Connections for the treatment of kinesthetic disorders

Description

Field of the Invention

[0001] The invention relates to compounds for modulating protein kinase enzymatic activity for modulating cellular activities such as proliferation, differentiation, programmed cell death, migration, and chemoinvasion. Even more specifically, the invention relates to compounds which inhibit, regulate, and / or modulate Axl and Mer receptor tyrosine kinases, compositions which contain these compounds, methods of using them to treat kinase-dependent diseases and conditions, synthesis of the compounds, and processes for formulating the compounds for pharmaceutical purposes.Background of the Invention

[0002] Human Axl belongs to the TAM subfamily of receptor tyrosine kinases that includes Mer. TAM kinases are characterized by an extracellular ligand binding domain consisting of two immunoglobulin-like domains and two fibronectin type III domains. Axl is overexpressed in a number of tumor cell types and was initially cloned from patients with chronic myelogenous leukemia. When overexpressed, Axl exhibits transforming potential. Axl signaling is believed to cause tumor growth through activation of proliferative and anti-apoptotic signaling pathways. Axl has been associated with cancers such as lung cancer, myeloid leukemia, uterine cancer, ovarian cancer, gliomas, melanoma, thyroid cancer, renal cell carcinoma, osteosarcoma, gastric cancer, prostate cancer, and breast cancer. The over-expression of Axl results in a poor prognosis for patients with the indicated cancers.

[0003] Activation of Mer, like Axl, conveys downstream signaling pathways that cause tumor growth and activation. Mer binds ligands such as the soluble protein Gas-6. Gas-6 binding to Mer induces autophosphorylation of Mer on its intracellular domain, resulting in downstream signal activation. Over-expression of Mer in cancer cells leads to increased metastasis most likely by generation of soluble Mer extracellular domain protein as a decoy receptor. Tumor cells secrete a soluble form of the extracellular Mer receptor which reduces the ability of soluble Gas-6 ligand to activate Mer on endothelial cells leading to cancer progression.

[0004] Therefore a need exists for compounds that inhibit TAM receptor tyrosine kinases such as Axl and Mer for the treatment of selected cancers.

[0005] WO 2016 / 184434 A1 discloses pyrido-azaheterecydic compounds and the use thereof as multi-target protein kinase inhibitors in the preparation of drugs for treating neoplastic diseases, in particular for c-Met related diseases. It is disclosed that the compounds have a highly effective inhibiting activity on tumor cells in which c-Met kinase highly expressed, and can effectively target the signaling pathway mediated by c-Met, so that they can be used in the treatment of tumors and other related diseases induced by overexpression of c-Met.Summary of the Invention

[0006] In one aspect, the present invention provides a compound of Formula I': or a pharmaceutically acceptable salt thereof, wherein: Y is selected from O, S, SO, SO 2 , NH, and -N(C 1-6 alkyl)-; ring A is wherein R 18 and R 19 are each independently selected from H, halo, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 6 -C 10 ) aryl, (C 3 -C 10 ) cycloalkyl, 4-14 membered heterocycloalkyl, phenyl, 5-14 membered heteroaryl, -CN, -NO 2 , -OR a< , -SR a< , -C(O)R a< , - C(O)NR a< R a< , -C(O)OR a< , -NHR a< , -NR a< R a< , and -NR a< C(O)R a< , wherein the (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 6 -C 10 ) aryl, (C 3 -C 10 ) cycloalkyl, 4-14 membered heterocycloalkyl, phenyl, and 5-14 membered heteroaryl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, (C 1 -C 6 ) alkyl, -CN, and -OH; or R 18 and R 19 taken together with the atoms to which they are attached form a fused C 3-7 cycloalkyl ring or a fused 4- to 10-membered heterocycloalkyl ring; R 10 and R 11 are -H; each R 13 is independently selected from the group consisting of -H; halo; -OH; -CN; optionally substituted (C 1 -C 6 ) alkyl; (C 1 -C 6 ) alkoxy; (C 1 -C 6 ) haloalkoxy; -NH 2 ; --NH(C 1 -C 6 )alkyl; -N(C 1 -C 6 alkyl) 2 ; and (C 3 -C 6 ) cycloalkyl; each R 14 is independently selected from the group consisting of -H, halo, and (C 1 -C 6 ) alkyl; R 15 is H; each R 12 is independently selected from the group consisting of -H and halo; each R a< is independently selected from the group consisting of -H, (C 1 -C 6 ) alkyl, (C 3 -C 10 ) cycloalkyl, 4-14 membered heterocycloalkyl, and (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-, wherein the (C 1 -C 6 ) alkyl, (C 3 -C 10 ) cycloalkyl, 4-14 membered heterocycloalkyl, and (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene- of R a< are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, and -C(O)O(C 1 -C 4 ) alkyl; the subscript n is an integer of 1, 2, 3, or 4; the subscript m is an integer of 1, 2, 3, 4, or 5; the subscript p is an integer of 0, 1, 2, 3, or 4; and X is N or CH.

[0007] In another aspect, the invention includes a pharmaceutical composition comprising a compound of the invention, and a pharmaceutically acceptable carrier or excipient.

[0008] In another aspect, the invention includes a compound or a pharmaceutical composition of the invention for use in therapy.

[0009] In the following description, references to methods of treatment by therapy are to be interpreted as references to compounds, pharmaceutical compositions and medicaments of the present disclosure for use in those methods.Summary of the disclosure

[0010] In addition to the invention as defined above, the present disclosure more generally provides, in one aspect a compound for modulating kinase activity according to Formula I', Formula I, or Formula II.

[0011] In one aspect, the disclosure includes a compound of Formula I': or a pharmaceutically acceptable salt thereof, wherein: X is N or CH; Y is selected from O, S, SO, SO 2 , NH, and -N(C 1-6 alkyl)-; (i) ring A is R 16 is selected from the group consisting of (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-14 membered heteroaryl; 4-14 membered heterocycloalkyl; -CN; -NHOH, -C(O)R a< ; -C(O)NR a< R a< ; -C(O)NHOR a< ; -C(O)OR a< ; -C(O)NR a< S(O) 2 R a< ; - OC(O)NR a< R a< ; C(=NR a< )R a< ; -C(=NOH)R a< ; -C(=NOH)NR a< ; -C(=NCN)NR a< R a< ; - NR a< C(=NCN)NR a< R a< ; -C(=NR a< )NR a< R a< ; -S(O)NR a< R a< ; -S(O) 2 NR a< C(O)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< ; and R 17 is selected from -H; halo; (C 1 -C 6 ) alkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; -CN; -NO 2 ; -OR a< ; -SR a< ; -NHOR a< ; -C(O)R a< ; -C(O)NR a< R a< ; -C(O)NHOR a< ; - C(O)OR a< ; -C(O)NR a< S(O) 2 R 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(=NR a< )R a< ; -NR a< C(O)OR a< ; -NR a< C(O)NR a< R a< ; -C(=NR a< )R a< ; -C(=NOH)R a< ; - C(=NOH)NR a< ; -C(=NCN)NR a< R a< ; -NR a< C(=NCN)NR a< R a< ; -C(=NR a< )NR a< R a< ; - NR a< C(=NR a< )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< ; -S(O) 2 NR a< C(O)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 -C 6 ) alkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene- of R 16 or R 17 are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R b< substituents, provided when R 16 or R 17 is 5-membered heteroaryl or 5-7 membered heterocycloalkyl, then the 5-membered heteroaryl or 5-7 membered heterocycloalkyl does not connect to the fused phenyl ring moiety through a ring nitrogen atom; or R 16 is selected from -H; halo; (C 1 -C 6 ) alkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-14 membered heteroaryl; 4-14 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; -CN; -NO 2 ; -OR a< ; -SR a< ; -NHOR a< ; -C(O)R a< ; -C(O)NR a< R a< ; -C(O)NHOR a< ; - C(O)OR a< ; -C(O)NR a< S(O) 2 R 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(=NR a< )R a< ; -NR a< C(O)OR a< ; -NR a< C(O)NR a< R a< ; -C(=NR a< )R a< ; -C(=NOH)R a< ; - C(=NOH)NR a< ; -C(=NCN)NR a< R a< ; -NR a< C(=NCN)NR a< R a< ; -C(=NR a< )NR a< R a< ; - NR a< C(=NR a< )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< ; -S(O) 2 NR a< C(O)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 -C 6 ) alkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-14 membered heteroaryl; 4-14 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene- of R 16 is each optionally substituted with 1, 2, 3, 4, or 5 independently selected R b< substituents; and R 17 is selected from the group consisting of (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; -CN; - NHOH, -C(O)R a< ; -C(O)NR a< R a< ; -C(O)NHOR a< ; -C(O)OR a< ; -C(O)NR a< S(O) 2 R a< ; -OC(O)NR a< R a< ; C(=NR a< )R a< ; -C(=NOH)R a< ; -C(=NOH)NR a< ; -C(=NCN)NR a< R a< ; -NR a< C(=NCN)NR a< R a< ; - C(=NR a< )NR a< R a< ; -S(O)NR a< R a< ; -S(O) 2 NR a< C(O)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< , provided when R 16 or R 17 is 5-membered heteroaryl or 5-7 membered heterocycloalkyl, then the 5-membered heteroaryl or 5-7 membered heterocycloalkyl does not connect to the fused phenyl ring moiety through a ring nitrogen atom; or R 16 and R 17 taken together with the atoms to which they are attached form a fused C 3-7 cycloalkyl ring or a fused 4- to 10-membered heterocycloalkyl ring; wherein the fused C 3-7 cycloalkyl ring and fused 4- to 10-membered heterocycloalkyl ring are each optionally substituted with 1, 2, or 3 independently selected R b< substituents; or (ii) ring A is R 18 and R 19 are each independently selected from -H; halo; (C 1 -C 6 ) alkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 )haloalkoxy; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; -CN; -NO 2 ; -OR a< ; -SR a< ; -NHOR a< ; -C(O)R a< ; -C(O)NR a< R a< ; -C(O)NHOR a< ; -C(O)OR a< ; - C(O)NR a< S(O) 2 R 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(=NR a< )R a< ; -NR a< C(O)OR a< ; -NR a< C(O)NR a< R a< ; -C(=NR a< )R a< ; -C(=NOH)R a< ; -C(=NOH)NR a< ; - C(=NCN)NR a< R a< ; -NR a< C(=NCN)NR a< R a< ; -C(=NR a< )NR a< R a< ; -NR a< C(=NR a< )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< ; -S(O) 2 NR a< C(O)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 -C 6 ) alkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C4) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene- of R 18 or R 19 are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R b< substituents; or R 18 and R 19 taken together with the atoms to which they are attached form a fused C 3-7 cycloalkyl ring or a fused 4- to 10-membered heterocycloalkyl ring; wherein the fused C 3-7 cycloalkyl ring and fused 4- to 10-membered heterocycloalkyl ring are each optionally substituted with 1, 2, or 3 independently selected R b< substituents; R 10 and R 11 are each independently selected from the group consisting of -H; halo; (C 1 -C 6 ) alkyl; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-14 membered heteroaryl; 4-14 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; -CN; -NO 2 ; -OR a< ; -SR a< ; -NHOR a< ; -C(O)R a< ; - C(O)NR a< R a< ; -C(O)OR a< ; -C(O)NR a< S(O) 2 R 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(=NR a< )R a< ; -NR a< C(O)OR a< ; -NR a< C(O)NR a< R a< ; -C(=NR a< )R a< ; -C(=NOH)R a< ; - C(=NOH)NR a< ; -C(=NCN)NR a< R a< ; -NR a< C(=NCN)NR a< R a< ; -C(=NR a< )NR a< R a< ; - NR a< C(=NR a< )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< ; -S(O) 2 NR a< C(O)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 -C 6 ) alkyl; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-14 membered heteroaryl; 4-14 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene- of R 1 or R 2 are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R b< substituents; each R 13 is independently selected from the group consisting of -H; halo; -OH; -CN; optionally substituted (C 1 -C 6 ) alkyl; (C 1 -C 6 ) alkoxy; (C 1 -C 6 ) haloalkoxy; -NH 2 ; --NH(C 1 -C 6 )alkyl; -N(C 1 -C 6 alkyl) 2 ; and (C 3 -C 6 ) cycloalkyl; wherein the (C 1 -C 6 ) alkoxy; -NH(C 1 -C 6 )alkyl; -N(C 1 -C 6 alkyl) 2 ; and (C 3 -C 6 ) cycloalkyl of R 3 are each optionally substituted with 1, 2, or 3 independently selected R g< substituents; each R 14 is independently selected from the group consisting of halo; -OH; -NH 2 ; - CN; (C 1 -C 6 ) alkyl; (C 1 -C 6 ) alkoxy; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; -COOH; -NH(C 1 -C 6 )alkyl; -N(C 1 -C 6 alkyl) 2 ; phenyl; phenyl-(C 1 -C 2 ) alkylene; (C 3 -C 6 ) cycloalkyl; (C 3 -C 6 ) cycloalkyl-(C 1 -C 4 ) alkylene-; 4- to 6-membered heterocycloalkyl; (4- to 6-membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; 5- to 6-membered heteroaryl; (5- to 6-membered heteroaryl)-(C 1 -C 4 ) alkylene-; and -OR e< ; wherein the (C 1 -C 6 ) alkyl; phenyl; phenyl-(C 1 -C 2 ) alkylene; (C 3 -C 6 ) cycloalkyl; (C 3 -C 6 ) cycloalkyl-(C 1 -C 4 ) alkylene-; 4- to 6-membered heterocycloalkyl; (4- to 6-membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; 5- to 6-membered heteroaryl; and (5- to 6-membered heteroaryl)-(C 1 -C 4 ) alkylene- of R 14 are each optionally substituted with 1, 2, or 3 independently selected R g< substituents; R 15 is H; each R 12 is independently selected from the group consisting of -H; halo; -OH; - COOR e< ; -CONR e< R e< ; -CN; -NH 2 ; -NH((C 1 -C 6 ) alkyl); -N((C 1 -C 6 ) alkyl) 2 ; (C 1 -C 6 ) alkyl; (C 1 -C6) alkoxy; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; -CONR a< R a< ; -NR a< COR a< ; -NR a< CONR a< R a< ; - SO 2 R a< ; -NR a< S(O) 2 R a< ; -NR a< S(O) 2 NR a< R a< ; (C 3 -C 6 ) cycloalkyl; 4- to 6-membered heterocycloalkyl; phenyl; 5- or 6-membered heteroaryl; (C 3 -C 6 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (4- to 6-membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; phenyl-(C 1 -C 2 ) alkylene; and (5- or 6-membered heteroaryl)-(C 1 -C 4 ) alkylene-; wherein the (C 1 -C 6 ) alkyl; (C 3 -C 6 ) cycloalkyl; 4- to 6-membered heterocycloalkyl; phenyl; 5- or 6-membered heteroaryl; (C 3 -C 6 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (4- to 6-membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; phenyl-(C 1 -C 2 ) alkylene; and (5- or 6-membered heteroaryl)-(C 1 -C 4 ) alkylene- of R 12 are each optionally substituted with 1, 2, or 3 independently selected R f< substituents; each R a< is independently selected from the group consisting of -H; -CN; (C 1 -C 6 ) alkyl; (C 1 -C 6 ) haloalkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-14 membered heteroaryl; 4-14 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; wherein the (C 1 -C 6 ) alkyl; (C 1 -C 6 ) haloalkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-14 membered heteroaryl; 4-14 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene- of R a< are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R d< substituents; each R b< is independently selected from the group consisting of halo; (C 1 -C 6 ) alkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-10 membered heteroaryl; 4-10 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-10 membered heteroaryl)-(C 1 -C 4 ) alkylene-; (4-10 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; -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< ; -Si(R c< ) 3 ; -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 -C 6 ) alkyl; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-10 membered heteroaryl; 4-10 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalky-(C 1 -C 4 ) alkylene-; (5-10 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-10 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene- 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 the group consisting of -H; (C 1 -C 6 ) alkyl; (C 1 -C 6 ) haloalkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-10 membered heteroaryl; 4-10 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-10 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-10 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; wherein the (C 1 -C 6 ) alkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-10 membered heteroaryl; 4-10 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-10 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-10 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene- of R c< are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R f< substituents; each R d< is independently selected from the group consisting of (C 1 -C 6 ) alkyl; (C 1 -C 6 ) haloalkyl; halo; (C 6 -C 10 ) aryl; 5-10 membered heteroaryl; (C 3 -C 10 ) cycloalkyl; 4-10 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-10 membered heteroaryl)-(C 1 -C 4 ) alkylene-; (4-10 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; -CN; -NH 2 ; -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< ; and -S(O) 2 NR e< R e< ; wherein the (C 1 -C 6 ) alkyl; (C 1 -C 6 ) haloalkyl; (C 6 -C 10 ) aryl; 5-10 membered heteroaryl; (C 3 -C 10 ) cycloalkyl; 4-10 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-10 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-10 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene- of R d< are each optionally substituted with 1, 2, or 3 independently selected R f< substituents; each R e< is independently selected from the group consisting of -H; (C 1 -C 6 ) alkyl; (C 3 -C 6 ) cycloalkyl; (C 3 -C 6 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (C 6 -C 10 ) aryl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; 5- or 6-membered heteroaryl; (5- or 6-membered heteroaryl)-(C 1 -C 4 ) alkylene-; 4-7-membered heterocycloalkyl; (4-7-membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; (C 2 -C 4 ) alkenyl; and (C 2 -C 4 ) alkynyl; wherein the (C 1 -C 4 ) alkyl; (C 3 -C 6 ) cycloalkyl; (C 6 -C 10 ) aryl; 5 or 6-membered heteroaryl; 4-7-membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (5- or 6-membered heteroaryl)-(C 1 -C 4 ) alkylene-; (4-7-membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; (C 2 -C 4 ) alkenyl; and (C 2 -C 4 ) alkynyl of R e< are each optionally substituted with 1, 2, or 3 R f< substituents; or any two R a< substituents together with the nitrogen atom to which they are attached form 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R f< substituents; or any two R c< substituents together with the nitrogen atom to which they are attached form 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R f< substituents; or any two R e< substituents together with the nitrogen atom to which they are attached form 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R f< substituents; each R f< is independently selected from the group consisting of halo; -OH; -CN; -COOH; - NH 2 ; -NH-(C 1 -C 6 ) alkyl; -N((C 1 -C 6 ) alky) 2 ; (C 1 -C 6 ) alkyl; (C 1 -C 6 ) alkoxy; (C 1 -C 6 ) alkylthio; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; phenyl; 5-6 membered heteroaryl; 4-6 membered heterocycloalkyl; and (C 3 -C 6 ) cycloalkyl; wherein the (C 1 -C 6 ) alkyl; phenyl; (C 3 -C 6 ) cycloalkyl; 4-6 membered heterocycloalkyl; and 5-6 membered heteroaryl of R f< are each optionally substituted with 1, 2, or 3 substituents selected from halo; -OH; -CN; -COOH; -NH 2 ; (C 1 -C 4 ) alkyl; (C 1 -C 4 ) alkoxy; (C 1 -C 4 ) haloalkyl; (C 1 -C 4 ) haloalkoxy; phenyl; (C 3 -C 10 ) cycloalkyl; 5-6 membered heteroaryl; and 4-6 membered heterocycloalkyl; each R g< is independently selected from the group consisting of halo; -OH; -CN; -COOH; -COO-(C 1 -C 4 ) alkyl; -NH 2 ; -NH-(C 1 -C 6 ) alkyl; -N((C 1 -C 6 ) alky) 2 ; (C 1 -C 6 ) alkyl; (C 1 -C 6 ) alkoxy; (C 1 -C 6 ) alkylthio; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; phenyl; 5-6 membered heteroaryl; 4-6 membered heterocycloalkyl; and (C 3 -C 6 ) cycloalkyl; the ring nitrogen atom on the quinoline moiety in Formula A is optionally oxidized; the subscript n is an integer of 1, 2, 3, or 4; the subscript m is an integer of 1, 2, 3, 4, or 5; and the subscript p is an integer of 0, 1, 2, 3, or 4; provided that when X is C-H, Ring A is or

