Tetrahydroimidazo[4,5-C]pyridine derivatives as PD-L1 internalization inducers

Description

TECHNICAL FIELD

[0001] The present application is concerned with pharmaceutically active compounds as well as their compositions and methods of use. The compounds cause internalization of PD-L1 from the cell surface and are useful in the treatment of various diseases including cancer.BACKGROUND

[0002] The immune system plays an important role in controlling and eradicating diseases such as cancer. However, cancer cells often develop strategies to evade or to suppress the immune system in order to favor their growth. One such mechanism is altering the expression of co-stimulatory and co-inhibitory molecules expressed on immune cells (Postow et al, J. Clinical Oncology 2015, 1-9). Blocking the signaling of an inhibitory immune checkpoint, such as Programmed cell death-1 (PD-1), has proven to be a promising and effective treatment modality.

[0003] 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 system to prevent the activation of T-cells, which in turn reduces autoimmunity and promotes self-tolerance. In addition, PD-1 is also known to play a critical role in the suppression of antigen-specific T cell response in diseases like cancer and viral infection (Sharpe et al, Nat Immunol 2007 8, 239-245; Postow et al, J. Clinical Oncol 2015, 1-9).

[0004] 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 in an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switch motif, which suggests 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), and they differ in their expression patterns. PD-L1 protein is upregulated on macrophages and dendritic cells in response to lipopolysaccharide and GM-CSF treatment, and on T cells and B cells upon T cell receptor and B cell receptor signaling. PD-L1 is also highly expressed on almost all tumor cells, and the expression is further increased after IFN-γ treatment (Iwai et al, PNAS2002, 99(19):12293-7; Blank et al, Cancer Res 2004, 64(3):1140-5). In fact, 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). PD-L2 expression, in contrast, is more restricted and is expressed mainly 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 delivers a signal that inhibits IL-2 and IFN-γ production, as well as cell proliferation induced upon 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). The mechanism involves recruitment of SHP-2 or SHP-1 phosphatases to 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 PKC-θ activation loop phosphorylation, which is necessary for the activation of NF-κB and API pathways, and 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).

[0005] 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 an LCMV model of chronic infection, it has been shown that PD-1 / PD-L1 interaction inhibits activation, expansion and acquisition of effector functions of virus-specific CD8 T cells (Barber et al, Nature 2006, 439, 682-7). Antibodies that block the PD-1 signaling by either binding to PD-1 or binding to PD-L1 have been shown to be effective in the treatment of cancer. Together, these data support the development of a therapeutic approach to block the PD-1-mediated inhibitory signaling cascade in order to augment or "rescue" T cell response. WO2011 / 082400 and US2015 / 0073024 disclose compounds useful as modulators of PD-1.

[0006] Accordingly, there is a need for new compounds that prevent PD-1 / PD-L1 protein / protein interaction.SUMMARY

[0007] The present invention provides a compound of Formula (IV): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: ring A is selected from: and each subscript q is independently an integer of 1, 2, 3 or 4; each R 28< is independently H or C 1-6 alkyl; the wavy line indicates the point of attachment to L; L is a bond, -NH-, -O-, -C(O)NH-, -C(=S)NH-, -C(=NH)NH-, -C(=NOH)NH-, -C(=NCN)NH-, -CH 2 O- or -OCH 2 -, wherein the carbonyl group in the -C(O)NH- linkage is attached to ring A; R 21< and R 22< are each independently halo, C 1-6 alkyl or CN; R 23< is H, C 1-6 alkyl or C 1-6 haloalkyl; R 25< is C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, halo, OH, -COOH, NH 2 , -NHC 1-4 alkyl or -N(C 1-4 alkyl) 2 ; R 26< is C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, halo, OH, -COOH, NH 2 , -NHC 1-4 alkyl or -N(C 1-4 alkyl) 2 ; R 24< is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, C(O)R a< , C(O)NR a< R a< , C(O)OR a< , C(=NR a< )R a< , C(=NOH)R a< , C(=NOH)NR a< , C(=NCN)NR a< R a< , C(=NR a< )NR a< R a< , S(O)R a< , S(O)NR a< R a< , S(O) 2 R a< , -P(O)R a< R a< , -P(O)(OR a< )(OR a< ), -B(OH) 2 , -B(OR a< ) 2 and S(O) 2 NR a< R a< , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R 24< are each optionally substituted with 1, 2, 3, 4 or 5 independently selected R b< substituents; R 20< is each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR a1< , SR a1< , NHOR a1< , C(O)R a1< , C(O)NR a1< R a1< , C(O)OR a1< , C(O)NR a1< S(O) 2 R a1< , OC(O)R a1< , OC(O)NR a1< R a1< , NHR a1< , NR a1< R a1< , NR a1< C(O)R a1< , NR a1< C(=NR a1< )R a1< , NR a1< C(O)OR a1< , NR a1< C(O)NR a1< R a1< , C(=NR a1< )R a1< , C(=NOH)R a1< , C(=NOH)NR a1< , C(=NCN)NR a1< R a1< , NR a1< C(=NCN)NR a1< R a1< , C(=NR a1< )NR a1< R a1< , NR a1< C(=NR a1< )NR a1< R a1< , NR a1< S(O)R a1< , NR a1< S(O) 2 R a1< , NR a1< S(O) 2 NR a1< R a1< , S(O)R a1< , S(O)NR a1< R a1< , S(O) 2 R a1< , S(O) 2 NR a1< C(O)R a1< , - P(O)R a1< R a1< , -P(O)(OR a1< )(OR a1< ), -B(OH) 2 , -B(OR a1< ) 2 and S(O) 2 NR a1< R a1< , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R 20< are each optionally substituted with 1, 2, 3, 4 or 5 independently selected R b< substituents; R 27< is each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR 32< , SR a2< , NHOR a2< , C(O)R a2< , C(O)NR a2< R a2< , C(O)OR a2< , C(O)NR a2< S(O) 2 R a2< , OC(O)R a2< , OC(O)NR a2< R a2< , NHR a2< , NR a2< R a2< , NR a2< C(O)R a2< , NR a2< C(=NR a2< )R a2< , NR a2< C(O)OR a2< , NR a2< C(O)NR a2< R a2< , C(=NR a2< )R a2< , C(=NOH)R a2< , C(=NOH)NR a2< , C(=NCN)NR a2< R a2< , NR a2< C(=NCN)NR a2< R a2< , C(=NR a2< )NR a2< R a2< , NR a2< C(=NR a2< )NR a2< R a2< , NR a2< S(O)R a2< , NR a2< S(O) 2 R a2< , NR a2< S(O) 2 NR a2< R a2< , S(O)R a2< , S(O)NR a2< R a2< , S(O) 2 R a2< , S(O) 2 NR a2< C(O)R a2< , - P(O)R a2< R a2< , -P(O)(OR a2< )(OR a2< ), -B(OH) 2 , -B(OR a2< ) 2 and S(O) 2 NR a2< R a2< , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R 27< are each optionally substituted with 1, 2, 3, 4 or 5 independently selected R b< substituents; or two R 20< substituents attached to the same ring carbon atom taken together with the ring carbon atom to which they are attached form spiro C 3-6 cycloalkyl or spiro 4- to 7-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R f< substituents; or two R 27< substituents attached to the same ring carbon atom taken together with the ring carbon atom to which they are attached form spiro C 3-6 cycloalkyl or spiro 4- to 7-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R f< substituents; each of R a< , R a1< and R a2< is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R a< , R a1< and R a2< are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R d< substituents; each R d< is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 6-10 aryl, 5-14 membered heteroaryl, C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NH 2 , NHOR e< , OR e< , SR e< , C(O)R e< , C(O)NR e< R e< , C(O)OR e< , C(O)NR e< S(O) 2 R e< , OC(O)R e< , OC(O)NR e< R e< , NHR e< , NR e< R e< , NR e< C(O)R e< , NR e< C(=NR e< )R e< , NR e< C(O)NR e< R e< , NR e< C(O)OR e< , C(=NR e< )NR e< R e< , NR e< C(=NR e< )NR e< R e< , NR e< C(=NOH)NR e< R e< , NR e< C(=NCN)NR e< R e< , S(O)R e< , S(O)NR e< R e< , S(O) 2 R e< , S(O) 2 NR e< C(O)R e< , NR e< S(O) 2 R e< , NR e< S(O) 2 NR e< R e< , -P(O)R e< R e< , -P(O)(OR e< )(OR e< ), -B(OH) 2 , -B(OR e< ) 2 and S(O) 2 NR e< R e< , wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, 5-14 membered heteroaryl, C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R d< are each optionally substituted with 1, 2, or 3 independently selected R f< substituents; each R e< is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R e< are each optionally substituted with 1, 2 or 3 independently selected R f< substituents; each R b< substituent is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, CN, OH, NH 2 , NO 2 ,NHOR c< , OR c< , SR c< , C(O)R c< , C(O)NR c< R c< , C(O)OR c< , C(O)NR c< S(O) 2 R c< , OC(O)R c< , OC(O)NR c< R c< , C(=NOH)R c< , C(=NOH)NR c< , C(=NCN)NR c< R c< , NR c< C(=NCN)NR c< R c< , C(=NR c< )NR c< R c< , NR c< C(=NR c< )NR c< R c< , NHR c< , NR c< R c< , NR c< C(O)R c< , NR c< C(=NR c< )R c< , NR c< C(O)OR c< , NR c< C(O)NR c< R c< , NR c< S(O)R c< , NR c< S(O) 2 R c< , NR c< S(O) 2 NR c< R c< , S(O)R c< , S(O)NR c< R c< , S(O) 2 R c< , S(O) 2 NR c< C(O)R c< , -P(O)R c< R c< , -P(O)(OR c< )(OR c< ), -B(OH) 2 , -B(OR c< ) 2 and S(O) 2 NR c< R c< ; wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R b< are each further optionally substituted with 1, 2 or 3 independently selected R d< substituents; each R c< is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R c< are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R f< substituents; each R f< is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, halo, CN, NHOR g< , OR g< , SR g< , C(O)R g< , C(O)NR g< R g< , C(O)OR g< , C(O)NR g< S(O) 2 R g< , OC(O)R g< , OC(O)NR g< R g< , NHR g< , NR g< R g< , NR g< C(O)R g< , NR g< C(=NR g< )R g< , NR g< C(O)NR g< R g< , NR g< C(O)OR g< , C(=NR g< )NR g< R g< , NR g< C(=NR g< )NR g< R g< , S(O)R g< , S(O)NR g< R g< , S(O) 2 R g< , S(O) 2 NR g< C(O)R g< , NR g< S(O) 2 R g< , NR g< S(O) 2 NR g< R g< , -P(O)R g< R g< , - P(O)(OR g< )(OR g< ), -B(OH) 2 , -B(OR g< ) 2 and S(O) 2 NR g< R g< ; wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R f< are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R n< substituents; each R n< is substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, halo, CN, NHOR o< , OR o< , SR°, C(O)R o< , C(O)NR o< R o< , C(O)OR o< , C(O)NR o< S(O) 2 R o< , OC(O)R o< , OC(O)NR o< R o< , NHR°, NR o< R o< , NR o< C(O)R o< , NR o< C(=NR o< )R o< , NR o< C(O)NR o< R o< , NR o< C(O)OR o< , C(=NR o< )NR o< R o< , NR o< C(=NR o< )NR o< R o< , S(O)R o< , S(O)NR o< R o< , S(O) 2 R o< , S(O) 2 NR o< C(O)R o< , NR o< S(O) 2 R o< , NR o< S(O) 2 NR o< R o< , -P(O)R o< R o< , - P(O)(OR o< )(OR o< ), -B(OH) 2 , -B(OR o< ) 2 and S(O) 2 NR o< R o< , wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R n< are each optionally substituted with 1, 2 or 3 independently selected R q< substituents; each R g< is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R g< are each optionally substituted with 1, 2, or 3 independently selected R p< substituents; each R p< is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, halo, CN, NHOR r< , OR r< , SR r< , C(O)R r< , C(O)NR r< R, r< C(O)OR r< , C(O)NR r< S(O) 2 R r< , OC(O)R r< , OC(O)NR r< R r< , NHR r< , NR r< R r< , NR r< C(O)R r< , NR r< C(=NR r< )R r< , NR r< C(O)NR r< R r< , NR r< C(O)OR r< , C(=NR r< )NR r< R r< , NR r< C(=NR r< )NR r< R r< , NR r< C(=NOH)NR r< R r< , NR r< C(=NCN)NR r< R r< , S(O)R r< , S(O)NR r< R r< , S(O) 2 R r< , S(O) 2 NR r< C(O)R r< , NR r< S(O) 2 R r< , NR r< S(O) 2 NR r< R r< , -P(O)R r< R r< , -P(O)(OR r< )(OR r< ), -B(OH) 2 , -B(OR r< ) 2 and S(O) 2 NR r< R r< , wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R p< is optionally substituted with 1, 2 or 3 independently selected R q< substituents; or any two R a< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 independently selected R h< substituents; or any two R a1< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 independently selected R h< substituents; or any two R a2< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 independently selected R h< substituents; each R h< is independently selected from C 1-6 alkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halo, CN, OR i< , SR i< , NHOR i< , C(O)R i< , C(O)NR i< R i< , C(O)OR i< , C(O)NR i< S(O) 2 R i< , OC(O)R i< , OC(O)NR i< R i< , NHR i< , NR i< R i< , NR i< C(O)R i< , NR i< C(=NR i< )R i< , NR i< C(O)NR i< R i< , NR i< C(O)OR i< , C(=NR i< )NR i< R i< , NR i< C(=NR i< )NR i< R i< , S(O)R i< , S(O)NR i< R i< , S(O) 2 R i< , S(O) 2 NR i< C(O)R i< , NR i< S(O) 2 R i< , NR i< S(O) 2 NR i< R i< , -P(O)R i< R i< , - P(O)(OR i< )(OR i< ), -B(OH) 2 , -B(OR i< ) 2 and S(O) 2 NR i< R i< , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R h< are each optionally substituted by 1, 2, or 3 independently selected R j< substituents; each R j< is independently selected from C 3-6 cycloalkyl, C 6-10 aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, NHOR k< , OR k< , SR k< , C(O)R k< , C(O)NR k< R k< , C(O)OR k< , C(O)NR k< S(O) 2 R k< , OC(O)R k< , OC(O)NR k< R k< , NHR k< , NR k< R k< , NR k< C(O)R k< , NR k< C(=NR k< )R k< , NR k< C(O)NR k< R k< , NR k< C(O)OR k< , C(=NR k< )NR k< R k< , NR k< C(=NR k< )NR k< R k< , S(O)R k< , S(O)NR k< R k< , S(O) 2 R k< , S(O) 2 NR k< C(O)R k< , NR k< S(O) 2 R k< , NR k< S(O) 2 NR k< R k< , -P(O)R k< R k< , -P(O)(OR k< )(OR k< ), - B(OH) 2 , -B(OR k< ) 2 and S(O) 2 NR k< R k< , wherein the C 1-4 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, and C 1-4 haloalkoxy of R j< are each optionally substituted with 1, 2 or 3 independently selected R q< substituents; or two R h< groups attached to the same carbon atom of the 4- to 10-membered heterocycloalkyl taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms as ring members selected from O, N or S; or any two R c< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h< substituents; or any two R e< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h< substituents; or any two R g< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h< substituents; or any two R i< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R q< substituents; or any two R k< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R q< substituents; or any two R o< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h< substituents; or any two R r< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h< substituents; each R i< , R k< , R o< or R r< is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkenyl, and C 2-4 alkynyl, wherein the C 1-4 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C 2-4 alkenyl, and C 2-4 alkynyl of R i< , R k< , R o< or R r< are each optionally substituted with 1, 2 or 3 independently selected R q< substituents; each R q< is independently selected from halo, OH, CN, -COOH, B(OH) 2 , NH 2 , -NH-C 1-6 alkyl, -N(C 1-6 alky) 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl and C 3-6 cycloalkyl, wherein the C 1-6 alkyl, phenyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl of R q< are each optionally substituted with 1, 2 or 3 substituents independently selected from halo, OH, CN, -COOH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, phenyl, C 3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl; the subscript m is an integer of 0, 1, 2 or 3; the subscript n is an integer of 0, 1, 2 or 3; the subscript p is an integer of 1, 2, 3, 4, 5 or 6; and is a single bond or a double bond to maintain the 5-membered imidazole ring being aromatic.

[0008] The present invention also provides pharmaceutical compositions comprising a compound of Formula (IV) or a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.

[0009] The present invention also provides a compound of Formula (IV) or a pharmaceutically acceptable salt or a stereoisomer thereof, or a composition of the invention for use in treating cancer or an infection.

[0010] The present invention also provides a compound of Formula (IV) or a pharmaceutically acceptable salt or a stereoisomer thereof, or a composition of the invention for use in a method of enhancing, stimulating and / or increasing the immune response in a patient, wherein the patient has cancer or an infection.

[0011] The present disclosure provides, inter alia, compounds that cause internalization of cell surface PD-L1. The compounds of this disclosure can be represented by any of the formulae and / or embodiments described herein. Reducing cell surface expression of PD-L1 results in reduced PD-L1 available for ligand engagement with PD-1 on an opposing cell and thereby reduces the inhibitory signaling that results from the PD-1-PD-L1 interaction. By reducing PD-1 inhibitory signaling, the compounds of the present disclosure increase an immune response and can be used to treat a PD-1-related disease or condition such as cancer.

[0012] In one aspect, the disclosure features a compound for use in a method of treating a PD-1-related disease or condition in a human subject in need thereof by administering to the human subject a therapeutically effective amount of a compound that binds to cell surface PD-L1 and induces PD-L1 internalization.

[0013] As used herein "internalization" refers to the transport of PD-L1 proteins from the surface of a cell to the interior of the cell. As used herein, a compound induces PD-L1 internalization if it causes PD-L1 internalization in the CHO / PD-L1 internalization assay described in Example 3A or causes PD-L1 internalization in primary cells from cancer patients as described in Example 12A. In some embodiments, the compound causes at least 50%, (e.g., at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99%) of cell surface PD-L1 to be internalized. In some embodiments, a compound induces PD-L1 internalization if it causes PD-L1 internalization in the MDA-MB231 / PD-L1 internalization assay described in Example 3A. In some embodiments, a compound induces PD-L1 internalization if it causes PD-L1 internalization in primary cells from cancer patients described in the example herein.

[0014] In some embodiments, the PD-1-related disease or condition is a cancer (e.g., melanoma, renal cancer, prostate cancer, breast cancer, colon cancer, lung cancer, squamous cell cancer, head and neck cancer, urothelial cancer, or a cancer with high microsatellite instability (MSI high< )).

[0015] In some embodiments, the PD-1-related disease or condition is sepsis.

[0016] In some embodiments, the PD-1-related disease or condition is a viral, bacterial, fungal, or parasitic infection.

[0017] In another aspect, the disclosure features a compound for use in a method of reducing the amount of cell surface PD-L1 by contacting a cell expressing PD-L1 with an effective amount of a compound that binds to cell surface PD-L1 and induces PD-L1 internalization.

[0018] In another aspect, the disclosure features a compound for use in a method of decreasing or reducing the interaction of PD-1 and PD-L1 by contacting a cell expressing PD-L1 with an effective amount of a compound that binds to cell surface PD-L1 and induces PD-L1 internalization.

[0019] In some embodiments, the cell is an immune cell (e.g., a monocyte or macrophage) or a tumor cell.

[0020] In another aspect, the disclosure features a compound for use in a method of enhancing, stimulating and / or increasing an immune response in a human subject in need thereof by administering to the human subject a therapeutically effective amount of a compound that binds to cell surface PD-L1 and induces PD-L1 internalization.

[0021] In some embodiments, the immune response is a T cell immune response (e.g., a cytotoxic or effector T cell response).

[0022] In some embodiments of any of the methods described herein, a second therapeutic agent (e.g., a chemotherapeutic, an immunomodulatory agent, or a kinase inhibitor) is administered in combination with the compound.

[0023] In another aspect, the disclosure features a method for assessing the ability of a compound to induce internalization of PD-L1 in a cell, wherein the method includes: contacting a cell expressing PD-L1 with a compound; and determining the amount of PD-L1 internalized in the cell in the presence of the compound as compared to the absence of the compound.

[0024] In another aspect, the disclosure features a method for assessing the ability of a compound to induce internalization of PD L1 in a cell, wherein the method includes: identifying a compound that binds to PD-L1; contacting a cell with the compound; and determining the amount of PD-L1 internalized in the cell in the presence of the compound as compared to the absence of the compound.

[0025] In another aspect, the disclosure features a method for assessing the ability of a compound to induce dimerization and internalization of PD-L1 in a cell, wherein the method includes: measuring the ability of a compound to induce dimerization of PD-L1; contacting a cell expressing PD-L1 with the compound; and determining the amount of PD-L1 internalized in the cell in the presence of the compound as compared to the absence of the compound.

[0026] In another aspect, the disclosure features a method for assessing the ability of a compound to induce dimerization and internalization of PD-L1 in a cell, wherein the method includes: identifying a compound that binds to PD-L1; measuring the ability of the compound to induce dimerization of PD-L1; contacting a cell expressing PD-L1 with the compound; and determining the amount of PD-L1 internalized in the cell in the presence of the compound as compared to the absence of the compound.

[0027] In some embodiments, the ability of the compound to induce internalization of cell surface PD-L1 is measured by contacting a PD-L1-expressing cell with the compound and detecting the amount of PD-L1 internalized in the cell after incubation of the cell with the compound.

[0028] In some embodiments, the ability of the compound to induce internalization of cell surface PD-L1 is measured by contacting a PD-L1-expressing cell with the compound and detecting the amount of PD-L1 remaining on the surface of the cell after incubation of the cell with the compound.

[0029] In some embodiments, the method further entails formulating the compound into a sterile pharmaceutical composition suitable for administration to a human subject.

[0030] In some embodiments, the pharmaceutical composition is a tablet, pill, capsule, or intravenous formulation.

[0031] In some embodiments, the pharmaceutical composition is suitable for oral, intravenous, subcutaneous administration.

[0032] In some embodiments of any of the methods described herein, the compound is a small molecule. In some embodiments, the compound has a molecular weight of less than 1000 daltons. In some embodiments, the compound has a molecular weight between 300 and 700 daltons.

[0033] In some embodiments of any of the methods described herein, the compound induces PD-L1 internalization with an IC 50 of 500 nM or lower.

[0034] In some embodiments of any of the methods described herein, the compound induces PD-L1 internalization with an IC 50 of 100 nM or lower.

[0035] In some embodiments of any of the methods described herein, the compound induces PD-L1 internalization with an IC 50 of 50 nM or lower.

[0036] Internalization can optionally be measured in the whole blood indirect internalization assay described in Example 3A.

[0037] In some embodiments of any of the methods described herein, the compound induces PD-L1 dimerization, and the dimerization occurs prior to PD-L1 internalization.

[0038] As used herein, a compound induces PD-L1 dimerization if it yields a score in the range of 1.75 to 2.29 in the PD-L1 homogeneous time-resolved fluorescence dimerization assay described in Example 2A.

[0039] In some embodiments of any of the methods described herein, the compound induces PD-L1 dimerization with a score in the range of 2.0 to 2.2 in the PD-L1 homogeneous time-resolved fluorescence dimerization assay described in Example 2A.

[0040] In some embodiments of any of the methods described herein, the compound inhibits binding between PD-L1 and PD-1. In some embodiments, the compound inhibits binding between PD-L1 and PD-1 with an IC 50 of less than 10 nM, less than 1 nM, or less than 0.5 nM.

[0041] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control. Suitable methods and materials are described below, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention. The materials, methods, and examples are illustrative only and not intended to be limiting.

[0042] Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 is a graph depicting the effect of Atezolizumab and control antibodies on PD-L1 internalization. Figure 2 is a graph depicting the internalization of a compound of the invention as exemplified in Table 2 using pleural effusion macrophages from a NSCLC patient treated with or without IFNg. Figure 3 is a graph depicting efficacy of a compound of the invention as exemplified in Table 2 in the MDA-MB-231 tumor model grafted into human CD34+ reconstituted NSG mice. Figures 4A and 4B are graphs depicting internalization of a compound of the invention as exemplified in Table 2 using CHOK1-PDL1 cells expressing moderate (Figure 4A) and high (Figure 4B) levels of PDL1. DETAILED DESCRIPTION

[0044] PD-1 negatively regulates immune responses upon interaction with its ligand PD-L1. The present disclosure provides compounds that cause internalization of cell surface PD-L1, thereby reducing inhibitory signaling that results from the PD-1-PD-L1 interaction.Compounds

[0045] Compounds used according to the methods described herein bind to cell surface PD-L1 and induce PD-L1 internalization. Compounds can be assessed for their ability to induce PD-L1 internalization by, for example, the indirect or direct PD-L1 internalization assays described in Example 3A. Optionally, compounds can also be assessed for their ability to induce PD-L1 dimerization, by, for example, the dimerization assay described in Example 2A. Dimerization of PD-L1 protein can result in the formation of various dimerized conformations. Only a subset of the conformations are capable of, configured to, or indicative of causing internalization of the cell surface PD-L1. A score in the range from about 1.75 to 2.29 according to the dimerization assay described in Example 2A indicates that a compound induces a structural conformation in PD-L1 that has a tendency towards PD-L1 internalization. Not all compounds that bind to PD-L1 and induce PD-L1 dimerization are able to also induce PD-L1 internalization. For example, some compounds that score outside the range of range of 1.75 to 2.29 in the PD-L1 dimerization assay are able to induce PD-L1 dimerization but are unable to induce PD-L1 internalization.

[0046] Examples of compounds that can be used to induce PD-L1 internalization in the methods described herein are described in Example 4A (see, e.g., compounds 7-26 in Table 2 and compounds 60-183 in Table 29) and Example 8A (see e.g., compounds in Examples 1-189).

[0047] In certain embodiments, compounds can be screened from large libraries of synthetic or natural compounds. One example is an FDA approved library of compounds that can be used by humans. In addition, compound libraries are commercially available from a number of companies including but not limited to Maybridge Chemical Co. (Trevillet, Cornwall, UK), Comgenex (Princeton, NJ), Microsource (New Milford, CT), Aldrich (Milwaukee, WI), AKos Consulting and Solutions GmbH (Basel, Switzerland), Ambinter (Paris, France), Asinex (Moscow, Russia), Aurora (Graz, Austria), BioFocus DPI, Switzerland, Bionet (Camelford, UK), ChemBridge, (San Diego, CA), ChemDiv, (San Diego, CA), Chemical Block Lt, (Moscow, Russia), ChemStar (Moscow, Russia), Exclusive Chemistry, Ltd (Obninsk, Russia), Enamine (Kiev, Ukraine), Evotec (Hamburg, Germany), Indofine (Hillsborough, NJ), Interbioscreen (Moscow, Russia), Interchim (Montlucon, France), Life Chemicals, Inc. (Orange, CT), Microchemistry Ltd. (Moscow, Russia), Otava, (Toronto, ON), PharmEx Ltd. (Moscow, Russia), Princeton Biomolecular (Monmouth Junction, NJ), Scientific Exchange (Center Ossipee, NH), Specs (Delft, Netherlands), TimTec (Newark, DE), Toronto Research Corp. (North York ON), UkrOrgSynthesis (Kiev, Ukraine), Vitas-M, (Moscow, Russia), Zelinsky Institute, (Moscow, Russia), and Bicoll (Shanghai, China).

[0048] The compounds of the present disclosure can have pseudo-symmetry with, or around, the core or central ring structure or structures (e.g., "BC"). As used herein the term "pseudo-symmetry" refers to the quality of the compounds of the present disclosure being made up of similar substituents around the core or central ring structure or structures. For example, the compounds can contain a core or central ring structure or structures including a bicyclic core or a spirocyclic core. The compounds can exhibit pseudo-symmetry by having, or the placement of, linking group-ring structures substituted on one or more of the central ring structure or structures. For example, each ring of a biphenyl core or central structure can be substituted with a linking group-ring structure.

[0049] The similarity of the substituents (e.g., the linking group-ring structure, substitute or unsubstituted) around the core or central ring structure or structures can have comparable molecular weights. The molecular weight of each of the substituents can be about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700 and about 750 Daltons. These values can be used to define a range, such as from about 50 Daltons to about 500 Daltons. The difference between the molecular weights of the substituents can be less than about 500, 450, 400, 350, 300, 250, 200, 150, 100 and about 50 Daltons. These values can be used to define a range, such as from about 200 Daltons to about 50 Daltons.

[0050] The similarity of the substituents (e.g., the linking group-ring structure, substitute or unsubstituted) around the core or central ring structure or structures can have a comparable number of non-hydrogen atoms. The number of non-hydrogen atoms of each substituent can be about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or about 28 atoms. These values can be used to define a range, such as from about 4 atoms to about 24 atoms. The difference between the number of non-hydrogen atoms of the substituents can be less than about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or about 1 atom. These values can be used to define a range, such as from about 12 atoms to about 2 atoms.

[0051] The similarity of the substituents (e.g., the linking group-ring structure, substitute or unsubstituted) around the core or central ring structure or structures can have a comparable number of ring structures. Each substituent can contain 1, 2 (e.g., two monocyclic rings or a bicyclic ring), 3 or 4 different ring structures. The difference in the number of ring structures of each substitute can be about, or less than about, 3, 2, 1 or 0. These values can be used to define a range, such as from about 3 rings to about 0 rings.

[0052] The compounds of the present disclosure can also have symmetry with, or around, the core or central ring structure or structures. As used, herein the term "symmetry" refers to the quality of the compounds of the present disclosure being made up of the same substituents around the core or central ring structure or structures. The compounds can exhibit symmetry by having a same linking group-ring structure substituted on one or more of the central ring structure or structures. For example, each ring of a biphenyl core or central structure can be substituted with the same linking group-ring structure.

