; (R)-1-((7-cyano-2-(3'-(7-(((S)-3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid; (R)-1-((7-cyano-2-(3'-(7-(((S)-1-hydroxypropan-2-ylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid; (R)-1-((7-cyano-2-(3'-(7-(((S)-2-hydroxypropylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid; (R)-1-((7-cyano-2-(3'-(7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid; (R)-1-((7-cyano-2-(3'-(7-(((R)-3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid; (R)-1-((7-cyano-2-(3'-(7-(((S)-3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid; (R)-1-((7-cyano-2-(3'-(7-(((S)-1-hydroxypropan-2-ylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid; (R)-1-((7-cyano-2-(3'-(7-(((S)-2-hydroxypropylamino)methyl)-2-methylpyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid; (R)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid; (R)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid; (R)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid; (R)-1-((7-cyano-2-(3'-(7-((3-hydroxypyrrolidin-1-yl)methyl)-2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid; (R)-1-((7-cyano-2-(3'-(7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid; and (R)-1-((7-cyano-2-(3'-(7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid The pharmaceutical composition of claim 1, which is selected from the following:

32. The compound is (S)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid; (S)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid; (R)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-4-methylpiperidine-4-carboxylic acid; (R)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-N,N-dimethylpiperidine-4-carboxamide; (R)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-N-methylpiperidine-4-carboxamide; (R)-3-(1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxamido)propanoic acid; (R)-1-((7-cyano-2-(3'-(2-cyclopropyl-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid; (R)-1-((2-(3'-(2-amino-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid; (R)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid; (S)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid; and (R)-1-((7-cyano-2-(3'-(2-(hydroxymethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid The pharmaceutical composition of claim 1, which is selected from the following:

33. The pharmaceutical composition according to claim 1, wherein the compound is (R)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid or a pharma- ceutical acceptable salt thereof.

34. The pharmaceutical composition according to claim 1, wherein the compound is (R)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid or a pharma- ceutical acceptable salt thereof.

35. The pharmaceutical agent according to claim 1, wherein the compound is (R)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid or a pharma- ceutical acceptable salt thereof.

36. The pharmaceutical agent according to claim 1, wherein the compound is (R)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid or a pharma- ceutically acceptable salt thereof.

37. The pharmaceutical composition according to claim 1, wherein the compound is (S)-1-((7-cyano-2-(3'-(2-(difluoromethyl)-7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid or a pharma- ceutically acceptable salt thereof.

38. The pharmaceutical composition according to any one of claims 1 to 37, wherein the disease or disorder is an infectious disease, inflammation, an autoimmune disease, cancer, or a neurodegenerative disorder.