[0012] In one instance, the compound of Formula I' is a compound of Formula I: wherein: X is selected from N and C-H; Y is O, S, SO, SO 2 , NH, or N-(C 1 -C 6 alkyl); R 13 is selected from -H, halo, -CN, and optionally substituted C 1-6 alkyl; R 12 is -H or halo; is optionally substituted with one, two, three, or four groups independently selected from the group consisting of halo, and C 1 -C 6 alkyl, wherein "" indicate points of attachment; is selected from the group consisting of and wherein R 18 and R 19 are selected from the group consisting of H, halo, -CN, optionally substituted C 1 -C 6 alkyl, C(O)NR 5 R 6 , optionally substituted 5 or 6-membered heteroaryl, and optionally substituted C 1 -C 6 alkoxy; or when is R 18 and R 19 can be joined together to form a 5 or 6-membered optionally substituted cycloalkyl or heterocycloalkyl; R 5 and R 6 are selected from the group consisting of H, optionally substituted C 1-6 alkyl, or R 5 and R 6 taken together with the nitrogen to which they are attached to form a 5- or 6-membered optionally substituted heterocycle; and m and n are each independently 1 or 2; provided that when is and X is C-H, R 19 is not optionally substituted C 1 -C 6 alkyl, halo, or optionally substituted C 1 -C 6 alkoxy.

[0013] In one instance, the compound of Formula I' is a compound of Formula II: or a pharmaceutically acceptable salt thereof, wherein: R 16 is selected from the group consisting of -CN and -CO-NR 5 R 6 ; R 17 is selected from H and optionally substituted C 1 -C 6 alkoxy; R 13 is selected from the group consisting of -H, halo, -CN, or optionally substituted C 1-6 alkyl; R 12 is -H or halo; is optionally substituted with one, two, three, or four groups independently selected from the group consisting of halo, and C 1 -C 6 alkyl, wherein "" indicate points of attachment; R 5 and R 6 are each independently selected from the group consisting of H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 heterocycloalkyl, and optionally substituted C 1 -C 6 cycloalkyl; Y is O, S, SO, SO 2 , NH, or N-(C 1 -C 6 alkyl); and m and n are each independently 1 or 2.

[0014] In one aspect, the disclosure includes a pharmaceutical composition comprising a compound described herein, and a pharmaceutically acceptable carrier or excipient.

[0015] In another aspect, the disclosure includes a method of treating a disease, disorder, or syndrome mediated at least in part by modulating in vivo activity of a protein kinase, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a pharmaceutical composition described herein.Detailed Description Abbreviations and Definitions

[0016] The following abbreviations and terms have the indicated meanings throughout: Abbreviation Meaning AcAcetylanhydAnhydrousAqAqueousArArgonBocTert-butoxycarbonylBrBroad°CDegrees Celsiusc-CyclocalcdCalculatedCBZCarboBenZoxy = benzyloxycarbonyldDoubletddDoublet of doubletsdddDoublet of doublets of doubletsdtDoublet of tripletsDCMDichloromethaneDMFN,N-DimethylformamideDMSODimethyl sulfoxideDppf1,1'-bis(diphenylphosphano)ferroceneEAElemental AnalysisEIElectron Impact ionizationeq or equivEquivalentFmocFluorenylmethyloxycarbonylgGram(s)h or hrHour(s)HPLCHigh pressure liquid chromatographyH2HydrogenLLiter(s)LiHMDSLithium bis(trimethylsilyl)azideMMolar or molaritymMultipletMHzMegahertz (frequency)MinMinute(s)mLMilliliter(s)MpMelting pointm / zMass to charge ratioµLMicroliter(s)MolMole(s)MSMass spectral analysisN2NitrogenNNormal or normalitynMNanomolarNMRNuclear magnetic resonance spectroscopyPd / CPalladium on carbonQQuartetRTRoom temperaturesSingletsolnSolutionS / CSubstrate / catalyst ratiot or trTripletTHFTetrahydrofuranTLCThin layer chromatographyv / vVolume to volume

[0017] The symbol "-" means a single bond, and "=" means a double bond.

[0018] As used herein, the singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise.

[0019] When a variable is defined generically, with a number of possible substituents, each individual radical can be defined with or without the bond. For example, if R z< can be hydrogen, this can be indicated as "-H" or "H" in the definition of R z< .

[0020] When chemical structures are depicted or described, unless explicitly stated otherwise, all carbons are assumed to have hydrogen substitution to conform to a valence of four. For example, in the structure on the left-hand side of the schematic below, there are nine hydrogens implied. The nine hydrogens are depicted in the right-hand structure. Sometimes a particular atom in a structure is described in textual formula as having a hydrogen or hydrogens as substitution (expressly defined hydrogen), for example, -CH 2 CH 2 -. It is understood by one of ordinary skill in the art that the aforementioned descriptive techniques are common in the chemical arts to provide brevity and simplicity to description of otherwise complex structures.

[0021] If a group "R" is depicted as "floating" on a ring system, as for example in the formula: then, unless otherwise defined, a substituent "R" may reside on any atom of the ring system, assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the ring atoms, so long as a stable structure is formed.

[0022] If a group "R" is depicted as floating on a fused ring system, as for example in the formulae: then, unless otherwise defined, a substituent "R" may reside on any atom of the fused ring system, assuming replacement of a depicted hydrogen (for example the -NH- in the formula above), implied hydrogen (for example, in the formula above, where the hydrogens are not shown but understood to be present), or expressly defined hydrogen (for example, where in the formula above, "Z" equals =CH-) from one of the ring atoms, so long as a stable structure is formed. In the example depicted, the "R" group may reside on either the 5-membered or the 6-membered ring of the fused ring system. When a group "R" is depicted as existing on a ring system containing saturated carbons, for example in the formula: where, in this example, "y" can be more than one, assuming each replaces a currently depicted, implied, or expressly defined hydrogen on the ring; then, unless otherwise defined, where the resulting structure is stable, two "R's" may reside on the same carbon. A simple example is when R is a methyl group, there can exist a geminal dimethyl on a carbon of the depicted ring (an "annular" carbon). In another example, two R's on the same carbon, including that carbon, may form a ring, thus creating a spirocyclic ring (a "spirocyclyl" group) structure with the depicted ring as for example in the formula:

[0023] "Halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0024] The term "C n-m " or "C n -C 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 -C 4 , C 1-6 , C 1 -C 6 , and the like.

[0025] "Alkyl" refers to a branched or straight hydrocarbon chain of one to eight carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl, and heptyl. (C 1 -C 6 )alkyl is preferred. The term "C n-m alkyl" or (C n -C m ) alkyl, refers to an alkyl group having n to m carbon atoms. When optionally substituted, one or more hydrogen atoms of the alkyl group (e.g., from 1 to 4, from 1 to 2, or 1) may be replaced with a moiety as described below under "Optional Substitution." In some aspects, the alkyl group is unsubstituted or not optionally substituted.

[0026] "Alkylene" refers to an optionally substituted bivalent saturated aliphatic radical having from 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms. When optionally substituted, one or more hydrogen atoms of the alkylene group (e.g., from 1 to 4, from 1 to 2, or 1) may be replaced with a moiety as described below under "Optional Substitution." In some aspects, the alkylene group is unsubstituted or not optionally substituted. The term "Cn-m alkylene" refers to an alkylene group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, methylene, ethan-1,2-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl, and the like.

[0027] The term "alkenyl" 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" or (C n -C m ) alkenyl refers to an alkenyl group having n to m carbons. In some instances, 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.

[0028] The term "alkynyl" 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" or (C n -C 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 instances, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0029] "Alkoxy" refers to a moiety of the formula -OR', wherein R' is an (C 1 -C 6 )alkyl moiety as defined herein. The term "C n-m alkoxy" or (C n -C m ) alkoxy refers to an alkoxy group, the alkyl group of which has n to m carbons. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

[0030] An alkoxy group can be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms of the alkoxy group (e.g., from 1 to 4, from 1 to 2, or 1) may be replaced with a moiety as described below under "Optional Substitution," with the proviso that no hydrogen atom alpha to the ether oxygen is replaced by a hydroxy, amino, or thio group. In some aspects, the alkoxy group is unsubstituted or not optionally substituted.

[0031] "Alkoxycarbonyl" refers to a group -C(O)-R' wherein R' is (C 1 -C 6 )alkoxy as defined herein.

[0032] The term "amino" refers to a group of formula -NH 2 .

[0033] The term "carbamyl" refers to a group of formula -C(O)NH 2 .

[0034] The term "carbonyl", employed alone or in combination with other terms, refers to a -C(=O)- group, which also may be written as C(O).

[0035] The term "cyano" or "nitrile" refers to a group of formula -C≡N, which also may be written as -CN or CN.

[0036] 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 instances, heterocyclic groups may be optionally substituted by 1 or 2 oxo (=O) substituents.

[0037] The term "sulfide" refers to a sulfur atom as a divalent substituent, forming a thiocarbonyl group (C=S) when attached to carbon.

[0038] The term "heteroatom" used herein is meant to include boron, phosphorus, sulfur, oxygen, and nitrogen.

[0039] 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" or (C n -C 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 instances, the halogen atoms are fluoro atoms. In some instances, 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 instances, the haloalkyl group is a fluoroalkyl group.

[0040] 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" or (C n -C 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 instances, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0041] "Aryl" means a monovalent six- to fourteen-membered, mono- or bi-carbocyclic ring (e.g., having two fused rings), wherein the monocyclic ring is aromatic and at least one of the rings in the bicyclic ring is aromatic. The term "C n-m aryl" or "(C n -C m ) aryl" refers to an aryl group having from n to m ring carbon atoms. In some instances, aryl groups have from 6 to about 10 carbon atoms. In some instances aryl groups have 6 carbon atoms. In some instances aryl groups have 10 carbon atoms. Unless stated otherwise, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. Representative examples include phenyl, naphthyl, and indanyl, and the like.

[0042] An aryl group can be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms of the aryl group (e.g., from 1 to 5, from 1 to 2, or 1) may be replaced with a moiety as described below under "Optional Substitution." In some aspects, the alkoxy group is unsubstituted or not optionally substituted.

[0043] "Arylene" means a divalent six- to fourteen-membered, mono- or bi-carbocyclic ring, wherein the monocyclic ring is aromatic and at least one of the rings in the bicyclic ring is aromatic. Representative examples include phenylene, naphthylene, and indanylene, and the like.

[0044] "Cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), including cyclized alkyl and alkenyl groups. The term "C n-m cycloalkyl" or "(C n -C 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, 7, 8, 9, 10, 11, 12, 13, or 14 ring-forming carbons (C 3-14 ). In some instances, the cycloalkyl group has 3 to 14 members, 3 to 10 members, 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some instances, the cycloalkyl group is monocyclic. In some instances, the cycloalkyl group is monocyclic or bicyclic. In some instances, 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 instances, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcamyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like. In some instances, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some instances, cycloalkyl includes a single saturated carbocyclic ring of three to eight ring carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl may optionally be substituted with one or more substituents, such as one, two, or three substituents. In some instances, the cycloalkyl substituent is selected from the group consisting of (C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, halo, amino, mono- and di(C 1 -C 6 )alkylamino, hetero(C 1 -C 6 )alkyl, acyl, aryl, and heteroaryl.

[0045] A cycloalkyl group can be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms of the cycloalkyl group (e.g., from 1 to 4, from 1 to 2, or 1) may be replaced with a moiety as described below under "Optional Substitution." In some aspects, a substituted cycloalkyl group can incorporate an exo- or endocyclic alkene (e.g., cyclohex-2-en-1-yl). In some aspects, a cycloalkyl group is unsubstituted or not optionally substituted.

[0046] "Cycloalkyloxycarbonyl" means a group -C(O)-OR' wherein R' is (C 3 -C 6 )cycloalkyl as defined herein.

[0047] "Phenyloxycarbonyl" refers to a group -C(O)-Ophenyl.

[0048] "Heteroaryl" means a monocyclic, fused bicyclic, or fused tricyclic, monovalent radical of 5 to 14 ring atoms containing one or more, preferably one, two, three, or four ring heteroatoms independently selected from -O-, -S(O) n - (n is 0, 1, or 2), -N-, and -N(R')-, and the remaining ring atoms being carbon, wherein the ring comprising a monocyclic radical is aromatic and wherein at least one of the fused rings comprising a bicyclic or tricyclic radical is aromatic. One or two ring carbon atoms of any nonaromatic rings comprising a bicyclic or tricyclic radical may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. R' is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl. Unless stated otherwise, the valency may be located on any atom of any ring of the heteroaryl group, valency rules permitting. In particular, when the point of valency is located on the nitrogen, an additional nitrogen substiuent is not present. More specifically, the term heteroaryl includes, but is not limited to, 1,2,4-triazolyl, 1,3,5-triazolyl, phthalimidyl, pyridinyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro-1H-indolyl (including, for example, 2,3-dihydro-1H-indol-2-yl or 2,3-dihydro-1H-indol-5-yl, and the like), isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, benzodioxol-4-yl, benzofuranyl, cinnolinyl, indolizinyl, naphthyridin-3-yl, phthalazin-3-yl, phthalazin-4-yl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isooxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl (including, for example, tetrahydroisoquinolin-4-yl or tetrahydroisoquinolin-6-yl, and the like), pyrrolo[3,2-c]pyridinyl (including, for example, pyrrolo[3,2-c]pyridin-2-yl or pyrrolo[3,2-c]pyridin-7-yl, and the like), benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl, benzothienyl, and the derivatives thereof, and N-oxide or a protected derivative thereof.

[0049] A five-membered heteroaryl ring is a heteroaryl group having five ring atoms wherein one or more ( e.g., 1, 2, 3, or 4) 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.

[0050] A six-membered heteroaryl ring is a heteroaryl group having six ring atoms wherein one or more ( e.g., 1, 2, 3, or 4) ring atoms are independently selected from N, O, and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

[0051] "Heteroarylene" means a monocyclic, fused bicyclic, or fused tricyclic, divalent radical of 5 to 14 ring atoms containing one or more, preferably one, two, three, or four ring heteroatoms independently selected from -O-, -S(O) n - (n is 0, 1, or 2), -N-, and -N(R 19< )-, and the remaining ring atoms being carbon, wherein the ring comprising a monocyclic radical is aromatic and wherein at least one of the fused rings comprising a bicyclic or tricyclic radical is aromatic. One or two ring carbon atoms of any nonaromatic rings comprising a bicyclic or tricyclic radical may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. R 19< is hydrogen, alkyl, or alkenyl. Unless stated otherwise, the valencies may be located on any atom of any ring of the heteroarylene group, valency rules permitting. In particular, when the point of valency is located on the nitrogen, an additional nitrogen substiuent is not present. More specifically, the term heteroaryl includes, but is not limited to, thien-diyl, benzo[d]isoxazol-diyl, benzo[d]isothiazol-diyl, 1H-indazol-diyl (optionally substituted at the N1 position with R 19< ), benzo[d]oxazol-diyl, benzo[d]thiazol-diyl, 1H-benzo[d]imidazol-diyl (optionally substituted at the N1 position with R 19< ), 1H-benzo[d][1,2,3]triazol-diyl (optionally substituted at the N1 position with R 19< ), imidazo[1,2-a]pyridin-diyl, cinnolin-diyl, quinolin-diyl, pyridin-diyl, 1-oxido-pyridin-diyl, [1,2,4]triazolo[4,3-a]pyridin-diyl, and 2,3-dihydroimidazo[1,2-a]pyridin-diyl, and the like.

[0052] As used herein, "heterocycloalkyl" or "heterocyclo" refer 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, nitrogen, sulfur, oxygen, and phosphorus, and which has 4-14 ring members, 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 or polycyclic (e.g., having two or three fused or bridged rings) ring systems or spirorcycles. In some instances, 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), S(O) 2 , N-oxide, and the like.) 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 instances, the heterocycloalkyl group contains 0 to 3 double bonds. In some instances, 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, and the like. 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, and thiomorpholino.

[0053] "Heterocycloalkyl" or "heterocyclo," can be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms of the group (e.g., from 1 to 4, from 1 to 2, or 1) may be replaced with a moiety independently selected from fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio. In some aspects, a substituted heterocycyl group can incorporate an exo- or endocyclic alkene (e.g., cyclohex-2-en-1-yl). In some aspects, the heterocycyl group is unsubstituted or not optionally substituted.Optional Substitution

[0054] A group is optionally substituted herein unless expressly provided otherwise. The term "optionally substituted" refers to being substituted or unsubstituted. In certain instances, alkyl, alkenyl, alkynyl, carbocycloalkyl, heterocyclyoalkyl, aryl, and heteroaryl groups are optionally substituted. "Optionally substituted" refers to a group which may be substituted or unsubstituted ( e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" "substituted" or "unsubstituted" cyclyoalkyl, "substituted" or "unsubstituted" heterocycloalkyl, "substituted" or "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted" means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term "substituted" is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The disclosure is not intended to be limited in any manner by the exemplary substituents described herein.