[0053] The compound used in a method described herein has Formula (I): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: ring A is a C 6-10 aryl, a 5- to 14-membered heteroaryl comprising carbon and 1, 2, 3, or 4 heteroatoms selected from N, O and S, a 4- to 14-membered heterocycloalkyl comprising carbon and 1, 2, 3, or 4 heteroatoms selected from N, O and S, or a C 3-14 cycloalkyl; ring BC is of formula (Ia) or (Ib); provided when ring BC is of formula (Ia) then ring B is a C 6-10 aryl, a 5- to 14-membered heteroaryl comprising carbon and 1, 2, 3, or 4 heteroatoms selected from N, O and S, a 4- to 14-membered heterocycloalkyl comprising carbon and 1, 2, 3, or 4 heteroatoms selected from N, O and S, or a C 3-14 cycloalkyl, and ring C is C 6-10 aryl, a 5- to 14-membered heteroaryl comprising carbon and 1, 2, 3, or 4 heteroatoms selected from N, O and S, a 4- to 14-membered heterocycloalkyl comprising carbon and 1, 2, 3, or 4 heteroatoms selected from N, O and S, or C 3-14 cycloalkyl; and the atoms on ring C, to which the substituent R 4< and ring B are attached can be either carbon or nitrogen; is a single bond or a double bond; provided when ring BC is of formula (Ib) then ring B and ring C are each independently a 4- to 14-membered heterocycloalkyl comprising carbon and 1, 2, 3, or 4 heteroatoms selected from N, O and S, or C 3-14 cycloalkyl; and ring B and ring C are joined together through a quaternary ring carbon atom to form a spiro structure; ring D is a C 6-10 aryl, a 5- to 14-membered heteroaryl comprising carbon and 1, 2, 3, or 4 heteroatoms selected from N, O and S, a 4- to 14-membered heterocycloalkyl comprising carbon and 1, 2, 3, or 4 heteroatoms selected from N, O and S, or a C 3-14 cycloalkyl; L 1< is a bond, -(CR 14< R 15< ) t C(O)NR 13< (CR 14< R 15< ) t -, -(CR 14< R 15< ) t NR 13< C(O)(CR 14< R 15< ) t -, -O-, - (CR 14< R 15< ) p -, -(CR 14< R 15< ) p -O-, -O(CR 14< R 15< ) p -, -(CR 14< R 15< ) p -O-(CR 14< R 15< ) p- , -NR 13< -,-(CR 14< R 15< ) t NR 13< (CR 14< R 15< ) t -, -NH-, -(CR 14< R 15< ) t NH(CR 14< R 15< ) t -, -CR 13< =CR 13< -, -C≡C-, -SO 2 -, - (CR 14< R 15< ) t SO 2 (CR 14< R 15< ) t -, -(CR 14< R 15< ) t SO 2 NR 13< (CR 14< R 15< ) t -, -(CR 14< R 15< ) t NR 13< SO 2 (CR 14< R 15< ) t -,-(CR 14< R 15< ) t NR 13< SO 2 NR 13< (CR 14< R 15< ) t -, -(CR 14< R 15< ) t NR 13< C(O)O(CR 14< R 15< ) t -, -NR 13< C(O)O-, - (CR 14< R 15< ) t O(CO)NR 13< (CR 14< R 15< ) t -, -O(CO)NR 13< -, -NR 13< C(O)NR 13< - or - (CR 14< R 15< ) t NR 13< C(O)NR 13< (CR 14< R 15< ) t ; L 2< is a bond, -(CR 29< R 30< ) t C(O)NR 28< (CR 29< R 30< ) t -, -(CR 29< R 30< ) t NR 28< C(O)(CR 29< R 30< ) t -, -O-, - (CR 29< R 30< ) q -, -(CR 29< R 30< ) q -O-, -O(CR 29< R 30< ) q -, -(CR 29< R 30< ) q -O-(CR 29< R 30< ) q -, -NR 28< -, - (CR 29< R 30< ) w NR 28< (CR 29< R 30< ) w -, -NH-, -(CR 29< R 30< ) w NH(CR 29< R 30< ) w -, -CR 28< =CR 28< -, -C≡C-, -SO 2 -, - (CR 29< R 30< ) w SO 2 (CR 29< R 30< ) w -, -(CR 29< R 30< ) w SO 2 NR 28< (CR 29< R 30< ) w -,-(CR 29< R 30< ) w NR 28< SO 2 (CR 29< R 30< ) w -, -(CR 29< R 30< ) w NR 28< SO 2 NR 28< (CR 29< R 30< ) w -, -(CR 29< R 30< ) w NR 28< C(O)O(CR 29< R 30< ) w -, -NR 28< C(O)O-, - (CR 29< R 30< ) w O(CO)NR 28< (CR 29< R 30< ) w -, -O(CO)NR 28< -, -NR 28< C(O)NR 28< - or - (CR 29< R 30< ) w NR 28< C(O)NR 28< (CR 29< R 30< ) w -; each R 13< is independently H, C 1-6 haloalkyl or C 1-6 alkyl optionally substituted with a substituent selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, halo, OH, - COOH, NH 2 , -NHC 1-4 alkyl and -N(C 1-4 alkyl) 2 ; R 14< and R 15< are each independently selected from H, halo, CN, OH, -COOH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , C 1-4 haloalkyl, and C 1-4 haloalkoxy; each R 28< is independently H, C 1-6 haloalkyl or C 1-6 alkyl optionally substituted with a substituent selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, halo, OH, - COOH, NH 2 , -NHC 1-4 alkyl and -N(C 1-4 alkyl) 2 ; R 29< and R 30< are each independently selected from H, halo, CN, OH, NH 2 , -COOH, C 1-4 alkyl, C 1-4 alkoxy, -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , C 1-4 haloalkyl, and C 1-4 haloalkoxy; R 4< is halo, oxo, CN, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, or C 1-6 haloalkoxy; R 5< , R 6< , R 31< and R 32< are each independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 ,OR a< , SR a< , NHOR a< , C(O)R a< , C(O)NR a< R a< , C(O)OR a< , OC(O)R a< , OC(O)NR a< R a< , NHR a< , NR a< R a< , NR a< C(O)R a< , NR a< C(O)OR a< , NR a< C(O)NR a< R a< , C(=NR a< )R a< , C(=NR a< )NR a< R a< , NR a< C(=NR a< )NR a< R a< , NR a< C(=NOH)NR a< R a< , NR a< C(=NCN)NR a< R a< , NR a< S(O)R a< , NR a< S(O) 2 R a< , NR a< S(O) 2 NR a< R a< , S(O)R a< , S(O)NR a< R a< , S(O) 2 R a< , and S(O) 2 NR a< R a< , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 5< , R 6< , R 31< and R 32< are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R b< ; alternatively, two adjacent R 5< substituents on ring D, taken together with the atoms to which they are attached, form a fused phenyl ring, a fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-6 cycloalkyl ring, wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S, and wherein the fused phenyl ring, fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 3-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 substituents independently selected from R b< ; alternatively, two R 5< substituents on the same ring carbon atom of ring D, taken together with the carbon atom to which they are attached, form a spiro 4-, 5-, 6- or 7-membered heterocycloalkyl ring, or a spiro C 3-6 cycloalkyl ring, wherein the spiro 4-, 5-, 6- or 7-membered heterocycloalkyl ring has 1-4 heteroatoms as ring members selected from N, O and S and wherein the spiro 4-, 5-, 6- or 7-membered heterocycloalkyl ring and spiro C 3-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 substituents independently selected from R b< ; alternatively, two adjacent R 6< substituents on ring A, taken together with the atoms to which they are attached, form a fused phenyl ring, a fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring, or a fused C 3-6 cycloalkyl ring, wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S, and wherein the fused phenyl ring, fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring, and fused C 3-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 substituents independently selected from R b< ; alternatively, two R 6< substituents on the same ring carbon atom of the ring A, taken together with the carbon atom to which they are attached, form a spiro 4-, 5-, 6- or 7-membered heterocycloalkyl ring, or a spiro C 3-6 cycloalkyl ring, wherein the spiro 4-, 5-, 6- or 7-membered heterocycloalkyl ring has 1-4 heteroatoms as ring members selected from N, O and S, and wherein the spiro 4-, 5-, 6- or 7-membered heterocycloalkyl ring and spiro C 3-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 substituents independently selected from R b< ; alternatively, two adjacent R 31< substituents on ring C, taken together with the atoms to which they are attached, form a fused phenyl ring, a fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring, or a fused C 3-6 cycloalkyl ring, wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S, and wherein the fused phenyl ring, fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 3-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 substituents independently selected from R b< ; alternatively, two R 31< substituents on the same ring carbon atom of ring C, taken together with the carbon atom to which they are attached, form a spiro 4-, 5-, 6- or 7-membered heterocycloalkyl ring, or a spiro C 3-6 cycloalkyl ring, wherein the spiro 4-, 5-, 6-or 7-membered heterocycloalkyl ring has 1-4 heteroatoms as ring members selected from N, O and S, and wherein the spiro 4-, 5-, 6- or 7-membered heterocycloalkyl ring and spiro C 3-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 substituents independently selected from R b< ; alternatively, two adjacent R 32< substituents on ring B, taken together with the atoms to which they are attached, form a fused phenyl ring, a fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring, or a fused C 3-6 cycloalkyl ring, wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S, and wherein the fused phenyl ring, fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 3-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 substituents independently selected from R b< ; alternatively, two R 32< substituents on the same ring carbon atom of ring B, taken together with the carbon atom to which they are attached, form a spiro 4-, 5-, 6- or 7-membered heterocycloalkyl ring, or a spiro C 3-6 cycloalkyl ring, wherein the spiro 4-, 5-, 6- or 7-membered heterocycloalkyl ring has 1-4 heteroatoms as ring members selected from N, O and S, and wherein the spiro 4-, 5-, 6- or 7-membered heterocycloalkyl ring and spiro C 3-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 substituents independently selected from R b< ; each R a< is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R a< are each optionally substituted with 1, 2 or 3 substituents independently selected from R d< ; each R b< substituent is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, OH, NH 2 , NO 2 , NHOR c< , OR c< , SR c< , C(O)R c< , C(O)NR c< R c< , C(O)OR c< , OC(O)R c< , OC(O)NR c< R c< , C(=NR c< )NR c< R c< , NR c< C(=NR c< )NR c< R c< , NR c< C(=NOH)NR c< R c,< , NR c< C(=NCN)NR c< R c< , NHR c< , NR c< R c< , NR c< C(O)R c< , NR c< C(O)OR c< , NR c< C(O)NR c< R c< , NR c< S(O)R c< , NR c< S(O) 2 R c< , NR c< S(O) 2 NR c< R c< , S(O)R c< , S(O)NR c< R c< , S(O) 2 R c< and S(O) 2 NR c< R c< ; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R b< are each further optionally substituted with 1, 2, or 3 substituents independently selected from R d< ; alternatively, two R b< substituents attached to the same ring carbon atom taken together with the ring carbon atom to which they are attached form spiro C 3-6 cycloalkyl or spiro 4- to 7-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R f< ; each R c< is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R c< are each optionally substituted with 1, 2 or 3 R f< substituents; each R f< is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, halo, CN, NHOR g< , OR g< , SR g< , C(O)R g< , C(O)NR g< R g< , C(O)OR g< , OC(O)R g< , OC(O)NR g< R g< , NHR g< , NR g< R g< , NR g< C(O)R g< , NR g< C(O)NR g< R g< , NR g< C(O)OR g< , C(=NR g< )NR g< R g< , NR g< C(=NR g< )NR g< R g< , NR g< C(=NOH)NR g< R g< , NR g< C(=NCN)NR g< R g< , S(O)R g< , S(O)NR g< R g< , S(O) 2 R g< , NR g< S(O) 2 R g< , NR g< S(O) 2 NR g< R g< , and S(O) 2 NR g< R g< ; wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R f< are each optionally substituted with 1, 2 or 3 R n< substituents; each R n< is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, NHOR°, OR°, SR°, C(O)R°, C(O)NROR°, C(O)OR°, OC(O)R°, OC(O)NROR°, NHR°, NR°R°, NR°C(O)R°, NR°C(O)NR°R°, NR°C(O)OR°, C(=NR°)NR°R°, NR°C(=NR°)NR°R°, S(O)R°, S(O)NR°R°, S(O) 2 R°, NR°S(O) 2 R°, NR°S(O) 2 NR°R°, and S(O) 2 NR°R°, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R n< is optionally substituted with 1, 2 or 3 R q< substituents; each R d< is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NH2, NHOR e< , OR e< , SR e< , C(O)R e< , C(O)NR e< R e< , C(O)OR e< , OC(O)R e< , OC(O)NR e< R e< , NHR e< , NR e< R e< , NR e< C(O)R e< , NR e< C(O)NR e< R e< , NR e< C(O)OR e< , C(=NR e< )NR e< R e< , NR e< C(=NR e< )NR e< R e< , NR e< C(=NOH)NR e< R e< , NR e< C(=NCN)NR e< R e< , S(O)R e< , S(O)NR e< R e< , S(O)2R e< , NR e< S(O)2R e< , NR e< S(O) 2 NR e< R e< , and S(O)2NR e< R e< , wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R d< are each optionally substituted with 1, 2, or 3 substituents independently selected from R f< ; each R e< is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R e< are each optionally substituted with 1, 2 or 3 substituents independently selected from R f< ; each R g< is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R g< are each optionally substituted with 1, 2, or 3 R P< substituents; each R p< is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, halo, CN, NHOR r< , OR r< , SR r< , C(O)R r< , C(O)NR r< R r< , C(O)OR r< , OC(O)R r< , OC(O)NR r< R r< , NHR r< , NR r< R r< . NR r< C(O)R r< , NR r< C(O)NR r< R r< , NR r< C(O)OR r< , C(=NR r< )NR r< R r< , NR r< C(=NR r< )NR r< R r< , NR r< C(=NOH)NR r< R r< , NR r< C(=NCN)NR r< R r< , S(O)R r< , S(O)NR r< R r< , S(O) 2 R r< , NR r< S(O) 2 R r< , NR r< S(O) 2 NR r< R r< and S(O) 2 NR r< R r< , wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R p< is optionally substituted with 1, 2 or 3 R q< substituents; alternatively, any two R a< substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 R h< substituents; each R h< is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, C 6-10 aryl-C 1-4 alkyl-, C 2-6 alkenyl, C 2-6 alkynyl, halo, CN, OR i< , SR i< , NHOR i< , C(O)R i< , C(O)NR i< R i< , C(O)OR i< , OC(O)R i< , OC(O)NR i< R i< , NHR i< , NR i< R i< , NR i< C(O)R i< , NR i< C(O)NR i< R i< , NR i< C(O)OR i< , C(=NR i< )NR i< R i< , NR i< C(=NR i< )NR i< R i< , NR i< C(=NOH)NR i< R i< , NR i< C(=NCN)NR i< R i< , S(O)R i< , S(O)NR i< R i< , S(O) 2 R i< , NR i< S(O) 2 R i< , NR i< S(O) 2 NR i< R i< , and S(O) 2 NR i< R i< , wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R h< are each optionally substituted by 1, 2, or 3 R i< substituents; each R j< is independently selected from C 1-4 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, NHOR k< , OR k< , SR k< , C(O)R k< , C(O)NR k< R k< , C(O)OR k< , OC(O)R k< , OC(O)NR k< R k< , NHR k< , NR k< R k< , NR k< C(O)R k< , NR k< C(O)NR k< R k< , NR k< C(O)OR k< , C(=NR k< )NR k< R k< , NR k< C(=NR k< )NR k< R k< , S(O)R k< , S(O)NR k< R k< , S(O) 2 R k< , NR k< S(O) 2 R k< , NR k< S(O) 2 NR k< R k< , and S(O) 2 NR k< R k< , wherein the C 1-4 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 2-4 alkenyl, C 1-4 haloalkyl, and C 1-4 haloalkoxy of R j< are each optionally substituted with 1, 2 or 3 substituents independently selected from R q< ; alternatively, two R h< groups attached to the same carbon atom of the 4- to 10-membered heterocycloalkyl, taken together with the carbon atom to which they are attached, form a C 3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms as ring members selected from O, N or S; alternatively, any two R c< substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from R f< ; alternatively, any two R e< substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from R f< ; alternatively, any two R g< substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from R p< ; alternatively, any two R i< substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from R q< ; alternatively, any two R k< substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from R q< ; alternatively, any two R o< substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from R q< ; and alternatively, any two R r< substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from R q< ; each R i< , R k< , R o< or R r< is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3 - 6 cycloalkyl, C 6-10 aryl, 4-6 membered heterocycloalkyl, 5 or 6-membered heteroaryl, C 1-4 haloalkyl, C 2-4 alkenyl, and C 2-4 alkynyl, wherein the C 1-4 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, 4-6 membered heterocycloalkyl, 5 or 6-membered heteroaryl, C 2-4 alkenyl, and C 2-4 alkynyl of R i< , R k< , R o< or R r< are each optionally substituted with 1, 2 or 3 R q< substituents; each R q< is independently selected from OH, CN, -COOH, NH 2 , halo, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C 3-6 cycloalkyl, NHR 12< and NR 12< R 12< , wherein the C 1-6 alkyl, phenyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl of R q< are each optionally substituted with halo, OH, CN, -COOH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, phenyl, 5-6 membered heteroaryl, C 3-10 cycloalkyl and 4-6 membered heterocycloalkyl and each R 12< is independently C 1-6 alkyl; the subscript n is an integer of 0, 1, 2, or 3; the subscript m is an integer of 0, 1, 2, or 3; the subscript u is an integer of 0, 1, 2, or 3; the subscript v is an integer of 0, 1, 2, or 3; each subscript p is independently an integer of 1, 2, or 3; each subscript t is independently an integer of 0, 1, 2, or 3; each subscript q is independently an integer of 1, 2, or 3; and each subscript w is independently an integer of 0, 1, 2, or 3.

[0054] The compound used in a method described herein is the compound of Formula (II): or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0055] The compound used in a method described herein is the compound of Formula (II): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein ring B is a C 6-10 aryl, a 5- to 10-membered heteroaryl comprising carbon and 1, 2, 3, or 4 heteroatoms selected from N, O and S, a 4- to 10-membered heterocycloalkyl comprising carbon and 1, 2, 3, or 4 heteroatoms selected from N, O and S, or a C 3-10 cycloalkyl; ring C is C 6-10 aryl, a 5- to 10-membered heteroaryl comprising carbon and 1, 2, 3, or 4 heteroatoms selected from N, O and S, a 4- to 10-membered heterocycloalkyl comprising carbon and 1, 2, 3, or 4 heteroatoms selected from N, O and S, or C 3-10 cycloalkyl; the atoms on ring C, to which the substituent R 4< and ring B are attached are carbon; and is a single bond or a double bond.

[0056] The compound used in a method described herein is the compound of Formula (II): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein ring B is a phenyl, a 5- to 6-membered heteroaryl comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, a 4- to 6-membered heterocycloalkyl comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, or a C 3-6 cycloalkyl; ring C is phenyl, a 5- to 6-membered heteroaryl comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, a 4- to 6-membered heterocycloalkyl comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, or a C 3-6 cycloalkyl; the atoms on ring C, to which the substituent R 4< and ring B are attached are carbon; and is a single bond or a double bond.

[0057] The compound used in a method described herein is the compound of Formula (III): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein ring B and ring C are each independently 4- to 11-membered heterocycloalkyl or C 3-10 cycloalkyl.

[0058] The compound used in a method described herein is the compound of Formula (III): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein ring B and ring C are each independently 4- to 7-membered heterocycloalkyl or C 3-7 cycloalkyl.

[0059] The compound used in a method described herein is the compound of Formula (IIa): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: Z 1< is N or CR 1< ; Z 2< is N or CR 2< ; Z 3< is N or CR 3< ; ring B is a phenyl, a 5- to 6-membered heteroaryl comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, a 4- to 6-membered heterocycloalkyl comprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S, or a C 3-6 cycloalkyl; R 1< , R 2< and R 3< are each independently selected from H, C 1-4 alkyl, C 1-4 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl-, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl-, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, C 2-4 alkenyl, C 2-4 alkynyl, halo, CN, OR 7< , C 1-4 haloalkyl, C 1-4 haloalkoxy, NH 2 , -NHR 7< , -NR 7< R 7< , NHOR 7< , C(O)R 7< , C(O)NR 7< R 7< , C(O)OR 7< , OC(O)R 7< , OC(O)NR 7< R 7< , NR 7< C(O)R 7< , NR 7< C(O)OR 7< , NR 7< C(O)NR 7< R 7< , C(=NR 7< )R 7< , C(=NR 7< )NR 7< R 7< , NR 7< C(=NR 7< )NR 7< R 7< , NR 7< S(O)R 7< , NR 7< S(O) 2 R 7< , NR 7< S(O) 2 NR 7< R 7< , S(O)R 7< , S(O)NR 7< R 7< , S(O) 2 R 7< , and S(O) 2 NR 7< R 7< , wherein each R 7< is independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl-, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-4 alkyl, C 1-4 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl-, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl-, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 1< , R 2< , R 3< and R 7< are each optionally substituted with 1 or 2 independently selected R d< substituents.

[0060] The compound used in a method described herein is the compound of Formula (IIb): or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0061] The compound used in a method described herein is the compound, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: substituent is or wherein X 1< , X 2< and X 3< are each independently N or CH; ring E is fused 5- or 6-membered heterocycloalkyl; R 6A< is H or C 1-6 alkyl; and each subscript m is independently an integer of 0, 1, or 2.

[0062] The compound used in a method described herein is the compound, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein each R 32< is independently C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, halo, OH, -COOH, NH 2 , -NHC 1-4 alkyl or -N(C 1-4 alkyl) 2 .

[0063] The compound used in a method described herein is the compound, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein Z 1< is CR 1< , Z 2< is CR 2< and Z 3< is CR 3< .

[0064] The compound used in a method described herein is the compound, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein Z 1< , Z 2< and Z 3< are each CH.

[0065] The compound used in a method described herein is the compound, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein L 1< is a bond, -(CR 14< R 15< ) t C(O)NR 13< (CR 14< R 15< ) t -, -(CR 14< R 15< ) t NR 13< C(O)(CR 14< R 15< ) t -, -O-,-(CR 14< R 15< ) p -, -(CR 14< R 15< ) p -O-, -O(CR 14< R 15< ) p -, -(CR 14< R 15< ) p -O-(CR 14< R 15< ) p -, -NR 13< -,-(CR 14< R 15< ) t NR 13< (CR 14< R 15< ) t -, -NH-, -(CR 14< R 15< ) t NH(CR 14< R 15< ) t -, -CR 13< =CR 13< -, -C≡C-, -SO 2 -,-(CR 14< R 15< ) t SO 2 (CR 14< R 15< ) t -, -(CR 14< R 15< ) t SO 2 NR 13< (CR 14< R 15< ) t -, -(CR 14< R 15< ) t NR1 3< SO 2 (CR 14< R 15< ) t -,-(CR 14< R 15< ) t NR 13< SO 2 NR 13< (CR 14< R 15< ) t -, -(CR 14< R 15< ) t NR 13< C(O)O(CR 14< R 15< ) t -, -NR 13< C(O)O-,-(CR 14< R 15< ) t O(CO)NR 13< (CR 14< R 15< ) t -, -O(CO)NR 13< -, -NR 13< C(O)NR 13< - or-(CR 14< R 15< ) t NR 13< C(O)NR 13< (CR 14< R 15< ) t ; each subscript p is independently an integer of 1 or 2; and each subscript t is independently an integer of 0, 1, or 2.

[0066] The compound used in a method described herein is the compound, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 13< is H, R 14< is H, and R 15< is H.

[0067] The compound used in a method described herein is the compound, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein L 1< is a bond, -C(O)NH-,-NHC(O)-, -O-, -NH-, -CH=CH-, -C=C-, -SO 2 -, -SO 2 NH-, -NHSO 2 -, -NHSO 2 NH-,-NHC(O)O-, -NHC(O)O-, -O(CO)NH-, -O(CO)NH-, -NHC(O)NH- or -NHC(O)NH.

[0068] The compound used in a method described herein is the compound, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein L 2< is a bond, -(CR 29< R 30< ) t C(O)NR 28< (CR 29< R 30< ) t -, -(CR 29< R 30< ) t NR 28< C(O)(CR 29< R 30< ) t -, -O-,-(CR 29< R 30< ) q - , -(CR 29< R 30< ) q -O-, -O(CR 29< R 30< ) q -, -(CR 29< R 30< ) q -O-(CR 29< R 30< ) q -, -NE 28< -,-(CR 29< R 30< ) W NR 28< (CR 29< R 30< ) W -, -NH-, -(CR 29< R 30< ) w NH(CR 29< R 30< ) w -, -CR 28< =CR 28< -, -C≡C-, -SO 2 -,-(CR 29< R 30< ) w SO 2 (CR 29< R 30< ) w -, (CR 29< R 30< ) w SO 2 NR 28< (CR 29< R 30< ) w -, (CR 29< R 30< ) w NR 28< SO 2 (CR 29< R 30< ) w -, -(CR 29< R 30< ) w NR 28< SO 2 NR 28< (CR 29< R 30< ) w -, -(CR 29< R 30< ) w NR 28< C(O)O(CR 29< R 30< ) w -, -NR 28< C(O)O-,-(CR 29< R 30< ) w O(CO)NR 28< (CR 29< R 30< ) w -, -O(CO)NR 28< -, -NR 28< C(O)NR 28< - or-(CR 29< R 30< ) w NR 28< C(O)NR 28< (CR 29< R 30< ) w -; each subscript t is independently an integer of 0, 1, or 2; each subscript q is independently an integer of 1 or 2; and each subscript w is independently an integer of 0, 1, or 2.

[0069] The compound used in a method described herein is the compound, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 28< is H, R 29< is H, and R 30< is H.

[0070] The compound used in a method described herein is the compound, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein L 2< is a bond, -C(O)NH-,-NHC(O)-, -O-, -NH-, -CH=CH-, -C=C-, -SO 2 -, -SO 2 NH-, -NHSO 2 -, -NHSO 2 NH-,-NHC(O)O-, -NHC(O)O-, -O(CO)NH-, -O(CO)NH-, -NHC(O)NH- or -NHC(O)NH