39. The pharmaceutical composition of claim 38, wherein the disease or disorder is cancer.

40. Cancers include bone cancer, spleen cancer, skin cancer, head and neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, testicular cancer, fallopian tube cancer, carcinoma of the endometrium, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia, childhood solid tumors, lymphocytic lymphoma, bladder cancer, kidney cancer, renal pelvis cancer, CNS neoplasms, primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary gland Cancer, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers including asbestos-induced cancer, melanoma, metastatic malignant melanoma, cutaneous melanoma, renal carcinoma, prostate cancer, hormone refractory prostate adenocarcinoma, breast cancer, invasive breast cancer, colon cancer, lung cancer, squamous cell carcinoma of the head and neck, squamous cell carcinoma of the head and neck, urothelial carcinoma, non-muscle invasive bladder cancer (NMIBC), microsatellite instability-high cancer (MSI-HSC), ｈｉｇｈ ), solid tumors, prostate cancer solid tumors, colon cancer solid tumors, esophageal cancer solid tumors, endometrial cancer solid tumors, kidney cancer solid tumors, liver cancer solid tumors, gastric cancer solid tumors, breast cancer solid tumors, lung cancer solid tumors, thyroid cancer solid tumors, glioblastoma solid tumors, sarcoma solid tumors, bladder cancer solid tumors, recurrent non-Hodgkin's lymphoma, refractory non-Hodgkin's lymphoma, recurrent follicular non-Hodgkin's lymphoma, Hodgkin's lymphoma, cholangiocarcinoma, bile duct cancer, biliary tract cancer, rhabdomyosarcoma, leiomyosarcoma, hepatocellular carcinoma, Ewing's sarcoma, brain cancer, brain tumor, astrocytoma, neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma, epithelioid sarcoma, eye cancer, gastrointestinal cancer, gastrointestinal stromal tumor, hairy cell leukemia, intestinal cancer, pancreatic islet cell carcinoma, oral cancer, cancer), throat cancer, laryngeal cancer, lip cancer, mesothelioma, neck cancer, nasal cavity cancer, ocular cancer cancer), ocular melanoma, pelvic cancer, renal cell carcinoma, salivary gland cancer, paranasal sinus cancer, spinal cancer, tongue cancer, tubular cancer, urethral cancer, ureteral cancer, genitourinary tract cancer, blood cancer, blood system lymphoma, blood system leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, myeloproliferative disorders, primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET), myelodysplastic syndromes (MDS), T-cell acute lymphoblastic leukemia (T-ALL), multiple myeloma (MM), sarcoma, osteosarcoma, liposarcoma, myxoma, rhabdomyoma , rhabdomyosarcoma, fibroma, lipoma, hamartoma, teratoma, non-small cell lung cancer (NSCLC), squamous cell non-small cell lung cancer (NSCLC), small cell lung carcinoma, bronchogenic carcinoma, squamous cell bronchogenic carcinoma, undifferentiated small cell bronchogenic carcinoma, undifferentiated large cell bronchogenic carcinoma, bronchogenic adenocarcinoma, alveolar (bronchial) carcinoma, bronchial adenoma, chondroitin hamartoma, esophageal carcinoma, esophageal squamous cell carcinoma, esophageal Adenocarcinoma, esophageal leiomyosarcoma, esophageal lymphoma, gastric carcinoma, gastric lymphoma, gastric leiomyosarcoma, gastric adenocarcinoma, pancreatic cancer, ductal adenocarcinoma, pancreatic islet cell tumor, glucagon-producing tumor, gastrin-producing tumor, pancreatic carcinoid tumor, VIP-producing tumor, small intestine cancer, small intestine adenocarcinoma, small intestine lymphoma, small intestine carcinoid tumor, Kaposi's sarcoma, small intestinal leiomyoma, small intestinal hemangioma, small intestinal lipoma, small intestinal neurofibroma,small intestinal fibroma, colon cancer, colon adenocarcinoma, colon tubular adenoma, colon villous adenoma, colon hamartoma, colon leiomyoma, colorectal cancer, colorectal adenocarcinoma, renal adenocarcinoma, Wilms' tumor [nephroblastoma], bladder squamous cell carcinoma, bladder transitional cell carcinoma, bladder adenocarcinoma, urethral squamous cell carcinoma, urethral transitional cell carcinoma, urethral adenocarcinoma, prostate adenocarcinoma, prostate sarcoma, testicular cancer, testicular seminoma, testicular teratoma, testicular embryonal carcinoma, testicular teratocarcinoma, testicular choriocarcinoma, testicular sarcoma, testicular stromal cell carcinoma, testicular fibroma, testicular fibroadenoma, testicular adenomatous tumor, testicular lipoma, urinary system cancer, papillary renal carcinoma, testis Germ cell carcinoma, chromophobe renal cell carcinoma, clear cell renal carcinoma, liver cancer, hepatocellular carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, fibrosarcoma, malignant fibrous histiocytoma, malignant lymphoma (reticulum cell sarcoma), malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign cartilage tumor, chondroblastoma, chondromyxofibroma, osteoid osteoma, giant cell tumor, nervous system cancer, skull cancer, osteoma, hemangioma, granuloma, xanthomas, osteitis deformans, meningeal cancer, meningioma, meningeal sarcoma (men ingiosarcoma), gliomatosis, brain astrocytoma, brain medulloblastoma, brain glioma, brain ependymoma, brain germinoma (pinealoma), brain glioblastoma, brain glioblastoma multiforme, brain oligodendroglioma, brain schwannoma, brain retinoblastoma, brain congenital tumor, spinal cord cancer, spinal cord neurofibroma, spinal cord meningioma, spinal cord glioma, spinal cord non-epithelial malignant tumor, Lhermitte-Dacros disease, gynecological cancer, uterine cancer, endometrial cancer, cervical cancer, pre-tumor cervical dysplasia, ovarian cancer, serous cystadenocarcinoma, serous adenocarcinoma, The medicament according to claim 39, which is selected from mucinous cystadenocarcinoma, unclassified carcinoma, granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma, vulvar squamous cell carcinoma, vulvar intraepithelial carcinoma, vulvar adenocarcinoma, vulvar fibrosarcoma, vulvar melanoma, vaginal clear cell carcinoma, vaginal squamous cell carcinoma, botryoid sarcoma, fetal tubal epithelial malignant tumor, squamous cell carcinoma, cutaneous squamous cell carcinoma, lenticular dysplastic nevus, dermal lipoma, hemangioma, dermatofibroma, keloid, triple-negative breast cancer (TNBC), esophageal cancer, and urothelial carcinoma.