[0055] Exemplary carbon atom substituents include, but are not limited to, halogen (halo), -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OR aa< , -ON(R bb< ) 2 , -N(R bb< ) 2 , -N(R bb< ) 3 +< X -,< -N(OR cc< )R bb< , -SH, -SR aa< , -SSR cc< , -C(=O)R aa< , -CO 2 H, -CHO, -C(OR cc< ) 2 , -CO 2 R aa< , -OC(=O)R aa< , -OCO 2 R aa< , -C(=O)N(R bb< ) 2 , -OC(=O)N(R bb< ) 2 , -NR bb< C(=O)R aa< , -NR bb< CO 2 R aa< , -NR bb< C(=O)N(R bb< ) 2 , -C(=NR bb< )R aa< , -C(=NR bb< )OR aa< , -OC(=NR bb< )R aa< , -OC(=NR bb< )OR aa< , -C(=NR bb< )N(R bb< ) 2 , -OC(=NR bb< )N(R bb< ) 2 , -NR bb< C(=NR bb< )N(R bb< ) 2 , -C(=O)NR bb< SO 2 R aa< , -NR bb< SO 2 R aa< , -SO 2 N(R bb< ) 2 , -SO 2 R aa< , -SO 2 OR aa< , -OSO 2 R aa< , -S(=O)R aa< , -OS(=O)R aa< , -Si(R aa< ) 3 , -OSi(R aa< ) 3 -C(=S)N(R bb< ) 2 , -C(=O)SR aa< , -C(=S)SR aa< , -SC(=S)SR aa< , -SC(=O)SR aa< , -OC(=O)SR aa< , -SC(=O)OR aa< , -SC(=O)R aa< , -P(=O) 2 R aa< , -OP(=O) 2 R aa< , -P(=O)(R aa< ) 2 , -OP(=O)(R aa< ) 2 , -OP(=O)(OR cc< ) 2 , -P(=O) 2 N(R bb< ) 2 , -OP(=O) 2 N(R bb< ) 2 , -P(=O)(NR bb< ) 2 , -OP(=O)(NR bb< ) 2 , -NR bb< P(=O)(OR cc< ) 2 , -NR bb< P(=O)(NR bb< ) 2 , -OP(R cc< ) 2 , -OP(R cc< ) 3 , -B(OR cc< ) 2 , -BR aa< (OR cc< ), C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, (C 3 -C 10 ) carbocycloalkyl, 3-14 membered heterocycloalkyl, (C 6 -C 14 ) aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd< groups; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(R bb< ) 2 , =NNR bb< C(=O)R aa< , =NNR bb< C(=O)OR aa< , =NNR bb< S(=O) 2 R aa< , =NR bb< , or =NOR cc< ; each instance of R aa< is, independently, selected from (C 1 -C 10 ) alkyl, (C 1 -C 10 ) perhaloalkyl, (C 2 -C 10 ) alkenyl, (C 2 -C 10 ) alkynyl, (C 3 -C 10 ) cycloalkyl, 3-14 membered heterocycloalkyl, (C 6 -C 14 ) aryl, and 5-14 membered heteroaryl, or two R aa< groups are joined to form a 3-14 membered heterocycloalkyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd< groups; each instance of R bb< is, independently, selected from hydrogen, (C 1 -C 10 ) perhaloalkyl, (C 2 -C 10 ) alkenyl, (C 2 -C 10 ) alkynyl, (C 3 -C 10 ) cycloalkyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R bb< groups are joined to form a 3-14 membered heterocycloalkyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd< groups; each instance of R cc< is, independently, selected from hydrogen, (C 1 -C 10 ) alkyl, (C 1 -C 10 ) perhaloalkyl, (C 2 -C 10 ) alkenyl, (C 2 -C 10 ) alkynyl, (C 3 -C 10 ) cycloalkyl, 3-14 membered heterocycloalkyl, (C 6 -C 14 ) aryl, and 5-14 membered heteroaryl, or two R cc< groups are joined to form a 3-14 membered heterocycloalkyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd< groups; each instance of R dd< is, independently, selected from halogen, -CN, -NO 2 , -SO 2 H, -SO 3 H, -OH, -OR ee< , -ON(R ff< ) 2 , -N(R ff< ) 2 , -N(R ff< ) 3 +< X -,< -N(OR ee< )R ff< , -SH, -SR ee< , -SSR ee< , -C(=O)R ee< , -CO 2 H, -CO 2 R ee< , -OC(=O)R ee< , -OCO 2 R ee< , -C(=O)N(R ff< ) 2 , -OC(=O)N(R ff< ) 2 , -NR ff< C(=O)R ee< , -NR ff< CO 2 R ee< , -NR ff< C(=O)N(R ff< ) 2 , -C(=NR ff< )OR ee< , -OC(=NR ff< )R ee< , -OC(=NR ff< )OR ee< , -C(=NR ff< )N(R ff< ) 2 , -OC(=NR ff< )N(R ff< ) 2 , -NR ff< C(=NR ff< )N(R ff< ) 2 , -NR ff< SO 2 R ee< , -SO 2 N(R ff< ) 2 , -SO 2 R ee< , -SO 2 OR ee< , -OSO 2 R ee< , -S(=O)R ee< , -Si(R ee< ) 3 , -OSi(R ee< ) 3 , -C(=S)N(R ff< ) 2 , -C(=O)SR ee< , -C(=S)SR ee< , -SC(=S)SR ee< , -P(=O) 2 R ee< , -P(=O)(R ee< ) 2 , -OP(=O)(R ee< ) 2 , -OP(=O)(OR ee< ) 2 , (C 1 -C 10 ) alkyl, (C 1 -C 10 ) perhaloalkyl, (C 2 -C 10 ) alkenyl, (C 2 -C 10 ) alkynyl, (C 3 -C 10 ) cycloalkyl, 3-10 membered heterocycloalkyl, (C 6 -C 10 ) aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg< groups, or two geminal R dd< substituents can be joined to form =O or =S; each instance of R ee< is, independently, selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) perhaloalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 3 -C 10 ) cycloalkyl, (C 6 -C 10 ) aryl, 3-10 membered heterocycloalkyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg< groups; each instance of R ff< is, independently, selected from hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) perhaloalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 3 -C 10 ) cycloalkyl, (C 6 -C 10 ) aryl, and 5-10 membered heteroaryl, or two R ff< groups are joined to form a 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg< groups; and each instance of R gg< is, independently, halogen, -CN, -NO 2 , -SO 2 H, -SO 3 H, -OH, -OC 1-6 alkyl, -ON(C 1-6 alkyl) 2 , -N(C 1-6 alkyl) 2 , -N(C 1-6 alkyl) 3 +< X -,< -NH(C 1-6 alkyl) 2 +< X -,< -NH 2 (C 1-6 alkyl) +< X -,< -NH 3 +< X -,< -N(OC 1-6 alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO 2 H, -CO 2 (C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO 2 (C 1-6 alkyl), -C(=O)NH 2 , -C(=O)N(C 1-6 alkyl) 2 , -OC(=O)NH(C 1-6 alkyl), -NHC(=O)( C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)( C 1-6 alkyl), -NHCO 2 (C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl) 2 , -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH 2 , -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 alkyl, -C(=NH)N(C 1-6 alkyl) 2 , -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH 2 , -OC(=NH)N(C 1-6 alkyl) 2 , -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH 2 , -NHC(NH)N(C 1-6 alkyl) 2 , -NHC(=NH)NH 2 , -NHSO 2 (C 1-6 alkyl), -SO 2 N(C 1-6 alkyl) 2 , -SO 2 NH(C 1-6 alkyl), -SO 2 NH 2 , -SO 2 C 1-6 alkyl, -SO 2 OC 1-6 alkyl, -OSO 2 C 1-6 alkyl, -SOC 1-6 alkyl, -Si(C 1-6 alkyl) 3 , -OSi(C 1-6 alkyl) 3 -C(=S)N(C 1-6 alkyl) 2 , C(=S)NH(C 1-6 alkyl), C(=S)NH 2 , -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 alkyl, -SC(=S)SC 1-6 alkyl, -P(=O) 2 (C 1-6 alkyl), -P(=O)(C 1-6 alkyl) 2 , -OP(=O)(C 1-6 alkyl) 2 , -OP(=O)(OC 1-6 alkyl) 2 , (C 1 -C 6 ) alkyl, (C 1 -C 6 ) perhaloalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 3 -C 10 ) cycloalkyl, (C 6 -C 10 ) aryl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl; or two geminal R gg< substituents can be joined to form =O or =S; wherein X -< is a counterion.

[0056] As noted previously, nitrogen atoms can be substituted or unsubstituted as valency permits and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR aa< , -N(R cc< ) 2 , -CN, -C(=O)R aa< , -C(=O)N(R cc< ) 2 , -CO 2 R aa< , -SO 2 R aa< , -C(=NR bb< )R aa< , -C(=NR cc< )OR aa< , -C(=NR cc< )N(R cc< ) 2 , -SO 2 N(R cc< ) 2 , -SO 2 R cc< , -SO 2 OR cc< , -SOR aa< , -C(=S)N(R cc< ) 2 , -C(=O)SR cc< , -C(=S)SR cc< , -P(=O) 2 R aa< , -P(=O)(R aa< ) 2 , -P(=O) 2 N(R cc< ) 2 , -P(=O)(NR cc< ) 2 , (C 1 -C 10 ) alkyl, (C 1 -C 10 ) perhaloalkyl, (C 2 -C 10 ) alkenyl, (C 2 -C 10 ) alkynyl, (C 3 -C 10 ) cycloalkyl, 3-14 membered heterocycloalkyl, (C 6 -C1 4 ) aryl, and 5-14 membered heteroaryl, or two R cc< groups attached to an N atom are joined to form a 3-14 membered heterocycloalkyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd< groups, and wherein R aa< , R bb< , R cc< and R dd< are as defined above.

[0057] In certain instances, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protecting groups include, but are not limited to, -OH, -OR aa< , -N(R cc< ) 2 , -C(=O)R aa< , -C(=O)N(R cc< ) 2 , -CO 2 R aa< , -SO 2 R aa< , -C(=NR cc< )R aa< , -C(=NR cc< )OR aa< , -C(=NR cc< )N(R cc< ) 2 , -SO 2 N(R cc< ) 2 , -SO 2 R cc< , -SO 2 OR cc< , -SOR aa< , -C(=S)N(R cc< ) 2 , -C(=O)SR cc< , -C(=S)SR cc< , (C 1 -C 10 ) alkyl ( e.g., aralkyl, heteroaralkyl), (C 2 -C 10 ) alkenyl, (C 2 -C 10 ) alkynyl, (C 3 -C 10 ) cycloalkyl, 3-14 membered heterocycloalkyl, (C 6 -C 14 ) aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd< groups, and wherein R aa< , R bb< , R cc< , and R dd< are as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999.

[0058] For example, nitrogen protecting groups such as amide groups ( e.g., -C(=O)R aa< ) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0059] Nitrogen protecting groups such as carbamate groups (e.g., -C(=O)OR aa< ) include, but are not limited to, methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate,p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0060] Nitrogen protecting groups such as sulfonamide groups ( e.g., -S(=O) 2 R aa< ) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0061] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivative, N'-p-toluenesulfonylaminoacyl derivative, N'-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

[0062] In certain instances, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an "hydroxyl protecting group"). Oxygen protecting groups include, but are not limited to, -R aa< , -N(R bb< ) 2 , -C(=O)SR aa< , -C(=O)R aa< , -CO 2 R aa< , -C(=O)N(R bb< ) 2 , -C(=NR bb< )R aa< , -C(=NR bb< )OR aa< , -C(=NR bb< )N(R bb< ) 2 , -S(=O)R aa< , -SO 2 R aa< , -Si(R aa< ) 3 , -P(R cc< ) 2 , -P(R cc< ) 3 , -P(=O) 2 R aa< , -P(=O)(R aa< ) 2 , -P(=O)(OR cc< ) 2 , -P(=O) 2 N(R bb< ) 2 , and -P(=O)(NR bb< ) 2 , wherein R aa< , R bb< , and R cc< are as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999.

[0063] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p'-dinitrobenzhydrvl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4"-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzyl sulfonate, and tosylate (Ts).

[0064] In certain instances, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group"). Sulfur protecting groups include, but are not limited to, -R aa< , -N(R bb< ) 2 , -C(=O)SR aa< , -C(=O)R aa< , -CO 2 R aa< , -C(=O)N(R bb< ) 2 , -C(=NR bb< )R aa< , -C(=NR bb< )OR aa< , -C(=NR bb< )N(R bb< ) 2 , -S(=O)R aa< , -SO 2 R aa< , -Si(R aa< ) 3 , -P(R cc< ) 2 , -P(R cc< ) 3 , -P(=O) 2 R aa< , -P(=O)(R aa< ) 2 , -P(=O)(OR cc< ) 2 , -P(=O) 2 N(R bb< ) 2 , and -P(=O)(NR bb< ) 2 , wherein R aa< , R bb< , and R cc< are as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999.

[0065] As used herein, a "leaving group" (LG) is an art-understood term referring to a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule. As used herein, a leaving group can be an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502). Exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo), -OR aa< (when the O atom is attached to a carbonyl group, wherein R aa< is as defined herein), -O(C=O)R LG< , or -O(SO) 2 R LG< (e.g., tosyl, mesyl, besyl), wherein R LG< is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl. In certain instances, the leaving group is a halogen.

[0066] The terms for which definitions are given above are specifically exemplified in the Examples.

[0067] "Yield" for each of the reactions described herein is expressed as a percentage of the theoretical yield.

[0068] "Patient" for the purposes of the present disclosure includes humans and any other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications. In a preferred instance the patient is a mammal, and in a most preferred instance the patient is human. Examples of the preferred mammals include mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, and primates.

[0069] "Kinase-dependent diseases or conditions" refer to pathologic conditions that depend on the activity of one or more kinases. Kinases either directly or indirectly participate in the signal transduction pathways of a variety of cellular activities including proliferation, adhesion, migration, differentiation, and invasion. Diseases associated with kinase activities include tumor growth, the pathologic neovascularization that supports solid tumor growth, and associated with other diseases where excessive local vascularization is involved such as ocular diseases (diabetic retinopathy, age-related macular degeneration, and the like) and inflammation (psoriasis, rheumatoid arthritis, and the like).

[0070] "Therapeutically effective amount" is an amount of a compound of the disclosure that, when administered to a patient, ameliorates a symptom of the disease. The amount of a compound of the disclosure which constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like. The therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.

[0071] "Cancer" refers to cellular-proliferative disease states, including but not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Head and neck: squamous cell carcinomas of the head and neck, laryngeal and hypopharyngeal cancer, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, salivary gland cancer, oral and orppharyngeal cancer; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma, non-small cell lung cancer), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Colon: colorectal cancer, adenocarcinoma, gastrointestinal stromal tumors, lymphoma, carcinoids, Turcot Syndrome; Gastrointestinal: gastric cancer, gastroesophageal junction adenocarcinoma, 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, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Breast: metastatic breast cancer, ductal carcinoma in situ, invasive ductal carcinoma, tubular carcinoma, medullary carcinoma, mucinous carcinoma, lobular carcinoma in situ, triple negative breast cancer; Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia, renal cell carcinoma), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, urothelial carcinoma), prostate (adenocarcinoma, sarcoma, castrate resistant prostate cancer), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma), clear cell carcinoma, papillary carcinoma; Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochrondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors; Thyroid: medullary thyroid cancer, differentiated thyroid cancer, papillary thyroid cancer, follicular thyroid cancer, hurthle cell cancer, and anaplastic thyroid cancer; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial cancer), 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], fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. Thus, the term "cancerous cell" as provided herein, includes a cell afflicted by any one of the above-identified conditions.

[0072] "Pharmaceutically acceptable salts" includes "pharmaceutically acceptable acid addition salts" and "pharmaceutically acceptable base addition salts." "Pharmaceutically acceptable acid addition salts" refers to those salts that retain the biological effectiveness of the free bases and that are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0073] "Pharmaceutically acceptable base addition salts" include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Exemplary salts are the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, for example, S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19.)

[0074] The term compound as used herein is meant to include all stereoisomers, tautomers, and isotopes of the structures depicted. The term is also meant to refer to compounds of the disclosure, regardless of how they are prepared, e.g., synthetically, through biological process (e.g., metabolism or enzyme conversion), or a combination thereof.

[0075] Compounds of the 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.

[0076] Any one of the process steps or sequences disclosed and / or claimed herein can be performed under an inert gas atmosphere, more particularly under argon or nitrogen. In addition, the methods of the present disclosure may be carried out as semi-continuous or continuous processes, more preferably as continuous processes.

[0077] Moreover, many of the process steps and sequences that are described herein can be telescoped.

[0078] In general, the nomenclature used in this Application is based on naming conventions adopted by the International Union of Pure and Applied Chemistry (IUPAC). Chemical structures shown herein were prepared using CHEMDRAW ®< . Any open valency appearing on a carbon, oxygen, or nitrogen atom in the structures herein indicates the presence of a hydrogen atom.Instances of the Disclosure

[0079] In one aspect, the present disclosure comprises a compound for modulating kinase activity according to Formula I', Formula I, or Formula II.