[0071] In some embodiments, the present disclosure provides compounds of Formula (IV): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: ring A is 5- to 14-membered heteroaryl, 4- to 14-membered heterocycloalkyl, C 6-10 aryl or C 3-10 cycloalkyl, wherein the 5- to 14-membered heteroaryl and 4- to 14-membered heterocycloalkyl each has 1-4 heteroatoms as ring members selected from B, P, N, O and S, wherein the N, P or S atom as ring members is optionally oxidized and one or more carbon atoms as ring members are each optionally replaced by a carbonyl group; and wherein ring A is optionally substituted with 1, 2, 3, 4 or 5 R 20< substituents; L is a bond, -NH-, -O-, -C(O)NH-, -C(=S)NH-, -C(=NH)NH-, -C(=NOH)NH-, -C(=NCN)NH-, -CH 2 O- or -OCH 2 -, wherein the carbonyl group in the -C(O)NH- linkage is attached to ring A; R 21< and R 22< are each independently halo, C 1-6 alkyl or CN; R 23< is H, C 1-6 alkyl or C 1-6 haloalkyl; R 25< is C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, halo, OH, -COOH, NH 2 , -NHC 1-4 alkyl or -N(C 1-4 alkyl) 2 ; R 26< is C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, halo, OH, -COOH, NH 2 , -NHC 1-4 alkyl or -N(C 1-4 alkyl) 2 ; R 24< is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, C(O)R a< , C(O)NR a< R a< , C(O)OR a< , C(=NR a< )R a< , C(=NOH)R a< , C(=NOH)NR a< , C(=NCN)NR a< R a< , C(=NR a< )NR a< R a< , S(O)R a< , S(O)NR a< R a< , S(O) 2 R a< , -P(O)R a< R a< , -P(O)(OR a< )(OR a< ), -B(OH) 2 , -B(OR a< ) 2 and S(O) 2 NR a< R a< , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R 24< are each optionally substituted with 1, 2, 3, 4 or 5 independently selected R b< substituents; R 20< is each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR a1< , SR a1< , NHOR a1< , C(O)R a1< , C(O)NR a1< R a1< , C(O)OR a1< , C(O)NR a1< S(O) 2 R a1< , OC(O)R a1< , OC(O)NR a1< R a1< , NHR a1< , NR a1< R a1< , NR a1< C(O)R a1< , NR a1< C(=NR a1< )R a1< , NR a1< C(O)OR a1< , NR a1< C(O)NR a1< R a1< , C(=NR a1< )R a1< , C(=NOH)R a1< , C(=NOH)NR a1< , C(=NCN)NR a1< R a1< , NR a1< C(=NCN)NR a1< R a1< , C(=NR a1< )NR a1< R a1< , NR a1< C(=NR a1< )NR a1< R a1< , NR a1< S(O)R a1< , NR a1< S(O) 2 R a1< , NR a1< S(O) 2 NR a1< R a1< , S(O)R a1< , S(O)NR a1< R a1< , S(O)2R a1< , S(O) 2 NR a1< C(O)R a1< ,-P(O)R a1< R a1< , -P(O)(OR a1< )(OR a1< ), -B(OH) 2 , -B(OR a1< ) 2 and S(O) 2 NR a1< R a1< , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R 20< are each optionally substituted with 1, 2, 3, 4 or 5 independently selected R b< substituents; R 27< is each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR a2< , SR a2< , NHOR a2< , C(O)R a2< , C(O)NR a2< R a2< , C(O)OR a2< , C(O)NR a2< S(O)2R a2< , OC(O)R a2< , OC(O)NR a2< R a2< , NHR a2< , NR a2< R a2< , NR a2< C(O)R a2< , NR a2< C(=NR a2< )R a2< , NR a2< C(O)OR a2< , NR a2< C(O)NR a2< R a2< , C(=NR a2< )R a2< , C(=NOH)R a2< , C(=NOH)NR a2< , C(=NCN)NR a2< R a2< , NR a2< C(=NCN)NR a2< R a2< , C(=NR a2< )NR a2< R a2< , NR a2< C(=NR a2< )NR a2< R a2< , NR a2< S(O)Ra 2< , NR a2< S(O) 2 R a2< , NR a2< S(O) 2 NR a2< R a2< , S(O)R a2< , S(O)NR a2< R a2< , S(O) 2 R a2< , S(O) 2 NR a2< C(O)R a2< , - P(O)R a2< R a2< , -P(O)(OR a2< )(OR a2< ), -B(OH)2, -B(OR a2< ) 2 and S(O) 2 NR a2< R a2< , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R 27< are each optionally substituted with 1, 2, 3, 4 or 5 independently selected R b< substituents; or two R 20< substituents attached to the same ring carbon atom taken together with the ring carbon atom to which they are attached form spiro C 3-6 cycloalkyl or spiro 4- to 7-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R f< substituents; or two R 27< substituents attached to the same ring carbon atom taken together with the ring carbon atom to which they are attached form spiro C 3-6 cycloalkyl or spiro 4- to 7-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R f< substituents; each of R a< , R a1< and R a2< is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R a< , R a1< and R 32< are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R d< substituents; each R d< is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 6-10 aryl, 5-14 membered heteroaryl, C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NH 2 , NHOR e< , OR e< , SR e< , C(O)R e< , C(O)NR e< R e< , C(O)OR e< , C(O)NR e< S(O) 2 R e< , OC(O)R e< , OC(O)NR e< R e< , NHR e< , NR e< R e< , NR e< C(O)R e< , NR e< C(=NR e< )R e< , NR e< C(O)NR e< R e< , NR e< C(O)OR e< , C(=NR e< )NR e< R e< , NR e< C(=NR e< )NR e< R e< , NR e< C(=NOH)NR e< R e< , NR e< C(=NCN)NR e< R e< , S(O)R e< , S(O)NR e< R e< , S(O) 2 R e< , S(O) 2 NR e< C(O)R e< , NR e< S(O) 2 R e< , NR e< S(O) 2 NR e< R e< , -P(O)R e< R e< , -P(O)(OR e< )(OR e< ), -B(OH)2, -B(OR e< ) 2 and S(O) 2 NR e< R e< , wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, 5-14 membered heteroaryl, C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R d< are each optionally substituted with 1, 2, or 3 independently selected R f< substituents; each R e< is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R e< are each optionally substituted with 1, 2 or 3 independently selected R f< substituents; each R b< substituent is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, CN, OH, NH 2 , NO 2 , NHOR c< , OR c< , SR c< , C(O)R c< , C(O)NR c< R c< , C(O)OR c< , C(O)NR c< S(O) 2 R c< , OC(O)R c< , OC(O)NR c< R c< , C(=NOH)R c< , C(=NOH)NR c< , C(=NCN)NR c< R c< , NR c< C(=NCN)NR c< R c< , C(=NR c< )NR c< R c< , NR c< C(=NR c< )NR c< R c< , NHR c< , NR c< R c< , NR c< C(O)R c< , NR c< C(=NR c< )R c< , NR c< C(O)OR c< , NR c< C(O)NR c< R c< , NR c< S(O)R c< , NR c< S(O) 2 R c< , NR c< S(O) 2 NR c< R c< , S(O)R c< , S(O)NR c< R c< , S(O) 2 R c< , S(O) 2 NR c< C(O)R c< , -P(O)R c< R c< , -P(O)(OR c< )(OR c< ), -B(OH) 2 , -B(OR c< ) 2 and S(O) 2 NR c< R c< ; wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R b< are each further optionally substituted with 1, 2 or 3 independently selected R d< substituents; each R c< is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R c< are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R f< substituents; each R f< is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, halo, CN, NHOR g< , OR g< , SR g< , C(O)R g< , C(O)NR g< R g< , C(O)OR g< , C(O)NR g< S(O) 2 R g< , OC(O)R g< , OC(O)NR g< R g< , NHR g< , NR g< R g< , NR g< C(O)R g< , NR g< C(=NR g< )R g< , NR g< C(O)NR g< R g< , NR g< C(O)OR g< , C(=NR g< )NR g< R g< , NR g< C(=NR g< )NR g< R g< , S(O)R g< , S(O)NR g< R g< , S(O) 2 R g< , S(O) 2 NR g< C(O)R g< , NR g< S(O) 2 R g< , NR g< S(O) 2 NR g< R g< , -P(O)R g< R g< , - P(O)(OR g< )(OR g< ), -B(OH) 2 , -B(OR g< ) 2 and S(O) 2 NR g< R g< ; wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R f< are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R n< substituents; each R n< is substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, halo, CN, NHOR o< , OR o< , SR o< , C(O)R o< , C(O)NR o< R o< , C(O)OR o< , C(O)NR o< S(O) 2 R o< , OC(O)R o< , OC(O)NR o< R o< , NHR o< , NR o< R o< , NR o< C(O)R o< , NR o< C(=NR o< )R o< , NR o< C(O)NR o< R o< , NR o< C(O)OR o< , C(=NR o< )NR o< R o< , NR o< C(=NR o< )NR o< R o< , S(O)R o< , S(O)NR o< R o< , S(O) 2 R o< , S(O) 2 NR o< C(O)R o< , NR o< S(O) 2 R o< , NR o< S(O) 2 NR o< R o< , -P(O)R o< R o< , - P(O)(OR o< )(OR o< ), -B(OH) 2 , -B(OR o< ) 2 and S(O) 2 NR o< R o< , wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R n< are each optionally substituted with 1, 2 or 3 independently selected R q< substituents; each R g< is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R g< are each optionally substituted with 1, 2, or 3 independently selected R p< substituents; each R p< is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, halo, CN, NHOR r< , OR r< , SR r< , C(O)R r< , C(O)NR r< R r< , C(O)OR r< , C(O)NR r< S(O) 2 R r< , OC(O)R r< , OC(O)NR r< R r< , NHR r< , NR r< R r< , NR r< C(O)R r< , NR r< C(=NR r< )R r< , NR r< C(O)NR r< R r< , NR r< C(O)OR r< , C(=NR r< )NR r< R r< , NR r< C(=NR r< )NR r< R r< , NR r< C(=NOH)NR r< R r< , NR r< C(=NCN)NR r< R r< , S(O)R r< , S(O)NR r< R r< , S(O) 2 R r< , S(O) 2 NR r< C(O)R r< , NR r< S(O) 2 R r< , NR r< S(O) 2 NR r< R r< , -P(O)R r< R r< , -P(O)(OR r< )(OR r< ), -B(OH)2, -B(OR r< ) 2 and S(O) 2 NR r< R r< , wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R p< is optionally substituted with 1, 2 or 3 independently selected R q< substituents; or any two R a< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 independently selected R h< substituents; or any two R a1< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 independently selected R h< substituents; or any two R a2< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 independently selected R h< substituents; each R h< is independently selected from C 1-6 alkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halo, CN, OR i< , SR i< , NHOR i< , C(O)R i< , C(O)NR i< R i< , C(O)OR i< , C(O)NR i< S(O) 2 R i< , OC(O)R i< , OC(O)NR i< R i< , NHR i< , NR i< R i< , NR i< C(O)R i< , NR i< C(=NR i< )R i< , NR i< C(O)NR i< R i< , NR i< C(O)OR i< , C(=NR i< )NR i< R i< , NR i< C(=NR i< )NR i< R i< , S(O)R i< , S(O)NR i< R i< , S(O) 2 R i< , S(O) 2 NR i< C(O)R i< , NR i< S(O) 2 R i< , NR i< S(O) 2 NR i< R i< , -P(O)R i< R i< , - P(O)(OR i< )(OR i< ), -B(OH) 2 , -B(OR i< ) 2 and S(O) 2 NR i< R i< , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R h< are each optionally substituted by 1, 2, or 3 independently selected R j< substituents; each R j< is independently selected from C 3-6 cycloalkyl, C 6-10 aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, NHOR k< , OR k< , SR k< , C(O)R k< , C(O)NR k< R k< , C(O)OR k< , C(O)NR k< S(O) 2 R k< , OC(O)R k< , OC(O)NR k< R k< , NHR k< , NR k< R k< , NR k< C(O)R k< , NR k< C(=NR k< )R k< , NR k< C(O)NR k< R k< , NR k< C(O)OR k< , C(=NR k< )NR k< R k< , NR k< C(=NR k< )NR k< R k< , S(O)R k< , S(O)NR k< R k< , S(O) 2 R k< , S(O) 2 NR k< C(O)R k< , NR k< S(O) 2 R k< , NR k< S(O) 2 NR k< R k< , -P(O)R k< R k< , -P(O)(OR k< )(OR k< ), - B(OH) 2 , -B(OR k< ) 2 and S(O) 2 NR k< R k< , wherein the C 1-4 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, and C 1-4 haloalkoxy of R j< are each optionally substituted with 1, 2 or 3 independently selected R q< substituents; or two R h< groups attached to the same carbon atom of the 4- to 10-membered heterocycloalkyl taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms as ring members selected from O, N or S; or any two R c< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h< substituents; or any two R e< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h< substituents; or any two R g< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h< substituents; or any two R i< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R q< substituents; or any two R k< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R q< substituents; or any two R o< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h< substituents; or any two R r< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h< substituents; each R i< , R k< , R o< or R r< is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkenyl, and C 2-4 alkynyl, wherein the C 1-4 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C 2-4 alkenyl, and C 2-4 alkynyl of R i< , R k< , R o< or R r< are each optionally substituted with 1, 2 or 3 independently selected R q< substituents; each R q< is independently selected from halo, OH, CN, -COOH, B(OH) 2 , NH 2 , -NH-C 1-6 alkyl, -N(C 1-6 alky) 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl and C 3-6 cycloalkyl, wherein the C 1-6 alkyl, phenyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl of R q< are each optionally substituted with 1, 2 or 3 substituents independently selected from halo, OH, CN, -COOH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, phenyl, C 3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl; the subscript m is an integer of 0, 1, 2 or 3; the subscript n is an integer of 0, 1, 2 or 3; the subscript p is an integer of 1, 2, 3, 4, 5 or 6; and is a single bond or a double bond to maintain the 5-membered imidazole ring being aromatic.

[0072] In certain embodiments, ring A is 5- to 14-membered heteroaryl, 4- to 14-membered heterocycloalkyl, C 6-10 aryl or C 3-10 cycloalkyl, wherein the 5- to 14-membered heteroaryl and 4- to 14-membered heterocycloalkyl each has 1-4 heteroatoms as ring members selected from B, P, N, O and S, wherein the N, P or S atom as ring members is optionally oxidized and one or more carbon atoms as ring members are each optionally replaced by a carbonyl group; and wherein ring A is optionally substituted with 1, 2, 3, 4 or 5 R 20< substituents; L is a bond, -NH-, -O-, -C(O)NH-, -CH 2 O- or -OCH 2 -, wherein the carbonyl group in the -C(O)NH- linkage is attached to ring A; R 21< and R 22< are each independently halo, C 1-6 alkyl or CN; R 23< is H, C 1-6 alkyl or C 1-6 haloalkyl; R 25< is C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, halo, OH, -COOH, NH 2 , -NHC 1-4 alkyl or -N(C 1-4 alkyl) 2 ; R 26< is C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, halo, OH, -COOH, NH 2 , -NHC 1-4 alkyl or -N(C 1-4 alkyl) 2 ; R 24< is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, C(O)R a< , C(O)NR a< R a< , C(O)OR a< , C(=NR a< )R a< , C(=NOH)R a< , C(=NOH)NR a< , C(=NCN)NR a< R a< , C(=NR a< )NR a< R a< , S(O)R a< , S(O)NR a< R a< , S(O) 2 R a< , -P(O)R a< R a< , -P(O)(OR a< )(OR a< ), -B(OH) 2 , -B(OR a< ) 2 and S(O) 2 NR a< R a< , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R 24< are each optionally substituted with 1, 2, 3, 4 or 5 independently selected R b< substituents; R 20< is each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR a1< , SR a1< , NHOR a1< , C(O)R a1< , C(O)NR a1< R a1< , C(O)OR a1< , OC(O)R a1< , OC(O)NR a1< R a1< , NHR a1< , NR a1< R a1< , NR a1< C(O)R a1< , NR a1< C(O)OR a1< , NR a1< C(O)NR a1< R a1< , C(=NR a1< )R a1< , C(=NOH)R a1< , C(=NOH)NR a1< , C(=NCN)NR a1< R a1< , NR a1< C(=NCN)NR a1< R a1< , C(=NR a1< )NR a1< R a1< , NR a1< C(=NR a1< )NR a1< R a1< , NR a1< S(O)R a1< , NR a1< S(O) 2 R a1< , NR a1< S(O) 2 NR a1< R a1< , S(O)R a1< , S(O)NR a1< R a1< , S(O) 2 R a1< , -P(O)R a1< R a1< , -P(O)(OR a1< )(OR a1< ), -B(OH)2, -B(OR a1< ) 2 and S(O) 2 NR a1< R a1< , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R 20< are each optionally substituted with 1, 2, 3, 4 or 5 independently selected R b< substituents; R 27< is each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR a2< , SR a2< , NHOR a2< , C(O)R a2< , C(O)NR a2< R a2< , C(O)OR a2< , OC(O)R a2< , OC(O)NR a2< R a2< , NHR a2< , NR a2< R a2< , NR a2< C(O)R a2< , NR a2< C(O)OR a2< , NR a2< C(O)NR a2< R a2< , C(=NR a2< )R a2< , C(=NOH)R a2< , C(=NOH)NR a2< , C(=NCN)NR a2< R a2< , NR a2< C(=NCN)NR a2< R a2< , C(=NR a2< )NR a2< R a2< , NR a2< C(=NR a2< )NR a2< R a2< , NR a2< S(O)R a2< , NR a2< S(O) 2 R a2< , NR a2< S(O) 2 NR a2< R a2< , S(O)R a2< , S(O)NR a2< R a2< , S(O) 2 R a2< , -P(O)R a2< R a2< , -P(O)(OR a2< )(OR a2< ), -B(OH)2, -B(OR a2< ) 2 and S(O) 2 NR a2< R a2< , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R 27< are each optionally substituted with 1, 2, 3, 4 or 5 independently selected R b< substituents; or two R 20< substituents attached to the same ring carbon atom taken together with the ring carbon atom to which they are attached form spiro C 3-6 cycloalkyl or spiro 4- to 7-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R f< substituents; or two R 27< substituents attached to the same ring carbon atom taken together with the ring carbon atom to which they are attached form spiro C 3-6 cycloalkyl or spiro 4- to 7-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R f< substituents; each of R a< , R a1< , and R a2< is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R a< , R a1< , and R a2< are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R d< substituents; each R d< is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 6-10 aryl, 5-14 membered heteroaryl, C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NH2, NHOR e< , OR e< , SR e< , C(O)R e< , C(O)NR e< R e< , C(O)OR e< , OC(O)R e< , OC(O)NR e< R e< , NHR e< , NR e< R e< , NR e< C(O)R e< , NR e< C(O)NR e< R e< , NR e< C(O)OR e< , C(=NR e< )NR e< R e< , NR e< C(=NR e< )NR e< R e< , NR e< C(=NOH)NR e< R e< , NR e< C(=NCN)NR e< R e< , S(O)R e< , S(O)NR e< R e< , S(O) 2 R e< , NR e< S(O) 2 R e< , NR e< S(O) 2 NR e< R e< , -P(O)R e< R e< , -P(O)(OR e< )(OR e< ), -B(OH)2, - B(OR e< ) 2 and S(O) 2 NR e< R e< , wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, 5-14 membered heteroaryl, C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R d< are each optionally substituted with 1, 2, or 3 independently selected R f< substituents; each R e< is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R e< are each optionally substituted with 1, 2 or 3 independently selected R f< substituents; each R b< substituent is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, CN, OH, NH 2 , NO 2 , NHOR c< , OR c< , SR c< , C(O)R c< , C(O)NR c< R c< , C(O)OR c< , OC(O)R c< , OC(O)NR c< R c< , C(=NOH)R c< , C(=NOH)NR c< , C(=NCN)NR c< R c< , NR c< C(=NCN)NR c< R c< , C(=NR c< )NR c< R c< , NR c< C(=NR c< )NR c< R c< , NHR c< , NR c< R c< , NR c< C(O)R c< , NR c< C(O)OR c< , NR c< C(O)NR c< R c< , NR c< S(O)R c< , NR c< S(O) 2 R c< , NR c< S(O) 2 NR c< R c< , S(O)R c< , S(O)NR c< R c< , S(O) 2 R c< , -P(O)R c< R c< , -P(O)(OR c< )(OR c< ), -B(OH)2, - B(OR c< ) 2 and S(O) 2 NR c< R c< ; wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R b< are each further optionally substituted with 1, 2 or 3 independently selected R d< substituents; each R c< is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R c< are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R f< substituents; each R f< is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, halo, CN, NHOR g< , OR g< , SR g< , C(O)R g< , C(O)NR g< R g< , C(O)OR g< , OC(O)R g< , OC(O)NR g< R g< , NHR g< , NR g< R g< , NR g< C(O)R g< , NR g< C(O)NR g< R g< , NR g< C(O)OR g< , C(=NR g< )NR g< R g< , NR g< C(=NR g< )NR g< R g< , S(O)R g< , S(O)NR g< R g< , S(O) 2 R g< , NR g< S(O) 2 R g< , NR g< S(O) 2 NR g< R g< , -P(O)R g< R g< , -P(O)(OR g< )(OR g< ), -B(OH) 2 , -B(OR g< ) 2 and S(O) 2 NR g< R g< ; wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R f< are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R n< substituents; each R n< is substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, halo, CN, NHOR o< , OR o< , SR°, C(O)R o< , C(O)NR o< R o< , C(O)OR o< , OC(O)R o< , OC(O)NR o< R o< , NHR o< , NR o< R o< , NR o< C(O)R o< , NR o< C(O)NR o< R o< , NR o< C(O)OR o< , C(=NR o< )NR o< R o< , NR o< C(=NR o< )NR o< R o< , S(O)R o< , S(O)NR o< R o< , S(O) 2 R o< , NR o< S(O) 2 R o< , NR o< S(O) 2 NR o< R o< , -P(O)R o< R o< , -P(O)(OR o< )(OR o< ), -B(OH) 2 , -B(OR o< ) 2 and S(O) 2 NR o< R o< , wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R n< are each optionally substituted with 1, 2 or 3 independently selected R q< substituents; each R g< is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R g< are each optionally substituted with 1, 2, or 3 independently selected R p< substituents; each R p< is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, halo, CN, NHOR r< , OR r< , SR r< , C(O)R r< , C(O)NR r< R r< , C(O)OR r< , OC(O)R r< , OC(O)NR r< R r< , NHR r< , NR r< R r< , NR r< C(O)R r< , NR r< C(O)NR r< R r< , NR r< C(O)OR r< , C(=NR r< )NR r< R r< , NR r< C(=NR r< )NR r< R r< , NR r< C(=NOH)NR r< R r< , NR r< C(=NCN)NR r< R r< , S(O)R r< , S(O)NR r< R r< , S(O) 2 R r< , NR r< S(O) 2 R r< , NR r< S(O) 2 NR r< R r< , -P(O)R r< R r< , -P(O)(OR r< )(OR r< ), -B(OH)2, - B(OR r< ) 2 and S(O) 2 NR r< R r< , wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R p< is optionally substituted with 1, 2 or 3 independently selected R q< substituents; or any two R a< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 independently selected R h< substituents; or any two R a1< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 independently selected R h< substituents; or any two R a2< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 independently selected R h< substituents; each R h< is independently selected from C 1-6 alkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halo, CN, OR i< , SR i< , NHOR i< , C(O)R i< , C(O)NR i< R i< , C(O)OR i< , OC(O)R i< , OC(O)NR i< R i< , NHR i< , NR i< R i< , NR i< C(O)R i< , NR i< C(O)NR i< R i< , NR i< C(O)OR i< , C(=NR i< )NR i< R i< , NR i< C(=NR i< )NR i< R i< , S(O)R i< , S(O)NR i< R i< , S(O) 2 R i< , NR i< S(O) 2 R i< , NR i< S(O) 2 NR i< R i< , -P(O)R i< R i< , -P(O)(OR i< )(OR i< ), -B(OH) 2 , -B(OR i< ) 2 and S(O) 2 NR i< R i< , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R h< are each optionally substituted by 1, 2, or 3 independently selected R j< substituents; each R j< is independently selected from C 3-6 cycloalkyl, C 6-10 aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1 - 4 haloalkoxy, CN, NHOR k< , OR k< , SR k< , C(O)R k< , C(O)NR k< R k< , C(O)OR k< , OC(O)R k< , OC(O)NR k< R k< , NHR k< , NR k< R k< , NR k< C(O)R k< , NR k< C(O)NR k< R k< , NR k< C(O)OR k< , C(=NR k< )NR k< R k< , NR k< C(=NR k< )NR k< R k< , S(O)R k< , S(O)NR k< Rk, S(O) 2 R k< , NR k< S(O) 2 R k< , NR k< S(O) 2 NR k< R k< , -P(O)R k< R k< , - P(O)(OR k< )(OR k< ), -B(OH) 2 , -B(OR k< ) 2 and S(O) 2 NR k< R k< , wherein the C 1-4 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, and C 1-4 haloalkoxy of R j< are each optionally substituted with 1, 2 or 3 independently selected R q< substituents; or two R h< groups attached to the same carbon atom of the 4- to 10-membered heterocycloalkyl taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms as ring members selected from O, N or S; or any two R c< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h< substituents; or any two R e< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h< substituents; or any two R g< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h< substituents; or any two R i< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R q< substituents; or any two R k< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R q< substituents; or any two R o< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h< substituents; or any two R r< substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h< substituents; each R i< , R k< , R o< or R r< is independently selected from H, C 1-64 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkenyl, and C 2-4 alkynyl, wherein the C 1-4 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C 2-4 alkenyl, and C 2-4 alkynyl of R i< , R k< , R o< or R r< are each optionally substituted with 1, 2 or 3 independently selected R q< substituents; each R q< is independently selected from halo, OH, CN, -COOH, B(OH) 2 , NH 2 , -NH-C 1-6 alkyl, -N(C 1-6 alky) 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl and C 3-6 cycloalkyl, wherein the C 1-6 alkyl, phenyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl of R q< are each optionally substituted with 1, 2 or 3 substituents independently selected from halo, OH, CN, -COOH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, phenyl, C 3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl; the subscript m is an integer of 0, 1, 2 or 3; the subscript n is an integer of 0, 1, 2 or 3; the subscript p is an integer of 1, 2, 3, 4, 5, or 6; and is a single bond or a double bond to maintain the 5-membered imidazole ring being aromatic.

[0073] In some embodiments of compounds of Formula (IV), (1) when L is a bond, ring A is not 2-benzoxazolyl; (2) when L is a bond, ring A is not [1,2,4]triazolo[1,5-a]pyridin-2-yl; (3) when L is -NH-, ring A is not 1,7-naphthyridin-8-yl or pyrido[3,2-d]pyrimidin-4-yl; and (4) when L is -C(O)NH-, ring A is not 2-pyridyl.

[0074] In some embodiments of compounds of Formula (IV), (1) when L is a bond, ring A is not 2-benzoxazolyl; (2) when L is -NH-, ring A is not 1,7-naphthyridin-8-yl or pyrido[3,2-d]pyrimidin-4-yl; and (3) when L is -C(O)NH-, ring A is not 2-pyridyl.

[0075] In some embodiments of compounds of Formula (IV), (1) when L is a bond, ring A is not 2-benzoxazolyl; (2) when L is a bond, ring A is not [1,2,4]triazolo[1,5-a]pyridin-2-yl; (3) when L is -NH-, ring A is not 1,7-naphthyridin-8-yl or pyrido[3,2-d]pyrimidin-4-yl; or (4) when L is -C(O)NH-, ring A is not 2-pyridyl.

[0076] In some embodiments of compounds of Formula (IV), (1) when L is a bond, ring A is not 2-benzoxazolyl; (2) when L is -NH-, ring A is not 1,7-naphthyridin-8-yl or pyrido[3,2-d]pyrimidin-4-yl; or (3) when L is -C(O)NH-, ring A is not 2-pyridyl.

[0077] In some embodiments, compounds of Formula (IV) have subformula (V): where ring A, linker L, the substituents R 20< , R 21< , R 22< , R 23< , R 24< , R 25< , R 26< and R 27< and the subscripts m, n and p are as defined in any embodiments of compounds of Formula (IV) or any embodiment as disclosed herein.

[0078] In some embodiments, compounds of Formula (IV) or (V) have subformula (Va): R 28< is H or C 1-6 alkyl. The subscript q is an integer of 1, 2 or 3. The subscript p is an integer of 1, 2, 3, 4, 5 or 6. In some embodiments, R 28< is H. In other embodiments, R 28< is methyl. In some embodiments, the subscript q is 1. Linker L, the substituents R 20< , R 21< , R 22< , R 23< , R 24< , R 25< , R 26< and R 27< and the subscripts m, n and p are as defined in any embodiments of compounds of Formula (IV) or any embodiment as disclosed herein.

[0079] In some embodiments, compounds of Formula (IV), (V) or (Va) have subformula (Va-1): R 28< is H or C 1-6 alkyl. In some instances, R 28< is H. In other instances, R 28< is methyl. Linker L and the substituents R 20< , R 21< , R 22< , R 23< and R 24< are as defined in any embodiments of compounds of Formula (IV) or any embodiment as disclosed herein.

[0080] In some embodiments, compounds of Formula (IV) or (V) have subformula (Vb): The subscript q is an integer of 1, 2 or 3. In some embodiments, the subscript q is 1. Linker L, the substituents R 20< , R 21< , R 22< , R 23< , R 24< , R 25< , R 26< and R 27< and the subscripts m, n and p are as defined in any embodiments of compounds of Formula (IV) or any embodiment as disclosed herein.

[0081] In some embodiments, compounds of Formula (IV), (V) or (Vb) have subformula (Vb-1): The subscript q is an integer of 1, 2 or 3. In some embodiments, the subscript q is 1. Linker L and the substituents R 20< , R 21< , R 22< , R 23< and R 24< are as defined in any embodiments of compounds of Formula (IV) or any embodiment as disclosed herein.

[0082] In some embodiments, compounds of Formula (IV) or (V) have subformula (Vc): The subscript q is an integer of 1, 2 or 3. In some embodiments, the subscript q is 1. Linker L, the substituents R 20< , R 21< , R 22< , R 23< , R 24< , R 25< , R 26< and R 27< and the subscripts m, n and p are as defined in any embodiments of compounds of Formula (IV) or any embodiment as disclosed herein.

[0083] In some embodiments, compounds of Formula (IV), (V) or (Vc) have subformula (Vc-1): The subscript q is an integer of 1, 2 or 3. In some embodiments, the subscript q is 1. Linker L and the substituents R 20< , R 21< , R 22< , R 23< and R 24< are as defined in any embodiments of compounds of Formula (IV) or any embodiment as disclosed herein.

[0084] In some embodiments, compounds of Formula (IV) or (V) have subformula (Vd): The subscript q is an integer of 1, 2 or 3. In some embodiments, the subscript q is 1. Linker L, the substituents R 20< , R 21< , R 22< , R 23< , R 24< , R 25< , R 26< and R 27< and the subscripts m, n and p are as defined in any embodiments of compounds of Formula (IV) or any embodiment as disclosed herein.

[0085] In some embodiments, compounds of Formula (IV), (V) or (Vd) have subformula (Vd-1): The subscript q is an integer of 1, 2 or 3. In some embodiments, the subscript q is 1. Linker L and the substituents R 20< , R 21< , R 22< , R 23< and R 24< are as defined in any embodiments of compounds of Formula (IV) or any embodiment as disclosed herein.

[0086] In some embodiments, compounds of Formula (IV) or (V) have subformula (Ve): R 28< is H or C 1-6 alkyl. The subscript q is an integer of 1, 2 or 3. In some instances, R 28< is H. In other instances, R 28< is methyl. In some instances, the subscript q is 1. Linker L, the substituents R 20< , R 21< , R 22< , R 23< , R 24< , R 25< , R 26< and R 27< and the subscripts m, n and p are as defined in any embodiments of compounds of Formula (IV) or any embodiment as disclosed herein.

[0087] In some embodiments, compounds of Formula (IV), (V) or (Ve) have subformula (Ve-1): R 28< is H or C 1-6 alkyl. The subscript q is an integer of 1, 2 or 3. In some instances, R 28< is H. In other instances, R 28< is methyl. In some instances, the subscript q is 1. Linker L and the substituents R 20< , R 21< , R 22< , R 23< and R 24< are as defined in any embodiments of compounds of Formula (IV) or any embodiment as disclosed herein.

[0088] In some embodiments, compounds of Formula (IV) or (V) have subformula (Vf): The subscript q is an integer of 1, 2 or 3. In some embodiments, the subscript q is 1. Linker L, the substituents R 20< , R 21< , R 22< , R 23< , R 24< , R 25< , R 26< and R 27< and the subscripts m, n and p are as defined in any embodiments of compounds of Formula (IV) or any embodiment as disclosed herein.

[0089] In some embodiments, compounds of Formula (IV), (V) or (Vf) have subformula (Vf-1): The subscript q is an integer of 1, 2 or 3. In some embodiments, the subscript q is 1. Linker L and the substituents R 20< , R 21< , R 22< , R 23< and R 24< are as defined in any embodiments of compounds of Formula (IV) or any embodiment as disclosed herein.

[0090] In some embodiments, compounds of Formula (IV) or (V) have subformula (Vg): The subscript q is an integer of 1, 2 or 3. In some embodiments, the subscript q is 1. Linker L, the substituents R 20< , R 21< , R 22< , R 23< , R 24< , R 25< , R 26< and R 27< and the subscripts m, n and p are as defined in any embodiments of compounds of Formula (IV) or any embodiment as disclosed herein.

[0091] In some embodiments, compounds of Formula (IV), (V) or (Vg) have subformula (Vg-1): Linker L, the substituents R 20< , R 21< , R 22< , R 23< , R 24< , R 25< , R 26< and R 27< and the subscripts m, n and p are as defined in any embodiments of compounds of Formula (IV) or any embodiment as disclosed herein.

[0092] In some embodiments, compounds of Formula (IV), (V) or (Vg) have subformula (Vg-2): Linker L and the substituents R 20< , R 21< , R 22< , R 23< and R 24< are as defined in any embodiments of compounds of Formula (IV) or any embodiment as disclosed herein.

[0093] In some embodiments, compounds of Formula (IV) or (V) have subformula (Vh): or a pharmaceutically acceptable salt or a stereoisomer thereof. Linker L, the substituents R 20< , R 21< , R 22< , R 23< , R 24< R 25< , R 26< , and R 27< , and the subscripts m, n, p, and q are as defined in any embodiments of compounds of Formula (IV) or any embodiment as disclosed herein.

[0094] In some embodiments, compounds of Formula (IV), (V) or (Vh) have subformula (Vh-1): or a pharmaceutically acceptable salt or a stereoisomer thereof. Linker L, the substituents R 20< , R 21< , R 22< , R 23< , R 24< , R 25< , R 26< , and R 27< and the subscripts m, n, and p are as defined in any embodiments of compounds of Formula (IV) or any embodiment as disclosed herein.