41. The pharmaceutical composition according to claim 39, wherein the cancer is a metastatic cancer that expresses PD-L1.

42. The pharmaceutical composition of claim 39, wherein the cancer is lung cancer.

43. The pharmaceutical composition of claim 42, wherein the lung cancer is small cell lung cancer.

44. The pharmaceutical composition of claim 42, wherein the lung cancer is non-small cell lung cancer.

45. The pharmaceutical composition according to claim 39, wherein the cancer is liver cancer.

46. The pharmaceutical composition according to claim 45, wherein the liver cancer is hepatocellular carcinoma.

47. The pharmaceutical composition of claim 39, wherein the cancer is melanoma.

48. The pharmaceutical composition of claim 39, wherein the cancer is bladder cancer.

49. The pharmaceutical composition of claim 39, wherein the cancer is urethral cancer.

50. The pharmaceutical composition of claim 39, wherein the cancer is renal cancer.

51. The pharmaceutical composition of claim 50, wherein the renal cancer is clear cell renal cancer.

52. The pharmaceutical composition of claim 39, wherein the cancer is cutaneous squamous cell carcinoma.

53. The one or more additional therapeutic agents are selected from the group consisting of Akt1 inhibitors, Akt2 inhibitors, Akt3 inhibitors, BCL2 inhibitors, CDK inhibitors, TGF-βR inhibitors, PKA inhibitors, PKG inhibitors, PKC inhibitors, CaM-kinase inhibitors, phosphorylase kinase inhibitors, MEKK inhibitors, ERK inhibitors, MAPK inhibitors, mTOR inhibitors, EGFR inhibitors, HER2 inhibitors, HER3 inhibitors, HER4 inhibitors, INS-R inhibitors, IDH2 inhibitors, IGF-1R inhibitors, IR-R inhibitors, PDGFαR inhibitors, PDGFβR inhibitors, PI3K alpha inhibitors, PI3 K beta inhibitors, PI3K gamma inhibitors, PI3K delta inhibitors, selective PI3K inhibitors, CSF1R inhibitors, KIT inhibitors, FLK-II inhibitors, KDR / FLK-1 inhibitors, FLK-4 inhibitors, flt-1 inhibitors, FGFR1 inhibitors, FGFR2 inhibitors, FGFR3 inhibitors, FGFR4 inhibitors, c-Met inhibitors, PARP inhibitors, Ron inhibitors, Sea inhibitors, TRKA inhibitors, TRKB inhibitors, TRKC inhibitors, TAM kinase inhibitors, Axl inhibitors, Mer inhibitors, Tyro3 inhibitors, FLT3 inhibitors, VEGFR / Flt2 inhibitors, Flt4 inhibitors, EphA1 inhibitors, EphA2 inhibitors, EphA3 inhibitors, EphB2 inhibitors, EphB4 inhibitors, Tie2 inhibitors, Src inhibitors, Fyn inhibitors, Lck inhibitors, Fgr inhibitors, Btk inhibitors, Fak inhibitors, SYK inhibitors, FRK inhibitors, JAK inhibitors, ABL inhibitors, ALK inhibitors, B-Raf inhibitors, IDO inhibitors, LSD1 inhibitors, TDO inhibitors, PI3K-gamma selective inhibitors, Pim inhibitors, ErB-1 inhibitors, HER-1 inhibitors, adenosine receptor antagonists, A2a / A2b receptor antagonists, HP K1 inhibitors, chemokine receptor inhibitors, CCR2 inhibitors, CCR5 inhibitors, SHP1 / 2 phosphatase inhibitors, histone deacetylase inhibitors (HDAC), HDAC8 inhibitors, angiogenesis inhibitors, interleukin receptor inhibitors, bromo and extra-terminal family member inhibitors, BET inhibitors, B-Raf inhibitor-MEK inhibitor combinations, arginase inhibitors, TLR7 agonists, KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors, TGFR beta inhibitors, and combinations thereof;The pharmaceutical composition according to any one of claims 1 to 52.