[0080] In one aspect, the disclosure includes a compound of Formula I': or a pharmaceutically acceptable salt thereof, wherein: Y is selected from O, S, SO, SO 2 , NH, and -N(C 1-6 alkyl)-; (i) ring A is and X is N; R 16 is selected from the group consisting of (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-14 membered heteroaryl; 4-14 membered heterocycloalkyl; -CN; -NHOH, -C(O)R a< ; -C(O)NR a< R a< ; -C(O)NHOR a< ; -C(O)OR a< ; -C(O)NR a< S(O) 2 R a< ; - OC(O)NR a< R a< ; C(=NR a< )R a< ; -C(=NOH)R a< ; -C(=NOH)NR a< ; -C(=NCN)NR a< R a< ; - NR a< C(=NCN)NR a< R a< ; -C(=NR a< )NR a< R a< ; -S(O)NR a< R a< ; -S(O) 2 NR a< C(O)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< ; and R 17 is selected from -H; halo; (C 1 -C 6 ) alkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; -CN; -NO 2 ; -OR a< ; -SR a< ; -NHOR a< ; -C(O)R a< ; -C(O)NR a< R a< ; -C(O)NHOR a< ; - C(O)OR a< ; -C(O)NR a< S(O) 2 R 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(=NR a< )R a< ; -NR a< C(O)OR a< ; -NR a< C(O)NR a< R a< ; -C(=NR a< )R a< ; -C(=NOH)R a< ; - C(=NOH)NR a< ; -C(=NCN)NR a< R a< ; -NR a< C(=NCN)NR a< R a< ; -C(=NR a< )NR a< R a< ; - NR a< C(=NR a< )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< ; -S(O) 2 NR a< C(O)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 -C 6 ) alkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene- of R 16 or R 17 are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R b< substituents, provided when R 16 or R 17 is 5-membered heteroaryl or 5-7 membered heterocycloalkyl, then the 5-membered heteroaryl or 5-7 membered heterocycloalkyl does not connect to the fused phenyl ring moiety through a ring nitrogen atom; or R 16 is selected from -H; halo; (C 1 -C 6 ) alkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-14 membered heteroaryl; 4-14 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; -CN; -NO 2 ; -OR a< ; -SR a< ; -NHOR a< ; -C(O)R a< ; -C(O)NR a< R a< ; -C(O)NHOR a< ; - C(O)OR a< ; -C(O)NR a< S(O) 2 R 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(=NR a< )R a< ; -NR a< C(O)OR a< ; -NR a< C(O)NR a< R a< ; -C(=NR a< )R a< ; -C(=NOH)R a< ; - C(=NOH)NR a< ; -C(=NCN)NR a< R a< ; -NR a< C(=NCN)NR a< R a< ; -C(=NR a< )NR a< R a< ; - NR a< C(=NR a< )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< ; -S(O) 2 NR a< C(O)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 -C 6 ) alkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-14 membered heteroaryl; 4-14 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene- of R 16 is each optionally substituted with 1, 2, 3, 4, or 5 independently selected R b< substituents; and R17 is selected from the group consisting of (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; -CN; - NHOH, -C(O)R a< ; -C(O)NR a< R a< ; -C(O)NHOR a< ; -C(O)OR a< ; -C(O)NR a< S(O) 2 R a< ; -OC(O)NR a< R a< ; C(=NR a< )R a< ; -C(=NOH)R a< ; -C(=NOH)NR a< ; -C(=NCN)NR a< R a< ; -NR a< C(=NCN)NR a< R a< ; - C(=NR a< )NR a< R a< ; -S(O)NR a< R a< ; -S(O) 2 NR a< C(O)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< , provided when R 16 or R 17 is 5-membered heteroaryl or 5-7 membered heterocycloalkyl, then the 5-membered heteroaryl or 5-7 membered heterocycloalkyl does not connect to the fused phenyl ring moiety through a ring nitrogen atom; or R 16 and R 17 taken together with the atoms to which they are attached form a fused C 3-7 cycloalkyl ring or a fused 4- to 10-membered heterocycloalkyl ring; wherein the fused C 3-7 cycloalkyl ring and fused 4- to 10-membered heterocycloalkyl ring are each optionally substituted with 1, 2, or 3 independently selected R b< substituents; or (ii) ring A is and X is N or CH, wherein R 18 and R 19 are each independently selected from -H; halo; (C 1 -C 6 ) alkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; -CN; -NO 2 ; -OR a< ; -SR a< ; -NHOR a< ; -C(O)R a< ; -C(O)NR a< R a< ; -C(O)NHOR a< ; -C(O)OR a< ; - C(O)NR a< S(O) 2 R 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(=NR a< )R a< ; -NR a< C(O)OR a< ; -NR a< C(O)NR a< R a< ; -C(=NR a< )R a< ; -C(=NOH)R a< ; -C(=NOH)NR a< ; - C(=NCN)NR a< R a< ; -NR a< C(=NCN)NR a< R a< ; -C(=NR a< )NR a< R a< ; -NR a< C(=NR a< )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< ; -S(O) 2 NR a< C(O)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 -C 6 ) alkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; (C 6 -C 10 ) aryl-(C 1- C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene- of R 18 or R 19 are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R b< substituents; or R 18 and R 19 taken together with the atoms to which they are attached form a fused C 3-7 cycloalkyl ring or a fused 4- to 10-membered heterocycloalkyl ring; wherein the fused C 3-7 cycloalkyl ring and fused 4- to 10-membered heterocycloalkyl ring are each optionally substituted with 1, 2, or 3 independently selected R b< substituents; R 10 and R 11 are each independently selected from the group consisting of -H; halo; (C 1 -C 6 ) alkyl; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-14 membered heteroaryl; 4-14 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; -CN; -NO 2 ; -OR a< ; -SR a< ; -NHOR a< ; -C(O)R a< ; - C(O)NR a< R a< ; -C(O)OR a< ; -C(O)NR a< S(O) 2 R 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(=NR a< )R a< ; -NR a< C(O)OR a< ; -NR a< C(O)NR a< R a< ; -C(=NR a< )R a< ; -C(=NOH)R a< ; - C(=NOH)NR a< ; -C(=NCN)NR a< R a< ; -NR a< C(=NCN)NR a< R a< ; -C(=NR a< )NR a< R a< ; - NR a< C(=NR a< )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< ; -S(O) 2 NR a< C(O)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 -C 6 ) alkyl; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-14 membered heteroaryl; 4-14 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene- of R 1 or R 2 are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R b< substituents; each R 13 is independently selected from the group consisting of -H; halo; -OH; -CN; optionally substituted (C 1 -C 6 ) alkyl; (C 1 -C 6 ) alkoxy; (C 1 -C 6 ) haloalkoxy; -NH 2 ; --NH(C 1 -C 6 )alkyl; -N(C 1 -C 6 alkyl) 2 ; and (C 3 -C 6 ) cycloalkyl; wherein the (C 1 -C 6 ) alkoxy; -NH(C 1 -C 6 )alkyl; -N(C 1 -C 6 alkyl) 2 ; and (C 3 -C 6 ) cycloalkyl of R 3 are each optionally substituted with 1, 2, or 3 independently selected R g< substituents; each R 14 is independently selected from the group consisting of halo; -OH; -NH 2 ; - CN; (C 1 -C 6 ) alkyl; (C 1 -C 6 ) alkoxy; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; -COOH; -NH(C 1 -C 6 )alkyl; -N(C 1 -C 6 alkyl) 2 ; phenyl; phenyl-(C 1 -C 2 ) alkylene; (C 3 -C 6 ) cycloalkyl; (C 3 -C 6 ) cycloalkyl-(C 1 -C 4 ) alkylene-; 4- to 6-membered heterocycloalkyl; (4- to 6-membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; 5- to 6-membered heteroaryl; (5- to 6-membered heteroaryl)-(C 1 -C 4 ) alkylene-; and -OR e< ; wherein the (C 1 -C 6 ) alkyl; phenyl; phenyl-(C 1 -C 2 ) alkylene; (C 3 -C 6 ) cycloalkyl; (C 3 -C 6 ) cycloalkyl-(C 1 -C 4 ) alkylene-; 4- to 6-membered heterocycloalkyl; (4- to 6-membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; 5- to 6-membered heteroaryl; and (5- to 6-membered heteroaryl)-(C 1 -C 4 ) alkylene- of R 14 are each optionally substituted with 1, 2, or 3 independently selected R g< substituents; R 15 is H; each R 12 is independently selected from the group consisting of -H; halo; -OH; - COOR e< ; -CONR e< R e< ; -CN; -NH 2 ; -NH((C 1 -C 6 ) alkyl); -N((C 1 -C 6 ) alkyl) 2 ; (C 1 -C 6 ) alkyl; (C 1 -C6) alkoxy; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; -CONR a< R a< ; -NR a< COR a< ; -NR a< CONR a< R a< ; - SO 2 R a< ; -NR a< S(O) 2 R a< ; -NR a< S(O) 2 NR a< R a< ; (C 3 -C 6 ) cycloalkyl; 4- to 6-membered heterocycloalkyl; phenyl; 5- or 6-membered heteroaryl; (C 3 -C 6 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (4- to 6-membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; phenyl-(C 1 -C 2 ) alkylene; and (5- or 6-membered heteroaryl)-(C 1 -C 4 ) alkylene-; wherein the (C 1 -C 6 ) alkyl; (C 3 -C 6 ) cycloalkyl; 4- to 6-membered heterocycloalkyl; phenyl; 5- or 6-membered heteroaryl; (C 3 -C 6 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (4- to 6-membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; phenyl-(C 1 -C 2 ) alkylene; and (5- or 6-membered heteroaryl)-(C 1 -C 4 ) alkylene- of R 12 are each optionally substituted with 1, 2, or 3 independently selected R f< substituents; each R a< is independently selected from the group consisting of -H; -CN; (C 1 -C 6 ) alkyl; (C 1 -C 6 ) haloalkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-14 membered heteroaryl; 4-14 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; wherein the (C 1 -C 6 ) alkyl; (C 1 -C 6 ) haloalkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-14 membered heteroaryl; 4-14 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene- of R a< are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R d< substituents; each R b< is independently selected from the group consisting of halo; (C 1 -C 6 ) alkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-10 membered heteroaryl; 4-10 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-10 membered heteroaryl)-(C 1 -C 4 ) alkylene-; (4-10 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; -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< ; -Si(R c< ) 3 ; -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 -C 6 ) alkyl; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-10 membered heteroaryl; 4-10 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalky-(C 1 -C 4 ) alkylene-; (5-10 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-10 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene- 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 the group consisting of -H; (C 1 -C 6 ) alkyl; (C 1 -C 6 ) haloalkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-10 membered heteroaryl; 4-10 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-10 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-10 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; wherein the (C 1 -C 6 ) alkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-10 membered heteroaryl; 4-10 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-10 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-10 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene- of R c< are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R f< substituents; each R d< is independently selected from the group consisting of (C 1 -C 6 ) alkyl; (C 1 -C 6 ) haloalkyl; halo; (C 6 -C 10 ) aryl; 5-10 membered heteroaryl; (C 3 -C 10 ) cycloalkyl; 4-10 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-10 membered heteroaryl)-(C 1 -C 4 ) alkylene-; (4-10 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; -CN; -NH 2 ; -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< ; and -S(O) 2 NR e< R e< ; wherein the (C 1 -C 6 ) alkyl; (C 1 -C 6 ) haloalkyl; (C 6 -C 10 ) aryl; 5-10 membered heteroaryl; (C 3 -C 10 ) cycloalkyl; 4-10 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-10 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-10 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene- of R d< are each optionally substituted with 1, 2, or 3 independently selected R f< substituents; each R e< is independently selected from the group consisting of -H; (C 1 -C 6 ) alkyl; (C 3 -C 6 ) cycloalkyl; (C 3 -C 6 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (C 6 -C 10 ) aryl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; 5- or 6-membered heteroaryl; (5- or 6-membered heteroaryl)-(C 1 -C 4 ) alkylene-; 4-7-membered heterocycloalkyl; (4-7-membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; (C 2 -C 4 ) alkenyl; and (C 2 -C 4 ) alkynyl; wherein the (C 1 -C 4 ) alkyl; (C 3 -C 6 ) cycloalkyl; (C 6 -C 10 ) aryl; 5 or 6-membered heteroaryl; 4-7-membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (5- or 6-membered heteroaryl)-(C 1 -C 4 ) alkylene-; (4-7-membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; (C 2 -C 4 ) alkenyl; and (C 2 -C 4 ) alkynyl of R e< are each optionally substituted with 1, 2, or 3 R f< substituents; or any two R a< substituents together with the nitrogen atom to which they are attached form 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R f< substituents; or any two R c< substituents together with the nitrogen atom to which they are attached form 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R f< substituents; or any two R e< substituents together with the nitrogen atom to which they are attached form 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R f< substituents; each R f< is independently selected from the group consisting of halo; -OH; -CN; - COOH; -NH 2 ; -NH-(C 1 -C 6 ) alkyl; -N((C 1 -C 6 ) alky) 2 ; (C 1 -C 6 ) alkyl; (C 1 -C 6 ) alkoxy; (C 1 -C 6 ) alkylthio; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; phenyl; 5-6 membered heteroaryl; 4-6 membered heterocycloalkyl; and (C 3 -C 6 ) cycloalkyl; wherein the (C 1 -C 6 ) alkyl; phenyl; (C 3 -C 6 ) cycloalkyl; 4-6 membered heterocycloalkyl; and 5-6 membered heteroaryl of R f< are each optionally substituted with 1, 2, or 3 substituents selected from halo; -OH; -CN; -COOH; - NH 2 ; (C 1 -C 4 ) alkyl; (C 1 -C 4 ) alkoxy; (C 1 -C 4 ) haloalkyl; (C 1 -C 4 ) haloalkoxy; phenyl; (C 3 -C 10 ) cycloalkyl; 5-6 membered heteroaryl; and 4-6 membered heterocycloalkyl; each R g< is independently selected from the group consisting of halo; -OH; -CN; - COOH; -COO-(C 1 -C 4 ) alkyl; -NH 2 ; -NH-(C 1 -C 6 ) alkyl; -N((C 1 -C 6 ) alky) 2 ; (C 1 -C 6 ) alkyl; (C 1 -C 6 ) alkoxy; (C 1 -C 6 ) alkylthio; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; phenyl; 5-6 membered heteroaryl; 4-6 membered heterocycloalkyl; and (C 3 -C 6 ) cycloalkyl; the ring nitrogen atom on the quinoline moiety in Formula A is optionally oxidized; the subscript n is an integer of 1, 2, 3, or 4; the subscript m is an integer of 1, 2, 3, 4, or 5; and the subscript p is an integer of 0, 1, 2, 3, or 4; provided that when X is C-H, Ring A is