[0095] In some embodiments, compounds of Formula (IV), (V) or (Vh) have subformula (Vh-2): or a pharmaceutically acceptable salt or a stereoisomer thereof. Linker L and the substituents R 20< , R 21< , R 22< , R 23< , and R 24< are as defined in any embodiments of compounds of Formula (IV) or any embodiment as disclosed herein.

[0096] In some embodiments, ring A is 5- to 14-membered heteroaryl, 4- to 14-membered heterocycloalkyl, or C 6-10 aryl, wherein the 5- to 14-membered heteroaryl and 4- to 14-membered heterocycloalkyl each has 1-4 heteroatoms as ring members selected from B, P, N, O and S, wherein the N, P or S atom as ring members is optionally oxidized and one or more carbon atoms as ring members are each optionally replaced by a carbonyl group; and wherein ring A is optionally substituted with 1, 2, or 3 R 20< substituents.

[0097] In some embodiments, ring A is 5- to 14-membered heteroaryl or 4- to 14-membered heterocycloalkyl, wherein the 5- to 14-membered heteroaryl and 4- to 14-membered heterocycloalkyl each has 1-4 heteroatoms as ring members selected from N, O and S, wherein the N or S atom as ring members is optionally oxidized and one or more carbon atoms as ring members are each optionally replaced by a carbonyl group; and wherein ring A is optionally substituted with 1, 2, or 3 R 20< substituents.

[0098] In some embodiments, ring A is 5- to 14-membered heteroaryl, wherein the 5- to 14-membered heteroaryl has 1-4 heteroatoms as ring members selected from N, O and S, wherein the N or S atom as ring members is optionally oxidized and one or more carbon atoms as ring members are each optionally replaced by a carbonyl group; and wherein ring A is optionally substituted with 1, 2, or 3 R 20< substituents. In some embodiments, ring A is 4- to 14-membered heterocycloalkyl, wherein the 4- to 14-membered heterocycloalkyl each has 1-4 heteroatoms as ring members selected from N, O and S, wherein the N or S atom as ring members is optionally oxidized and one or more carbon atoms as ring members are each optionally replaced by a carbonyl group; and wherein ring A is optionally substituted with 1, 2, or 3 R 20< substituents.

[0099] In some embodiments of compounds of Formula (IV) or (V), or any embodiment disclosed herein, ring A is selected from: and wherein each subscript q is independently an integer of 1, 2, 3 or 4; each R 28< is independently H or C 1-6 alkyl; and the wavy line indicates the point of attachment to L. In some instances, q is 1. In other instances, R 28< is H. In other instances, R 28< is methyl.

[0100] In some embodiments of compounds of Formula (IV) or (V), or any embodiment disclosed herein, ring A is

[0101] In some embodiments of compounds of Formula (IV) or (V), or any embodiment disclosed herein, ring A is

[0102] In some embodiments of compounds of Formula (IV) or (V), or any embodiment disclosed herein, ring A is

[0103] In some embodiments of compounds of Formula (IV) or (V), or any embodiment disclosed herein, ring A is

[0104] In some embodiments of compounds of Formula (IV) or (V), or any embodiment disclosed herein, ring A is

[0105] In some embodiments of compounds of Formula (IV) or (V), or any embodiment disclosed herein, ring A is

[0106] In some embodiments of compounds of Formula (IV) or (V), or any embodiment disclosed herein, ring A is

[0107] In some embodiments of compounds of Formula (IV) or (V), or any embodiment disclosed herein, ring A is

[0108] In some embodiments of compounds of Formula (IV) or (V), or any embodiment disclosed herein, ring A is

[0109] In some embodiments of compounds of Formula (IV) or (V), or any embodiment disclosed herein, ring A is

[0110] In some embodiments of compounds of Formula (IV) or (V), or any embodiment disclosed herein, ring A is

[0111] In some embodiments of compounds of Formula (IV), (V), (Va), (Va-1), (Vb), (Vb-1), (Vc), (Vc-1), (Vd), (Vd-1), (Ve), (Ve-1), (Vf), (Vf-1), (Vg), (Vg-1), (Vg-2), (Vh), (Vh-1), or (Vh-2), or any embodiment disclosed herein, L is -C(O)NH-, wherein the carbonyl group in the -C(O)NH- linkage is attached to ring A. In other embodiments, L is NH. In other embodiments, L is a bond. In other embodiments, L is -OCH 2 -, wherein the oxygen atom in the -OCH 2 - linkage is attached to ring A. In some embodiments, L is a bond, -C(O)NH-, or -OCH 2 -, wherein the carbonyl group in the -C(O)NH- linkage and the oxygen atom in the - OCH 2 - linkage is attached to ring A. In some embodiments, L is a bond or -C(O)NH-, wherein the carbonyl group in the -C(O)NH- linkage is attached to ring A. In some embodiments, L is a bond, -NH-, or -C(O)NH-, wherein the carbonyl group in the -C(O)NH-linkage is attached to ring A.

[0112] In some embodiments of compounds of Formula (IV), (V), (Va), (Va-1), (Vb), (Vb-1), (Vc), (Vc-1), (Vd), (Vd-1), (Ve), (Ve-1), (Vf), (Vf-1), (Vg), (Vg-1), (Vg-2), (Vh), (Vh-1), or (Vh-2), or any embodiment disclosed herein, R 21< and R 22< are each independently Cl, CN or methyl. In some instances, R 21< and R 22< are each C 1-6 alkyl. In other instances, R 21< and R 22< are each methyl. In other instances, R 21< and R 22< are each halo. In other instances, R 21< and R 22< are each Cl. In other instances, R 21< is halo and R 22< is C 1-6 alkyl. In other instances, R 21< is C 1-6 alkyl and R 22< is halo. In other instances, R 21< is methyl and R 22< is Cl. In other instances, R 21< is Cl and R 22< is methyl. In some instances, substituents R 21< and R 22< are the same (e.g., both R 21< and R 22< are methyl, Cl, or CN). In some instances, substituents R 21< and R 22< are different.

[0113] In some embodiments of compounds of Formula (IV), (V), (Va), (Va-1), (Vb), (Vb-1), (Vc), (Vc-1), (Vd), (Vd-1), (Ve), (Ve-1), (Vf), (Vf-1), (Vg), (Vg-1), (Vg-2), (Vh), (Vh-1), or (Vh-2), or any embodiment disclosed herein, R 20< is H, C 1-6 alkyl optionally substituted with 1, 2 or 3 independently selected R b< substituents, halo, CN, C 3-6 cycloalkyl optionally substituted with 1, 2 or 3 independently selected R b< substituents, 4-6 membered heterocycloalkyl optionally substituted with 1, 2 or 3 independently selected R b< substituents, phenyl optionally substituted with 1, 2 or 3 independently selected R b< substituents or 5-6membered heteroaryl optionally substituted with 1, 2 or 3 independently selected R b< substituents. In some embodiments, each R 20< is independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR a1< , SR a1< , NHOR a1< , C(O)R a1< , C(O)NR a1< R a1< , C(O)OR a1< , OC(O)R a1< , OC(O)NR a1< R a1< , NHR a1< , NR a1< R a1< , NR a1< C(O)R a1< , and NR a1< C(O)OR a1< , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R 20< are each optionally substituted with 1, 2, or 3 independently selected R b< substituents. In some embodiments, each R 20< is independently selected from H, halo, C 1-6 alkyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, CN, OR a1< , and C(O)R a1< , wherein the C 1-6 alkyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R 20< are each optionally substituted with 1, 2, or 3 independently selected R b< substituents.

[0114] In some instances, R 20< is H, C 1-6 alkyl, 2-hydroxypropyl, (R)-2-hydroxypropyl, (S)-2-hydroxypropyl, 2-hydroxyethyl, 1-(methylsulfonyl)piperidin-4-yl, tetrahydro-2H-pyran-4-yl, (tetrahydro-2H-pyran-4-yl)methyl, 1-(hydroxymethyl)cyclopropyl)methyl, (S)-(2,3-dihydroxypropyl)-1-methyl, (2,3-dihydroxypropyl)-1-methyl, (R)-(2,3-dihydroxypropyl)-1-methyl, carboxymethyl, 1-acetylpiperidin-4-yl, 4-carboxy-4-methylcyclohexyl, 3-(methylsulfonamido)propyl, trans-(4-carboxycyclohexyl)methyl, cis-(4-carboxycyclohexyl)methyl, (3-carboxypyrrolidin-1-yl)methyl, (R)-(3-carboxypyrrolidin-1-yl)methyl, (S)-(3-carboxypyrrolidin-1-yl)methyl, (3-hydroxypyrrolidin-1-yl)methyl, (R)-(3-hydroxypyrrolidin-1-yl)methyl, (S)-(3-hydroxypyrrolidin-1-yl)methyl, pyrrolidin-1-ylmethyl, 2-(dimethylamino)acetyl, (5-cyanopyridin-3-yl)methoxy, (2-carboxypiperidin-1-yl)methyl, (R)-(2-carboxypiperidin-1-yl)methyl, (S)-(2-carboxypiperidin-1-yl)methyl, halo, cyclobutyl, cyclopropylmethyl, or CN. In other instances, R 20< is C 1-6 alkyl, 2-hydroxypropyl, (R)-2-hydroxypropyl, (S)-2-hydroxypropyl, 2-hydroxyethyl, 1-(methylsulfonyl)piperidin-4-yl, tetrahydro-2H-pyran-4-yl, (tetrahydro-2H-pyran-4-yl)methyl, 1-(hydroxymethyl)cyclopropyl)methyl, (S)-(2,3-dihydroxypropyl)-1-methyl, (2,3-dihydroxypropyl)-1-methyl, (R)-(2,3-dihydroxypropyl)-1-methyl, carboxymethyl, 1-acetylpiperidin-4-yl, 4-carboxy-4-methylcyclohexyl, 3-(methylsulfonamido)propyl, trans-(4-carboxycyclohexyl)methyl, cis-(4-carboxycyclohexyl)methyl, (3-carboxypyrrolidin-1-yl)methyl, (R)-(3-carboxypyrrolidin-1-yl)methyl, (S)-(3-carboxypyrrolidin-1-yl)methyl, (3-hydroxypyrrolidin-1-yl)methyl, (R)-(3-hydroxypyrrolidin-1-yl)methyl, (S)-(3-hydroxypyrrolidin-1-yl)methyl, pyrrolidin-1-ylmethyl, 2-(dimethylamino)acetyl, (5-cyanopyridin-3-yl)methoxy, (2-carboxypiperidin-1-yl)methyl, (R)-(2-carboxypiperidin-1-yl)methyl, (S)-(2-carboxypiperidin-1-yl)methyl, halo, cyclobutyl, cyclopropylmethyl, or CN. In some instantces, R 20< is H, C 1-6 alkyl (e.g., methyl) or 2-hydroxypropyl (e.g., (R)-2-hydroxypropyl and (S)-2-hydroxypropyl). In some instantces, R 20< is C 1-6 alkyl (e.g., methyl). In other instatnces, R 20< is (R)-2-hydroxypropyl or (S)-2-hydroxypropyl.

[0115] In some instances, R 20< is H, C 1-6 alkyl, 2-hydroxypropyl, (R)-2-hydroxypropyl, (S)-2-hydroxypropyl, 2-hydroxyethyl, 1-(methylsulfonyl)piperidin-4-yl, tetrahydro-2H-pyran-4-yl, (tetrahydro-2H-pyran-4-yl)methyl, 1-(hydroxymethyl)cyclopropyl)methyl, (S)-(2,3-dihydroxypropyl)-1-methyl, (2,3-dihydroxypropyl)-1-methyl, (R)-(2,3-dihydroxypropyl)-1-methyl, carboxymethyl, 1-acetylpiperidin-4-yl, 4-carboxy-4-methylcyclohexyl, 3-(methylsulfonamido)propyl, trans-(4-carboxycyclohexyl)methyl, cis-(4-carboxycyclohexyl)methyl, (3-carboxypyrrolidin-1-yl)methyl, (R)-(3-carboxypyrrolidin-1-yl)methyl, (S)-(3-carboxypyrrolidin-1-yl)methyl, (3-hydroxypyrrolidin-1-yl)methyl, (R)-(3-hydroxypyrrolidin-1-yl)methyl, (S)-(3-hydroxypyrrolidin-1-yl)methyl, pyrrolidin-1-ylmethyl, 2-(dimethylamino)acetyl, (5-cyanopyridin-3-yl)methoxy, (2-carboxypiperidin-1-yl)methyl, (R)-(2-carboxypiperidin-1-yl)methyl, (S)-(2-carboxypiperidin-1-yl)methyl, halo, cyclobutyl, cyclopropylmethyl, CN, trans-(4-carboxycyclohexyl)ethyl, cis-(4-carboxycyclohexyl)ethyl, 4-carboxycyclohexyl, trans-4-carboxycyclohexyl, cis-4-carboxycyclohexyl, 4-carboxybenzyl, 4-carboxyphenethyl, 2-(4-carboxy-4-methylcyclohexyl)methyl, 2-(4-carboxy-4-methylcyclohexyl)ethyl, (4-carboxybicyclo[2.2.2]octan-1-yl)methyl, 4-carboxybicyclo[2.2.1]heptan-1-yl, (4-carboxybicyclo[2.2.1]heptan-1-yl)methyl, 4-carboxy-4-methylcyclohexyl, (S)-3-hydroxypyrrolidin-1-yl)acetyl, (R)-3-hydroxypyrrolidin-1-yl)acetyl, 4-carboxy-4-ethylcyclohexyl, N-isopropyl-N-methylglycyl, (R)-3-carboxy-3-methylpyrrolidin-1-yl, (S)-3-carboxy-3-methylpyrrolidin-1-yl, (S)-1-hydroxypropan-2-yl)glycyl, (R)-1-hydroxypropan-2-yl)glycyl, (3-hydroxycyclobutyl)glycyl, cis-(3-hydroxycyclobutyl)glycyl, trans-(3-hydroxycyclobutyl)glycyl, dimethylglycyl, N-ethyl-N-methylglycyl, ethyl(methyl)amino)propanoyl, or 1-carboxyadamant-4-yl.

[0116] In some embodiments of compounds of Formula (IV), (V), (Va), (Va-1), (Vb), (Vb-1), (Vc), (Vc-1), (Vd), (Vd-1), (Ve), (Ve-1), (Vf), (Vf-1), (Vg), (Vg-1), (Vg-2), (Vh), (Vh-1), or (Vh-2), or any embodiment disclosed herein, R 23< is H, methyl, CF 3 , CF 2 H, or CH 2 F. In some instances, R 23< is H. In other instances, R 23< is C 1-6 alkyl. In other instances, R 23< is methyl. In other instances, R 23< is C 1-6 haloalkyl.

[0117] In some embodiments of compounds of Formula (IV), or any embodiment disclosed herein, R 24< is selected from H, C 1-6 alkyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, C(O)R a< , C(O)NR a< R a< , and C(O)OR a< , wherein the C 1-6 alkyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R 24< are each optionally substituted with 1, 2, or 3 independently selected R b< substituents. In some embodiments of compounds of Formula (IV), or any embodiment disclosed herein, R 24< is selected from H, C 1-6 alkyl, C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 3-14 cycloalkyl-C 1-4 alkyl-, (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, and C(O)R a< , wherein the C 1-6 alkyl, C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 3-14 cycloalkyl-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R 24< are each optionally substituted with 1 or 2 independently selected R b< substituents.

[0118] In some embodiments of compounds of Formula (IV), or any embodiment disclosed herein, R 24< is H, C 1-6 alkyl optionally substituted with 1, 2 or 3 independently selected R b< substituents, halo, CN, C 3-6 cycloalkyl optionally substituted with 1, 2 or 3 independently selected R b< substituents, 4-6 membered heterocycloalkyl optionally substituted with 1, 2 or 3 independently selected R b< substituents, phenyl optionally substituted with 1, 2 or 3 independently selected R b< substituents or 5-6membered heteroaryl optionally substituted with 1, 2 or 3 independently selected R b< substituents. In some instances, R 24< is H, C 1-6 alkyl optionally substituted with 1, 2 or 3 independently selected R b< substituents. In other instances, R 24< is H. In other instances, R 24< is C 1-6 alkyl (e.g., methyl). In other instances, R 24< is C 1-6 alkyl substituted with 1, 2 or 3 independently selected R b< substituents. In other instances, R 24< is H, C 1-6 alkyl, 2-hydroxypropyl, (R)-2-hydroxypropyl, (S)-2-hydroxypropyl, 2-hydroxyethyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl-, 1-(methylsulfonyl)piperidin-4-yl or tetrahydro-2H-pyran-4-yl.

[0119] In some instances, R 24< is H, C 1-6 alkyl, 2-hydroxypropyl, (R)-2-hydroxypropyl, (S)-2-hydroxypropyl, 2-hydroxyethyl, 1-(methylsulfonyl)piperidin-4-yl, tetrahydro-2H-pyran-4-yl, (tetrahydro-2H-pyran-4-yl)methyl, 1-(hydroxymethyl)cyclopropyl)methyl, (S)-(2,3-dihydroxypropyl)-1-methyl, (2,3-dihydroxypropyl)-1-methyl, (R)-(2,3-dihydroxypropyl)-1-methyl, carboxymethyl, 1-acetylpiperidin-4-yl, 4-carboxy-4-methylcyclohexyl, 3-(methylsulfonamido)propyl, trans-(4-carboxycyclohexyl)methyl, cis-(4-carboxycyclohexyl)methyl, (3-carboxypyrrolidin-1-yl)methyl, (R)-(3-carboxypyrrolidin-1-yl)methyl, (S)-(3-carboxypyrrolidin-1-yl)methyl, (3-hydroxypyrrolidin-1-yl)methyl, (R)-(3-hydroxypyrrolidin-1-yl)methyl, (S)-(3-hydroxypyrrolidin-1-yl)methyl, pyrrolidin-1-ylmethyl, 2-(dimethylamino)acetyl, (5-cyanopyridin-3-yl)methoxy, (2-carboxypiperidin-1-yl)methyl, (R)-(2-carboxypiperidin-1-yl)methyl, (S)-(2-carboxypiperidin-1-yl)methyl, halo, cyclobutyl, cyclopropylmethyl, or CN. In some instances, R 24< is C 1-6 alkyl, 2-hydroxypropyl, (R)-2-hydroxypropyl, (S)-2-hydroxypropyl, 2-hydroxyethyl, 1-(methylsulfonyl)piperidin-4-yl, tetrahydro-2H-pyran-4-yl, (tetrahydro-2H-pyran-4-yl)methyl, 1-(hydroxymethyl)cyclopropyl)methyl, (S)-(2,3-dihydroxypropyl)-1-methyl, (2,3-dihydroxypropyl)-1-methyl, (R)-(2,3-dihydroxypropyl)-1-methyl, carboxymethyl, 1-acetylpiperidin-4-yl, 4-carboxy-4-methylcyclohexyl, 3-(methylsulfonamido)propyl, trans-(4-carboxycyclohexyl)methyl, cis-(4-carboxycyclohexyl)methyl, (3-carboxypyrrolidin-1-yl)methyl, (R)-(3-carboxypyrrolidin-1-yl)methyl, (S)-(3-carboxypyrrolidin-1-yl)methyl, (3-hydroxypyrrolidin-1-yl)methyl, (R)-(3-hydroxypyrrolidin-1-yl)methyl, (S)-(3-hydroxypyrrolidin-1-yl)methyl, pyrrolidin-1-ylmethyl, 2-(dimethylamino)acetyl, (5-cyanopyridin-3-yl)methoxy, (2-carboxypiperidin-1-yl)methyl, (R)-(2-carboxypiperidin-1-yl)methyl, (S)-(2-carboxypiperidin-1-yl)methyl, halo, cyclobutyl, cyclopropylmethyl, or CN.In some instantces, R 24< is H, C 1-6 alkyl (e.g., methyl) or 2-hydroxypropyl (e.g., (R)-2-hydroxypropyl and (S)-2-hydroxypropyl). In other instatnces, R 24< is (R)-2-hydroxypropyl or (S)-2-hydroxypropyl.

[0120] In some instances, R 24< is H, C 1-6 alkyl, 2-hydroxypropyl, (R)-2-hydroxypropyl, (S)-2-hydroxypropyl, 2-hydroxyethyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl-, 1-(methylsulfonyl)piperidin-4-yl, or tetrahydro-2H-pyran-4-yl, 4-hydroxycyclohexyl, trans-(4-carboxycyclohexyl)methyl, cis-(4-carboxycyclohexyl)methyl, (4-carboxycyclohexyl)ethyl, 4-carboxy-4-methylcyclohexyl, or 2-(4-carboxycyclohexyl)ethyl.

[0121] In some embodiments, substituents R 20< and R 24< are the same. In some embodiments, substituents R 20< and R 24< are different.

[0122] In some embodiments of compounds of Formula (IV), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vg-1), (Vh), or (Vh-1), or any embodiment disclosed herein, R 25< and R 26< are each H. In some embodiments, m and n are each 0.

[0123] In some embodiments of compounds of Formula (IV), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vg-1), (Vh), or (Vh-1), or any embodiment disclosed herein, the subscript m, n and p are each an integer of 1.

[0124] In some embodiments of compounds of Formula (IV), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vg-1), (Vh), or (Vh-1), or any embodiment disclosed herein, R 25< , R 26< and R 27< are each H.

[0125] In some embodiments, each of R a< R a1< , and R a2< is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, (5-14 membered heteroaryl)-C 1-4 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R a< , R a1< and R a2< are each optionally substituted with 1, 2 or 3 independently selected R d< substituents. In some embodiments, each of R a< , R a1< and R a2< is independently selected from H, C 1-6 alkyl and (5-14 membered heteroaryl)-C 1-4 alkyl-, wherein the C 1-6 alkyl and (5-14 membered heteroaryl)-C 1-4 alkyl- of R a< , R a1< and R a2< are each optionally substituted with 1 or 2 independently selected R d< substituents.

[0126] In some embodiments, each R d< is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, NH2, OR e< , SR e< , C(O)R e< , C(O)NR e< R e< , C(O)OR e< , and NR e< S(O) 2 R e< . In some embodiments, each R d< is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, NH 2 , OR e< , and NR e< S(O)2R e< .

[0127] In some embodiments, each R e< is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl. In some embodiments, each R e< is independently selected from H and C 1-6 alkyl. In some embodiments, R e< is H. In other embodiments, R e< is C 1-6 alkyl.

[0128] In some embodiments, each R b< substituent is independently selected from halo, C 1-6 alkyl, CN, OH, NH 2 , OR c< , SR c< , C(O)R c< , C(O)NR c< R c< , C(O)OR c< , NR c< R c< , NR c< C(O)R c< , S(O)NR c< R c< , and S(O) 2 R c< ; wherein the C 1-6 alkyl of R b< is optionally substituted with 1 or 2 independently selected R d< substituents. In some embodiments, each R b< substituent is independently selected from C 1-6 alkyl, OH, OR c< , C(O)R c< , C(O)OR c< , and S(O) 2 R c< ; wherein the C 1-6 alkyl of R b< is optionally substituted with 1 or 2 independently selected R d< substituents.

[0129] In some embodiments, each R c< is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl. In some embodiments, each R c< is independently selected from H and C 1-6 alkyl. In some embodiments, R c< is H. In some embodiments, R c< is C 1-6 alkyl.

[0130] In some embodiments of compounds of Formula (IV), or any embodiment disclosed herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: ring A is 5- to 14-membered heteroaryl, 4- to 14-membered heterocycloalkyl, or C 6-10 aryl, wherein the 5- to 14-membered heteroaryl and 4- to 14-membered heterocycloalkyl each has 1-4 heteroatoms as ring members selected from N, O and S, wherein the N or S atom as ring members is optionally oxidized and one or more carbon atoms as ring members are each optionally replaced by a carbonyl group; and wherein ring A is optionally substituted with 1, 2, or 3 R 20< substituents; L is a bond, -C(O)NH-, -CH 2 O- or -OCH 2 -, wherein the carbonyl group in the - C(O)NH- linkage is attached to ring A; R 21< and R 22< are each independently halo, C 1-6 alkyl or CN; R 23< is H, C 1-6 alkyl or C 1-6 haloalkyl; R 24< is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, C(O)R a< , C(O)NR a< R a< , and C(O)OR a< , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R 24< are each optionally substituted with 1, 2, or 3 independently selected R b< substituents; R 20< is each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, CN, OR a1< , SR a1< , NHOR a1< , C(O)R a1< , C(O)NR a1< R a1< , and C(O)OR a1< , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R 20< are each optionally substituted with 1, 2, or 3 independently selected R b< substituents; R 27< is each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, CN, OR a2< , SR a2< , NHOR a2< , C(O)R a2< , C(O)NR a2< R a2< , and C(O)OR a1< , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-14 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R 27< are each optionally substituted with 1, 2, or 3 independently selected R b< substituents; each of R a< , R a1< , and R 32< is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, (5-14 membered heteroaryl)-C 1-4 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R a< , R a1< and R a2< are each optionally substituted with 1, 2, or 3 independently selected R d< substituents; each R d< is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, NH 2 , OR e< , SR e< , C(O)R e< , C(O)NR e< R e< , C(O)OR e< , NHR e< , NR e< R e< , NR e< C(O)R e< , S(O)R e< , S(O)NR e< R e< , S(O) 2 R e< , NR e< S(O) 2 R e< , and S(O) 2 NR e< R e< , wherein the C 1-6 alkyl of R d< is optionally substituted with 1, 2, or 3 independently selected R f< substituents; each R e< is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; each R b< substituent is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, CN, OH, NH 2 , OR c< , SR c< , C(O)R c< , C(O)NR c< R c< , C(O)OR c< , S(O)R c< , S(O)NR c< R c< , S(O) 2 R c< , and S(O) 2 NR c< R c< ; wherein the C 1-6 alkyl of R b< is optionally substituted with 1, 2 or 3 independently selected R d< substituents; each R c< is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; the subscript m is an integer of 0; the subscript n is an integer of 0; the subscript p is an integer of 1, 2, 3, 4, 5 or 6; and is a single bond or a double bond to maintain the 5-membered imidazole ring being aromatic.

[0131] In some embodiments of compounds of Formula (IV), or any embodiment disclosed herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: ring A is 5- to 14-membered heteroaryl, 4- to 14-membered heterocycloalkyl, or C 6-10 aryl, wherein the 5- to 14-membered heteroaryl and 4- to 14-membered heterocycloalkyl each has 1-4 heteroatoms as ring members selected from N, O and S, wherein the N or S atom as ring members is optionally oxidized and one or more carbon atoms as ring members are each optionally replaced by a carbonyl group; and wherein ring A is optionally substituted with 1, 2, or 3 R 20< substituents; L is a bond,-C(O)NH-, -CH 2 O- or -OCH 2 -, wherein the carbonyl group in the - C(O)NH- linkage is attached to ring A; R 21< and R 22< are each independently halo, C 1-6 alkyl or CN; R 23< is H or C 1-6 alkyl; R 24< is selected from H, C 1-6 alkyl, C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 3-14 cycloalkyl-C 1-4 alkyl-, (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, and C(O)R a< , wherein the C 1-6 alkyl, C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 3-14 cycloalkyl-C 1-4 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R 24< are each optionally substituted with 1 or 2 independently selected R b< substituents; R 20< is each independently selected from H, halo, C 1-6 alkyl, C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 3-14 cycloalkyl-C 1-4 alkyl-, (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, CN, OR a1< , and C(O)R a1< , wherein the C 1-6 alkyl, C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 3-14 cycloalkyl-C 1-4 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R 20< are each optionally substituted with 1 or 2 independently selected R b< substituents; R 27< are each independently selected from H, halo, C 1-6 alkyl, C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 3-14 cycloalkyl-C 1-4 alkyl-, (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, CN, OR a2< , and C(O)R a2< , wherein the C 1-6 alkyl, C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 3-14 cycloalkyl-C 1-4 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R 27< are each optionally substituted with 1 or 2 independently selected R b< substituents; each of R a< , R a1< , and R a2< is independently selected from H, C 1-6 alkyl, 5-14 membered heteroaryl, and (5-14 membered heteroaryl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, 5-14 membered heteroaryl, and (5-14 membered heteroaryl)-C 1-4 alkyl- of R a< , R a1< , and R a2< are each optionally substituted with 1 or 2 independently selected R d< substituents; each R d< is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, NH 2 , OR e< , NHR e< , NR e< R e< , and NR e< S(O) 2 R e< ; each R e< is independently selected from H and C 1-6 alkyl; each R b< substituent is independently selected from halo, C 1-6 alkyl, CN, OH, NH 2 , OR c< , SR c< , C(O)R c< , C(O)NR c< R c< , C(O)OR c< , and S(O) 2 R c< ; wherein the C 1-6 alkyl of R b< is optionally substituted with 1 or 2 independently selected R d< substituents; each R c< is independently selected from H and C 1-6 alkyl, the subscript m is an integer of 0; the subscript n is an integer of 0; the subscript p is an integer of 1, 2, 3, 4, 5, or 6; and is a single bond or a double bond to maintain the 5-membered imidazole ring being aromatic.

[0132] In some embodiments, the present disclosure provides any of the compounds set forth in Table 2 and described in the examples, such as Examples 1-183, or pharmaceutically acceptable salts or stereoisomers thereof. In certain embodiments, the present disclosure provides any of the compounds in Examples 13-54, or pharmaceutically acceptable salts or stereoisomers thereof.

[0133] It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment (while the embodiments are intended to be combined as if written in multiply dependent form). Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. Thus, it is contemplated as features described as embodiments of the compounds of the Formulas of the present disclosure (e.g., Formula (I)) can be combined in any suitable combination.

[0134] At various places in the present specification, certain features of the compounds are disclosed in groups or in ranges. It is specifically intended that such a disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the term "C 1-6 alkyl" is specifically intended to individually disclose (without limitation) methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl and C 6 alkyl.

[0135] The term "n-membered," where n is an integer, typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. 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.

[0136] At various places in the present specification, variables defining divalent linking groups may be described. It is specifically intended that each linking substituent include both the forward and backward forms of the linking substituent. For example, -NR(CR'R") n -includes both -NR(CR'R") n - and -(CR'R") n NR- and is intended to disclose each of the forms individually. Where the structure requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl" then it is understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

[0137] The term "substituted" means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group. The term "substituted", unless otherwise indicated, refers to any level of substitution, e.g., mono-, di-, tri-, tetra- or penta-substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. It is to be understood that substitution at a given atom is limited by valency. It is to 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 is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms.