54. The one or more additional therapeutic agents may be pemigatinib (INCY54828), INCB62079, ruxolitinib, baricitinib, itacitinib (INCB39110), epacadostat, NLG919, BMS-986205, MK7162, INCB59872, INCB60003, parsaclisib (INCB50465), INCB50797, INCB53914, erlotinib, gefitinib, vandetanib, osimertinib, cetuximab, necitumumab, panitumumab, bevacizumab, pazopanib, sunitinib, , sorafenib, axitinib, regorafenib, ponatinib, cabozantinib, axitinib, vandetanib, ramucirumab, lenvatinib, ziv-aflibercept, olaparib, rucaparib, veliparib, talazoparib, niraparib, INCB54329, INCB57643, INCB001158, sitravatinib, encorafenib and binimetinib, dabrafenib and trametinib, cobimetinib and vemurafenib, imiquimod, abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretaminium , anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, intravenous busulfan, oral busulfan, calcitabine, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane , docetaxel, doxorubicin, dromostanolone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alpha 2a, irinotecan,Lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab, pegasparga , pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, Retinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat zoledronate, nivolumab, pembrolizumab (MK-3475), pidilizumab, SHR-1210, PDR001, AMP-224, BMS-935559, MEDI4736, MPDL3280A (RG7446), MSB0010718C, ipilimumab, tremelimumab, BMS-986016, LAG525 , INCAGN2385, INCAGN2390, MBG453, TSR-022, TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, MEDI1873, MEDI0562, MOXR-0916, PF-04518600, GSK3174998, BMS-986178, and combinations thereof.

55. The pharmaceutical agent according to any one of claims 1 to 52, wherein the one or more additional therapeutic agents are selected from an anti-PD1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-LAG3 antibody, an anti-TIM3 antibody, an anti-GITR antibody, an anti-OX40 antibody, and combinations thereof.

56. The pharmaceutical agent of any one of claims 1 to 52, wherein the one or more additional therapeutic agents are VEGFR inhibitors.

57. The pharmaceutical composition of any one of claims 1 to 52, wherein the one or more additional therapeutic agents is an anti-CTLA-4 antibody.

58. The pharmaceutical agent of any one of claims 1 to 52, wherein the one or more additional therapeutic agents is axitinib.

59. The method of any one of claims 1 to 58, wherein the compound or a pharma- ceutically acceptable salt or stereoisomer thereof and the one or more additional therapeutic agents are administered simultaneously.

60. The method of any one of claims 1 to 58, wherein the compound or a pharma- ceutically acceptable salt or stereoisomer thereof and the one or more additional therapeutic agents are administered sequentially.

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