[0081] In one aspect, the disclosure includes a compound of Formula I': or a pharmaceutically acceptable salt thereof, wherein: X is N or CH; Y is selected from O, S, SO, SO 2 , NH, and -N(C 1-6 alkyl)-; (i) ring A is R 16 is selected from the group consisting of (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-14 membered heteroaryl; 4-14 membered heterocycloalkyl; -CN; -NHOH, -C(O)R a< ; -C(O)NR a< R a< ; -C(O)NHOR a< ; -C(O)OR a< ; -C(O)NR a< S(O) 2 R a< ; - OC(O)NR a< R a< ; C(=NR a< )R a< ; -C(=NOH)R a< ; -C(=NOH)NR a< ; -C(=NCN)NR a< R a< ; - NR a< C(=NCN)NR a< R a< ; -C(=NR a< )NR a< R a< ; -S(O)NR a< R a< ; -S(O) 2 NR a< C(O)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< ; and R 17 is selected from -H; halo; (C 1 -C 6 ) alkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; -CN; -NO 2 ; -OR a< ; -SR a< ; -NHOR a< ; -C(O)R a< ; -C(O)NR a< R a< ; -C(O)NHOR a< ; - C(O)OR a< ; -C(O)NR a< S(O) 2 R 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(=NR a< )R a< ; -NR a< C(O)OR a< ; -NR a< C(O)NR a< R a< ; -C(=NR a< )R a< ; -C(=NOH)R a< ; - C(=NOH)NR a< ; -C(=NCN)NR a< R a< ; -NR a< C(=NCN)NR a< R a< ; -C(=NR a< )NR a< R a< ; - NR a< C(=NR a< )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< ; -S(O) 2 NR a< C(O)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 -C 6 ) alkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene- of R 16 or R 17 are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R b< substituents, provided when R 16 or R 17 is 5-membered heteroaryl or 5-7 membered heterocycloalkyl, then the 5-membered heteroaryl or 5-7 membered heterocycloalkyl does not connect to the fused phenyl ring moiety through a ring nitrogen atom; or R 16 is selected from -H; halo; (C 1 -C 6 ) alkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-14 membered heteroaryl; 4-14 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; -CN; -NO 2 ; -OR a< ; -SR a< ; -NHOR a< ; -C(O)R a< ; -C(O)NR a< R a< ; -C(O)NHOR a< ; - C(O)OR a< ; -C(O)NR a< S(O) 2 R 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(=NR a< )R a< ; -NR a< C(O)OR a< ; -NR a< C(O)NR a< R a< ; -C(=NR a< )R a< ; -C(=NOH)R a< ; - C(=NOH)NR a< ; -C(=NCN)NR a< R a< ; -NR a< C(=NCN)NR a< R a< ; -C(=NR a< )NR a< R a< ; - NR a< C(=NR a< )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< ; -S(O) 2 NR a< C(O)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 -C 6 ) alkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-14 membered heteroaryl; 4-14 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene- of R 16 is each optionally substituted with 1, 2, 3, 4, or 5 independently selected R b< substituents; and R 17 is selected from the group consisting of (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; -CN; - NHOH, -C(O)R a< ; -C(O)NR a< R a< ; -C(O)NHOR a< ; -C(O)OR a< ; -C(O)NR a< S(O) 2 R a< ; -OC(O)NR a< R a< ; C(=NR a< )R a< ; -C(=NOH)R a< ; -C(=NOH)NR a< ; -C(=NCN)NR a< R a< ; -NR a< C(=NCN)NR a< R a< ; - C(=NR a< )NR a< R a< ; -S(O)NR a< R a< ; -S(O) 2 NR a< C(O)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< , provided when R 16 or R 17 is 5-membered heteroaryl or 5-7 membered heterocycloalkyl, then the 5-membered heteroaryl or 5-7 membered heterocycloalkyl does not connect to the fused phenyl ring moiety through a ring nitrogen atom; or R 16 and R 17 taken together with the atoms to which they are attached form a fused C 3-7 cycloalkyl ring or a fused 4- to 10-membered heterocycloalkyl ring; wherein the fused C 3-7 cycloalkyl ring and fused 4- to 10-membered heterocycloalkyl ring are each optionally substituted with 1, 2, or 3 independently selected R b< substituents; or (ii) ring A is R 18 and R 19 are each independently selected from -H; halo; (C 1 -C 6 ) alkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; -CN; -NO 2 ; -OR a< ; -SR a< ; -NHOR a< ; -C(O)R a< ; -C(O)NR a< R a< ; -C(O)NHOR a< ; -C(O)OR a< ; - C(O)NR a< S(O) 2 R 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(=NR a< )R a< ; -NR a< C(O)OR a< ; -NR a< C(O)NR a< R a< ; -C(=NR a< )R a< ; -C(=NOH)R a< ; -C(=NOH)NR a< ; - C(=NCN)NR a< R a< ; -NR a< C(=NCN)NR a< R a< ; -C(=NR a< )NR a< R a< ; -NR a< C(=NR a< )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< ; -S(O) 2 NR a< C(O)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 -C 6 ) alkyl; (C2-C6) alkenyl; (C2-C6) alkynyl; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; (C 6 -C 10 ) aryl-(C 1- C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene- of R 18 or R 19 are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R b< substituents; or R 18 and R 19 taken together with the atoms to which they are attached form a fused C 3-7 cycloalkyl ring or a fused 4- to 10-membered heterocycloalkyl ring; wherein the fused C 3-7 cycloalkyl ring and fused 4- to 10-membered heterocycloalkyl ring are each optionally substituted with 1, 2, or 3 independently selected R b< substituents; R 10 and R 11 are each independently selected from the group consisting of -H; halo; (C 1 -C 6 ) alkyl; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-14 membered heteroaryl; 4-14 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; -CN; -NO 2 ; -OR a< ; -SR a< ; -NHOR a< ; -C(O)R a< ; - C(O)NR a< R a< ; -C(O)OR a< ; -C(O)NR a< S(O) 2 R 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(=NR a< )R a< ; -NR a< C(O)OR a< ; -NR a< C(O)NR a< R a< ; -C(=NR a< )R a< ; -C(=NOH)R a< ; - C(=NOH)NR a< ; -C(=NCN)NR a< R a< ; -NR a< C(=NCN)NR a< R a< ; -C(=NR a< )NR a< R a< ; - NR a< C(=NR a< )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< ; -S(O) 2 NR a< C(O)R a< ; -P(O)R a< R a< ; -P(O)(OR a< )(OR a< ); -B(OH) 2 ; -B(OR a< ) 2 ; and S(O)aNR a< R a< ; wherein the (C 1 -C 6 ) alkyl; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-14 membered heteroaryl; 4-14 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene- of R 1 or R 2 are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R b< substituents; each R 13 is independently selected from the group consisting of -H; halo; -OH; -CN; optionally substituted (C 1 -C 6 ) alkyl; (C 1 -C 6 ) alkoxy; (C 1 -C 6 ) haloalkoxy; -NH 2 ; --NH(C 1 -C 6 )alkyl; -N(C 1 -C 6 alkyl) 2 ; and (C 3 -C 6 ) cycloalkyl; wherein the (C 1 -C 6 ) alkoxy; -NH(C 1 -C 6 )alkyl; -N(C 1 -C 6 alkyl) 2 ; and (C 3 -C 6 ) cycloalkyl of R 3 are each optionally substituted with 1, 2, or 3 independently selected R g< substituents; each R 14 is independently selected from the group consisting of halo; -OH; -NH 2 ; - CN; (C 1 -C 6 ) alkyl; (C 1 -C 6 ) alkoxy; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; -COOH; -NH(C 1 -C 6 )alkyl; -N(C 1 -C 6 alkyl) 2 ; phenyl; phenyl-(C 1 -C 2 ) alkylene; (C 3 -C 6 ) cycloalkyl; (C 3 -C 6 ) cycloalkyl-(C 1 -C 4 ) alkylene-; 4- to 6-membered heterocycloalkyl; (4- to 6-membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; 5- to 6-membered heteroaryl; (5- to 6-membered heteroaryl)-(C 1 -C 4 ) alkylene-; and -OR e< ; wherein the (C 1 -C 6 ) alkyl; phenyl; phenyl-(C 1- C 2 ) alkylene; (C 3 -C 6 ) cycloalkyl; (C 3 -C 6 ) cycloalk-yl-(C 1 -C 4 ) alkylene-; 4- to 6-membered heterocycloalkyl; (4- to 6-membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; 5- to 6-membered heteroaryl; and (5- to 6-membered heteroaryl)-(C 1- C 4 ) alkylene- of R 14 are each optionally substituted with 1, 2, or 3 independently selected R g< substituents; R 15 is H; each R 12 is independently selected from the group consisting of -H; halo; -OH; - COOR e< ; -CONR e< R e< ; -CN; -NH 2 ; -NH((C 1- C 6 ) alkyl); -N((C 1- C 6 ) alkyl) 2 ; (C 1 -C 6 ) alkyl; (C 1 -C6) alkoxy; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; -CONR a< R a< ; -NR a< COR a< ; -NR a< CONR a< R a< ; - SO 2 R a< ; -NR a< S(O) 2 R a< ; -NR a< S(O) 2 NR a< R a< ; (C 3 -C 6 ) cycloalkyl; 4- to 6-membered heterocycloalkyl; phenyl; 5- or 6-membered heteroaryl; (C 3 -C 6 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (4- to 6-membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; phenyl-(C 1 -C 2 ) alkylene; and (5- or 6-membered heteroaryl)-(C 1 -C 4 ) alkylene-; wherein the (C 1 -C 6 ) alkyl; (C 3 -C 6 ) cycloalkyl; 4- to 6-membered heterocycloalkyl; phenyl; 5- or 6-membered heteroaryl; (C 3 -C 6 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (4- to 6-membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; phenyl-(C 1 -C 2 ) alkylene; and (5- or 6-membered heteroaryl)-(C 1 -C 4 ) alkylene- of R 12 are each optionally substituted with 1, 2, or 3 independently selected R f< substituents; each R a< is independently selected from the group consisting of -H; -CN; (C 1 -C 6 ) alkyl; (C 1 -C 6 ) haloalkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-14 membered heteroaryl; 4-14 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; wherein the (C 1 -C 6 ) alkyl; (C 1 -C 6 ) haloalkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-14 membered heteroaryl; 4-14 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene- of R a< are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R d< substituents; each R b< is independently selected from the group consisting of halo; (C 1 -C 6 ) alkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-10 membered heteroaryl; 4-10 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-10 membered heteroaryl)-(C 1 -C 4 ) alkylene-; (4-10 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; -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< ; -Si(R c< ) 3 ; -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 -C 6 ) alkyl; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-10 membered heteroaryl; 4-10 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalky-(C 1 -C 4 ) alkylene-; (5-10 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-10 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene- 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 the group consisting of -H; (C 1 -C 6 ) alkyl; (C 1 -C 6 ) haloalkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-10 membered heteroaryl; 4-10 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-10 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-10 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; wherein the (C 1 -C 6 ) alkyl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; (C 6 -C 10 ) aryl; (C 3 -C 10 ) cycloalkyl; 5-10 membered heteroaryl; 4-10 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-10 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-10 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene- of R c< are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R f< substituents; each R d< is independently selected from the group consisting of (C 1 -C 6 ) alkyl; (C 1 -C 6 ) haloalkyl; halo; (C 6 -C 10 ) aryl; 5-10 membered heteroaryl; (C 3 -C 10 ) cycloalkyl; 4-10 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-10 membered heteroaryl)-(C 1 -C 4 ) alkylene-; (4-10 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; -CN; -NH 2 ; -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< ; and -S(O) 2 NR e< R e< ; wherein the (C 1 -C 6 ) alkyl; (C 1 -C 6 ) haloalkyl; (C 6 -C 10 ) aryl; 5-10 membered heteroaryl; (C 3 -C 10 ) cycloalkyl; 4-10 membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (5-10 membered heteroaryl)-(C 1 -C 4 ) alkylene-; and (4-10 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene- of R d< are each optionally substituted with 1, 2, or 3 independently selected R f< substituents; each R e< is independently selected from the group consisting of -H; (C 1 -C 6 ) alkyl; (C 3 -C 6 ) cycloalkyl; (C 3- C 6 ) cycloalkyl-(C 1 -C 4 ) alkylene-; (C 6 -C 10 ) aryl; (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-; 5- or 6-membered heteroaryl; (5- or 6-membered heteroaryl)-(C 1- C4) alkylene-; 4-7-membered heterocycloalkyl; (4-7-membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-; (C 1 -C 6 ) haloalkyl; (C 1- C 6 ) haloalkoxy; (C 2 -C 4 ) alkenyl; and (C 2 -C 4 ) alkynyl; wherein the (C 1 -C 4 ) alkyl; (C 3 -C 6 ) cycloalkyl; (C 6 -C 10 ) aryl; 5 or 6-membered heteroaryl; 4-7-membered heterocycloalkyl; (C 6 -C 10 ) aryl-(C 1- C 4 ) alkylene-; (5- or 6-membered heteroaryl)-(C 1- C 4 ) alkylene-; (4-7-membered heterocycloalkyl)-(C 1- C 4 ) alkylene-; (C 2 -C 4 ) alkenyl; and (C 2 -C 4 ) alkynyl of R e< are each optionally substituted with 1, 2, or 3 R f< substituents; or any two R a< substituents together with the nitrogen atom to which they are attached form 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R f< substituents; or any two R c< substituents together with the nitrogen atom to which they are attached form 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R f< substituents; or any two R e< substituents together with the nitrogen atom to which they are attached form 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R f< substituents; each R f< is independently selected from the group consisting of halo; -OH; -CN; -COOH; - NH 2 ; -NH-(C 1- C 6 ) alkyl; -N((C 1- C 6 ) alky) 2 ; (C 1 -C 6 ) alkyl; (C 1 -C 6 ) alkoxy; (C 1 -C 6 ) alkylthio; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; phenyl; 5-6 membered heteroaryl; 4-6 membered heterocycloalkyl; and (C 3 -C 6 ) cycloalkyl; wherein the (C 1 -C 6 ) alkyl; phenyl; (C 3 -C 6 ) cycloalkyl; 4-6 membered heterocycloalkyl; and 5-6 membered heteroaryl of R f< are each optionally substituted with 1, 2, or 3 substituents selected from halo; -OH; -CN; -COOH; -NH 2 ; (C 1 -C 4 ) alkyl; (C 1 -C 4 ) alkoxy; (C 1 -C 4 ) haloalkyl; (C 1 -C 4 ) haloalkoxy; phenyl; (C 3 -C 10 ) cycloalkyl; 5-6 membered heteroaryl; and 4-6 membered heterocycloalkyl; each R g< is independently selected from the group consisting of halo; -OH; -CN; -COOH; -COO-(C 1 -C 4 ) alkyl; -NH 2 ; -NH-(C 1- C 6 ) alkyl; -N((C 1- C 6 ) alky) 2 ; (C 1 -C 6 ) alkyl; (C 1 -C 6 ) alkoxy; (C 1 -C 6 ) alkylthio; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) haloalkoxy; phenyl; 5-6 membered heteroaryl; 4-6 membered heterocycloalkyl; and (C 3- C 6 ) cycloalkyl; the ring nitrogen atom on the quinoline moiety in Formula A is optionally oxidized; the subscript n is an integer of 1, 2, 3, or 4; the subscript m is an integer of 1, 2, 3, 4, or 5; and the subscript p is an integer of 0, 1, 2, 3, or 4; provided that when X is C-H, Ring A is or

[0082] In one instance of this aspect, X is N. In another instance, X is CH;

[0083] In one instance of this aspect, Y is selected from O, NH, and -N(C 1-6 alkyl)-. In a further aspect, Y is O.

[0084] In one instance of this aspect, R 16 is selected from -H, halo, -CN, (C 1 -C 6 ) alkyl, (C 6 -C 10 ) aryl, (C 3 -C 10 ) cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, - CN, -NO 2 , -OR a< , -SR a< , -NHOR a< , -C(O)R a< , -C(O)NR a< R a< , -C(O)NHOR a< , -C(O)OR a< , - C(O)NR a< S(O)2R a< , -OC(O)R a< , -OC(O)NR a< R a< , -NHR a< , -NR a< R a< , and -NR a< C(O)R a< . In a further instance, R 16 is selected from -H, halo, -CN, (C 1 -C 6 ) alkyl, 5-14 membered heteroaryl, -O(C 1 -C 6 ), -C(O)(C 1 -C 6 alkyl), -C(O)N(C 1 -C 6 alkyl) 2 , -C(O)NH(C 1 -C 6 alkyl), -C(O)NH 2 , - C(O)NH(4-6 membered heterocycloalkyl), -C(O)NH(C 3 -C 10 cycloalkyl), -C(O)NH(C 1 -C 4 alkylene-(4-6 membered heterocycloalkyl)), -C(O)NH(C 1 -C 4 alkylene-(C 3 -C 10 cycloalkyl)), - C(O)O(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , and -NHC(O)(C 1 -C 6 alkyl). In still a further instance, R 16 is selected from -H, -CN, 5-14 membered heteroaryl, -C(O)NH 2 , - C(O)NH(4-6 membered heterocycloalkyl), -C(O)NH(C 3 -C 10 cycloalkyl), -C(O)NH(C 1 -C 4 alkylene-(4-6 membered heterocycloalkyl)), -C(O)O(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , and -NHC(O)(C 1 -C 6 alkyl).

[0085] In some instances, each (C 1 -C 6 ) alkyl, (C 6 -C 10 ) aryl, (C 3 -C 10 ) cycloalkyl, 5-14 membered heteroaryl, or 4-14 membered heterocycloalkyl of R 16 is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, (C 1 -C 6 ) alkyl, -CN, -NO 2 , phenyl, (C 1 -C 6 ) alkoxy, and oxo. In a further instance, each (C 1 -C 6 ) alkyl, (C 6 -C 10 ) aryl, (C 3 -C 10 ) cycloalkyl, 5-14 membered heteroaryl, or 4-14 membered heterocycloalkyl of R 16 is optionally substituted with 1, 2, 3, 4, or 5 (C 1 -C 6 ) alkyl substituents.

[0086] In one instance, R 16 is selected from H, -CN, (oxetan-3-yl)carbamoyl, cyclopropylcarbamoyl, carbamoyl, 2-(pyrrolidin-1-yl)ethylcarbamoyl, 1-(t-butoxycarbonylpyrrolidin-2-yl)methylcarbamoyl, 1-(pyrrolidin-2-yl)methylcarbamoyl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl.

[0087] In some instances, R 17 is selected from the group consisting of -H, halo, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, -CN, -NO 2 , -OR a< , -SR a< , -NHOH, -C(O)R a< , - C(O)NR a< R a< , -C(O)NHOR a< , -C(O)OR a< , -C(O)NR a< S(O) 2 R a< , -OC(O)NR a< R a< , C(=NR a< )R a< , - C(=NOH)R a< , -C(=NOH)NR a< , -C(=NCN)NR a< R a< , -NR a< C(=NCN)NR a< R a< , -C(=NR a< )NR a< R a< , - S(O)NR a< R a< , -S(O) 2 NR a< C(O)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< . In a further instance, R 17 is selected from the group consisting of -H, halo, (C 1 -C 6 ) alkyl, -CN, -NO 2 , -O(C 1 -C 6 ) alkyl, -C(O)(C 1 -C 6 ) alkyl, -C(O)NH(C 1 -C 6 ) alkyl, - C(O)N((C 1 -C 6 ) alkyl) 2 , and -C(O)O(C 1 -C 6 ) alkyl. In still a further instance, R 17 is selected from the group consisting of -H, halo, (C 1 -C 6 ) alkyl, -CN, -NO 2 , and -O(C 1 -C 6 ) alkyl. In yet a further instance, R 17 is selected from the group consisting of -H, halo, (C 1 -C 6 ) alkyl, and - O(C 1 -C 6 ) alkyl. In yet a further instance, R 17 is selected from the group consisting of -H, and methoxy.

[0088] In one instance of this aspect, ring A is In another instance of this aspect, ring A is In yet another instance of this aspect, ring A is According to the invention, ring A is

[0089] In one instance of this aspect, R 18 and R 19 are each independently selected from -H, halo, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 6 -C 10 ) aryl, (C 3 -C 10 ) cycloalkyl, 4-14 membered heterocycloalkyl, phenyl, 5-14 membered heteroaryl, (C 6 -C 10 ) aryl-(C 1- C 4 ) alkylene-, (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-, (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-, (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-, -CN, -NO 2 , -OR a< , -SR a< , - NHOR a< , -C(O)R a< , -C(O)NR a< R a< , -C(O)NHOR a< , -C(O)OR a< , -C(O)NR a< S(O) 2 R 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(=NR a< )R a< , -NR a< C(O)OR a< , and - NR a< C(O)NR a< R a< . In another instance, R 18 and R 19 are each independently selected from -H, halo, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 6 -C 10 ) aryl, (C 3 -C 10 ) cycloalkyl, 4-14 membered heterocycloalkyl, phenyl, 5-14 membered heteroaryl, -CN, -NO 2 , -OR a< , -SR a< , -C(O)R a< , -C(O)NR a< R a< , -C(O)OR a< , -NHR a< , -NR a< R a< , and -NR a< C(O)R a< . In a further instance, R 18 and R 19 are each independently selected from -H, halo, (C 1 -C 6 ) alkyl, phenyl, (C 3 -C 10 ) cycloalkyl, 4-14 membered heterocycloalkyl, 5-14 membered heteroaryl, -CN, -O(C 1 -C 6 ) alkyl, -C(O)(C 1 -C 6 ) alkyl, -C(O)NH 2 , -C(O)NH(C 1 -C 6 ) alkyl, -C(O)N((C 1 -C 6 ) alkyl) 2 , - C(O)O(C 1 -C 6 ) alkyl, -NH(C 1 -C 6 ) alkyl, -N((C 1 -C 6 ) alkyl) 2 , and -NHC(O)(C 1 -C 6 ) alkyl. In a further instance, R 18 and R 19 are each independently selected from -H, halo, (C 1 -C 6 ) alkyl, 5-14 membered heteroaryl, -CN, -O(C 1 -C 4 alkylene-(4-14 membered heterocycloalkyl)), O(C 1 -C 6 alkoxy-C 1 -C 6 alkyl)), -C(O)NH 2 , -C(O)NH(C 1 -C 6 ) alkyl, -C(O)N((C 1 -C 6 ) alkyl) 2 , and - NH 2 .

[0090] In one instance, the (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1- C 6 )haloalkoxy, (C 6 -C 10 ) aryl, (C 3 -C 10 ) cycloalkyl, 4-14 membered heterocycloalkyl, phenyl, 5-14 membered heteroaryl, (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-, (C 3 -C 10 ) cycloalkyl-(C 1- C 4 ) alkylene-, (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-, or (4-14 membered heterocycloalkyl)-(C 1- C 4 ) alkylene-, of R 18 or R 19 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, (C 1 -C 6 ) alkyl, -CN, -OH, and -C(O)OR x , wherein R x is (C 1 -C 6 ) alkyl, phenyl, or benzyl. In a further instance, the (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 6 -C 10 ) aryl, (C 3 -C 10 ) cycloalkyl, 4-14 membered heterocycloalkyl, phenyl, 5-14 membered heteroaryl, (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-, (C 3 -C 10 ) cycloalkyl-(C 1- -C 4 ) alkylene-, (5-14 membered heteroaryl)-(C 1 -C 4 ) alkylene-, or (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-, of R 18 or R 19 are each optionally substituted with - C(O)OR x , wherein R x is (C 1 -C 6 ) alkyl, phenyl, or benzyl.