[0138] The term "C n-m " indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C 1-4 , C 1-6 and the like.

[0139] The term "aryl," employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2 fused rings). The term "C n-m aryl" refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, indanyl, indenyl and the like. In some embodiments, aryl groups have from 6 to about 10 carbon atoms. In some embodiments, aryl groups have 6 carbon atoms. In some embodiments, aryl groups have 10 carbon atoms. In some embodiments, the aryl group is phenyl. In some embodiments, the aryl group is naphthyl.

[0140] The term "heteroaryl," employed 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 a 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 5-10 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 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membered heteroaryl ring. In other embodiments, the heteroaryl is an eight-membered, nine-membered or ten-membered fused bicyclic heteroaryl ring. Example 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.

[0141] A five-membered heteroaryl ring is a heteroaryl group having five ring atoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independently selected from N, O and S. Exemplary five-membered ring 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.

[0142] A six-membered heteroaryl ring is a heteroaryl group having six ring atoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independently selected from B, P, N, O and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

[0143] The term "heterocycloalkyl," employed 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, which has at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur oxygen and phosphorus, and which has 4-10 ring members, 4-7 ring members, or 4-6 ring members. Included within the term "heterocycloalkyl" are monocyclic 4-, 5-, 6- and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can include mono- or bicyclic (e.g., having two fused or bridged rings) ring systems. In some embodiments, the heterocycloalkyl group is a monocyclic group having 1, 2 or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally oxidized to form an oxo or sulfido group or other oxidized linkage (e.g., C(O), S(O), C(S) or S(O) 2 , N-oxide etc.) or a nitrogen atom can be quaternized. The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the heterocycloalkyl ring, e.g., benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom 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, 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, and thiomorpholino.

[0144] At certain places, the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas an azetidin-3-yl ring is attached at the 3-position.

[0145] The term "cycloalkyl," employed alone or in combination with other terms, refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), including cyclized alkyl and alkenyl groups. The term "C n-m cycloalkyl" refers to a cycloalkyl that has n to m ring member carbon atoms. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6 or 7 ring-forming carbons (C 3-7 ). In some embodiments, the cycloalkyl group has 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 a C 3-6 monocyclic cycloalkyl group. Ring-forming carbon atoms of a cycloalkyl group can be optionally oxidized to form an oxo or sulfido group. Cycloalkyl groups also include cycloalkylidenes. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, e.g., benzo or thienyl derivatives of cyclopentane, cyclohexane and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom 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, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0146] The term "haloalkyl" as used herein refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by a halogen atom. The term "C n-m haloalkyl" refers to a C n-m alkyl group having n to m carbon atoms and from at least one up to {2(n to m)+1} halogen atoms, which may either be the same or different. In some embodiments, the halogen atoms are fluoro atoms. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CCl 3 , CHCl 2 , C 2 Cl 5 and the like. In some embodiments, the haloalkyl group is a fluoroalkyl group.

[0147] The term "alkyl" employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chained or branched. The term "C n-m 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 by the point of attachment of the alkyl group to the remainder of the compound. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 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; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl and the like.The term "alkenyl" employed 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 with one C-H bond replaced by the point of attachment of the alkenyl group to the remainder of the compound. The term "C n-m 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. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl and the like.

[0148] The term "alkynyl" employed 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 with one C-H bond replaced by the point of attachment of the alkyl group to the remainder of the compound. The term "C n-m alkynyl" refers to an alkynyl group having n to m carbons. Example 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.

[0149] The term "alkoxy", employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group is as defined above. The term "C n-m alkoxy" refers to an alkoxy group, the alkyl group of which 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.

[0150] The term "haloalkoxy", employed alone or in combination with other terms, refers to a group of formula -O-haloalkyl, wherein the haloalkyl group is as defined above. The term "C n-m haloalkoxy" refers to a haloalkoxy group, the haloalkyl group of which has n to m carbons. Example 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.

[0151] The terms "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, halo groups are F.

[0152] The term "oxo" refers to an oxygen atom as a divalent substituent, forming a carbonyl group when attached to carbon, or attached to a heteroatom forming a sulfoxide or sulfone group, or an N-oxide group. In some embodiments, heterocyclic groups may be optionally substituted by 1 or 2 oxo (=O) substituents.

[0153] The term "fused" refers to having a bond in common with, such as a fused ring.The term "alkylthio" refers to an --S-alkyl group. Example alkylthio groups include meththio, ethylthio, propylthio (e.g., n-propylthio and isopropylthio), and the like.

[0154] The term "sulfido" refers to a sulfur atom as a divalent substituent, forming a thiocarbonyl group (C=S) when attached to carbon.

[0155] The term "heteroatom" used herein is meant to include boron, phosphorus, sulfur, oxygen and nitrogen.

[0156] As used herein, the term "about" generally refers to that the actual value is within 10%, 5%, 1%, or 0.5% of a particular value or range. The term "about" means herein that the actual value is within an acceptable standard error of the mean, depending on the considerations of those ordinary skill in the art to which this invention belongs. Besides the experimental examples, or unless stated specifically otherwise, it should be understood that the ranges, amounts, numerical values, and percentages used herein are modified by "about". Therefore, unless stated otherwise, the numerical values or parameters disclosed in the specification and claims are all rough values and may be varied as desired.

[0157] Compounds of the present disclosure can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having 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 disclosure can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance. In some embodiments, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in a compound of the present disclosure can be replaced or substituted by deuterium. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms. Synthetic methods for including isotopes into organic compounds are known in the art.

[0158] 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 present disclosure, regardless of how they are prepared, e.g., synthetically, through biological process (e.g., metabolism or enzyme conversion), or a combination thereof.

[0159] All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated. When in the solid state, the compounds described herein and salts thereof may occur in various forms and may, e.g., take the form of solvates, including hydrates. The compounds may be in any solid state form, such as a polymorph or solvate, so unless clearly indicated otherwise, reference in the specification to compounds and salts thereof should be understood as encompassing any solid state form of the compound.

[0160] In some embodiments, the compounds of the present disclosure, or salts thereof, are substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, e.g., a composition enriched in the compounds of the present disclosure. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the present disclosure, or salt thereof.

[0161] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0162] The expressions, "ambient temperature" and "room temperature," as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, e.g., a temperature from about 20 °C to about 30 °C.

[0163] The present disclosure also includes pharmaceutically acceptable salts of the compounds described herein. The term "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral 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 pharmaceutically acceptable salts of the present disclosure include the non-toxic salts of the parent compound formed, e.g., from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19 and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). In some embodiments, the compounds described herein include the N-oxide forms.Uses of the Compounds

[0164] Compounds of the present disclosure can reduce PD-1 / PD-L1 protein / protein interaction and, thus, are useful in treating diseases and disorders associated with activity of PD-1 and the diseases and disorders associated with PD-L1 including its interaction with other proteins such as PD-1 and B7-1 (CD80). Collectively, these are referred to herein as "PD-1-related diseases or conditions." In certain embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts or stereoisomers thereof, are useful for therapeutic administration to enhance, stimulate and / or increase immunity in cancer, chronic infection, or sepsis, including enhancement of response to vaccination. In some embodiments, the present disclosure provides a compound for use in a method for reducing the PD-1 / PD-L1 protein / protein interaction. The method includes administering to an individual or a patient a compound described herein or a pharmaceutically acceptable salt or a stereoisomer thereof. The compounds of the present disclosure can be used alone, in combination with other agents or therapies or as an adjuvant or neoadjuvant for the treatment of diseases or disorders, including cancer or infection diseases. For the uses described herein, any of the compounds of the disclosure, including any of the embodiments thereof, may be used.

[0165] The compounds of the present disclosure reduce the PD-1 / PD-L1 protein / protein interaction, resulting in a PD-1 pathway blockade. The blockade of PD-1 can enhance the immune response to cancerous cells and infectious diseases in mammals, including humans. In some embodiments, the present disclosure provides treatment of an individual or a patient in vivo using a compound described herein or a salt or stereoisomer thereof such that growth of cancerous tumors is inhibited. A compound described herein or a salt or stereoisomer thereof, can be used to inhibit the growth of cancerous tumors. Alternatively, a compound described herein or a salt or stereoisomer thereof, can be used in conjunction with other agents or standard cancer treatments, as described below. In one embodiment, the present disclosure provides a method for inhibiting growth of tumor cells in vitro. The method includes contacting the tumor cells in vitro with a compound described herein or of a salt or stereoisomer thereof. In another embodiment, the present disclosure provides a method for inhibiting growth of tumor cells in an individual or a patient. The method includes administering to the individual or patient in need thereof a therapeutically effective amount of a compound described herein or a salt or a stereoisomer thereof.

[0166] In some embodiments, provided herein is a compound for use in a method for treating cancer. The method includes administering to a patient in need thereof, a therapeutically effective amount of a compound described herein or a salt thereof. Examples of cancers include those whose growth may be inhibited using compounds of the disclosure and cancers typically responsive to immunotherapy.

[0167] In some embodiments, the present disclosure provides a compound for use in a method of enhancing, stimulating and / or increasing the immune response in a patient. The method includes administering to the patient in need thereof a therapeutically effective amount of a compound described herein or a salt thereof.

[0168] Examples of cancers that are treatable using the compounds of the present disclosure include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, endometrial cancer, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or urethra, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T -cell lymphoma, environmentally induced cancers including those induced by asbestos, and combinations of said cancers. The compounds of the present disclosure are also useful for the treatment of metastatic cancers, especially metastatic cancers that express PD-L1.

[0169] In some embodiments, cancers treatable with compounds of the present disclosure include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g. hormone refractory prostate adenocarcinoma), breast cancer, triple-negative breast cancer, colon cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), squamous cell head and neck cancer, urothelial cancer (e.g., bladder) and cancers with high microsatellite instability (MSI high< ). Additionally, the disclosure includes refractory or recurrent malignancies whose growth may be inhibited using the compounds of the disclosure.

[0170] In some embodiments, cancers that are 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, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), hematological cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma or multiple myeloma) and combinations of said cancers.

[0171] In some embodiments, cancers that are treatable using the compounds of the present disclosure include, but are not limited to, cholangiocarcinoma, bile duct 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 tumors, hairy cell leukemia, intestinal cancer, islet cell cancer, oral cancer, mouth cancer, throat cancer, laryngeal cancer, lip cancer, mesothelioma, neck cancer, nasal cavity cancer, ocular cancer, ocular melanoma, pelvic cancer, rectal cancer, renal cell carcinoma, salivary gland cancer, sinus cancer, spinal cancer, tongue cancer, tubular carcinoma, urethral cancer, and ureteral cancer.

[0172] In some embodiments, diseases and indications that are treatable using the compounds of the present disclosure include, but are not limited to hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

[0173] Exemplary hematological cancers include lymphomas and leukemias such as acute lymphoblastic leukemia (ALL), acute myelogenous 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 lymphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma, myeloproliferative diseases (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL) and multiple myeloma (MM).

[0174] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, and teratoma.

[0175] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer, bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, and mesothelioma.

[0176] Exemplary gastrointestinal cancers include cancers of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.

[0177] Exemplary genitourinary tract cancers include cancers of the kidney (adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma).

[0178] Exemplary liver cancers include hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0179] 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, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors

[0180] Exemplary nervous system cancers include cancers of the skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma, glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.

[0181] Exemplary gynecological cancers include cancers of the uterus (endometrial carcinoma), cervix (cervical carcinoma, pre -tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), and fallopian tubes (carcinoma).

[0182] Exemplary skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids. In some embodiments, diseases and indications that are 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 syndromes, testicular cancer, bile duct cancer, esophageal cancer, and urothelial carcinoma.

[0183] PD-1 pathway blockade with compounds of the present disclosure can also be used for treating infections such as viral, bacteria, fungus and parasite infections. The present disclosure provides a compound for use in a method for treating infections such as viral infections. The method includes administering to a patient in need thereof, a therapeutically effective amount of a compound described herein or a salt thereof. Examples of viruses causing infections treatable by methods of the present disclosure include, but are not limit to, human immunodeficiency virus, human papillomavirus, influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpes simplex viruses, human cytomegalovirus, severe acute respiratory syndrome virus, ebola virus, and measles virus. In some embodiments, viruses causing infections treatable by methods of the present disclosure include, but are not limit to, hepatitis (A, B, or C), herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus, mumpsvirus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus.

[0184] The present disclosure provides a compound for use in a method for treating bacterial infections. The method includes administering to a patient in need thereof, a therapeutically effective amount of a compound described herein or a salt thereof. Non-limiting examples of pathogenic bacteria causing infections treatable by methods of the 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's disease bacteria.

[0185] The present disclosure provides a compound for use in a method for treating fungus infections. The method includes administering to a patient in need thereof, a therapeutically effective amount of a compound described herein or a salt thereof. Non-limiting examples of pathogenic fungi causing infections treatable by methods of the 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.

[0186] The present disclosure provides a compound for use in a method for treating parasite infections. The method includes administering to a patient in need thereof, a therapeutically effective amount of a compound described herein or a salt thereof. Non-limiting examples of pathogenic parasites causing infections treatable by methods of the disclosure include Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus brasiliensis.

[0187] The present disclosure provides a compound for use in a method for treating sepsis. The method includes treating sepsis by administering to a patient in need thereof, a therapeutically effective amount of a compound described herein or a salt thereof.

[0188] The terms "individual" or "patient," used interchangeably, refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

[0189] The phrase "therapeutically effective amount" refers to the amount of 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, medical doctor or other clinician.

[0190] As used herein, the term "treating" or "treatment" refers to one or more of (1) inhibiting the disease; e.g., inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomatology); and (2) ameliorating the disease; e.g., ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology) such as decreasing the severity of disease.

[0191] In some embodiments, the compounds of the present disclosure are useful in preventing or reducing the risk of developing any of the diseases referred to herein; e.g., 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 does not yet experience or display the pathology or symptomatology of the disease.Combination Therapies

[0192] Cancer cell growth and survival can be impacted by multiple signaling pathways. Thus, it is useful to combine different enzyme / protein / receptor inhibitors, exhibiting different preferences in the targets which they modulate the activities of, to treat such conditions. Targeting more than one signaling pathway (or more than one biological molecule involved in a given signaling pathway) may reduce the likelihood of drug-resistance arising in a cell population, and / or reduce the toxicity of treatment.

[0193] The compounds of the present disclosure can be used in combination with one or more other enzyme / protein / receptor inhibitors or one or more therapies for the treatment of diseases, such as cancer or infections. Examples of diseases and indications treatable with combination therapies include those as described herein. Examples of cancers include solid tumors and liquid tumors, such as blood cancers. Examples of infections include viral infections, bacterial infections, fungus infections or parasite infections. For example, the compounds of the present disclosure can be combined with one or more inhibitors of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, TGF-βR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, PI3K (alpha, beta, gamma, delta), CSFIR, KIT, FLK-II, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, 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 infections. Non-limiting examples of inhibitors that can be combined with the compounds of the present disclosure for treatment of cancer and infections include an FGFR inhibitor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., INCB54828, INCB62079 and INCB63904), a JAK inhibitor (JAK1 and / or JAK2, e.g., ruxolitinib, baricitinib or INCB39110), an IDO inhibitor (e.g., epacadostat, NLG919, and BMS-986205), an LSD1 inhibitor (e.g., INCB59872 and INCB60003), a TDO inhibitor, a PI3K-delta inhibitor (e.g., INCB50797 and INCB50465), a PI3K-gamma inhibitor such as a PI3K-gamma selective inhibitor, a Pim inhibitor (INCB53914), a CSFIR inhibitor, a TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer), a histone deacetylase inhibitor (HDAC) such as an HDAC8 inhibitor, an angiogenesis inhibitor, an interleukin receptor inhibitor, bromo and extra terminal family members inhibitors (for example, bromodomain inhibitors or BET inhibitors such as INCB54329 and INCB57643), a poly ADP ribose polymerase (PARP) inhibitor such as rucaparib, olaparib, niraparib, veliparib, or talazoparib, and an adenosine receptor antagonist and an arginase inhibitor (INCB01158) or combinations thereof.

[0194] Compounds of the present disclosure can be used in combination with one or more immune checkpoint inhibitors. Exemplary immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as 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, 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 can 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.

[0195] In some embodiments, the inhibitor of an immune checkpoint molecule is anti-PDl antibody, anti-PD-Ll antibody, or anti-CTLA-4 antibody.

[0196] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., 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-PDl antibody is nivolumab. In some embodiments, the anti-PDl antibody is pembrolizumab. In some embodiments, the anti PD-1 antibody is SHR-1210.

[0197] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-Ll monoclonal antibody. In some embodiments, the anti-PD-Ll monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-Ll monoclonal antibody is MPDL3280A or MEDI4736.

[0198] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab.

[0199] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525 or INCAGN2385.

[0200] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

[0201] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518 or MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, MEDI1873.

[0202] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562, MOXR-0916, PF-04518600, GSK3174998, BMS-986178. In some embodiments, the OX40L fusion protein is MEDI6383.

[0203] Compounds of the present disclosure can be used in combination with one or more agents for the treatment of diseases such as cancer. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of an alkylating agent include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM).

[0204] The compounds of the present disclosure can further be used in combination with other methods of treating cancers, for example by chemotherapy, irradiation therapy, tumortargeted therapy, adjuvant therapy, immunotherapy or surgery. Examples of immunotherapy include cytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccine, monoclonal antibody, adoptive T cell transfer, Toll receptor agonists, STING agonists, oncolytic virotherapy and immunomodulating small molecules, including thalidomide or JAK1 / 2 inhibitor and the like. The compounds can be administered in combination with one or more anti-cancer drugs, such as a chemotherapeutics. Example chemotherapeutics include any of: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral, calusterone, 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 alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, olaparib, oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, rucaparib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, niraparib, veliparib, talazoparib and zoledronate.

[0205] Other anti-cancer agent(s) include antibody therapeutics such as trastuzumab (Herceptin), antibodies to costimulatory molecules such as CTLA-4 (e.g., ipilimumab), 4-1BB (e.g., urelumab, utomilumab), antibodies to PD-1 and PD-L1, or antibodies to cytokines (IL-10, TGF-β, etc.). Examples of antibodies to PD-1 and / or PD-L1 that can be combined with compounds of the present disclosure for the treatment of cancer or infections such as viral, bacteria, fungus and parasite infections include, but are not limited to, nivolumab, pembrolizumab, MPDL3280A, MEDI-4736 and SHR-1210.

[0206] The compounds of the present disclosure can further be used in combination with one or more anti-inflammatory agents, steroids, immunosuppressants or therapeutic antibodies.

[0207] The compounds described herein or salts 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.

[0208] The compounds described herein or salts thereof can be used in combination with a vaccination protocol for the treatment of cancer. In some embodiments, the tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines include the proteins from viruses implicated in human cancers such as Human Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) and Kaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, the compounds of the present disclosure can be used in combination with tumor specific antigen such as heat shock proteins isolated from tumor tissue itself. In some embodiments, the compounds described herein or salts thereof can be combined with dendritic cells immunization to activate potent anti-tumor responses.

[0209] The compounds of the present disclosure can be used in combination with bispecific macrocyclic peptides that target Fe alpha or Fe gamma receptor-expressing effectors cells to tumor cells. The compounds of the present disclosure can also be combined with macrocyclic peptides that activate host immune responsiveness.

[0210] The compounds of the present disclosure can be used in combination with bone marrow transplant for the treatment of a variety of tumors of hematopoietic origin.

[0211] The compounds described herein or salts thereof can be used in combination with vaccines, to stimulate the immune response to pathogens, toxins, and self antigens. Examples of pathogens for which this therapeutic approach may be particularly useful, include pathogens for which there is currently no effective vaccine, or pathogens for which conventional vaccines are less than completely effective. These include, but are not limited to, HIV, Hepatitis (A, B, & C), Influenza, Herpes, Giardia, Malaria, Leishmania, Staphylococcus aureus, Pseudomonas Aeruginosa.

[0212] Viruses causing infections treatable by methods of the present disclosure include, but are not limit to human papillomavirus, influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpes simplex viruses, 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), flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus, mumpsvirus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus.

[0213] Pathogenic bacteria causing infections treatable by methods of the 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's disease bacteria.

[0214] Pathogenic fungi causing infections treatable by methods of the disclosure include, but are not limited to, 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.

[0215] Pathogenic parasites causing infections treatable by methods of the disclosure include, but are not limited to, Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus brasiliensis.

[0216] When more than one pharmaceutical agent is administered to a patient, they can be administered simultaneously, separately, sequentially, or in combination (e.g., for more than two agents).Formulation, Dosage Forms and Administration

[0217] When employed as pharmaceuticals, the compounds of the present disclosure can be administered in the form of pharmaceutical compositions. Thus the present disclosure provides a composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, or any of the embodiments thereof, and at least one pharmaceutically acceptable carrier or excipient. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is indicated and upon the area to be treated. Administration may be topical (including transdermal, epidermal, ophthalmic and to 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 or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, e.g., by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0218] This present disclosure also includes pharmaceutical compositions which contain, as the active ingredient, the compound of the present disclosure or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the composition is suitable for topical administration. In making the compositions of the present disclosure, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, e.g., a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, e.g., up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

[0219] In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.

[0220] The compounds of the present disclosure may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the present disclosure can be prepared by processes known in the art see, e.g., WO 2002 / 000196.

[0221] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the present disclosure can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.

[0222] In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose (SMCC) and at least one compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the silicified microcrystalline cellulose comprises about 98% microcrystalline cellulose and about 2% silicon dioxide w / w.

[0223] In some embodiments, the composition is a sustained release composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the composition comprises at least one compound described herein, or a pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 ™< ).

[0224] In some embodiments, a wet granulation process is used to produce the composition. In some embodiments, a dry granulation process is used to produce the composition.

[0225] The compositions can be formulated in a unit dosage form, each dosage containing from about 0.5 to about 1,000 mg, or from about 5 to about 1,000mg (1 g), or from about 100mg to about 500 mg, of the active ingredient. In some embodiments, each dosage contains about 1 mg of the active ingredient. In some embodiments, each dosage contains about 5 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 forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0226] The components used to formulate the pharmaceutical compositions are of high purity and are 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 composition is preferably manufactured or formulated under Good Manufacturing Practice standards as defined in the 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 Good Manufacturing Practice regulations of the U.S. Food and Drug Administration.

[0227] The active compound may be effective over a wide dosage range and is generally administered in a therapeutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms and the like.

[0228] The therapeutic dosage of a compound of the present disclosure can vary according to, e.g., the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the present disclosure in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds of the present disclosure can be provided in an aqueous physiological buffer solution containing from about 0.01 to about 10% w / v, or from about 0.1 to about 10% w / v, of the compound for parenteral administration. Some typical dose ranges are from about 0.1 µg / kg to about 1 g / kg, or from about 1 µg / kg to about 1 g / kg, of body weight per day. In some embodiments, the dose range is from about 0.001 mg / kg to about 100 mg / kg, or from 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 status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0229] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present disclosure. When referring to these preformulation compositions as homogeneous, 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 from, e.g., about 0.01 to about 1000 mg, or about 0.1 to about 1000 mg, of the active ingredient of the present disclosure.

[0230] The tablets or pills of the present disclosure can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

[0231] The liquid forms in which the compounds and compositions of the present disclosure can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0232] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.

[0233] Topical formulations can contain one or more conventional carriers. In some embodiments, ointments can contain water and one or more hydrophobic carriers selected from, e.g., liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and the like. Carrier compositions of creams can be based on water in combination with glycerol and one or more other components, e.g., glycerinemonostearate, PEG-glycerinemonostearate and cetylstearyl alcohol. Gels can be formulated using isopropyl alcohol and water, suitably in combination with other components such as, e.g., glycerol, hydroxyethyl cellulose, and the like. In some embodiments, topical formulations contain at least about 0.01, at least about 0.05, 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 wt % of the compound of the present disclosure. The topical formulations can be suitably packaged in tubes of, e.g., 100 g which are optionally associated with instructions for the treatment of the select indication, e.g., psoriasis or other skin condition.

[0234] The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration and the like. In therapeutic applications, compositions can 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. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient and the like.

[0235] The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers or stabilizers will result in the formation of pharmaceutical salts.

[0236] The therapeutic dosage of a compound of the present disclosure can vary according to, e.g., the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the present disclosure in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds of the present disclosure can be provided in an aqueous physiological buffer solution containing about 0.01 to about 10% w / v, or from about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dose ranges are from about 0.1 µg / kg to about 1 g / kg, or from about 1 µg / kg to about 1 g / kg, of body weight per day. In some embodiments, the dose range is from 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 status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.Labeled Compounds and Assay Methods

[0237] The compounds of the present disclosure can further be useful in investigations of biological processes in normal and abnormal tissues. Thus, another aspect of the present invention relates to labeled compounds of the invention (radio-labeled, fluorescent-labeled, etc.) that would be useful not only in imaging techniques but also in assays, both in vitro and in vivo, for localizing and quantitating PD-1 or PD-L1 protein in tissue samples, including human, and for identifying PD-L1 ligands by inhibition binding of a labeled compound. Accordingly, the present invention includes PD-1 / PD-L1 binding assays that contain such labeled compounds.

[0238] The present invention further includes isotopically-substituted compounds of the disclosure. An "isotopically-substituted" compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having the same atomic number but a different atomic mass or mass number e.g., a different atomic mass or mass number from the atomic mass or mass number typically found in nature (i.e., naturally occurring). It is to be understood that a "radio-labeled" compound is a compound that has incorporated at least one isotope that is radioactive (e.g., radionuclide). Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 3< H (also 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 in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro PD-L1 protein labeling and competition assays, compounds that incorporate 3< H, 14< C, 82< Br, 125< I, 131< I, 35< S or will generally be most useful. For radio-imaging applications 11< C, 18< F, 125< I, 123< I, 124< I, 131< I, 75< Br, 76< Br or 77< Br will generally be most useful.

[0239] In some embodiments the radionuclide is selected from the group consisting of 3< H, 14< C, 125< I, 35< S and 82< Br. Synthetic methods for incorporating radio-isotopes into organic compounds are known in the art.

[0240] Specifically, a labeled compound of the invention can be used in a screening assay to identify and / or evaluate compounds. For example, a newly synthesized or identified compound (i.e., test compound) which is labeled can be evaluated for its ability to bind a PD-L1 protein by monitoring its concentration variation when contacting with the PD-L1 protein, through tracking of the labeling. For example, a test compound (labeled) can be evaluated for its ability to reduce binding of another compound which is known to bind to a PD-L1 protein (i.e., standard compound). Accordingly, the ability of a test compound to compete with the standard compound for binding to the PD-L1 protein directly correlates to its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and test compounds are unlabeled. Accordingly, the concentration of the labeled standard compound is monitored in order to evaluate the competition between the standard compound and the test compound, and the relative binding affinity of the test compound is thus ascertained.Kits

[0241] The present disclosure also includes pharmaceutical kits useful, e.g., in the treatment or prevention of diseases or disorders associated with the activity of PD-L1 including its interaction with other proteins such as PD-1 and B7-1 (CD80), such as cancer or infections, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), or any of the embodiments thereof. Such kits can further include one or more of various conventional pharmaceutical kit components, such as, e.g., containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit.