[0091] In another instance, R 18 and R 19 taken together with the atoms to which they are attached form a fused C 3- C 7 cycloalkyl ring or a fused 4- to 10-membered heterocycloalkyl ring, wherein the fused C 3 -C 7 cycloalkyl ring and fused 4- to 10-membered heterocycloalkyl ring are each optionally substituted with 1, 2, or 3 independently selected R b< substituents. In a further instance, R 18 and R 19 taken together with the atoms to which they are attached form a fused C 3 -C 7 cycloalkyl ring or a fused 4- to 10-membered heterocycloalkyl ring, wherein the fused C 3 -C 7 cycloalkyl ring and fused 4- to 10-membered heterocycloalkyl ring are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, -CN, - NO 2 , -OH, oxo, (C 1 -C 6 ) alkyl, -O(C 1 -C 6 ) alkyl, -C(O)(C 1 -C 6 ) alkyl, -C(O)NH 2 , -C(O)NH(C 1 -C 6 ) alkyl, -C(O)N((C 1 -C 6 ) alkyl) 2 , -C(O)O(C 1 -C 6 ) alkyl, -NH(C 1 -C 6 ) alkyl, -N((C 1 -C 6 ) alkyl) 2 , and -NHC(O)(C 1 -C 6 ) alkyl. In still a further instance, R 18 and R 19 taken together with the atoms to which they are attached form a fused C 3 -C 7 cycloalkyl ring or a fused 4- to 10-membered heterocycloalkyl ring, wherein the fused C 3 -C 7 cycloalkyl ring and fused 4- to 10-membered heterocycloalkyl ring are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, (C 1 -C 6 ) alkyl, and -O(C 1 -C 6 ) alkyl. In yet a further instance, R 18 and R 19 taken together with the atoms to which they are attached form a fused ring selected from According to the invention, in one embodiment, R 18 and R 19 are each independently selected from H, halo, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1- C 6 ) haloalkoxy, (C 6 -C 10 ) aryl, (C 3 -C 10 ) cycloalkyl, 4-14 membered heterocycloalkyl, phenyl, 5-14 membered heteroaryl, -CN, -NO 2 , -OR a< , -SR a< , -C(O)R a< , -C(O)NR a< R a< , -C(O)OR a< , -NHR a< , - NR a< R a< , and -NR a< C(O)R a< , wherein the (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 6 -C 10 ) aryl, (C 3 -C 10 ) cycloalkyl, 4-14 membered heterocycloalkyl, phenyl, and 5-14 membered heteroaryl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, (C 1 -C 6 ) alkyl, -CN, and -OH. According to the invention, in another embodiment, R 18 and R 19 taken together with the atoms to which they are attached form a fused C 3-7 cycloalkyl ring or a fused 4- to 10-membered heterocycloalkyl ring.

[0092] In one instance, R 18 is selected from H, halo, NH 2 , methoxy, methyl, -CN, carbamoyl, dimethylcarbamoyl, methylcarbamoyl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, and 2-methyl-pyrazol-3-yl.

[0093] In one instance, R 19 is selected from H, halo, methoxy, methyl, 3-morphlinopropoxy, 2-methoxyethoxy, 1-methyl-pyrazol-4-yl.

[0094] In one instance of this aspect, each R 13 is independently selected from the group consisting of -H, halo, -OH, -CN, optionally substituted (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, -NH 2 , -NH(C 1 -C 6 )alkyl, -N(C 1 -C 6 alkyl) 2 , and (C 3 -C 6 ) cycloalkyl, wherein the (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, -NH(C 1 -C 6 )alkyl, -N(C 1 -C 6 alkyl) 2 , and (C 3 -C 6 ) cycloalkyl of R 3 are each optionally substituted with 1, 2, or 3 independently selected R g< substituents. In a further instances of this aspect, each R 13 is independently selected from the group consisting of -H, halo, -OH, -CN, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, -NH 2 , -NH(C 1 -C 6 )alkyl, and -N(C 1 -C 6 alkyl) 2 , wherein the (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, -NH(C 1 -C 6 )alkyl, and -N(C 1 -C 6 alkyl) 2 of R 3 are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, -OH, -CN, (C 1 -C 6 ) alkyl, and -NH 2 . In still further instances of this aspect, each R 13 is independently selected from the group consisting of -H, halo, (C 1 -C 6 ) alkyl, and (C 1 -C 6 ) alkoxy. According to the invention, each R 13 is independently selected from the group consisting of -H; halo; -OH; -CN; optionally substituted (C 1 -C 6 ) alkyl; (C 1 -C 6 ) alkoxy; (C 1 -C 6 ) haloalkoxy; -NH 2 ; --NH(C 1 -C 6 )alkyl; -N(C 1 -C 6 alkyl) 2 ; and (C 3 -C 6 ) cycloalkyl.

[0095] In one instance of this aspect, each R 14 is independently selected from the group consisting of H, halo, -OH, -NH 2 , -CN, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, -COOH, -NH(C 1 -C 6 )alkyl, -N(C 1 -C 6 alkyl) 2 , phenyl, phenyl-(C 1 -C 2 ) alkylene, (C 3 -C 6 ) cycloalkyl, (C 3 -C 6 ) cycloalkyl-(C 1- C 4 ) alkylene-, and 4- to 6-membered heterocycloalkyl. In a further instance, each R 14 is independently selected from the group consisting of H, halo, -OH, -NH 2 , -CN, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, -COOH, -NH(C 1 -C 6 )alkyl, -N(C 1 -C 6 alkyl) 2 , and phenyl. According to the invention, each R 14 is independently selected from the group consisting of H, halo, and (C 1 -C 6 ) alkyl. In yet a further instance, R 14 is H.

[0096] In one instance of this aspect, each R 12 is independently selected from the group consisting of -H, halo, -OH, -COO(C 1- C 6 ) alkyl, -CN, -NH 2 , -NH((C 1- C 6 ) alkyl), -N((C 1- C 6 ) alkyl) 2 , -C(O)NH 2 , -C(O)NH((C 1- C 6 ) alkyl), -C(O)N((C 1- C 6 ) alkyl) 2 , (C 1- C 6 ) alkyl, (C 1- C 6 ) alkoxy, (C 3 -C 6 ) cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl. In a further instance, each R 12 is independently selected from the group consisting of -H, halo, -OH, -CN, -NH 2 , -NH((C 1- C 6 ) alkyl), -N((C 1- C 6 ) alkyl) 2 , (C 1- C 6 ) alkyl, and (C 1 -C 6 ) alkoxy. According to the invention, each R 12 is independently selected from the group consisting of -H and halo. In yet a further instance, m is one and R 12 is F. In still a further instance, m is one and R 12 is F, which is para to the amine substituent on the phenyl ring.

[0097] In one instance of this aspect, each R a< is independently selected from the group consisting of -H, -CN, (C 1 -C 6 ) alkyl, (C 3 -C 10 ) cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-, and (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-, wherein the (C 1 -C 6 ) alkyl, (C 3 -C 10 ) cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-, and (4-14 membered heterocycloalkyl)-(C 1- C 4 ) alkylene- of R a< are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R d< substituents. According to the invention, each R a< is independently selected from the group consisting of -H, (C 1 -C 6 ) alkyl, (C 3 -C 10 ) cycloalkyl, 4-14 membered heterocycloalkyl, and (4-14 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-, wherein the (C 1 -C 6 ) alkyl, (C 3 -C 10 ) cycloalkyl, 4-14 membered heterocycloalkyl, and (4-14 membered heterocycloalkyl)-(C 1- C 4 ) alkylene- of R a< are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, and -C(O)O(C 1 -C 4 ) alkyl.

[0098] In one instance of this aspect, each R b< is independently selected from the group consisting of halo, (C 1 -C 6 ) alkyl, -CN, -OH, -NH 2 , -NO 2 , and -C(O)O(C 1 -C 4 ) alkyl. In a further instance, each R b< is independently selected from the group consisting of (C 1 -C 6 ) alkyl and -C(O)O(C 1 -C 4 ) alkyl.

[0099] In one instance of this aspect, each R c< is -H or (C 1 -C 6 ) alkyl.

[0100] In one instance of this aspect, each R d< is independently selected from the group consisting of (C 1- C 6 ) alkyl, halo, phenyl, 5-10 membered heteroaryl, (C 3 -C 10 ) cycloalkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-, -CN, and - C(O)O(C 1 -C 4 ) alkyl.

[0101] In one instance of this aspect, each R e< is -H or (C 1- C 6 ) alkyl, .

[0102] In another instance, any two R a< substituents together with the nitrogen atom to which they are attached form a 5 or 6-membered heterocycloalkyl.

[0103] In another instance, any two R c< substituents together with the nitrogen atom to which they are attached form a 5 or 6-membered heterocycloalkyl.

[0104] In another instance, any two R e< substituents together with the nitrogen atom to which they are attached form a 5 or 6-membered heterocycloalkyl.

[0105] In one instance, each R f< is independently selected from the group consisting of halo, -OH, -CN, -COOH, -NH 2 , (C 1- C 6 ) alkyl, and (C 1- C 6 ) alkoxy.

[0106] In one instance, each R g< is independently selected from the group consisting of halo, -OH, -CN, -COOH, (C 1- C 6 ) alkyl, (C 1- C 6 ) alkoxy, and -C(O)O(C 1 -C 4 ) alkyl.

[0107] In one instance, n is 1 or 2;

[0108] In one instance, m is 1 or 2. In further instance, m is 1.

[0109] In one instance, p is 1 or 2.

[0110] In one instance of this aspect, the compound of Formula I' is a compound of Formula I'a, wherein the variables R 10 - R 17 are defined herein:

[0111] In another instance of this aspect, the compound of Formula I' is a compound of Formula I'b, I'c or I'd, wherein the variables R 10 - R 19 are defined herein:

[0112] In another instance of this aspect, the compound of Formula I' is a compound of Formula (I'a-1), wherein the variables R 10 - R 17 are defined herein:

[0113] In another instance of this aspect, the compound of Formula I' is a compound of Formula (I'b-1), wherein the variables R 10 - R 19 are defined herein:

[0114] In another instance of this aspect, the compound of Formula I' is a compound of Formula (I'b-2), wherein the variables R 10 - R 19 are defined herein:

[0115] In another instance of this aspect, the compound of Formula I' is a compound of Formula (I'c-1) wherein the variables R 10 - R 19 are defined herein:

[0116] In another instance of this aspect, the compound of Formula I' is a compound of Formula (I'c-2), wherein the variables R 10 - R 19 are defined herein:

[0117] In another instance of this aspect, the compound of Formula I' is a compound of Formula (I'd-1), wherein the variables R 10 - R 18 are defined herein:

[0118] In another instance of this aspect, the compound of Formula I' is a compound of Formula (I'd-2), wherein the variables R 10 - R 18 are defined herein:

[0119] In one instance, R 16 is selected from -H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, -C(=NO-(C 1- C 6 ) alkyl)R a< ; halo, -CN, OR a< , -C(O)OR a< ; -C(O)NR a< R a< , -C(O)NHOR a< , - S(O)aNR a< R a< , phenyl, 5- to 6-membered heteroaryl, (C 3 -C 6 ) cycloalkyl, and 4- to 6-membered heterocycloalkyl, wherein the (C 1 -C 6 ) alkyl; (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, phenyl, 5- to 6-membered heteroaryl, (C 3 -C 6 ) cycloalkyl, and 4- to 6-membered heterocycloalkyl of R 16 are each optionally substituted with 1, 2, or 3 R g< substituents.

[0120] In one instance, R 17 is selected from -H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, -C(=NO-(C 1- C 6 ) alkyl)R a< , halo, -CN, OR a< , -C(O)OR a< , -C(O)NR a< R a< , -C(O)NHOR a< , - S(O)aNR a< R a< , phenyl, 5- to 6-membered heteroaryl, (C 3 -C 6 ) cycloalkyl, and 4- to 6-membered heterocycloalkyl, wherein the(C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, phenyl, 5- to 6-membered heteroaryl, (C 3 -C 6 ) cycloalkyl, and 4- to 6-membered heterocycloalkyl of R 17 are each optionally substituted with 1, 2, or 3 R g< substituents.

[0121] In one instance, R 18 and R 19 are each independently selected from -H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, -C(=NO-(C 1- C 6 ) alkyl)R a< , halo, -CN, OR a< , -C(O)OR a< , - C(O)NR a< R a< , -C(O)NHOR a< , -S(O) 2 NR a< R a< , phenyl, 5- to 6-membered heteroaryl, (C 3- C 6 ) cycloalkyl, and 4- to 6-membered heterocycloalkyl, wherein the (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, phenyl, 5- to 6-membered heteroaryl, (C 3 -C 6 ) cycloalkyl, and 4- to 6-membered heterocycloalkyl of R 18 or R 19 are each optionally substituted with 1, 2, or 3 R b< substituents.

[0122] In one instance, R 16 is selected from H, halo, NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl), methoxy, methyl, CN, 3-morphlinopropoxy, 2-methoxyethoxy, (oxetan-3-yloxy)carbamoyl, cyclopropylcarbamoyl, carbamoyl, 2-(pyrrolidin-1-yl)ethylcarbamoyl, 1-(t-butoxycarbonylpyrrolidin-2-yl)methylcarbamoyl, 1-(pyrrolidin-2-yl)methylcarbamoyl, 2-methoxyethylamino, azetidin-1-yl, dimethylcarbamoyl, methylamino, 3-morpholinopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, propoxy, 2-hydroxypropoxy, methoxycarbonyl, carboxy, methylcarbamoyl, 2-oxazolyl, pyrazol-3-yl, pyrazol-4-yl, 4-isoxazolyl, 3,5-dimethylisoxazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methyl-pyrazol-3-yl, 2-ethyl-pyrazol-3-yl, 2-(2-hydroxyethyl)-pyrazol-3-yl, 2-(2,2,2-trifluoroethyl)-pyrazol-3-yl, 2-(2-fluoroethyl)-pyrazol-3-yl, 2-(2,2-difluoroethyl)-pyrazol-3-yl, 2-trifluoromethyl-pyrazol-3-yl, 2-difluoromethyl-pyrazol-3-yl, 1-methyl-imidazol-4-yl, 1-methyl-imidazol-2-yl, 1H-imidazol-2-yl, (2-hydroxyethoxy)carbamoyl, (2,2-dihydroxyethoxy)carbamoyl, (oxetan-3-yl)carbamoyl, methoxycarbamoyl, 2-trimethylsilylethynyl, ethynyl, 1,3,4-oxadiazol-3-yl, 1H-1,2,3-triazol-5-yl, sulfamoyl, acetyl, and -C(=NOCH 3 )CH 3 .

[0123] In one instance, R 18 and R 19 are each independently selected from H, halo, NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl), methoxy, methyl, CN, 3-morphlinopropoxy, 2-methoxyethoxy, (oxetan-3-yloxy)carbamoyl, cyclopropylcarbamoyl, carbamoyl, 2-(pyrrolidin-1-yl)ethylcarbamoyl, 1-(t-butoxycarbonylpyrrolidin-2-yl)methylcarbamoyl, 1-(pyrrolidin-2-yl)methylcarbamoyl, 2-methoxyethylamino, azetidin-1-yl, dimethylcarbamoyl, methylamino, 3-morpholinopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, propoxy, 2-hydroxypropoxy, methoxycarbonyl, carboxy, methylcarbamoyl, 2-oxazolyl, pyrazol-3-yl, pyrazol-4-yl, 4-isoxazolyl, 3,5-dimethylisoxazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methyl-pyrazol-3-yl, 2-ethyl-pyrazol-3-yl, 2-(2-hydroxyethyl)-pyrazol-3-yl, 2-(2,2,2-trifluoroethyl)-pyrazol-3-yl, 2-(2-fluoroethyl)-pyrazol-3-yl, 2-(2,2-difluoroethyl)-pyrazol-3-yl, 2-trifluoromethyl-pyrazol-3-yl, 2-difluoromethyl-pyrazol-3-yl, 1-methyl-imidazol-4-yl, 1-methyl-imidazol-2-yl, 1H-imidazol-2-yl, (2-hydroxyethoxy)carbamoyl, (2,2-dihydroxyethoxy)carbamoyl, (oxetan-3-yl)carbamoyl, methoxycarbamoyl, 2-trimethylsilylethynyl, ethynyl, 1,3,4-oxadiazol-3-yl, 1H-1,2,3-triazol-5-yl, sulfamoyl, acetyl, and -C(=NOCH 3 )CH 3 .

[0124] In one instance, R 16 is R a< NHC(O)- and R 17 is H or -OR a< .

[0125] In another instance, R 16 is 5- or 6-membered heteroaryl optionally substituted with 1, 2, or 3 independently selected R b< substituents and R 17 is H.

[0126] In another instance, R 16 is H and R 17 is 5- or 6-membered heteroaryl optionally substituted with 1, 2, or 3 independently selected R b< substituents.

[0127] In one instance, R 18 and R 19 are each independently H, halo, CN, R a< NHC(O)-, -OR a< or 5- or 6-membered heteroaryl optionally substituted with 1-3 independently selected R b< substituents.

[0128] In another instance, R 18 is H and R 19 is -OR a< .

[0129] In another instance, R 19 is and R 18 is -OR a< .

[0130] In another instance, R 18 and R 19 are each independently -OR a< .

[0131] In another instance, R 18 is 5- or 6-membered heteroaryl optionally substituted with 1-3 independently selected R b< substituents and R 19 is H or-OR a< .

[0132] In another instance, R 18 is H or -OR a< and R 19 is 5- or 6-membered heteroaryl optionally substituted with 1-3 independently selected R b< substituents.

[0133] In another instance, R 18 is R a< NHC(O)- and R 19 is H or -OR a< .

[0134] In another instance, R 19 is R a< NHC(O)- and R 18 is H or -OR a< .

[0135] According to the invention, R 10 and R 11 are each H.

[0136] In one instance, the subscript m is 1.

[0137] In another instance, the subscript n is 1.

[0138] In another instance, the subscript p is 1.

[0139] In some instances, is

[0140] In some instances, the compound of Formula I', or a pharmaceutically acceptable salt thereof, is selected from the compounds listed in Table 1, or a pharmaceutically acceptable salt thereof. Table 1: Compounds of Formula I' Comp. Structure IUPAC Name 7 1-N'-(4-fluorophenyl)-1-N-(4-pyrido[3,2-d]pyrimidin-4-yloxyphenyl)cyclopropane-1,1-dicarboxamide12 1-N-[4-(7-chloropyrido[3,2-d]pyrimidin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide13 1-N-[4-(7-bromopyrido[3,2-d]pyrimidin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide16 1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxypyrido[3,2-d]pyrimidin-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide19 1-N'-[2,5-difluoro-4-(7-methoxypyrido[3,2-d]pyrimidin-4-yl)oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide28 1-N-[4-(6,7-dimethoxypyrido[3,2-d]pyrimidin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide29 1-N'-[3-chloro-4-(6,7-dimethoxypyrido[3,2-d]pyrimidin-4-yl)oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide30 1-N'-[4-(6,7-dimethoxypyrido[3,2-d]pyrimidin-4-yl)oxy-3-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide31 1-N'-[4-(6,7-dimethoxypyrido[3,2-d]pyrimidin-4-yl)oxy-2-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide32 1-N'-[2-chloro-4-(6,7-dimethoxypyrido[3,2-d]pyrimidin-4-yl)oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide33 1-N'-[4-(6,7-dimethoxypyrido[3,2-d]pyrimidin-4-yl)oxy-2-methylphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide34 1-N'-[4-(6,7-dimethoxypyrido[3,2-d]pyrimidin-4-yl)oxy-2,3-difluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide35 1-N'-[4-(6,7-dimethoxypyrido[3,2-d]pyrimidin-4-yl)oxy-2,5-difluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide43 1-N-[4-(6,7-dimethylpyrido[3,2-d]pyrimidin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide52 1-N'-(4-fluorophenyl)-1-N-[4-(6,7,8,9-tetrahydropyrimido[5,4-b]quinolin-4-yloxy)phenyl]cyclopropane-1,1-dicarboxamide57 1-N-[4-(6-cyano-7-methoxypyrido[3,2-d]pyrimidin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide65 1-N'-(4-fluorophenyl)-1-N-[4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide66 1-N'-[3-chloro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide67 1-N'-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide68 1-N-(4-fluorophenyl)-1-N'-[4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxy-3-methylphenyl]cyclopropane-1,1-dicarboxamide69 1-N'-[2-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide70 1-N'-[2-chloro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide71 1-N-(4-fluorophenyl)-1-N'-[4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxy-2-methylphenyl]cyclopropane-1,1-dicarboxamide72 1-N'-[2,5-difluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide73 1-N'-[2,3-difluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide74 1-N-(4-fluorophenyl)-1-N'-[3-methoxy-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide75 1-N'-[3-cyano-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide76 1-N'-[3,5-difluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide78 1-N'-(4-fluorophenyl)-1-N-[4-[6-methoxy-7-(2-methoxyethoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide79 1-N'-[3-fluoro-4-[6-methoxy-7-(2-methoxyethoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide80 1-N'-[3-chloro-4-[6-methoxy-7-(2-methoxyethoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide81 1-N'-[2-fluoro-4-[6-methoxy-7-(2-methoxyethoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide82 1-N'-[2,3-difluoro-4-[6-methoxy-7-(2-methoxyethoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide83 1-N'-[2,5-difluoro-4-[6-methoxy-7-(2-methoxyethoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide85 1-N'-(4-fluorophenyl)-1-N-(4-pyrido[3,4-d]pyrimidin-4-yloxyphenyl)cyclopropane-1,1-dicarboxamide88 1-N-[4-(6-chloropyrido[3,4-d]pyrimidin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide91 1-N'-(4-fluorophenyl)-1-N-[4-(6-methoxypyrido[3,4-d]pyrimidin-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide95 1-N'-(4-fluorophenyl)-1-N-(4-pyrido[4,3-d]pyrimidin-4-yloxyphenyl)cyclopropane-1,1-dicarboxamide101 1-N-[4-(7-chloropyrido[4,3-d]pyrimidin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide104 1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxypyrido[4,3-d]pyrimidin-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide106 1-N-[4-(6-cyanoquinazolin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide115 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(oxetan-3-ylcarbamoyl)quinazolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide116 1-N-[4-[6-(cyclopropylcarbamoyl)-7-methoxyquinazolin-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide117 1-N-[4-(6-carbamoyl-7-methoxyquinazolin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide118 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(2-pyrrolidin-1-ylethylcarbamoyl)quinazolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide119 tert-butyl (2R)-2-[[[4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopro panecarbonyl]amino]phenoxy]-7-methoxyquinazoline-6-carbonyl]amino]methyl]pyrrolidin e-1-carboxylate120 tert-butyl (2S)-2-[[[4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopro panecarbonyl]amino]phenoxy]-7-methoxyquinazoline-6-carbonyl]amino]methyl]pyrrolidin e-1-carboxylate121 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-[[(2R)-pyrrolidin-2-yl]methylcarbamoyl]quinazolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide122 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-[[(2S)-pyrrolidin-2-yl]methylcarbamoyl]quinazolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide126 1-N'-(4-fluorophenyl)-1-N-[4-[6-(1-methylpyrazol-4-yl)quinazolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide129 1-N'-(4-fluorophenyl)-1-N-[4-[7-(1-methylpyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide130 1-N'-(4-fluorophenyl)-1-N-[4-[7-(1-methylpyrazol-4-yl)pyrido[4,3-d]pyrimidin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide139 1-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide140 1-N'-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide141 1-N'-[3-chloro-4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide142 1-N'-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-2,5-difluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide149 1-N'-(4-fluorophenyl)-1-N-[4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]cyclopropane-1,1-dicarboxamide150 1-N'-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide151 1-N'-[3-chloro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide152 1-N'-[2,5-difluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide153 1-N'-[2,5-difluoro-4-[[6-methoxy-7-(2-morpholin-4-ylethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide157 1-N-[4-(2,3-dihydro-[1,4]dioxino[2,3-b][1,5]naphthyridin-6-yloxy)phenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide158 1-N'-[4-(2,3-dihydro-[1,4]dioxino[2,3-b][1,5]naphthyridin-6-yloxy)-3-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide159 1-N'-[3-chloro-4-(2,3-dihydro-[1,4]dioxino[2,3-b][1,5]naphthyridin-6-yloxy)phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide164 1-N-[4-[(6-cyano-7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide165 1-N'-[4-[(6-cyano-7-methoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide166 1-N'-[3-chloro-4-[(6-cyano-7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide167 1-N-[4-[(6-carbamoyl-7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide168 1-N'-[4-[(6-carbamoyl-7-methoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide169 1-N'-[4-[(6-carbamoyl-7-methoxy-1,5-naphthyridin-4-yl)oxy]-3-chlorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide172 1-N'-(4-fluorophenyl)-1-N-[4-[[7-methoxy-6-(methylcarbamoyl)-1,5-naphthyridin-4-yl]oxy]phenyl]cyclopropane-1,1-dicarboxamide173 1-N'-[3-fluoro-4-[[7-methoxy-6-(methylcarbamoyl)-1,5-naphthyridin-4-yl]oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide174 1-N-[4-[[6-(dimethylcarbamoyl)-7-methoxy-1,5-naphthyridin-4-yl]oxy]phenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide176 1-N'-[2,5-difluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide181 1-N-[4-[(6-amino-7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide182 1-N'-(4-fluorophenyl)-1-N-[4-[[7-methoxy-6-(1-methylpyrazol-4-yl)-1,5-naphthyridin-4-yl]oxy]phenyl]cyclopropane-1,1-dicarboxamide183 1-N'-(4-fluorophenyl)-1-N-[4-[[7-methoxy-6-(1H-pyrazol-4-yl)-1,5-naphthyridin-4-yl]oxy]phenyl]cyclopropane-1,1-dicarboxamide184 1-N'-(4-fluorophenyl)-1-N-[4-[[7-methoxy-6-(2-methylpyrazol-3-yl)-1,5-naphthyridin-4-yl]oxy]phenyl]cyclopropane-1,1-dicarboxamide189 1-N'-(4-fluorophenyl)-1-N-[4-[[6-(1-methylpyrazol-4-yl)-1,5-naphthyridin-4-yl]oxy]phenyl]cyclopropane-1,1-dicarboxamide

[0141] In one instance, the compound of Formula I' is a compound of Formula I: wherein: X is selected from N and C-H; Y is O, S, SO, SO 2 , NH, or N-(C 1 -C 6 alkyl); R 13 is selected from -H, halo, -CN, and optionally substituted C 1-6 alkyl; R 12 is -H or halo; is optionally substituted with one, two, three, or four groups independently selected from the group consisting of halo, and C 1 -C 6 alkyl, wherein "" indicate points of attachment; is selected from the group consisting of and wherein R 18 and R 19 are selected from the group consisting of H, halo, -CN, optionally substituted C 1 -C 6 alkyl, C(O)NR 5 R 6 , optionally substituted 5 or 6-membered heteroaryl, and optionally substituted C 1 -C 6 alkoxy; or when is R 18 and R 19 can be joined together to form a 5 or 6-membered optionally substituted cycloalkyl or heterocycloalkyl; R 5 and R 6 are selected from the group consisting of H, optionally substituted C 1-6 alkyl, or R 5 and R 6 taken together with the nitrogen to which they are attached to form a 5- or 6-membered optionally substituted heterocycle; and m and n are each independently 1 or 2; provided that when is and X is C-H, R 19 is not optionally substituted C 1 -C 6 alkyl, halo, or optionally substituted C 1 -C 6 alkoxy.

[0142] In one instance, R 19 is selected from the group consisting of optionally substituted C 1 -C 6 alkoxy and -CN. In a further instance, the C 1 -C 6 alkoxy is optionally substituted with alkoxy or heterocycloalkyl.

[0143] In some instances, is

[0144] In one instance, X is N.

[0145] In another instance, R 13 is H.

[0146] In one instance, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from the compounds listed in Table 2, or a pharmaceutically acceptable salt thereof. Table 2: Compounds of Formula I Comp. Structure IUPAC Name 7 1-N'-(4-fluorophenyl)-1-N-(4-pyrido[3,2-d]pyrimidin-4-yloxyphenyl)cyclopropane-1,1-dicarboxamide12 1-N-[4-(7-chloropyrido[3,2-d]pyrimidin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide13 1-N-[4-(7-bromopyrido[3,2-d]pyrimidin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide16 1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxypyrido[3,2-d]pyrimidin-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide19 1-N'-[2,5-difluoro-4-(7-methoxypyrido[3,2-d]pyrimidin-4-yl)oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide28 1-N-[4-(6,7-dimethoxypyrido[3,2-d]pyrimidin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide29 1-N'-[3-chloro-4-(6,7-dimethoxypyrido[3,2-d]pyrimidin-4-yl)oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide30 1-N'-[4-(6,7-dimethoxypyrido[3,2-d]pyrimidin-4-yl)oxy-3-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide31 1-N'-[4-(6,7-dimethoxypyrido[3,2-d]pyrimidin-4-yl)oxy-2-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide32 1-N'-[2-chloro-4-(6,7-dimethoxypyrido[3,2-d]pyrimidin-4-yl)oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide33 1-N'-[4-(6,7-dimethoxypyrido[3,2-d]pyrimidin-4-yl)oxy-2-methylphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide34 1-N'-[4-(6,7-dimethoxypyrido[3,2-d]pyrimidin-4-yl)oxy-2,3-difluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide35 1-N'-[4-(6,7-dimethoxypyrido[3,2-d]pyrimidin-4-yl)oxy-2,5-difluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide43 1-N-[4-(6,7-dimethylpyrido[3,2-d]pyrimidin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide52 1-N'-(4-fluorophenyl)-1-N-[4-(6,7,8,9-tetrahydropyrimido[5,4-b]quinolin-4-yloxy)phenyl]cyclopropane-1,1-dicarboxamide57 1-N-[4-(6-cyano-7-methoxypyrido[3,2-d]pyrimidin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide65 1-N'-(4-fluorophenyl)-1-N-[4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide66 1-N'-[3-chloro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide67 1-N'-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide68 1-N-(4-fluorophenyl)-1-N'-[4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxy-3-methylphenyl]cyclopropane-1,1-dicarboxamide69 1-N'-[2-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide70 1-N'-[2-chloro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide71 1-N-(4-fluorophenyl)-1-N'-[4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxy-2-methylphenyl]cyclopropane-1,1-dicarboxamide72 1-N'-[2,5-difluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide73 1-N'-[2,3-difluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide74 1-N-(4-fluorophenyl)-1-N'-[3-methoxy-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide75 1-N'-[3-cyano-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide76 1-N'-[3,5-difluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide78 1-N'-(4-fluorophenyl)-1-N-[4-[6-methoxy-7-(2-methoxyethoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide79 1-N'-[3-fluoro-4-[6-methoxy-7-(2-methoxyethoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide80 1-N'-[3-chloro-4-[6-methoxy-7-(2-methoxyethoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide81 1-N'-[2-fluoro-4-[6-methoxy-7-(2-methoxyethoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide82 1-N'-[2,3-difluoro-4-[6-methoxy-7-(2-methoxyethoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide83 1-N'-[2,5-difluoro-4-[6-methoxy-7-(2-methoxyethoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide85 1-N'-(4-fluorophenyl)-1-N-(4-pyrido[3,4-d]pyrimidin-4-yloxyphenyl)cyclopropane-1,1-dicarboxamide88 1-N-[4-(6-chloropyrido[3,4-d]pyrimidin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide91 1-N'-(4-fluorophenyl)-1-N-[4-(6-methoxypyrido[3,4-d]pyrimidin-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide95 1-N'-(4-fluorophenyl)-1-N-(4-pyrido[4,3-d]pyrimidin-4-yloxyphenyl)cyclopropane-1,1-dicarboxamide101 1-N-[4-(7-chloropyrido[4,3-d]pyrimidin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide104 1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxypyrido[4,3-d]pyrimidin-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide129 1-N'-(4-fluorophenyl)-1-N-[4-[7-(1-methylpyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide130 1-N'-(4-fluorophenyl)-1-N-[4-[7-(1-methylpyrazol-4-yl)pyrido[4,3-d]pyrimidin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide139 1-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide140 1-N'-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide141 1-N'-[3-chloro-4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide142 1-N'-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-2,5-difluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide149 1-N'-(4-fluorophenyl)-1-N-[4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]cyclopropane-1,1-dicarboxamide150 1-N'-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide151 1-N'-[3-chloro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide152 1-N'-[2,5-difluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide153 1-N'-[2,5-difluoro-4-[[6-methoxy-7-(2-morpholin-4-ylethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide157 1-N-[4-(2,3-dihydro-[1,4]dioxino[2,3-b][1,5]naphthyridin-6-yloxy)phenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide158 1-N'-[4-(2,3-dihydro-[1,4]dioxino[2,3-b][1,5]naphthyridin-6-yloxy)-3-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide159 1-N'-[3-chloro-4-(2,3-dihydro-[1,4]dioxino[2,3-b][1,5]naphthyridin-6-yloxy)phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide164 1-N-[4-[(6-cyano-7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide165 1-N'-[4-[(6-cyano-7-methoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide166 1-N'-[3-chloro-4-[(6-cyano-7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide167 1-N-[4-[(6-carbamoyl-7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide168 1-N'-[4-[(6-carbamoyl-7-methoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide169 1-N'-[4-[(6-carbamoyl-7-methoxy-1,5-naphthyridin-4-yl)oxy]-3-chlorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide172 1-N'-(4-fluorophenyl)-1-N-[4-[[7-methoxy-6-(methylcarbamoyl)-1,5-naphthyridin-4-yl]oxy]phenyl]cyclopropane-1,1-dicarboxamide173 1-N'-[3-fluoro-4-[[7-methoxy-6-(methylcarbamoyl)-1,5-naphthyridin-4-yl]oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide174 1-N-[4-[[6-(dimethylcarbamoyl)-7-methoxy-1,5-naphthyridin-4-yl]oxy]phenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide176 1-N'-[2,5-difluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide181 1-N-[4-[(6-amino-7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide182 1-N'-(4-fluorophenyl)-1-N-[4-[[7-methoxy-6-(1-methylpyrazol-4-yl)-1,5-naphthyridin-4-yl]oxy]phenyl]cyclopropane-1,1-dicarboxamide183 1-N'-(4-fluorophenyl)-1-N-[4-[[7-methoxy-6-(1H-pyrazol-4-yl)-1,5-naphthyridin-4-yl]oxy]phenyl]cyclopropane-1,1-dicarboxamide184 1-N'-(4-fluorophenyl)-1-N-[4-[[7-methoxy-6-(2-methylpyrazol-3-yl)-1,5-naphthyridin-4-yl]oxy]phenyl]cyclopropane-1,1-dicarboxamide189 1-N'-(4-fluorophenyl)-1-N-[4-[[6-(1-methylpyrazol-4-yl)-1,5-naphthyridin-4-yl]oxy]phenyl]cyclopropane-1,1-dicarboxamide

[0147] In one instance, the compound of Formula I' is a compound of Formula II: or a pharmaceutically acceptable salt thereof, wherein: R 16 is selected from the group consisting of -CN and -CO-NR 5 R 6 ; R 17 is selected from H and optionally substituted C 1 -C 6 alkoxy; R 13 is selected from the group consisting of -H, halo, -CN, or optionally substituted C 1-6 alkyl; R 12 is -H or halo; is optionally substituted with one, two, three, or four groups independently selected from the group consisting of halo, and C 1 -C 6 alkyl, wherein "" indicate points of attachment; R 5 and R 6 are each independently selected from the group consisting of H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 heterocycloalkyl, and optionally substituted C 1 -C 6 cycloalkyl; Y is O, S, SO, SO 2 , NH, or N-(C 1 -C 6 alkyl); and m and n are each independently 1 or 2.

[0148] In one instance, R 17 is H.

[0149] In another instance, is not substituted.

[0150] In another instance, R 12 is halo.

[0151] In a further instance, R 12 is para fluoro.

[0152] In one instance, R 16 is -CN or -CO-NR 5 R 6 .

[0153] In a further instance, R 16 is -CO-NH 2 .

[0154] In one instance, R 16 and R 17 are joined together, with the atoms to which they are attached, to form a 5- or 6-membered optionally substituted heterocycloalkyl.

[0155] In one instance, Y is O.