[0242] The following are examples of the practice of the invention. They are not to be construed as limiting the scope of the invention in any way.EXAMPLES Examples 1A and 1B: PD-1 / PD-L1 Binding Assay Example 1A: Alphascreen

[0243] Binding assays were conducted in a low volume white 384-well polystyrene plate in a final volume of 20 µL. Compounds to be analyzed were first serially diluted in DMSO and added to the plate wells before the addition of other reaction components. The final concentration of DMSO in the assay was 1%. The assay was carried out at 25° C in the PBS buffer (pH 7.4) with 0.05% Tween-20 and 0.1% BSA. Recombinant human PD-L1 protein (19-238) with a His-tag at the C-terminus was purchased from AcroBiosystems (PD1-H5229). Recombinant human PD-1 protein (25-167) with Fc tag at the C-terminus was also from AcroBiosystems (PD1-H5257). PD-L1 and PD-1 proteins were diluted in the assay buffer (final concentration - 0.67 and 0.20 nM respectively) and 10 µL was added to the plate well. Plates were centrifuged and proteins were preincubated with compounds for 40 minutes. The incubation was followed by the addition of 10 µL of assay buffer supplemented with Alphascreen Ni chelate donor beads (PerkinElmer - AS101D) and Protein A Acceptor beads (PerkinElmer - 6760137) at final concentration 2.5 µg / mL under reduced light. After plate sealing, the plate was incubated in the dark at room temperature for 120 minutes before reading on a PHERAstar FS plate reader (BMG Labtech). IC 50 determination was performed by fitting the curve of percent control activity versus the log of the compound concentration using the GraphPad Prism 5.0 software.Example 1B; Homogeneous Time-Resolved Fluorescence (HTRF)

[0244] The assays were conducted in a standard black 384-well polystyrene plate with a final volume of 20 µL. Inhibitors were first serially diluted in DMSO and then added to the plate wells before the addition of other reaction components. The final concentration of DMSO in the assay was 1%. The assays were carried out at 25° C in the PBS buffer (pH 7.4) with 0.05% Tween-20 and 0.1% BSA. Recombinant human PD-L1 protein (19-238) with a His-tag at the C-terminus was purchased from AcroBiosystems (PD1-H5229). Recombinant human PD-1 protein (25-167) with Fc tag at the C-terminus was also purchased from AcroBiosystems (PD1-H5257). PD-L1 and PD-1 proteins were diluted in the assay buffer and 10 µL was added to the plate well. Plates were centrifuged and proteins were preincubated with inhibitors for 40 minutes. The incubation was followed by the addition of 10 µL of HTRF detection buffer supplemented with Europium cryptate-labeled anti-human IgG (PerkinElmer-AD0212) specific for Fc and anti-His antibody conjugated to SureLight ®< -Allophycocyanin (APC, PerkinElmer-AD0059H). After centrifugation, the plate was incubated at 25° C for 60 min. before reading on a PHERAstar FS plate reader (665nm / 620nm 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.ICso determination was performed by fitting the curve of percent control activity versus the log of the inhibitor concentration using the GraphPad Prism 5.0 software.Example 2A: PD-L1 Homogeneous Time-Resolved Fluorescence (HTRF) Dimerization Assay

[0245] Dimerization assays were conducted in a standard black 384-well polystyrene plate in a final volume of 20 µL. Compounds to be analyzed were diluted in DMSO and added to the plate wells before the addition of other reaction components. The final concentration of tested compounds was 10 µM and DMSO was at 1%. The assays were carried out at 25°C in PBS buffer (pH 7.4) with 0.05% Tween-20 and 0.1% BSA. Recombinant human PD-L1 protein (19-238) with a His-tag at the C-terminus was purchased from AcroBiosystems (PD1-H5229). Recombinant human PD-L1 protein (19-239) with Fc tag at the C-terminus was purchased from BPS Bioscience (#71104). PD-L1 proteins were diluted in the assay buffer, mixed, and 10 ul was added to the plate well. Plates were centrifuged and proteins were preincubated with compounds for 40 minutes. The incubation was followed by the addition of 10 µL of HTRF detection buffer supplemented with Europium cryptate-labeled anti-human IgG (PerkinElmer-AD0074) specific for Fc and anti-His antibody conjugated to SureLight ®< -Allophycocyanin (APC, PerkinElmer-AD0059H). Final concentrations in the assay were: 30 nM PD-L1 (Fc-tag), 100 nM PD-L1 (His-tag), 10 nM europium anti-human IgG and 200 nM anti-His-Allophycocyanin. After centrifugation, the plate was incubated at 25°C for 60 minutes before reading on a PHERAstar FS plate reader (665nm / 620nm ratio). The dimerization ratio was calculated based on the assay signal in the presence of compound divided by the signal in the presence of DMSO.Example 3A: PD-L1 Internalization Assays

[0246] Endocytosis or internalization of PD-L1 was measured by two different methods, one direct and the other indirect. In the direct method, an anti PD-L1 antibody labeled with a pH sensitive fluorophore is incubated with PD-L1 expressing cells. Upon internalization and trafficking of the antibody-PD-L1 complex to low pH endosomes, fluorescence is emitted. In the indirect method, cell surface PD-L1 is measured using an anti PD-L1 antibody after incubation with a compound to determine remaining, non-internalized receptor.Direct Method Assessing for PD-L1 Internalization

[0247] For the direct measurement, biotinylated anti-PD-Ll antibody (BPS Biosciences) or Atezolizumab, biotinylated with a 20-fold excess of biotin using the EZ-Link ™< Sulfo-NHS-LC-Biotin reagents (ThermoFisher), were labeled with pHrodo ™< Red Avidin (Life Technologies) conjugate. Equimolar solutions of the antibody and pHrodo ™< Red avidin (4.2 uM each) were incubated on ice for 2 hours in the dark in a buffer composed of 40 mM Tris-HCl, pH 8.0, 110 mM NaCl, 2.2 mM KCl, 20% glycerol, and 1% bovine serum albumin. The mixture was centrifuged for 1 minute at 1000 rpm, and the clarified supernatant was used in subsequent assays. As an isotype control, a biotinylated Human IgG1κ antibody (Ancell) was labeled using the same protocol. For the assay, 2×10^5 CHO-PD-L1 cells (Promega) were seeded into each well of a 6-well tissue culture plate in 2ml of F-12 medium supplemented with 10% FBS, 200 µg / ml Hydromycin and 250 µg / ml Geneticin. Cells were allowed to attach for 24 hours, and then 40 nM of the anti-PD-Ll-biotin / pHrodo-Avidin, Atezolizumab / pHrodo-Avidin or IgG-biotin / pHrodo-Avidin complex was added to the cells and allowed to incubate at 37°C for 5 to 16 hours. The cells were washed twice with PBS (Mg, Ca free) and harvested using non-enzymatic lift buffer (10mM Tris (pH 7.5), 140 mM NaCl, ImM EDTA), collected by centrifugation, and re-suspended in 400 µL of PBS. The cells were analyzed by flow cytometry, and internalized antibody-receptor complex was detected using a C6 Accuri Flow Cytometer (excitation with 488 nM laser and emission collected with a 585 / 40 bandpass filter). There was no difference between IgG control and Atezolizumab, demonstrating that Atezolizumab dos not cause PD-L1 internalization.Indirect Method for Assessing for PD-L1 Internalization

[0248] For the indirect analysis, cell surface PD-L1 was detected with fluorescently labeled anti-PD-Ll (CD274) antibodies. CHO-PD-L1 cells were seeded at 2×10^5 cells per well of a 6-well tissue culture plate in 2ml of F-12 medium supplemented with 10% FBS, 200 µg / ml Hydromycin and 250 µg / ml Geneticin and allowed to attach for 24 hours. After 24 hours, test compounds were added to a final concentration of 1uM from DMSO stocks, and an equal volume of DMSO was added to control wells. Cells were incubated in the presence of a compound for 16 hours at 37°C, 5% CO2. Prior to analysis, the cells were washed twice with 1 mL of Ca, Mg free PBS and detached with 1 mL of lift buffer (10mM Tris, 140mM NaCl, ImM EDTA). The collected cells were stained with PE-conjugated mouse anti-human CD274 antibody according to manufacturer instructions: BD Pharmigen #557924 Clone MIH1 (20 µL of Ab per 100uL of BSA based staining buffer) or eBioscience #12-5983 Clone MIH1 (2 µl per 100ul of BSA based staining buffer). Cells were incubated at room temperature for 20 minutes, protected from light, washed twice with Ca, Mg free PBS and resuspended in 400 µL of PBS. Antibody binding was detected by flow cytometry using an Accuri C6 instrument. Isotype control antibody-stained cells were used as a negative control. To test that lack of PD-L1 cell surface staining was not due to inhibition of detection antibody binding by the test article, an acid-wash procedure was used. After 16 hours of incubation in the presence of a compound or anti-PD-L1 antibody, the remaining, non-internalized a compound or antibody was stripped from the cell surface using freshly prepared, ice-cold acid stripping buffer (DMEM / 0.2% BSA, pH 3.5). Cells were washed in this manner three times for 5 minutes each on a shaking platform. The stripped cells were then washed with ice-cold PBS three times for 5 minutes each with gentle shaking, harvested with lift buffer and stained with PE-mouse anti human CD274 antibodies as described.

[0249] For the indirect method of assessing PD-L1 internalization using the MDA-MB231 breast cancer cell line, the procedure for the assays was the same as described for the CHO-PD-L1 cells with the following changes. MDA-MB231 were seeded at 2×10^5 cells per well of a 6-well tissue culture plate in 2ml of RPMI1640 medium supplemented with 10% FBS. After compound treatment for 16 hrs, the cells were treated with the stripping buffer (DMEM / 0.2% BSA, pH 3.5) prior to staining with the anti-CD274 antibodies as described.Indirect Whole Blood Assay

[0250] To determine PD-L1 internalization in human whole blood, normal human blood (Biological Specialty Corp, Colmar. PA) was incubated in the presence or absence of a concentration range of test compounds and 1 ng / ml human interferon γ (R&D Systems Inc. Minn. MN) in a 96 well round bottom plate (Corning, Corning, NY) for 18 hours at 37 0< C. Blood was then transferred into 96 well "2ml Assay Block" (Corning, Corning NY) and stained with 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 cells were lysed / fixed (lysis buffer BD Biosciences) for 5 minutes at 37 0< C in dark and then centrifuged at 1600 RPM for 5 minutes and cells were transferred into 96 well round bottom plates (Corning). Cells were gated on CD14+ (BD Biosciences) and PD-L1 expression determined by mean fluorescence intensity (MFI) (BD LSRFortessa ™< X-20). IC 50 determination was performed by fitting the curve of compound percent inhibition versus the log of the compound concentration using the GraphPad Prism 7.0 software.Example 4A: Results of Binding, Dimerization, and Internalization Assays

[0251] Several compounds were assessed in each of the PD-1-PD-L1 Alphascreen binding assay (Example 1A), the PD-L1 dimerization assay (Example 2A), the indirect CHO / PD-L1 internalization assay (Example 3A), the indirect whole blood PD-L1 internalization assay (Example 3A), and the internalization assays using the MDA-MB231 breast cancer cell line (Example 3A). Compounds described herein were also assessed in PD-1-PD-L1 HTRF binding assay (Example IB). The cutoffs for ranges of values observed in each of the assays is shown in Table 1. The results obtained for the tested compounds are shown in Table 2, Table 3, and Table 4. Table 1Cutoffs++++++++++PD-1-PD-L1 Binding IC 50 (nM) (Alphascreen)<= 0.1 nM> 0.1 to <=1 nM> 1 nMPD-1-PD-L1 Binding IC 50 (nM) (HTRF)<= 10 nM> 10 to < = 100PD-L1 Dimerization ratio>=1.88 to <=2.16>=1.75 to <1.88 or >2.16 to <=2.29<1.75 or > 2.29Indirect PD-L1 Internalization Assay using CHO-PD-L1 cells> 90 % internalized<= 90% internalizedIndirect PD-L1 Internalization Assay using MDA-MB231 cells IC 50 (nM)<10 nM>=10 nM to <100 nM>=100 nM to <=500 nM>500 nMPD-L1 Whole Blood Internalization IC 50 (nM)<100 nM>=100 nM to <1000 nM>=1000 nM to <=5000 nM>5000 nM Table 2 CpdStructurePD-1-PD-L1 Binding IC 50 (nM) (Alphascr een)PD-L1 Dimerizat - ion Cpd / DMSO ratioPD-L1 Indirect Internalizat -ion Assay using CHO-PD-L1 cellsPD-L1 Whole Blood Internalizat -ion IC 50 (nM)1 +++++++++++2 ++++++++++++3 ++++++++++++4 +++++++++++5 ++++++++++++6 ++++++++++++7 ++++8 +++++9 +++++10 +++++11 +++++12 +++++++13 +++++++14 ++++++15 ++++++16 ++++++17 +++++++18 ++++++19 ++++++20 ++++++21 ++++++22 ++++++23 ++++++24 ++++++25 +++++++26 ++++++27∗∗∗++++++++NA ∗∗∗< The structure of compound 27 is: see WO 2014 / 151634, the content of which is incorporated herein by reference. Table 3 Compound from Example NumberPD-1-PD-L1 Binding IC 50 (nM) (HTRF)13+14+15+16+17+18+19+20+21+22+23+24+25+26+27+28+29+30+31+32+33+34+35+36+37+38+39+40+41+42+43+44+45+46+47+48+49+50+51+52+53+54+ Table 4 Compound from Table 2Indirect PD-L1 Internalization Assay using MDA-MB231 cells IC 50 (nM)7+8+9+10+11+12++13++14+15+16++17+++18+19++++20+21++22+23++24++25++26++ Example 5A: Effects of Antibodies on PD-L1 Internalization

[0252] In addition to small molecules disclosed as PD-1-PD-L1 inhibitors, a monoclonal antibody disclosed as a PD-1-PD-L1 inhibitor was also tested. Atezolizumab is a fully humanized, engineered monoclonal antibody of IgG1 isotype against the PD-L1. Atezolizumab was tested in the direct method for assessing PD-L1 internalization described in Example 3A. The commercially available tool anti PD-L1 antibody (BPS Biosciences) was used as a control. The tool anti-PD-Ll antibody is known to cause internalization. Atezolizumab was tested against tool anti-PD-Ll antibody to determine if it would also cause PD-L1 internalization. Figure 1 show the internalization results. The tool anti-PD-L1 antibody resulted in an increase in mean fluorescence relative to the control IgG, indicative of internalization. Atezolizumab produced no intensity shift relative to the control IgG antibody. These results demonstrate that the tool anti-PD-Ll antibody results in PD-L1 internalization and Atezolizumab does not result in PD-L1 internalization.

[0253] The test involved a 40nM Atezolizumab / pHrodo-Avidin complex incubated with CHO / PD-L1 cells for 5 or 16 hr. FACS analysis was performed as described in the direct method with internalization being measured by increased fluorescence as assessed by a rightward shift in the curve relative to IgG control (3). Figure 1 shows the PD-L1 fluorescence - shown on X-axis in LOG10 scale. No difference was observed between IgG control (Curve 3) and Atezolizumab (Curve 2) demonstrating that Atezolizumab does not cause PD-L1 internalization.Example 6A: Whole Blood Interferon γ Assay

[0254] To determine the increase of Interferon γ in whole blood, normal human blood (Biological Specialty Corp, Colmar. PA) diluted 1 / 10 in AIM-V media (Life Technologies) is incubated in the presence or absence of a concentration range of test compounds and 5 ng / ml Staphylococcal enterotoxin B (Toxin Technologies Sarasota, FL) in a 96 well U bottom Tissue Culture Plate (Corning) for 3 days at 37 0< C. Plates are centrifuged at 1400 RPM for 5 minutes, and supernatants collected and tested for presence of Interferon γ in a commercial Interferon γ ELISA kit (R&D Human IFN-γ Quantikine ELISA (R&D Systems, Minneapolis, MN).Example 7A: Animal Models

[0255] Studies to assess pharmacokinetics, pharmacodynamics, and efficacy are conducted in mice engrafted with human CD34+ cells and mice engineered to express human checkpoint molecules. Both preclinical models have been validated with approved therapeutics targeting the PD-1:PD-L1-axisHumanized CD34+ mice

[0256] Humanized CD34+ mice have been used commonly to study immune-oncology, infectious diseases and graft rejection research. In brief, immune-compromised NSG mice (NOD scid IL2Rg null< ; Jackson Laboratory) receive total body irradiation to deplete existing bone marrow cells. CD34+ human stem cells derived from umbilical cord blood are then engrafted to establish a fully human immune system over a 12-14 week period. Alternative mouse strains may also be used to improve the engraftment of stem cells and enhance the development of myeloid lineage cells, which are the main PD-L1-expressing host immune cells. For example, the NSG-SGM3 mice were engineered to produce human cytokines (SCF, IL-3 and GM-CSF) that allow full differentiation of the myeloid lineage [Jackson Laboratory]. Cell-derived xenograft models are selected based on tumor and host PD-L1 expression, as well as their response to anti-PD-L1 antibody treatment. PD-L1 internalization induced by small molecules targeting PD-L1 are the main pharmacodynamic biomarker and are determined by measuring the remaining PD-L1 expression on both tumor and host immune cellsHuman checkpoint molecule knock-in mice

[0257] Human-mouse chimeric models have been developed to allow binding of humanspecific antibodies to the human protein while using fully intact mouse immune biology. This approach is utilized to evaluate small molecules targeting PD-L1. To this end, the relevant extracellular domain of the human gene is integrated into the locus of the mouse gene by homologous recombination ('knock-in'). For example, the HuGEMM model for PD-1 and PD-L1 uses a human PD-1 knock-in strain that is engrafted with the mouse colon carcinoma cell line MC38 recombinantly expressing human PD-L1 [HuCELL; Crown Bioscience]. Human PD-L1 and PD-1 double knock-in animals with engraftment of MC38-huPD-L1 are developed and used to evaluate PD-L1 internalization induced by small molecules targeting PD-L1 in both tumor and host immune cells.Example 8A: Synthesis of Exemplary Compounds

[0258] Compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes. Synthesis of exemplary compounds are provided herein.Example 1 (S)-1-((2-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo [d] oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid

[0259] Step 1: methyl 3-chloro-4-hydroxy-5-nitrobenzoate

[0260]

[0261] To a solution of methyl 3-chloro-4-hydroxybenzoate (Alfa Aesar, #A512389: 10.0 g, 53.6 mmol) in acetic acid (20.0 mL, 352 mmol) was added a mixture of acetic acid (20.0 mL, 352 mmol) and nitric acid (4.72 mL, 112 mmol) dropwise at 0 °C. Then the ice bath was removed and the thick mixture was stirred at room temperature for 2 hrs. Then an equal volume of water was added to the reaction suspension at 0 °C. The mixture was filtered and washed with cold water. The resulting yellow solid was used directly in the next step without further purification. LC-MS calculated for C 8 H 7 ClNO 5 (M+H) +< : m / z = 232.0; found 232.0.Step 2: methyl 3-amino-5-chloro-4-hydroxybenzoate

[0262]

[0263] 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) for 1 h. The resulting suspension was filtered through a pad of Celite ®< , washed with EtOAc, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (eluting with MeOH / DCM 0%-10%). LC-MS calculated for C 8 H 9 ClNO 3 (M+H) +< : m / z = 202.0; found 202.0.Step 3: methyl 2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazole-5-carboxylate

[0264]

[0265] 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 redissovled 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 an aqueous Na 2 S 2 O 3 solution and NaHCO 3 solution. The organic phase was dried over MgSO 4 , filtered and the filtrate was concentrated. The crude residue was used directly in the next step without further purification. LC-MS calculated for C 16 H 12 BrClNO 3 (M+H) +< : m / z = 380.0, 382.0; found 379.9, 381.9.Step 4: (2-(3-bromo-2-methylphenyl)-7-chlorobenzo[d]oxazol-5-yl)methanol

[0266]

[0267] 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 up to 0 °C. Then the mixture was quenched with EtOAc and DCM, followed by addition of an aqueous Rochelle salt solution. The mixture was stirred vigorously at room temperature for 1 h. The organic phase was dried over MgSO 4 before filtering through a short pad of Celite ®< to remove solids. The filtrate was concentrated and purified by column chromatography (eluting with 0-5% MeOH / DCM) to give the desired product. LC-MS calculated for C 15 H 12 BrClNO 2 (M+H) +< : m / z = 352.0, 354.0; found 352.0, 354.0.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

[0268]

[0269] 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 mL) was purged with nitrogen then stirred at 110 °C for 2 h. The crude was diluted with DCM, and then filtered through Celite ®< . The filtrate was concentrated, and the resulting residue was purified by flash chromatography (eluting with EtOAc / Hexanes, 0-40%). LC-MS calculated for C 21 H 24 BClNO 4 (M+H) +< : m / z = 400.1; found 400.2.Step 6: tert-butyl 1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

[0270]

[0271] A solution of 1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine (Accela, cat#SY032476: 2.0 g, 14.58 mmol) and (Boc) 2 O (3.38 mL, 14.58 mmol) in dichloromethane (60 mL) was stirred at room temperature for 1 h. The reaction was quenched with saturated aqueous NaHCO 3 solution, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS calculated for C 12 H 20 N 3 O 2 (M+H) +< : m / z = 238.2; found 238.2.Step 7: 5-tert-butyl 2-methyl 1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-2,5(4H)-dicarboxylate

[0272]

[0273] n-Butyllithium in hexanes (2.5 M, 7.00 mL, 17.49 mmol) was added to a cold (-78 °C) solution of tert-butyl 1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (crude product from Step 6) in tetrahydrofuran (60.0 mL). The reaction mixture was stirred at -78 °C for 10 min prior to the addition of methyl chloroformate (1.7 mL, 21.9 mmol). After being stirred at -78 °C for 30 min, the reaction was then quenched with saturated aqueous NaHCO 3 solution, and extracted with ethyl acetate, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with 0 to 100% ethyl acetate in hexanes to afford the desired product. LC-MS calculated for C 14 H 22 N 3 O 4 (M+H) +< : m / z = 296.2; found 296.3.Step 8: tert-butyl 2-((3-bromo-2-chlorophenyl)carbamoyl)-1-methyl-1, 4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

[0274]

[0275] Potassium tert-butoxide in THF (1.0 M, 3.39 mL, 3.39 mmol) was added to a solution of 5-tert-butyl 2-methyl 1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-2,5(4H)-dicarboxylate (500 mg, 1.69 mmol) and 3-bromo-2-chloroaniline (Astatech, cat#CL9068; 348 mg, 1.69 mmol) in tetrahydrofuran (12.0 mL). After being stirred at room temperature for 1 h, the reaction mixture was quenched with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with 50% ethyl acetate in hexanes to afford the desired product. LC-MS calculated for C 19 H 23 BrClN 4 O 3 (M+H) +< : m / z = 469.1; found 469.1.Step 9: N-(3-bromo-2-chlorophenyl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide

[0276]

[0277] A solution of tert-butyl 2-((3-bromo-2-chlorophenyl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (300 mg, 0.64 mmol) in trifluoroacetic acid (0.2 mL) and dichloromethane (0.4 mL) was stirred at room temperature for 1 h. The solvent was evaporated, and the residue was dissolved in THF (1.0 mL). 37wt% Formaldehyde in water (0.48 mL, 6.39 mmol) and sodium triacetoxyborohydride (406 mg, 1.92 mmol) were successively added. After being stirred at room temperature for 1 h, the mixture was quenched with sat. NaHCO 3 solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with 10% methanol in dichloromethane to afford the desired product. LC-MS calculated for C 15 H 17 BrClN 4 O (M+H) +< : m / z = 383.0; found 383.0.Step 10: N-(2-chloro-3'-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2'-methylbiphenyl-3-yl)-1,5-dimethyl-4,5, 6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide

[0278]

[0279] A mixture of N-(3-bromo-2-chlorophenyl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide (150mg, 0.391 mmol), (7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methanol (Step 5: 188 mg, 0.469 mmol), and Dichloro[1,1'-bis(dicyclohexylphosphino)ferrocene]palladium(II) (17.7 mg, 0.023 mmol) in t-BuOH (5 ml) was added cesium carbonate (255 mg, 0.782 mmol) and a few drops of water. The reaction mixture was purged with nitrogen and then stirred at 100 °C for 5 hrs. After being cooled to room temperature, the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with 0 to 10% methanol in DCM to afford the desired product. LC-MS calculated for C 30 H 28 Cl 2 N 5 O 3 (M+H) +< : m / z = 576.2 ; found 576.1.Step 11: N-(2-chloro-3'-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2'-methylbiphenyl-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide

[0280]

[0281] A mixture of N-(2-chloro-3'-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide (140 mg, 0.24 mmol), tBuXPhos Pd G3 (19.3 mg, 0.024 mmol), potassium hexacyanoferrate(II) trihydrate (103 mg, 0.24 mmol) and potassium acetate (4.8 mg, 0.049 mmol) in 1,4-dioxane (3.0 mL) / Water (3.0 mL) was purged with nitrogen and then stirred at 100 °C for 1 h. After being cooled to room temperature, the reaction was extracted with ethyl acetate. The combined organic phases was dried over Na 2 SO 4 and concentrated under reduced pressure. The crude was used directly in the next step without further purification. LC-MS calculated for C 31 H 28 ClN 6 O 3 (M+H) +< : m / z = 567.2; found 567.2.Step 12: N-(2-chloro-3''-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2'-methylbiphenyl-3-yl)-1,5-dimethyl-4, 5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide

[0282]

[0283] To a stirred solution of N-(2-chloro-3'-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide (140.0 mg, 0.247 mmol) in DCM (3.0 ml) was added sodium bicarbonate (207 mg, 2.47 mmol) and dess-martin periodinane (157 mg, 0.370 mmol). The resulted mixture was stirred at rt for 2 hrs, then filtered. The filtrate was concentrated under reduced pressure. The residue was used in the next step directly without further purification. LC-MS calculated for C 31 H 26 ClN 6 O 3 (M+H) +< : m / z = 565.2; found 565.1.Step 13: (S)-1-((2-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid

[0284] To a solution of N-(2-chloro-3'-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide (65 mg, 0.115 mmol) in DCM (1 ml) was added (S)-pyrrolidine-3-carboxylic acid (66.2 mg, 0.575 mmol) and DIEA (0.161 ml, 0.920 mmol). The mixture was stirred at r.t. for 60 min, then sodium triacetoxyborohydride (73.1 mg, 0.345 mmol) was added. The resulting mixture was stirred at r.t. overnight then concentrated. The residue was purified via prep-HPLC (pH=2, MeCN / water with TFA) to give the desired product as the TFA salt. LC-MS calculated for C 36 H 35 ClN 7 O 4 (M+H) +< : m / z = 664.2; found 664.2.Example 2 (R)-1-((2-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-7-cyanobenzo [d] oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid

[0285]

[0286] This compound was prepared using similar procedure as described for Example 1 with (R)-pyrrolidine-3-carboxylic acid replacing (S)-pyrrolidine-3-carboxylic acid in Step 13. It was purified via pH 2 preparative HPLC (MeCN / water with TFA) to give the desired product as its TFA salt. LC-MS calculated for C 36 H 35 ClN 7 O 4 (M+H) +< : m / z = 664.2; found 664.3.Example 3 (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid

[0287] Step 1: 8-chloro-3-vinyl-1,7-naphthyridine

[0288]

[0289] A mixture of 3-bromo-8-chloro-1,7-naphthyridine (PharmaBlock, cat#PBLJ2743: 1221 mg, 5.01 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (927 mg, 6.02 mmol), sodium carbonate (1329 mg, 12.54 mmol) and tetrakis(triphenylphosphine)palladium(0) (290 mg, 0.25 mmol) in t-butanol (12 ml) and water (12 ml) was purged with nitrogen and sealed. It was stirred at 90 °C for 2 h. The reaction mixture was cooled to room temperature then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO 4 , filtered and concentrated under reduced pressure. The crude residue was used directly in the next step without further purification. LC-MS calculated for C 10 H 8 ClN 2 (M+H) +< : m / z = 191.0; found 191.0.Step 2: N-(3-bromo-2-methylphenyl)-3-vinyl-1, 7-naphthyridin-8-amine

[0290]

[0291] A mixture of 3-bromo-2-methylaniline (139 mg, 0.74 mmol), 8-chloro-3-vinyl-l,7-naphthyridine (142 mg, 0.74 mmol) and HCl in dioxane (4.0 M, 186 µL, 0.74 mmol) in t-butanol (3.7 mL) was heated at 130 °C for 2 h. The reaction mixture was then cooled to room temperature and diluted with DCM. The reaction was quenched by aqueous NaHCO 3 solution, extracted with DCM. The organic phase was dried over MgSO 4 , filtered and the filtrate was concentrated. The residue was used directly for next step. LC-MS calculated for C 17 H 15 BrN 3 (M+H) +< : m / z = 340.0; found 340.1.Step 3: 8-(3-bromo-2-methylphenylamino)-1, 7-naphthyridine-3-carbaldehyde

[0292]

[0293] A vial was charged with N-(3-bromo-2-methylphenyl)-3-vinyl-1,7-naphthyridin-8-amine (281 mg, 0.826 mmol), a stir bar, 1,4-dioxane (6.2 ml) and water (2.0 ml). To this suspension was added osmium tetroxide (4% w / w in water, 324 µl, 0.041 mmol). The reaction was stirred for 5 min then sodium periodate (883 mg, 4.13 mmol) was added. After stirring at room temperature for 1 h, the reaction mixture was quenched with a saturated aqueous solution of sodium thiosulfate. The mixture was then extracted with ethyl acetate, and the combined organic layers were separated, washed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The crude residue was used directly in the next step without further purification. LC-MS calculated for C 16 H 13 BrN 3 O (M+H) +< : m / z = 342.0; found 342.0.Step 4: (R)-1-((8-(3-bromo-2-methylphenylamino)-1, 7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol

[0294]

[0295] A mixture of 8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde (102 mg, 0.298 mmol) and (R)-pyrrolidin-3-ol (51.9 mg, 0.596 mmol) in DCM (1490 µl) was stirred at room temperature for 0.5 h. Then sodium triacetoxyborohydride (95 mg, 0.447 mmol) and acetic acid (25.0 µl, 0.447 mmol) were added. The mixture was further stirred at room temperature for 1 h. The reaction mixture was quenched by NH 4 OH aqueous solution then extracted with DCM. The organic phases were combined and dried over MgSO 4 , then filtered. The filtrate was concentrated and used directly in the next step without further purification. LC-MS calculated for C 20 H 22 BrN 4 O (M+H) +< : m / z = 413.1; found 413.1.Step 5: (R)-1-((8-(3'-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2'-dimethylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol

[0296]

[0297] A mixture of (R)-1-((8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol (419 mg, 1.01 mmol), (7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methanol (Example 1, Step 5: 611 mg, 1.12 mmol), sodium carbonate (269 mg, 2.53 mmol) and tetrakis(triphenylphosphine)palladium(0) (117 mg, 0.101 mmol) in water (1.7 mL) and 1,4-dioxane (8.4 mL) was purged with N 2 and then stirred at 100 °C for 4 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and then washed with H 2 O. The organic layer was dried over MgSO 4 and filtered. The filtrate was concentrated to give a crude residue, which was purified by flash chromatography on a silica gel column eluting with 0 to 15 % MeOH / DCM to give the desired product. LC-MS calculated for C 35 H 33 ClN 5 O 3 (M+H) +< : m / z = 606.2; found 606.4.Step 6: (R)-5-(hydroxymethyl)-2-(3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1, 7-naphthyridin-8-ylamino)-2, 2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile

[0298]

[0299] A mixture of (R)-1-((8-((3'-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol (79 mg, 0.13 mmol), [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1, 1'-biphenyl)] palladium(II) methanesulfonate (10.4 mg, 0.013 mmol), potassium hexacyanoferrate(II) trihydrate (55.1 mg, 0.130 mmol) and potassium acetate (2.6 mg, 0.026 mmol) in 1,4-dioxane (650 µl) and water (650 µl) was stirred and heated at 100 °C for 4 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and water, extracted with EtOAc. The combined organic phases was dried over MgSO 4 , and then filtered. The filtrate was concentrated. The crude material was purified by column chromatography (0-8% MeOH in DCM) to give the desired product. LC-MS calculated for C 36 H 33 N 6 O 3 (M+H) +< : m / z = 597.3; found 597.2.Step 7: (R)-5-formyl-2-(3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1, 7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazole-7-carbonitrile

[0300]

[0301] A suspension of (R)-5-(hydroxymethyl)-2-(3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile (72 mg, 0.12 mmol) and manganese dioxide (231 mg, 2.65 mmol) in DCM (1.2 mL) was stirred at 45 °C for 25 min. The reaction mixture was cooled to room temperature, filtered through a short pad of Celite ®< and then concentrated to yield a crude residue, which was used directly in the next step without further purification. LC-MS calculated for C 36 H 3 iN 6 0 3 (M+H) +< : m / z = 595.2; found 595.2.Step 8: (R)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-l-yl)methyl)-1, 7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid

[0302] A mixture of (R)-5-formyl-2-(3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazole-7-carbonitrile (72 mg, 0.12 mmol), (R)-pyrrolidine-3-carboxylic acid (27.9 mg, 0.242 mmol) and triethylamine (34 µl, 0.24 mmol) in DCM (800 µl) was stirred at room temperature for 2 h. Then sodium triacetoxyborohydride (38.5 mg, 0.182 mmol) and acetic acid (10.5 µl, 0.18 mmol) were added. The mixture was further stirred at room temperature for 1 h. The reaction mixture was diluted with MeOH and then purified by prep-HPLC (pH = 2, acetonitrile / water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C 41 H 40 N 7 O 4 (M+H) +< : m / z = 694.3; found 694.3. 1< H NMR (500 MHz, DMSO) δ 9.07 (s, 1H), 8.55 - 8.48 (m, 1H), 8.40 (d, J = 1.5 Hz, 1H), 8.25 - 8.10 (m, 3H), 8.04 (d, J = 5.8 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.48 (dd, J = 7.6, 1.4 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.23 (d, J = 6.0 Hz, 1H), 7.06 (d, J = 7.3 Hz, 1H), 4.86 - 4.36 (m, 5H), 3.88 - 3.00 (m, 9H), 2.49 (s, 3H), 2.42 - 2.15 (m, 2H), 2.06 (s, 3H), 2.02 - 1.80 (m, 2H).Example 4 (S)-1-((7-cyano-2-(3'-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo [d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid

[0303]

[0304] This compound was prepared using similar procedures as described for Example 3 with (S)-pyrrolidine-3-carboxylic acid replacing (R)-pyrrolidine-3-carboxylic acid in Step 8. The reaction mixture was diluted with MeOH and then purified by prep-HPLC (pH = 2, acetonitrile / water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C 41 H 40 N 7 O 4 (M+H) +< : m / z = 694.3 ; found 694.3. 1< H NMR (500 MHz, DMSO) δ 9.09 (s, 1H), 8.53 (s, 1H), 8.40 (d, J = 1.6 Hz, 1H), 8.20 (dd, J = 8.0, 1.4 Hz, 1H), 8.17 - 8.06 (m, 2H), 8.01 (d, J= 6.8 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.48 (dd, J = 7.7, 1.4 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.24 (d, J = 6.0 Hz, 1H), 7.09 (d, J = 7.7 Hz, 1H), 4.82 - 4.37 (m, 5H), 3.77 - 3.06 (m, 9H), 2.50 (s, 3H), 2.43 - 1.82 (m, 4H), 2.06 (s, 3H).Example 5(R)-1-((7-cyano-2-(3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo [d] oxazol-5-yl)methyl)azetidine-3-carboxylic acid

[0305]

[0306] This compound was prepared using similar procedures as described for Example 3 with azetidine-3-carboxylic acid replacing (R)-pyrrolidine-3-carboxylic acid in Step 8. The reaction mixture was diluted with MeOH and then purified by prep-HPLC (pH = 10, acetonitrile / water+NH 4 OH) to give the desired product. LC-MS calculated for C 40 H 38 N 7 O 4 (M+H) +< : m / z = 680.3 ; found 680.3.Example 6(R)-3-((7-cyano-2-(3'-(3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2'-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methylamino)-2,2-dimethylpropanoic acid

[0307]

[0308] This compound was prepared using similar procedures as described for Example 3 with 3-amino-2,2-dimethylpropanoic acid replacing (R)-pyrrolidine-3-carboxylic acid in Step 8. The reaction mixture was diluted with MeOH and then purified by prep-HPLC (pH = 10, acetonitrile / water+NH 4 OH) to give the desired product. LC-MS calculated for C 41 H 42 N 7 O 4 (M+H) +< : m / z = 696.3 ; found 696.3.Example 7(R)-1-((2-(2'-chloro-3'-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)-7-cyanobenzo [d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid

[0309] Step 1: 8-chloro-3-vinyl-1,7-naphthyridine

[0310]

[0311] A mixture of 3-bromo-8-chloro-1,7-naphthyridine (PharmaBlock, cat#PBLJ2743: 770 mg, 3.16 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (584 mg, 3.79 mmol), sodium carbonate (838 mg, 7.91 mmol) and tetrakis(triphenylphosphine)palladium(0) (183 mg, 0.158 mmol) in t-butanol (8 ml) and water (8 ml) was degassed and sealed. It was stirred at 80 °C for 2 h. The reaction mixture was cooled then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO 4 , and filtered. The filtrate was concentrated under reduced pressure. The crude residue was used directly in the next step without further purification. LC-MS calculated for C 10 H 8 ClN 2 (M+H) +< : m / z = 191.0; found 191.0.Step 2: N-(3-bromo-2-chlorophenyl)-3-vinyl-1, 7-naphthyridin-8-amine

[0312]

[0313] A mixture of 3-bromo-2-chloroaniline (Astatech, cat#CL9068; 536 mg, 2.59 mmol), 8-chloro-3-vinyl-1,7-naphthyridine (471 mg, 2.47 mmol) and 4M HCl in dioxane (618 µl, 2.47 mmol) in t-butanol (12.4 mL) was heated at 120°C for 2h. The reaction mixture was cooled to room temperature, diluted with DCM then quenched by aqueous NaHCO 3 solution and extracted with DCM. The organic phase was dried over MgSO 4 , filtered and the filtrate was concentrated. The residue was used directly in the next step without further purification. LC-MS calculated for C 16 H 12 BrClN 3 (M+H) +< : m / z = 360.0; found 360.0.Step 3: 8-(3-bromo-2-chlorophenylamino)-1, 7-naphthyridine-3-carbaldehyde

[0314]

[0315] To the solution of N-(3-bromo-2-chlorophenyl)-3-vinyl-1,7-naphthyridin-8-amine (135 mg, 0.374 mmol) in 1,4-dioxane (2.8 mL) and water (0.9 mL) was added osmium tetroxide (4% w / w in water, 147 µl, 0.019 mmol). The mixture was stirred at room temperature for 5 min then sodium periodate (400 mg, 1.872 mmol) was added. After stirring at room temperature for 1 h, the reaction mixture was quenched with a saturated aqueous solution of sodium thiosulfate. The mixture was then extracted with ethyl acetate, and the combined organic layers were separated, washed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The crude residue was used directly in the next step without further purification. LC-MS calculated for C 15 H 10 BrClN 3 O (M+H) +< : m / z = 362.0; found 362.0.Step 4: (S)-1-((8-(3-bromo-2-chlorophenylamino)-1, 7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol

[0316]

[0317] A mixture of 8-((3-bromo-2-chlorophenyl)amino)-1,7-naphthyridine-3-carbaldehyde (384 mg, 1.06 mmol) and (S)-pyrrolidin-3-ol (185 mg, 2.12 mmol) in DCM (5.3 mL) was stirred at room temperature for 0.5 h. Then sodium triacetoxyborohydride (337 mg, 1.59 mmol) and acetic acid (91 µl, 1.59 mmol) were added. The mixture was further stirred at room temperature for 1 h. The reaction mixture was quenched by NH 4 OH aqueous solution and extracted with DCM. The organic phases were combined and dried over MgSO 4 , then filtered. The filtrate was concentrated and the residue was purified by column chromatography on a silica gel column eluting with 0 to 8 % MeOH / DCM to give the desired product. LC-MS calculated for C 19 H 19 BrClN 4 O (M+H) +< : m / z = 433.0; found 433.0.Step 5: (S)-1-((8-(2-chloro-3'-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2'-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol

[0318]

[0319] A mixture of (S)-1-((8-(3-bromo-2-chlorophenylamino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol (10.3 mg, 0.024 mmol), (7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-5-yl)methanol (Example 1, Step 5: 9.5 mg, 0.024 mmol), sodium carbonate (6.30 mg, 0.059 mmol) and tetrakis(triphenylphosphine) palladium(0) (2.75 mg, 2.377 µmol) in water (40 µl) and 1,4-dioxane (200 µl) was purged with N 2 and then stirred at 100 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and then washed with H 2 O. The organic layer was dried MgSO 4 and filtered. The filtrate was concentrated to give a crude residue, which was purified by flash chromatography on a silica gel column eluting with 0 to 15 % MeOH / DCM to give the desired product. LC-MS calculated for C 34 H 30 Cl 2 N 5 O 3 (M+H) +< : m / z = 626.2; found 626.2.Step 6: (S)-2-(2'-chloro-3'-(3-((3-hydroxypyrrolidin-1-yl)tnethyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)-5-(hydroxymethyl)benzo[d]oxazole-7-carbonitrile

[0320]

[0321] A mixture of (S)-1-((8-((2-chloro-3'-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol (114 mg, 0.182 mmol), [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl)-2-(2'-amino-1,1-biphenyl)] palladium(II) methanesulfonate (14.4 mg, 0.018 mmol), potassium hexacyanoferrate(II) trihydrate (77 mg, 0.18 mmol) and potassium acetate (3.6 mg, 0.036 mmol) in 1,4-dioxane (910 µl) and water (910 µl) was stirred and heated at 100 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and water, and the layers were separated. The aqueous layer was further extracted with EtOAc and the combined organic phases were dried over MgSO 4 , and then filtered. The filtrate was concentrated and the crude material was purified by column chromatography (0-8% MeOH in DCM) to give the desired product. LC-MS calculated for C 35 H 30 ClN 6 O 3 (M+H) +< : m / z = 617.2; found 617.4.Step 7: (S)-2-(2'-chloro-3'-(3-((3-hydroxypyrrolidin-1-yl)tnethyl)-], 7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile

[0322]

[0323] A suspension of (S)-2-(2'-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)-5-(hydroxymethyl)benzo[d]oxazole-7-carbonitrile (64 mg, 0.104 mmol) and manganese dioxide (198 mg, 2.28 mmol) in DCM (1.0 mL) was stirred at 45 °C for 15 min. The reaction was filtered through a short pad of Celite ®< and then concentrated to yield a crude residue, which was used directly in the next step without further purification. LC-MS calculated for C 35 H 28 CIN 6 O 3 (M+H) +< : m / z = 615.2; found 615.2.Step 8: (R)-1-((2-(2'-chloro-3'-(3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylbiphenyl-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid

[0324] A mixture of (S)-2-(2'-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)-5-formylbenzo[d]oxazole-7-carbonitrile (10.2 mg, 0.017 mmol), (R)-3-methylpyrrolidine-3-carboxylic acid (J&W Pharmlab, #75R0495: 6.4 mg, 0.050 mmol) and triethylamine (6.9 µl, 0.050 mmol) in DCM (120 µl) was stirred at rt for 2 h. Then sodium triacetoxyborohydride (10.5 mg, 0.050 mmol) and acetic acid (3.0 µl, 0.050 mmol) were added. The mixture was further stirred at rt for 1 h. The reaction was diluted with MeOH and then purified by prep-HPLC (pH = 2, acetonitrile / water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C 41 H 39 CIN 7 O 4 (M+H) +< : m / z = 728.3; found 728.3.Example 8 (R)-1-((8-((3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1, 7-naphthyridin-8-yl)amino)- 2,2' -dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid

[0325] Step1: (R)-1-((8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol

[0326]

[0327] A mixture of 8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridine-3-carbaldehyde (Example 3, Step 3; 0.100g, 0.292 mmol) and (R)-3-hydroxypyrrolidine (Combi-Blocks, #AM-2005: 0.025 g, 0.292 mmol) in 1,2-dichloroethane (1.461 ml) and N,N diisopropylethylamine (0.051 ml, 0.292 mmol) was stirred at rt for 1 h. Sodium triacetoxyborohydride (0.093 g, 0.438 mmol) was carefully added in portions. The reaction was stirred at rt for 2 h, then quenched with a saturated aqueous solution of sodium bicarbonate. The mixture was then extracted with a 3:1 mixture of chlorofom / IPA. The combined organic layers were dried over sodium sulfate, and then concentrated in vacuo. The crude residue was purified by silica gel chromatography (0 → 30% methanol / DCM). LC-MS calculated for C 20 H 22 BrN 4 O (M+H) +< : m / z = 413.1; found 413.1.Step 2: (8-((2-methyl-3-(4,4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-1,7-naphthyridin-3-yl)methanol

[0328]

[0329] A mixture of (8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methanol (Affinity Research Chemicals, #ARI-0169: 0.300 g, 0.872 mmol), bis(pinacolato)diboron (Aldrich, #473294: 0.266 g, 1.046 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.071 g, 0.087 mmol) and potassium acetate (0.214 g, 2.179 mmol) was charged 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, and the resulting residue was used directly in the next step without further purification. LC-MS calculated for C 22 H 27 BN 3 O 3 (M+H) +< : m / z = 392.2; found 392.3.Step 3: (R)-1-((8-((3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dirnethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol

[0330]

[0331] To a vial was added (8-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-1,7-naphthyridin-3-yl)methanol (0.162 g, 0.414 mmol), (R)-1-((8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol (0.163g, 0.394 mmol), 1 M aqueous sodium carbonate (0.789 mmol), [1,1'-bis(di-cyclohexylphosphino)ferrocene]-dichloropalladium (II) (0.029 g, 0.039 mmol), and 1,4-dioxane (3.48 ml). The mixture was degassed, sealed, and heated to 90 °C whilst stirring for 2 h. The mixture was cooled, diluted with EtOAc and filtered through Celite ®< . The filtrate was concentrated and purified using silica gel chromatography (20% MeOH / DCM) to provide the desired compound as an orange solid. LC-MS calculated for C 36 H 36 N 7 O 2 (M+H) +< : m / z = 598.3; found 598.4.Step 4: (R)-8-((3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,11'-biphenyl]-3-yl)amino)-1,7-naphthyridine-3-carbaldehyde

[0332]

[0333] To a solution of (R)-1-((8-((3'-((3-(hydroxymethyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol (0.0715 g, 0.120 mmol) in DCM (1.196 ml) was added manganese dioxide (0.208 g, 2.392 mmol). The resulting mixture was heated at 45 °C for 30 min. After cooling, the mixture was filtered through Celite ®< and the filtrate was concentrated. The crude orange solid was used directly in the next step without further purification. LC-MS calculated for C 36 H 34 N 7 O 2 (M+H) +< : m / z = 596.3; found 596.5.Step 5: (R)-1-((8-((3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid

[0334] To a vial was added (R)-8-((3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridine-3-carbaldehyde (0.013 g, 0.022 mmol), (R)-pyrrolidine-3-carboxylic acid (Combi-Blocks, #ST-7698: 7.5 mg, 0.065 mmol), 1,2-dichloroethane (0.336 ml) and triethylamine (9.13 µl, 0.065 mmol). The reaction was stirred at rt for 2 h, then sodium triacetoxyborohydride (0.023 g, 0.109 mmol) and acetic acid (3.75 µl, 0.065 mmol) were added. The reaction was stirred for 2 h, then the mixture was diluted with methanol and purified by prep-HPLC (pH = 2, acetonitrile / water+TFA) to give the desired product as TFA salt. LC-MS calculated for C 41 H 43 N 8 O 3 (M+H) +< : m / z = 695.3; found 695.3. 1< H NMR (500 MHz, DMSO) δ 10.72 (br s, 2H), 9.11 (m, 2H), 8.54 (m, 2H), 8.02 (m, 4H), 7.42 (m, 2H), 7.26 (m, 2H), 7.11 (m, 2H), 4.70 (m, 4H), 4.47 (m, 1H), 3.82 - 3.08 (m, 10H), 2.38 - 2.18 (m, 2H), 2.10 (s, 6H), 2.05 - 1.82 (m, 2H).Example 9 (S)-1-((8-((3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid

[0335]

[0336] This compound was prepared using similar procedures as described for Example 8 with (S)-pyrrolidine-3-carboxylic acid (Combi-Blocks, #ST-1381) replacing (R)-pyrrolidine-3-carboxylic acid in Step 5. The reaction was diluted with MeOH and then purified by prep-HPLC (pH = 2, acetonitrile / water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C 41 H 43 N 8 O 3 (M+H) +< : m / z = 695.3 ; found 695.3.Example 10 (R)-1-((7-cyano-2-(2,2'-dimethyl-3'-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid

[0337] Step 1: (2-(3'-bromo-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-7-chlorobenzo[d]oxazol-5-yl)methanol

[0338]

[0339] To a solution 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 (Example 1, Step 5: 11.3 g, 28.4 mmol) and 1,3-dibromo-2-methylbenzene (14.17 g, 56.7 mmol) in H 2 O (30 mL) and 1,4-dioxane (120 ml) was added Na 2 CO 3 (6.01 g, 56.7 mmol) and PdCl 2 (dppf)-CH 2 Cl 2 adduct (2.316 g, 2.84 mmol). The resulted mixture was stirred in a closed vial flushed with argon at 100 °C for 1.5 h. The reaction mixture was concentrated, followed by extraction with dichloromethane (25 mL x 3). The combined organic layers were dried Na 2 SO 4 , filtered and concentrated. The crude product was added to a silica gel column and was eluted with ethyl acetate / dichloromethane from 0% to 40% to give (2-(3'-bromo-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-7-chlorobenzo[d]oxazol-5-yl)methanol (10.2 g, 23.0 mmol, 81 % yield). LC-MS calculated for C 22 H 18 BrClNO 2 (M+H) +< : m / z = 442.0; found 442.1.Step 2: (7-chloro-2-(2, 2 '-dimethyl-3'-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1 '-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methanol

[0340]

[0341] (2-(3'-bromo-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-7-chlorobenzo[d]oxazol-5-yl)methanol (6.52 g, 14.7 mmol) was dissolved in dioxane (14.7 mL) to give a pale yellow solution. B 2 Pin 2 (4.49 g, 17.7 mmol), potassium acetate (2.89 g, 29.5 mmol) and PdCl 2 (dppf)-CH 2 Cl 2 adduct (1.20 g, 1.47 mmol) were added to the reaction mixture. The reaction mixture was heated to 100 °C. After 12 h, saturated NaHCO 3 (25 mL) was added to the reaction mixture followed by extraction with dichloromethane (25 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated. The crude product was added to a silica gel column and was eluted with ethyl acetate / hexane from 0% to 60% to give (7-chloro-2-(2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methanol (6.33 g, 12.9 mmol, 88 % yield) as a yellow foam. LC-MS calculated for C 28 H 30 BClNO 4 (M+H) +< : m / z = 490.2; found 490.1.Step 3: tert-butyl 2-(3'-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate

[0342]

[0343] (7-chloro-2-(2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methanol (2.98 g, 6.08 mmol), tert-butyl 2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (AstaTech, cat#AB1021: 2.33 g, 7.29 mmol), Na 2 CO 3 (1.29 g, 12.2 mmol) and PdCl 2 (dppf)-CH 2 Cl 2 adduct (496 mg, 0.608 mmol) in 1,4-dioxane (60 ml) and water (15 mL) were stirred in a closed vial flushed with argon at 100 °C for 1 h. Saturated NaHCO 3 (50 mL) was added to the reaction mixture followed by extraction with dichloromethane (25 mL x 4). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated. The crude product was added to a silica gel column and was eluted with ethyl acetate / hexane from 0% to 60% to give tert-butyl 2-(3'-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (1.80 g, 2.99 mmol, 49.2 % yield) as a yellow oil. LC-MS calculated for C 33 H 33 ClN 3 O 4 S (M+H) +< : m / z = 602.2; found 602.1.Step 4: tert-butyl 2-(3'-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6,7-dihydrothiazolof-5,4-c]pyridine-5(4H)-carboxylate

[0344]

[0345] In a 4 dram vial tert-butyl 2-(3'-(7-chloro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyndine-5(4H)-carboxylate (900 mg, 1.50 mmol) and potassium ferrocyanide(II) hydrate (947 mg, 2.24 mmol) were dissolved in 1,4-dioxane (10 ml) and water (4.5 ml). Potassium acetate (367 mg, 3.74 mmol) and [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1, 1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)] palladium(II) methanesulfonate (119 mg, 0.15 mmol) were added to the reaction mixture. The reaction mixture was heated to 100 °C. After 2 h, saturated NaHCO 3 (15 mL) was added to the reaction mixture followed by extraction with dichloromethane (10 mL x 4). The combined organic layers were dried Na 2 SO 4 , filtered and concentrated. The crude product was added to a silica gel column and was eluted with ethyl acetate / hexane from 10% to 60% to give tert-butyl 2-(3'-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (702 mg, 1.18 mmol, 79 % yield) as a yellow oil. LC-MS calculated for C 34 H 33 N 4 O 4 S (M+H) +< : m / z = 593.2; found 593.1.Step 5: tert-butyl 2-(3'-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate

[0346]

[0347] To a solution of tert-butyl 2-(3'-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (150 mg, 0.253 mmol) in DCM (2 mL) was added Dess-Martin periodinane (161 mg, 0.380 mmol). After 1 h, saturated NaHCO 3 (5 mL) was added to the reaction mixture followed by extraction with dichloromethane (5 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated. The crude product was used for next step without further purification. LC-MS calculated for C 34 H 31 N 4 O 4 S (M+H) +< : m / z = 591.2 ; found 591.3.Step 6: (R)-1-((7-cyano-2-(2,2'-dimethyl-3'-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)biphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid

[0348] To a mixture of tert-butyl 2-(3'-(7-cyano-5-formylbenzo[d]ox...

Claims

1. A compound of Formula (IV): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: ring A is selected from: and each subscript q is independently an integer of 1, 2, 3 or 4; each R28 is independently H or C1-6 alkyl; the wavy line indicates the point of attachment to L; L is a bond, -NH-, -O-, -C(O)NH-, -C(=S)NH-, -C(=NH)NH-, -C(=NOH)NH-, -C(=NCN)NH-, -CH2O- or -OCH2-, wherein the carbonyl group in the -C(O)NH- linkage is attached to ring A; R21 and R22 are each independently halo, C1-6 alkyl or CN; R23 is H, C1-6 alkyl or C1-6 haloalkyl; R25 is C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, halo, OH, -COOH, NH2, -NHC1-4 alkyl or -N(C1-4 alkyl)2; R26 is C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, halo, OH, -COOH, NH2, -NHC1-4 alkyl or -N(C1-4 alkyl)2; R24 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-14 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-14 membered heterocycloalkyl)-C1-4 alkyl-, C(O)Ra, C(O)NRaRa, C(O)ORa, C(=NRa)Ra, C(=NOH)Ra, C(=NOH)NRa, C(=NCN)NRaRa, C(=NRa)NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, -P(O)RaRa, -P(O)(ORa)(ORa), -B(OH)2, -B(ORa)2 and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-14 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl- and (4-14 membered heterocycloalkyl)-C1-4 alkyl- of R24 are each optionally substituted with 1, 2, 3, 4 or 5 independently selected Rb substituents; R20 is each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-14 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-14 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa1, SRa1, NHORa1, C(O)Ra1, C(O)NRa1Ra1, C(O)ORa1, C(O)NRa1S(O)2Ra1, OC(O)Ra1, OC(O)NRa1Ra1, NHRa1, NRa1Ra1, NRa1C(O)Ra1, NRa1C(=NRa1)Ra1, NRa1C(O)ORa1, NRa1C(O)NRa1Ra1, C(=NRa1)Ra1, C(=NOH)Ra1, C(=NOH)NRa1, C(=NCN)NRa1Ra1 , NRa1C(=NCN)NRa1Ra1, C(=NRa1)NRa1Ra1, NRa1C(=NRa1)NRa1Ra1, NRa1S(O)Ra1, NRa1S(O)2Ra1, NRa1S(O)2NRa1Ra1, S(O)Ra1, S(O)NRa1Ra1, S(O)2Ra1, S(O)2NRa1C(O)Ra1, - P(O)Ra1Ra1, -P(O)(ORa1)(ORa1), -B(OH)2, -B(ORa1)2 and S(O)2NRa1Ra1, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-14 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl- and (4-14 membered heterocycloalkyl)-C1-4 alkyl- of R20 are each optionally substituted with 1, 2, 3, 4 or 5 independently selected Rb substituents; R27 is each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-14 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-14 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa2, SRa2, NHORa2, C(O)Ra2, C(O)NRa2Ra2, C(O)ORa2, C(O)NRa2S(O)2Ra2, OC(O)Ra2, OC(O)NRa2Ra2 NHRa2, NRa2Ra2, NRa2C(O)Ra2, NRa2C(=NRa2)Ra2, NRa2C(O)ORa2, NRa2C(O)NRa2Ra2, C(=NRa2)Ra2, C(=NOH)Ra2, C(=NOH)NRa2, C(=NCN)NRa2Ra2 , NRa2C(=NCN)NRa2Ra2, C(=NRa2)NRa2Ra2, NRa2C(=NRa2)NRa2Ra2, NRa2S(O)Ra2, NRa2S(O)2Ra2, NRa2S(O)2NRa2Ra2, S(O)Ra2, S(O)NRa2Ra2, S(O)2Ra2, S(O)2NRa2C(O)Ra2, - P(O)Ra2Ra2, -P(O)(ORa2)(ORa2), -B(OH)2, -B(ORa2)2 and S(O)2NRa2Ra2, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-14 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl- and (4-14 membered heterocycloalkyl)-C1-4 alkyl- of R27 are each optionally substituted with 1, 2, 3, 4 or 5 independently selected Rb substituents; or two R20 substituents attached to the same ring carbon atom taken together with the ring carbon atom to which they are attached form spiro C3-6 cycloalkyl or spiro 4- to 7-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected Rf substituents; or two R27 substituents attached to the same ring carbon atom taken together with the ring carbon atom to which they are attached form spiro C3-6 cycloalkyl or spiro 4- to 7-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected Rf substituents; each of Ra, Ra1 and Ra2 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-14 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, and (4-14 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-14 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl- and (4-14 membered heterocycloalkyl)-C1-4 alkyl- of Ra, Ra1 and Ra2 are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rd substituents; each Rd is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-14 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-14 membered heterocycloalkyl)-C1-4 alkyl-, CN, NH2, NHORe, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, C(O)NReS(O)2Re, OC(O)Re, OC(O)NReRe, NHRe, NReRe, NReC(O)Re, NReC(=NRe)Re, NReC(O)NReRe, NReC(O)ORe, C(=NRe)NReRe, NReC(=NRe)NReRe, NReC(=NOH)NReRe, NReC(=NCN)NReRe, S(O)Re, S(O)NReRe, S(O)2Re, S(O)2NReC(O)Re, NReS(O)2Re, NReS(O)2NReRe, -P(O)ReRe, -P(O)(ORe)(ORe), -B(OH)2, -B(ORe)2 and S(O)2NReRe, wherein the C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-14 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, and (4-14 membered heterocycloalkyl)-C1-4 alkyl- of Rd are each optionally substituted with 1, 2, or 3 independently selected Rf substituents; each Re is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Re are each optionally substituted with 1, 2 or 3 independently selected Rf substituents; each Rb substituent is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-14 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-14 membered heterocycloalkyl)-C1-4 alkyl-, CN, OH, NH2, NO2, NHORc, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, C(O)NRcS(O)2Rc, OC(O)Rc, OC(O)NRcRc, C(=NOH)Rc, C(=NOH)NRc, C(=NCN)NRcRc, NRcC(=NCN)NRcRc, C(=NRc)NRcRc, NRcC(=NRc)NRcRc, NHRc, NRcRc, NRcC(O)Rc, NRcC(=NRc)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S(O)2Rc, S(O)2NRcC(O)Rc, -P(O)RcRc, -P(O)(ORc)(ORc), -B(OH)2, -B(ORc)2 and S(O)2NRcRc; wherein the C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-14 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl- and (4-14 membered heterocycloalkyl)-C1-4 alkyl- of Rb are each further optionally substituted with 1, 2 or 3 independently selected Rd substituents; each Rc is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-14 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, and (4-14 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-14 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl- and (4-14 membered heterocycloalkyl)-C1-4 alkyl- of Rc are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rf substituents; each Rf is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, halo, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, C(O)NRgS(O)2Rg, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, NRgC(O)Rg, NRgC(=NRg)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(=NRg)NRgRg, NRgC(=NR9)NRgRg, S(O)Rg, S(O)NRgRg, S(O)2Rg, S(O)2NRgC(O)Rg, NRgS(O)2Rg, NRgS(O)2NRgRg, -P(O)RgRg, - P(O)(ORg)(ORg), -B(OH)2, -B(ORg)2 and S(O)2NRgRg; wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rf are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rn substituents; each Rn is substituents independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, halo, CN, NHORo, ORo, SRo, C(O)Ro, C(O)NRoRo, C(O)ORo, C(O)NRoS(O)2Ro, OC(O)Ro, OC(O)NRoRo, NHRo, NRoRo, NRoC(O)Ro, NRoC(=NRo)Ro, NRoC(O)NRoRo, NRoC(O)ORo, C(=NRo)NRoRo, NRoC(=NRo)NRoRo, S(O)Ro, S(O)NRoRo, S(O)2Ro, S(O)2NRoC(O)Ro, NRoS(O)2Ro, NRoS(O)2NRoRo, -P(O)RoRo, - P(O)(ORo)(ORo), -B(OH)2, -B(ORo)2 and S(O)2NRoRo, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rn are each optionally substituted with 1, 2 or 3 independently selected Rq substituents; each Rg is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rg are each optionally substituted with 1, 2, or 3 independently selected Rp substituents; each Rp is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, halo, CN, NHORr, ORr, SRr, C(O)Rr, C(O)NRrRr, C(O)ORr, C(O)NRrS(O)2Rr, OC(O)Rr, OC(O)NRrRr, NHRr, NRrRr, NRrC(O)Rr, NRrC(=NRr)Rr, NRrC(O)NRrRr, NRrC(O)ORr, C(=NRr)NRrRr, NRrC(=NRr)NRrRr, NRrC(=NOH)NRrRr, NRrC(=NCN)NRrRr, S(O)Rr, S(O)NRrRr, S(O)2Rr, S(O)2NRrC(O)Rr, NRrS(O)2Rr, NRrS(O)2NRrRr, -P(O)RrRr, -P(O)(ORr)(ORr), -B(OH)2, -B(ORr)2 and S(O)2NRrRr, wherein the C1-6 alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rp is optionally substituted with 1, 2 or 3 independently selected Rq substituents; or any two Ra substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 independently selected Rh substituents; or any two Ra1 substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 independently selected Rh substituents; or any two Ra2 substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 independently selected Rh substituents; each Rh is independently selected from C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, halo, CN, ORi, SRi, NHORi, C(O)Ri, C(O)NRiRi, C(O)ORi, C(O)NRiS(O)2Ri, OC(O)Ri, OC(O)NRiRi, NHRi, NRiRi, NRiC(O)Ri, NRiC(=NRi)Ri, NRiC(O)NRiRi, NRiC(O)ORi, C(=NRi)NRiRi, NRiC(=NRi)NRiRi, S(O)Ri, S(O)NRiRi, S(O)2Ri, S(O)2NRiC(O)Ri, NRiS(O)2Ri, NRiS(O)2NRiRi, -P(O)RiRi, - P(O)(ORi)(ORi), -B(OH)2, -B(ORi)2 and S(O)2NRiRi, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rh are each optionally substituted by 1, 2, or 3 independently selected Rj substituents; each Rj is independently selected from C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C2-4 alkenyl, C2-4 alkynyl, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, CN, NHORk, ORk, SRk, C(O)Rk, C(O)NRkRk, C(O)ORk, C(O)NRkS(O)2Rk, OC(O)Rk, OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, NRkC(=NRk)Rk, NRkC(O)NRkRk, NRkC(O)ORk, C(=NRk)NRkRk, NRkC(=NRk)NRkRk, S(O)Rk, S(O)NRkRk, S(O)2Rk, S(O)2NRkC(O)Rk, NRkS(O)2Rk, NRkS(O)2NRkRk, -P(O)RkRk, -P(O)(ORk)(ORk), - B(OH)2, -B(ORk)2 and S(O)2NRkRk, wherein the C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, and C1-4 haloalkoxy of Rj are each optionally substituted with 1, 2 or 3 independently selected Rq substituents; or two Rh groups attached to the same carbon atom of the 4- to 10-membered heterocycloalkyl taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms as ring members selected from O, N or S; or any two Rc substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents; or any two Re substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents; or any two Rg substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents; or any two Ri substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rq substituents; or any two Rk substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rq substituents; or any two Ro substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents; or any two Rr substituents together with the boron, phosphorus or nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents; each Ri, Rk, Ro or Rr is independently selected from H, C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C1-4 haloalkyl, C1-4 haloalkoxy, C2-4 alkenyl, and C2-4 alkynyl, wherein the C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C2-4 alkenyl, and C2-4 alkynyl of Ri, Rk, Ro or Rr are each optionally substituted with 1, 2 or 3 independently selected Rq substituents; each Rq is independently selected from halo, OH, CN, -COOH, B(OH)2, NH2, -NH-C1-6 alkyl, -N(C1-6 alky)2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 haloalkoxy, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl and C3-6 cycloalkyl, wherein the C1-6 alkyl, phenyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl of Rq are each optionally substituted with 1, 2 or 3 substituents independently selected from halo, OH, CN, -COOH, NH2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, phenyl, C3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl; the subscript m is an integer of 0, 1, 2 or 3; the subscript n is an integer of 0, 1, 2 or 3; the subscript p is an integer of 1, 2, 3, 4, 5 or 6; and is a single bond or a double bond to maintain the 5-membered imidazole ring being aromatic.

2. The compound of claim 1, having Formula (V): or a pharmaceutically acceptable salt or a stereoisomer thereof.

3. The compound of any one of claims 1-2, having: (a) Formula (Va): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R28 is H or C1-6 alkyl and the subscript q is an integer of 1, 2 or 3; or (b) Formula (Va-1): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R28 is H or C1-6 alkyl.

4. The compound of any one of claims 1-2, having: (a) Formula (Vb): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the subscript q is an integer of 1, 2 or 3; or (b) Formula (Vb-1): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the subscript q is an integer of 1, 2 or 3.

5. The compound of any one of claims 1-2, having: (a) Formula (Vc): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the subscript q is an integer of 1, 2 or 3; or (b) Formula (Vc-1): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the subscript q is an integer of 1, 2 or 3.

6. The compound of any one of claims 1-2, having: (a) Formula (Vd): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the subscript q is an integer of 1, 2 or 3; or (b) Formula (Vd-1): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the subscript q is an integer of 1, 2 or 3.

7. The compound of any one of claims 1-2, having: (a) Formula (Ve): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R28 is H or C1-6 alkyl and the subscript q is an integer of 1, 2 or 3; or (b) Formula (Ve-1): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the subscript q is an integer of 1, 2 or 3.

8. The compound of any one of claims 1-2, having: (a) Formula (Vf): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the subscript q is an integer of 1, 2 or 3; or (b) Formula (Vf-1): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the subscript q is an integer of 1, 2 or 3.

9. The compound of any one of claims 1-2, having: (a) Formula (Vg): or a pharmaceutically acceptable salt or a stereoisomer thereof; or (b) Formula (Vg-1): or a pharmaceutically acceptable salt or a stereoisomer thereof; or (c) Formula (Vg-2): or a pharmaceutically acceptable salt or a stereoisomer thereof.

10. The compound of any one of claims 1-2, having: (a) Formula (Vh): or a pharmaceutically acceptable salt or a stereoisomer thereof; or (b) Formula (Vh-1): or a pharmaceutically acceptable salt or a stereoisomer thereof; or (c) Formula (Vh-2): or a pharmaceutically acceptable salt or a stereoisomer thereof.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: (a) R20 is H, C1-6 alkyl, 2-hydroxypropyl, (R)-2-hydroxypropyl, (S)-2-hydroxypropyl, 2-hydroxyethyl, 1-(methylsulfonyl)piperidin-4-yl, tetrahydro-2H-pyran-4-yl, (tetrahydro-2H-pyran-4-yl)methyl, 1-(hydroxymethyl)cyclopropyl)methyl, (S)-(2,3-dihydroxypropyl)-1-methyl, (2,3-dihydroxypropyl)-1-methyl, (R)-(2,3-dihydroxypropyl)-1-methyl, carboxymethyl, 1-acetylpiperidin-4-yl, 4-carboxy-4-methylcyclohexyl, 3-(methylsulfonamido)propyl, trans-(4-carboxycyclohexyl)methyl, cis-(4-carboxycyclohexyl)methyl, (3-carboxypyrrolidin-1-yl)methyl, (R)-(3-carboxypyrrolidin-1-yl)methyl, (S)-(3-carboxypyrrolidin-1-yl)methyl, (3-hydroxypyrrolidin-1-yl)methyl, (R)-(3-hydroxypyrrolidin-1-yl)methyl, (S)-(3-hydroxypyrrolidin-1-yl)methyl, pyrrolidin-1-ylmethyl, 2-(dimethylamino)acetyl, (5-cyanopyridin-3-yl)methoxy, (2-carboxypiperidin-1-yl)methyl, (R)-(2-carboxypiperidin-1-yl)methyl, (S)-(2-carboxypiperidin-1-yl)methyl, halo, cyclobutyl, cyclopropylmethyl, or CN; or (b) R20 is H, C1-6 alkyl, 2-hydroxypropyl, (R)-2-hydroxypropyl, (S)-2-hydroxypropyl, 2-hydroxyethyl, 1-(methylsulfonyl)piperidin-4-yl, tetrahydro-2H-pyran-4-yl, (tetrahydro-2H-pyran-4-yl)methyl, 1-(hydroxymethyl)cyclopropyl)methyl, (S)-(2,3-dihydroxypropyl)-1-methyl, (2,3-dihydroxypropyl)-1-methyl, (R)-(2,3-dihydroxypropyl)-1-methyl, carboxymethyl, 1-acetylpiperidin-4-yl, 4-carboxy-4-methylcyclohexyl, 3-(methylsulfonamido)propyl, trans-(4-carboxycyclohexyl)methyl, cis-(4-carboxycyclohexyl)methyl, (3-carboxypyrrolidin-1-yl)methyl, (R)-(3-carboxypyrrolidin-1-yl)methyl, (S)-(3-carboxypyrrolidin-1-yl)methyl, (3-hydroxypyrrolidin-1-yl)methyl, (R)-(3-hydroxypyrrolidin-1-yl)methyl, (S)-(3-hydroxypyrrolidin-1-yl)methyl, pyrrolidin-1-ylmethyl, 2-(dimethylamino)acetyl, (5-cyanopyridin-3-yl)methoxy, (2-carboxypiperidin-1-yl)methyl, (R)-(2-carboxypiperidin-1-yl)methyl, (S)-(2-carboxypiperidin-1-yl)methyl, halo, cyclobutyl, cyclopropylmethyl, CN, trans-(4-carboxycyclohexyl)ethyl, cis-(4-carboxycyclohexyl)ethyl, 4-carboxycyclohexyl, trans-4-carboxycyclohexyl, cis-4-carboxycyclohexyl, 4-carboxybenzyl, 4-carboxyphenethyl, 2-(4-carboxy-4-methylcyclohexyl)methyl, 2-(4-carboxy-4-methylcyclohexyl)ethyl, (4-carboxybicyclo[2.2.2]octan-1-yl)methyl, 4-carboxybicyclo[2.2.1]heptan-1-yl, (4-carboxybicyclo[2.2.1]heptan-1-yl)methyl, 4-carboxy-4-methylcyclohexyl, (S)-3-hydroxypyrrolidin-1-yl)acetyl, (R)-3-hydroxypyrrolidin-1-yl)acetyl, 4-carboxy-4-ethylcyclohexyl, N-isopropyl-N-methylglycyl, (R)-3-carboxy-3-methylpyrrolidin-1-yl, (S)-3-carboxy-3-methylpyrrolidin-1-yl, (S)-1-hydroxypropan-2-yl)glycyl, (R)-1-hydroxypropan-2-yl)glycyl, (3-hydroxycyclobutyl)glycyl, cis-(3-hydroxycyclobutyl)glycyl, trans-(3-hydroxycyclobutyl)glycyl, dimethylglycyl, N-ethyl-N-methylglycyl, ethyl(methyl)amino)propanoyl, or 1-carboxyadamant-4-yl.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: (a) L is -C(O)NH-; or (b) L is a bond.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R21 and R22 are each independently Cl, CN or methyl.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R23 is methyl.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: (a) R24 is H, C1-6 alkyl, 2-hydroxypropyl, (R)-2-hydroxypropyl, (S)-2-hydroxypropyl, 2-hydroxyethyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-4 alkyl-, 1-(methylsulfonyl)piperidin-4-yl or tetrahydro-2H-pyran-4-yl; or (b) R24 is H, C1-6 alkyl, 2-hydroxypropyl, (R)-2-hydroxypropyl, (S)-2-hydroxypropyl, 2-hydroxyethyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-4 alkyl-, 1-(methylsulfonyl)piperidin-4-yl, or tetrahydro-2H-pyran-4-yl, 4-hydroxycyclohexyl, trans-(4-carboxycyclohexyl)methyl, cis-(4-carboxycyclohexyl)methyl, (4-carboxycyclohexyl)ethyl, 4-carboxy-4-methylcyclohexyl, or 2-(4-carboxycyclohexyl)ethyl.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the subscript q is 1.

17. The compound of claim 1, wherein the compound is selected from: (a) N,N'-(2-chloro-2'-cyanobiphenyl-3,3'-diyl)bis(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide); N-(2-chloro-2'-cyano-3'-(3-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide; N-(2'-chloro-2-cyano-3'-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamido)biphenyl-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; N-(2'-chloro-2-cyano-3'-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamido)biphenyl-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; N,N'-(2,2'-dichlorobiphenyl-3,3'-diyl)bis(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide); N,N'-(2-chloro-2'-methyl-[1,1'-biphenyl]-3,3'-diyl)bis(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide); N-(2-chloro-2'-cyano-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide; N,N'-(2-chloro-2'-cyanobiphenyl-3,3'-diyl)bis(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide); N,N'-(2-chloro-2'-methylbiphenyl-3,3'-diyl)bis(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide); (S)-N,N'-(2-chloro-2'-methylbiphenyl-3,3'-diyl)bis(5-((S)-2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide); N,N'-(2-chloro-2'-methylbiphenyl-3,3'-diyl)bis(5-(2-hydroxyethyl)-1-methyl-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine-2-carboxamide); (S)-N-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-5-(2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; (R)-N-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-5-(2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; (S)-N-(2-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2'-methylbiphenyl-3-yl)-5-(2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; (S)-N-(2,2'-dichloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-yl)-5-(2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; N-(2-chloro-2'-methyl-3'-(1-methyl-5-(1-(methylsulfonyl)piperidin-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine-2-carboxamide; N-(2-chloro-2'-methyl-3'-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; N-(2-chloro-2'-methyl-3'-(1-methyl-5-((tetrahydro-2H-pyran-4-yl)methyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; N-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-5-((1-(hydroxymethyl)cyclopropyl)methyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; (S)-N-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-5-(2,3-dihydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; 2-(2-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)acetic acid; 5-(1-acetylpiperidin-4-yl)-N-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; 4-(2-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)-1-methylcyclohexanecarboxylic acid; N-(2-chloro-2'-methyl-3'-(1-methyl-5-(3-(methylsulfonamido)propyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; Trans-4-((2-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexane-1-carboxylic acid; N-(2-chloro-2'-cyano-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-yl)-5-(2-hydroxyethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; (S)-N-(2-chloro-2'-cyano-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-yl)-5-(2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; (R)-N-(2-chloro-2'-cyano-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-yl)-5-(2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; (S)-N-(2'-chloro-2-methyl-3'-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)-5-(2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine-2-carboxamide; (S)-N-(2'-chloro-3'-(5-(2-hydroxyethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-yl)-5-(2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine-2-carboxamide; (S)-N-(2'-chloro-2-methyl-3'-(1-methyl-5-(1-(methylsulfonyl)piperidin-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-yl)-5-(2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; (S)-N-(2-chloro-3'-(5-(2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2'-methylbiphenyl-3-yl)-5-cyclobutyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; (S)-N-(2-chloro-3'-(5-(2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2'-methylbiphenyl-3-yl)-5-isopropyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; (S)-N-(2-chloro-3'-(5-(2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2'-methylbiphenyl-3-yl)-5-(cyclopropylmethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; (S)-N-(2'-chloro-2-methyl-3'-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-yl)-5-(2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; (R)-N-(2-chloro-3'-(5-((3-hydroxypyrrolidin-1-yl)methyl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido)-2'-methylbiphenyl-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; (R)-1-((5-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid; N-(2-chloro-2'-methyl-3'-(1-methyl-2-oxo-5-(pyrrolidin-1-ylmethyl)-1,2-dihydropyridine-3-carboxamido)biphenyl-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; N-(2-chloro-3'-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido)-2'-methylbiphenyl-3-yl)-5-((S)-2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; (S)-N-(2-chloro-2'-methyl-3'-(1-methyl-2-oxo-5-(pyrrolidin-1-ylmethyl)-1,2-dihydropyridine-3-carboxamido)biphenyl-3-yl)-5-(2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; N-(2-chloro-3'-(5-(2-(dimethylamino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2'-methylbiphenyl-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; and (S)-l-(5-chloro-4-((2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid; or a pharmaceutically acceptable salt; or (b) trans-4-((2-(2,2'-dichloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexane-1-carboxylic acid; trans-4-((2-(2,2'-dichloro-3'-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexane-1-carboxylic acid; trans-4-((2-(2,2'-dichloro-3'-(5-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexane-1-carboxylic acid; trans-4-((2-(2,2'-dichloro-3'-(5-(cyclopropylmethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexane-1-carboxylic acid; trans-4-((2-(2,2'-dichloro-3'-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexane-1-carboxylic acid; trans-4-((2-((2,2'-dichloro-3'-(5-(2-hydroxyethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylic acid; trans-4-((2-((2,2'-dichloro-3'-(5-((S)-2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylic acid; trans-4-((2-((2,2'-dichloro-3'-(5-((R)-2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylic acid; cis-4-((2-((2,2'-dichloro-3'-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylicacid; cis-4-((2-((2,2'-dichloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylic acid; cis-4-((2-((2,2'-dichloro-3'-(5-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylic acid; cis-4-((2-((2,2'-dichloro-3'-(5-(cyclopropylmethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylic acid; cis-4-((2-((2,2'-dichloro-3'-(5-isopropyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylicacid; cis-4-((2-((2,2'-dichloro-3'-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylic acid; cis-4-((2-((2,2'-dichloro-3'-(5-(2-hydroxyethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylic acid; cis-4-((2-((2,2'-dichloro-3'-(5-((S)-2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylic acid; cis-4-((2-((2,2'-dichloro-3'-(5-((R)-2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylic acid; 4-(2-(2-((2,2'-dichloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; 4-(2-(2-((2,2'-dichloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)benzoic acid; 4-(2-((2,2'-dichloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)cyclohexane-1-carboxylic acid; 4-(2-((2,2'-dichloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1-methylcyclohexane-1-carboxylic acid; 4-((2-((2,2'-dichloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)bicyclo[2.2.2]octane-1-carboxylic acid; 4-((2-((2,2'-dichloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)-1-methylcyclohexane-1-carboxylic acid; 4-(2-((2,2'-dichloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1-ethylcyclohexane-1-carboxylic acid; 4-((2-((2,2'-dichloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)bicyclo[2.2.1]heptane-1-carboxylic acid; trans-4-(2-(2-((2,2'-dichloro-3'-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-(2-(2-((2,2'-dichloro-3'-(5-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-(2-(2-((2,2'-dichloro-3'-(5-(cyclopropylmethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-(2-(2-((2,2'-dichloro-3'-(5-isopropyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-(2-(2-((2,2'-dichloro-3'-(5-cyclobutyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-(2-(2-((2,2'-dichloro-3'-(5-cyclopentyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-(2-(2-((2,2'-dichloro-3'-(5-cyclohexyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-(2-(2-((2,2'-dichloro-3'-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-(2-(2-((2,2'-dichloro-3'-(5-(2-hydroxyethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-(2-(2-((2,2'-dichloro-3'-(5-((S)-2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-(2-(2-((2,2'-dichloro-3'-(5-((R)-2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; 4-(2-(2-((2,2'-dichloro-3'-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)benzoic acid; 4-(2-((2,2'-dichloro-3'-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)cyclohexane-1-carboxylic acid; 4-(2-((2,2'-dichloro-3'-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1-methylcyclohexane-1-carboxylic acid; 4-(2-((2,2'-dichloro-3'-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1-ethylcyclohexane-1-carboxylic acid; trans-4-(2-(2-((2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; 4-(2-(2-((2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)benzoic acid; 4-((2-((2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)bicyclo[2.2.1]heptane-1-carboxylic acid; 4-((2-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)bicyclo[2.2.2]octane-1-carboxylic acid; 4-(2-((2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1-ethylcyclohexane-1-carboxylic acid; 4-(2-((2'-chloro-3'-(5-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1-methylcyclohexane-1-carboxylic acid; 4-(2-((2'-chloro-3'-(5-isopropyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1-methylcyclohexane-1-carboxylic acid; 4-(2-((2'-chloro-3'-(5-cyclohexyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1-methylcyclohexane-1-carboxylic acid; 4-(2-((2'-chloro-2-methyl-3'-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1-methylcyclohexane-1-carboxylic acid; trans-4-(2-(2-((2'-chloro-2-methyl-3'-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-((2-((2'-chloro-2-methyl-3'-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylic acid; 4-(2-((2'-chloro-2-methyl-3'-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)cyclohexane-1-carboxylic acid; 4-(2-((2'-chloro-2-methyl-3'-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1-ethylcyclohexane-1-carboxylic acid; cis-4-((2-((2'-chloro-2-methyl-3'-(l-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylicacid; cis-4-((2-((2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylicacid; trans-4-(2-(2-((2-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-((2-((2-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylic acid; 4-(2-(2-((2-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)benzoic acid; 4-(2-((2-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1-methylcyclohexane-1-carboxylic acid; 4-((2-((2-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)bicyclo[2.2.1]heptane-1-carboxylic acid; 4-((2-((2-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)-1-methylcyclohexane-1-carboxylic acid; 4-(2-((2-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1-ethylcyclohexane-1-carboxylic acid; trans-4-(2-(2-((2-chloro-2'-methyl-3'-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-((2-((2-chloro-2'-methyl-3'-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylic acid; 4-(2-(2-((2-chloro-2'-methyl-3'-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)benzoic acid; 4-(2-((2-chloro-2'-methyl-3'-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)cyclohexane-1-carboxylic acid; trans-4-(2-(2-((2-chloro-2'-methyl-3'-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-(2-(2-((2-chloro-3'-(5-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-(2-(2-((2-chloro-3'-(5-(cyclopropylmethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-(2-(2-((2-chloro-3'-(5-isopropyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-(2-(2-(2-chloro-3'-(5-cyclopentyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-(2-(2-((2-chloro-3'-(5-cyclohexyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-(2-(2-((2-chloro-3'-(5-(2-hydroxyethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-(2-(2-(2-chloro-3'-(5-((S)-2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexane-1-carboxylic acid; cis-4-((2-((2-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylicacid; trans-4-(2-(2-(2-chloro-3'-(5-(4-hydroxycyclohexyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexane-1-carboxylic acid; cis-4-((2-((2-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylicacid; cis-4-((2-((2-chloro-2'-methyl-3'-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylic acid; cis-4-((2-((2-chloro-3'-(5-((R)-2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylic acid; cis-4-((2-((2-chloro-3'-(5-(4-hydroxycyclohexyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylic acid; 4-(2-((2-chloro-3'-(5-cyclohexyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1-methylcyclohexane-1-carboxylic acid; 4-(2-((2-chloro-3'-(5-(4-hydroxycyclohexyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1-methylcyclohexane-1-carboxylic acid; (R)-4-(2-((2-chloro-3'-(5-(2-hydroxypropyl)-l-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1-methylcyclohexane-1-carboxylic acid; 4-(2-((2-chloro-2'-methyl-3'-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1-methylcyclohexane-1-carboxylic acid; (S)-4-(2-((2-chloro-3'-(5-(2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1-methylcyclohexane-1-carboxylic acid; trans-4-((2-((2,2'-dichloro-3'-(5-(4-hydroxycyclohexyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylic acid; cis-4-((2-((2,2'-dichloro-3'-(5-(4-hydroxycyclohexyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylic acid; trans-4-(2-(2-((2,2'-dichloro-3'-(5-(4-hydroxycyclohexyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-((2-((2'-chloro-2-cyano-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylic acid; trans-4-(2-(2-((2'-chloro-2-cyano-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-((2-((2-chloro-2'-cyano-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylic acid; trans-4-(2-(2-(2-chloro-2'-cyano-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-(2-(2-((2-chloro-2'-cyano-3'-(5-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-(2-(2-((2-chloro-2'-cyano-3'-(5-isopropyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-(2-(2-((2-chloro-2'-cyano-3'-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-(2-(2-((2'-chloro-2-cyano-3'-(5-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-(2-(2-((2'-chloro-2-cyano-3'-(5-isopropyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-((2-((2'-chloro-2-cyano-3'-(5-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylic acid; trans-4-((2-((2'-chloro-2-cyano-3'-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylic acid; trans-4-((2-(2-chloro-3'-(5-(2-(isopropyl(methyl)amino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexane-1-carboxylic acid; (S)-1-(2-(2-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methyl-[1,1-biphenyl]-3-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-oxoethyl)-3-methylpyrrolidine-3-carboxylic acid; (S)-N-(2-chloro-3'-(5-((S)-(1-hydroxypropan-2-yl)glycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; N-(2-chloro-3'-(5-((cis-3-hydroxycyclobutyl)glycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; N-(2-chloro-3'-(5-((trans-3-hydroxycyclobutyl)glycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2'-methyl-[1,l'-biphenyl]-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide; 1-(2-(2-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methyl-[1,1'-biphenyl]-3-yl)-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-2-oxoethyl)piperidine-4-carboxylic acid; 4-(2-((2-chloro-3'-(5-(dimethylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1-methylcyclohexane-1-carboxylic acid; 4-(2-(2-((2,2'-dichloro-3'-(5-(N-ethyl-N-methylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)cyclohexane-1-carboxylic acid; 4-(2-(2-(2,2'-dichloro-3'-(5-(2-(3-hydroxyazetidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexane-1-carboxylic acid; (R)-4-(2-(2-(2,2'-dichloro-3'-(5-(2-(3-hydroxypyrrolidin-1-yl)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexane-1-carboxylic acid; trans-4-((2-((2,2'-dichloro-3'-(5-(N-ethyl-N-methylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)cyclohexane-1-carboxylicacid; 4-(2-((3'-(5-(N-ethyl-N-methylglycyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1-methylcyclohexane-1-carboxylic acid; 4-(2-((2,2'-dichloro-3'-(5-(3-(ethyl(methyl)amino)propanoyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1-methylcyclohexane-1-carboxylic acid; 4-(2-((2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)adamantane-1-carboxylic acid; 4-((2-(2,2'-dichloro-3'-(5-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-lH-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)bicyclo[2.2.1]heptane-1-carboxylic acid; 4-((2-(2,2'-dichloro-3'-(5-isopropyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)bicyclo[2.2.1]heptane-1-carboxylic acid; 4-((2-(2,2'-dichloro-3'-(5-cyclobutyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)bicyclo[2.2.1]heptane-1-carboxylic acid; 4-((2-(2,2'-dichloro-3'-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)bicyclo[2.2.1]heptane-1-carboxylic acid; 4-((2-(2,2'-dichloro-3'-(5-(2-hydroxyethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)bicyclo[2.2.1]heptane-1-carboxylic acid; (S)-4-((2-(2,2'-dichloro-3'-(5-(2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)bicyclo[2.2.1]heptane-1-carboxylic acid; (R)-4-((2-(2,2'-dichloro-3'-(5-(2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)bicyclo[2.2.1]heptane-1-carboxylic acid; and 4-((2-(2,2'-dichloro-3'-(5-(4-hydroxycyclohexyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)biphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)bicyclo[2.2.1]heptane-1-carboxylic acid; or a pharmaceutically acceptable salt thereof.

18. A compound of claim 1, which is trans-4-((2-(2-chloro-3'-(5-(2-(ethyl(methyl)amino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

19. A compound of claim 1, which is cis-4-((2-(2-chloro-3'-(5-(2-(ethyl(methyl)amino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methyl)cyclohexane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

20. A compound of claim 1, which is 4-(2-(2-(2-chloro-3'-(5-(2-(ethyl(methyl)amino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

21. A compound of claim 1, which is 4-(2-(2-(2-chloro-3'-(5-(2-(isopropyl(methyl)amino)acetyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2'-methylbiphenyl-3-ylcarbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)cyclohexane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising a compound of any one of claims 1-16, or a pharmaceutically acceptable salt or a stereoisomer thereof, or a compound of any one of claims 17-21, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

23. A compound of any one of claims 1-16, or a pharmaceutically acceptable salt or a stereoisomer thereof; a compound of any one of claims 17-21, or a pharmaceutically acceptable salt thereof; or a composition of claim 22, for use in a method of treating a disease or disorder, wherein the disease or disorder is cancer or an infection.

24. The compound, salt, stereoisomer, or composition for use according to claim 23, wherein the disease or disorder is an infection, and the infection is a viral infection.

25. The compound, salt, stereoisomer, or composition for use according to claim 23, wherein the disease or disorder is cancer.

26. The compound, salt, stereoisomer, or composition for use according to claim 24, wherein the cancer is selected from bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, endometrial cancer, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias, solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, of the renal pelvis, neoplasm of the central nervous system (CNS), primary central nervous system (CNS) lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, melanoma, metastatic malignant melanoma, renal cancer, clear cell carcinoma, prostate cancer, hormone refractory prostate adenocarcinoma, breast cancer, triple-negative breast cancer, colon cancer, lung cancer, non-small cell lung cancer (NSCLC), small cell lung cancer, squamous cell head and neck cancer, urothelial cancer, cancers with high microsatellite instability (MSIhigh), solid tumors, hepatic cancer, gastric cancer, thyroid cancer, glioblastoma, sarcoma, cholangiocarcinoma, bile duct cancer, rhabdomyosarcoma, 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 tumors, hairy cell leukemia, intestinal cancer, islet cell cancer, oral cancer, mouth cancer, throat cancer, laryngeal cancer, lip cancer, mesothelioma, neck cancer, nasal cavity cancer, ocular cancer, ocular melanoma, pelvic cancer, renal cell carcinoma, salivary gland cancer, sinus cancer, spinal cancer, tongue cancer, tubular carcinoma, ureteral cancer, genitourinary tract cancers, liver cancers, nervous system cancers, gynecological cancers, hematological cancers, lymphoma, leukemia, acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, relapsed or refractory non-Hodgkin lymphoma (NHL), recurrent follicular lymphoma, Hodgkin lymphoma, myeloproliferative diseases, primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET), myelodysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma (MM), osteosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, teratoma, bronchogenic carcinoma, squamous cell sarcoma, undifferentiated small cell sarcoma, undifferentiated large cell sarcoma, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, squamous cell carcinoma, cancers of the stomach, carcinoma, cancers of the pancreas, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma, cancers of the small bowel, leiomyoma, hemangioma, cancers of the large bowel, tubular adenoma, villous adenoma, hamartoma, colorectal cancer, cancers of the kidney, Wilm's tumor [nephroblastoma], transitional cell carcinoma, cancers of the testis, seminoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, interstitial cell carcinoma, fibroadenoma, adenomatoid tumors, , hepatoblastoma, hepatocellular adenoma, malignant fibrous histiocytoma, malignant lymphoma, reticulum cell sarcoma, malignant giant cell tumor chordoma, osteochronfroma, osteocartilaginous exostoses, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, giant cell tumors, cancers of the skull, osteoma, granuloma, xanthoma, osteitis deformans, meninges, meningioma, meningiosarcoma, gliomatosis, meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, cancers of the spinal cord, Lhermitte-Duclos disease, endometrial carcinoma, cancers of the cervix, cervical carcinoma, pre-tumor cervical dysplasia, ovarian carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma, cancers of the vulva, intraepithelial carcinoma, cancers of the vagina, botryoid sarcoma, embryonal rhabdomyosarcoma, , moles dysplastic nevi, angioma, dermatofibroma, keloids, and urothelial carcinoma.

27. The compound, salt, stereoisomer, or composition for use according to claim 24, wherein the cancer is a metastatic cancer that expresses PD-L1.

28. A compound of any one of claims 1-16, or a pharmaceutically acceptable salt or a stereoisomer thereof; a compound of any one of claims 17-21, or a pharmaceutically acceptable salt thereof; or a composition of claim 22, for use in a method of enhancing, stimulating and / or increasing the immune response in a patient, wherein the patient has cancer or an infection.