[0156] In some instances, is or

[0157] In one instance, the compound of Formula II, or a pharmaceutically acceptable salt thereof, is selected from the compounds listed in Table 3, or a pharmaceutically acceptable salt thereof. Table 3: Compounds of Formula II Comp. Structure IUPAC Name 106 1-N-[4-(6-cyanoquinazolin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide115 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(oxetan-3-ylcarbamoyl)quinazolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide116 1-N-[4-[6-(cyclopropylcarbamoyl)-7-methoxyquinazolin-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide117 1-N-[4-(6-carbamoyl-7-methoxyquinazolin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide118 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(2-pyrrolidin-1-ylethylcarbamoyl)quinazolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide119 tert-butyl (2R)-2-[[[4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopro panecarbonyl]amino]phenoxy]-7-methoxyquinazoline-6-carbonyl]amino]methyl]pyrrolidine -1-carboxylate120 tert-butyl (2S)-2-[[[4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopro panecarbonyl]amino]phenoxy]-7-methoxyquinazoline-6-carbonyl]amino]methyl]pyrrolidine -1-carboxylate121 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-[[(2R)-pyrrolidin-2-yl]methylcarbamoyl]quinazolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide122 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-[[(2S)-pyrrolidin-2-yl]methylcarbamoyl]quinazolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide126 1-N'-(4-fluorophenyl)-1-N-[4-[6-(1-methylpyrazol-4-yl)quinazolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide

[0158] In one aspect, the disclosure includes a pharmaceutical composition comprising a compound described herein, and a pharmaceutically acceptable carrier or excipient.

[0159] In another aspect, the disclosure includes a method of treating a disease, disorder, or syndrome mediated at least in part by modulating in vivo activity of a protein kinase, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutical composition thereof.General Administration

[0160] Administration of the compounds disclosed herein, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities. Thus, administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, aerosols, and the like, preferably in unit dosage forms suitable for simple administration of precise dosages.

[0161] The compositions will include a conventional pharmaceutical carrier or excipient and a compound of the disclosure as the / an active agent, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, and the like. Compositions of the disclosure may be used in combination with anticancer or other agents that are generally administered to a patient being treated for cancer. Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate, and gelatin.

[0162] If desired, a pharmaceutical composition of the disclosure may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, and the like.

[0163] Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0164] One preferable route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.

[0165] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, magnesium stearate, and the like (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.

[0166] Solid dosage forms as described above can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain pacifying agents and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0167] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, and the like., a compound(s) of the disclosure, or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, and dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan; or mixtures of these substances, and the like, to thereby form a solution or suspension.

[0168] Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.

[0169] Compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of the present disclosure with for example suitable nonirritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore melt while in a suitable body cavity and release the active component therein.

[0170] Dosage forms for topical administration of a compound of this disclosure include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated.

[0171] Generally, depending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of the disclosure, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient. In one example, the composition will be between about 5% and about 75% by weight of a compound(s) of the disclosure, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.

[0172] Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance with the teachings of this disclosure.

[0173] The compounds of the disclosure, or their pharmaceutically acceptable salts, are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability, and length of action of the compound, the age, body weight, general health, sex, diet, mode, and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy. The compounds of the present disclosure can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example. The specific dosage used, however, can vary. For example, the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art.Combination Therapy

[0174] A compound as disclosed herein can be administered as a single therapy or in combination ("co-administered") with one or more additional therapies for the treatment of a disease or disorder, for instance a disease or disorder associated with hyper-proliferation such as cancer. Therapies that may be used in combination with a compound disclosed herein include: (i) surgery; (ii) radiotherapy (for example, gamma radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes); (iii) endocrine therapy; (iv) adjuvant therapy, immunotherapy, CAR T-cell therapy; and (v) other chemotherapeutic agents.

[0175] The term " co-administered" ("co-administering") refers to either simultaneous administration, or any manner of separate sequential administration, of a compound of Formula I' or a salt thereof, and a further active pharmaceutical ingredient or ingredients, including cytotoxic agents and radiation treatment. If the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.

[0176] Typically, any agent that has activity against a disease or condition being treated may be co-administered. Examples of such agents for cancer treatment can be found, for instance, at https: / / www.cancer.gov / about-cancer / treatment / drugs (last visited January 22, 2019) and in publically available sources such as Cancer Principles and Practice of Oncology by V. T. Devita and S. Hellman (editors), 11th edition (2018), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the disease involved.

[0177] In one instance, the treatment method includes the co-administration of a compound as disclosed herein or a pharmaceutically acceptable salt thereof and at least one immunotherapy. Immunotherapy (also called biological response modifier therapy, biologic therapy, biotherapy, immune therapy, or biological therapy) is treatment that uses parts of the immune system to fight disease. Immunotherapy can help the immune system recognize cancer cells, or enhance a response against cancer cells. Immunotherapies include active and passive immunotherapies. Active immunotherapies stimulate the body's own immune system while passive immunotherapies generally use immune system components created outside of the body.

[0178] Examples of active immunotherapies include, but are not limited to vaccines including cancer vaccines, tumor cell vaccines (autologous or allogeneic), dendritic cell vaccines, antigen vaccines, anti-idiotype vaccines, DNA vaccines, viral vaccines, or Tumor-Infiltrating Lymphocyte (TIL) Vaccine with Interleukin-2 (IL-2) or Lymphokine-Activated Killer (LAK) Cell Therapy.

[0179] Examples of passive immunotherapies include but are not limited to monoclonal antibodies and targeted therapies containing toxins. Monoclonal antibodies include naked antibodies and conjugated monoclonal antibodies (also called tagged, labeled, or loaded antibodies). Naked monoclonal antibodies do not have a drug or radioactive material attached whereas conjugated monoclonal antibodies are joined to, for example, a chemotherapy drug (chemolabeled), a radioactive particle (radiolabeled), or a toxin (immunotoxin). Examples of these naked monoclonal antibody drugs include, but are not limited to Rituximab (Rituxan), an antibody against the CD20 antigen used to treat, for example, B cell non-Hodgkin lymphoma; Trastuzumab (Herceptin), an antibody against the HER2 protein used to treat, for example, advanced breast cancer; Alemtuzumab (Campath), an antibody against the CD52 antigen used to treat, for example, B cell chronic lymphocytic leukemia (B-CLL); Cetuximab (Erbitux), an antibody against the EGFR protein used, for example, in combination with irinotecan to treat, for example, advanced colorectal cancer and head and neck cancers; and Bevacizumab (Avastin) which is an antiangiogenesis therapy that works against the VEGF protein and is used, for example, in combination with chemotherapy to treat, for example, metastatic colorectal cancer. Examples of the conjugated monoclonal antibodies include, but are not limited to Radiolabeled antibody Ibritumomab tiuxetan (Zevalin) which delivers radioactivity directly to cancerous B lymphocytes and is used to treat, for example, B cell non-Hodgkin lymphoma; radiolabeled antibody Tositumomab (Bexxar) which is used to treat, for example, certain types of non-Hodgkin lymphoma; and immunotoxin Gemtuzumab ozogamicin (Mylotarg) which contains calicheamicin and is used to treat, for example, acute myelogenous leukemia (AML). BL22 is a conjugated monoclonal antibody for treating, for example, hairy cell leukemia, immunotoxins for treating, for example, leukemias, lymphomas, and brain tumors, and radiolabeled antibodies such as OncoScint for example, for colorectal and ovarian cancers and ProstaScint for example, for prostate cancers.

[0180] Further examples of therapeutic antibodies that can be used include, but are not limited to, HERCEPTIN ™™< (Trastuzumab) (Genentech, Calif.) which is a humanized anti-HER2 monoclonal antibody for the treatment of patients with metastatic breast cancer; REOPRO.RTM. (abciximab) (Centocor) which is an anti-glycoprotein IIb / IIIa receptor on the platelets for the prevention of clot formation; ZENAPAX ™< (daclizumab) (Roche Pharmaceuticals, Switzerland) which is an immunosuppressive, humanized anti-CD25 monoclonal antibody for the prevention of acute renal allograft rejection; PANOREX ™< which is a murine anti-17-IA cell surface antigen IgG2a antibody (Glaxo Wellcome / Centocor); BEC2 which is a murine anti-idiotype (GD3epitope) IgG antibody (ImClone System); IMC-C225 which is a chimeric anti-EGFR IgG antibody (ImClone System); VITAXIN ™< which is a humanized anti-alpha V beta 3 integrin antibody (Applied Molecular Evolution / Medlmmune); Campath 1H / LDP-03 which is a humanized anti CD52 IgG1 antibody (Leukosite); Smart M195 which is a humanized anti-CD33 IgG antibody (Protein Design Lab / Kanebo); RITUXAN ™< which is a chimeric anti-CD20 IgG1 antibody (IDEC Pharm / Genentech, Roche / Zettyaku); LYMPHOCIDE ™< which is a humanized anti-CD22 IgG antibody (Immunomedics); LYMPHOCIDE ™< Y-90 (Immunomedics); Lymphoscan (Tc-99m-labeled; radioimaging; Immunomedics); Nuvion (against CD3; Protein Design Labs); CM3 is a humanized anti-ICAM3 antibody (ICOS Pharm); IDEC-114 is a primatized anti-CD80 antibody (IDEC Pharm / Mitsubishi); ZEVALIN ™< is a radiolabelled murine anti-CD20 antibody (IDEC / Schering AG); IDEC-131 is a humanized anti-CD40L antibody (IDEC / Eisai); IDEC-151 is a primatized anti-CD4 antibody (IDEC); IDEC-152 is a primatized anti-CD23 antibody (IDEC / Seikagaku); SMART anti-CD3 is a humanized anti-CD3 IgG (Protein Design Lab); 5G1.1 is a humanized anti-complement factor 5 (C5) antibody (Alexion Pharm); D2E7 is a humanized anti-TNF-alpha antibody (CAT / BASF); CDP870 is a humanized anti-TNF-alpha. Fab fragment (Celltech); IDEC-151 is a primatized anti-CD4 IgG1 antibody (IDEC Pharm / SmithKline Beecham); MDX-CD4 is a human anti-CD4 IgG antibody (Medarex / Eisai / Genmab): CD20-sreptdavidin (+biotin-yttrium 90; NeoRx); CDP571 is a humanized anti-TNF-alpha. IgG4 antibody (Celltech); LDP-02 is a humanized anti-alpha4 beta7 antibody (LeukoSite / Genentech); OrthoClone OKT4A is a humanized anti-CD4 IgG antibody (Ortho Biotech); ANTOVA.TM. is a humanized anti-CD40L IgG antibody (Biogen); ANTEGREN ™< is a humanized anti-VLA-4 IgG antibody (Elan); and CAT-152 is a human anti-TGF-beta 2 antibody (Cambridge Ab Tech). Others are provided in later paragraphs.

[0181] Immunotherapies that can be used in combination with a compound as disclosed herein include adjuvant immunotherapies. Examples include cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte-colony stimulating factor (G-CSF), macrophage inflammatory protein (MIP)-1-alpha, interleukins (including IL-1, IL-2, IL-4, IL-6, IL-7, IL-12, IL-15, IL-18, IL-21, and IL-27), tumor necrosis factors (including TNF-alpha), and interferons (including IFN-alpha, IFN-beta, and IFN-gamma); aluminum hydroxide (alum); Bacille Calmette-Guerin (BCG); Keyhole limpet hemocyanin (KLH); Incomplete Freund's adjuvant (IFA); QS-21; DETOX; Levamisole; and Dinitrophenyl (DNP), and combinations thereof, such as, for example, combinations of, interleukins, for example, IL-2 with other cytokines, such as IFN-alpha.

[0182] In various instances, an immunological therapy or an immunological therapeutic agent can include, one or more of the following: an adoptive cell transfer, an angiogenesis inhibitor, Bacillus Calmette-Guerin therapy, biochemotherapy, a cancer vaccine, a chimeric antigen receptor (CAR) T-cell therapy, a cytokine therapy, gene therapy, an immune checkpoint modulator, an immunoconjugate, a radioconjugate, an oncolytic virus therapy, or a targeted drug therapy. The function or at least one of the functions of the immunological therapy or immunological therapeutic agent, collectively referred to herein as an "immunotherapeutic agent".

[0183] The present disclosure provides a method for preventing, treating, reducing, inhibiting or controlling a neoplasia, a tumor or a cancer in a subject in need thereof, involving administering a therapeutically effective amount of a combination comprising a compound of Formula I' and an immunotherapeutic agent. In one non-limiting instance, the method comprises administering a therapeutically effective amount of a combination comprising a compound of Formula I' in combination with an immunotherapeutic agent. In various instances, the combination provides a cooperative effect, an additive effect, or a synergistic effect in reducing the number of cancer cells when treated with the combination as compared to each treatment alone. In some instances, administration of a therapeutically effective amount of a combination comprising a compound of Formula I' and an immunotherapeutic agent, results in synergistic anti-tumor activity and / or antitumor activity that is more potent than the additive effect of administration of a compound of Formula I' or immunotherapeutic agent alone.

[0184] Human cancers harbor numerous genetic and epigenetic alterations, generating neoantigens potentially recognizable by the immune system (Sjoblom et al. (2006) Science 314:268-74). The adaptive immune system, comprised of T and B lymphocytes, has powerful anti-cancer potential, with a broad capacity and exquisite specificity to respond to diverse tumor antigens. Further, the immune system demonstrates considerable plasticity and a memory component. The successful harnessing of all these attributes of the adaptive immune system would make immunotherapy unique among all cancer treatment modalities.

[0185] The present disclosure provides a combination of a compound of Formula I' and an immunotherapeutic agent. These exemplified combinations can be used to treat a subject with a cancer. In various instances, immunotherapeutic agents that find utility in the present compositions, formulations, and methods can include one or more agents or therapies, including: an adoptive cell transfer, an angiogenesis inhibitor, Bacillus Calmette-Guerin therapy, biochemotherapy, a cancer vaccine, a chimeric antigen receptor (CAR) T-cell therapy, a cytokine therapy, gene therapy, an immune checkpoint modulator, for example an immune checkpoint inhibitor, an immunoconjugate, a radioconjugate, an oncolytic virus therapy, or a targeted drug therapy.

[0186] In certain instances of the present disclosure, a therapeutically effective combination comprises a compound of Formula I' and an immunotherapeutic agent. In various related instances, the compound of Formula I' enhances the activity of the immunotherapeutic agent.

[0187] In certain instances of each of the aforementioned aspects, as well as other aspects and instances described elsewhere herein, the immunotherapeutic agent enhances the activity of the compound of Formula I'.

[0188] In certain instances of each of the aforementioned aspects, as well as other aspects and instances described elsewhere herein, the compound of Formula I' and the immunotherapeutic agent act synergistically. In various instances described herein, an exemplary immunotherapeutic agent is an immune cell (e.g. T-cell, dendritic cell, a natural killer cell and the like) modulator chosen from an agonist or an activator of a costimulatory molecule, wherein the modulator is a monoclonal antibody, a bispecific antibody comprising one or more immune checkpoint antigen binding moieties, a trispecific antibody, or an immune cell-engaging multivalent antibody / fusion protein / construct known in the art). In some instances, the immunotherapeutic agent can be an antibody that modulates a costimulatory molecule, bind to an antigen on the surface of an immune cell, or a cancer cell. In each of these different instances, the antibody modulator can be a monoclonal antibody, a polyclonal antibody, a bispecific antibody, a trispecific or multispecific format antibody, a fusion protein, or a fragment thereof, for example, a Diabody, a Single-chain (sc)-diabody (scFv)2, a Miniantibody, a Minibody, a Barnase-barstar, a scFv-Fc, a sc(Fab)2, a Trimeric antibody construct, a Triabody antibody construct, a Trimerbody antibody construct, a Tribody antibody constuct, a Collabody antibody construct, a (scFv-TNFa)3, or a F(ab)3 / DNL antibody construct.

[0189] In certain instances of each of the aforementioned aspects, as well as other aspects and instances described elsewhere herein, the immunotherapeutic agent is an agent that modulates immune responses, for example, a checkpoint inhibitor or a checkpoint agonist. In some instances, the immunotherapeutic agent is an agent that enhances anti-tumor immune responses. In some instances, the immunotherapeutic agent is an agent that increases cell-mediated immunity. In some instances, the immunotherapeutic agent is an agent that increases T-cell activity. In some instances, the immunotherapeutic agent is an agent that increases cytolytic T-cell (CTL) activity. In some instances, the immunotherapeutic agent is an antibody modulator that targets PD-1, PD-L1, PD-L2, CEACAM (e.g., CEACAM-1, -3 and / or -5), CTLA-4, TIM-3, LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, TGF beta, OX40, 41BB, LIGHT, CD40, GITR, TGF-beta, TIM-3, SIRP-alpha, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS, B7H3, B7H4, FAS, and / or BTNL2 among others known in the art, . In some instances, the immunotherapeutic agent is an agent that increases natural killer (NK) cell activity. In some instances, the immunotherapeutic agent is an agent that inhibits suppression of an immune response. In some instances, the immunotherapeutic agent is an agent that inhibits suppressor cells or suppressor cell activity. In some instances, the immunotherapeutic agent is an agent or therapy that inhibits Treg activity. In some instances, the immunotherapeutic agent is an agent that inhibits the activity of inhibitory immune checkpoint receptors. In some instances, the combination of the present disclosure comprises a compound of Formula I' and an immunotherapeutic agent, wherein the immunotherapeutic agent includes a T cell modulator chosen from an agonist or an activator of a costimulatory molecule. In one instance, the agonist of the costimulatory molecule is chosen from an agonist (e.g., an agonistic antibody or antigen-binding fragment thereof, or a soluble fusion) of GITR, OX40, ICOS, SLAM (e.g., SLAMF7), HVEM, LIGHT, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), CD30, CD40, BAFFR, CD7, NKG2C, NKp80, CD160, B7-H3, or CD83 ligand. In other instances, the effector cell combination includes a bispecific T cell engager (e.g., a bispecific antibody molecule that binds to CD3 and a tumor antigen (e.g., EGFR, PSCA, PSMA, EpCAM, HER2 among others).

[0190] In some instances, the immunotherapeutic agent is a modulator of PD-1 activity, a modulator of PD-L1 activity, a modulator of PD-L2 activity, a modulator of CTLA-4 activity, a modulator of CD28 activity, a modulator of CD80 activity, a modulator of CD86 activity, a modulator of 4-1BB activity, an modulator of OX40 activity, a modulator of KIR activity, a modulator of Tim-3 activity, a modulator of LAG3 activity, a modulator of CD27 activity, a modulator of CD40 activity, a modulator of GITR activity, a modulator of TIGIT activity, a modulator of CD20 activity, a modulator of CD96 activity, a modulator of IDO1 activity, a modulator of SIRP-alpha activity, a modulator of TIGIT activity, a modulator of VSIG8 activity, a modulator of BTLA activity, a modulator of SIGLEC7 activity, a modulator of SIGLEC9 activity, a modulator of ICOS activity, a modulator of B7H3 activity, a modulator of B7H4 activity, a modulator of FAS activity, a modulator of BTNL2 activity, a cytokine, a chemokine, an interferon, an interleukin, a lymphokine, a member of the tumor necrosis factor (TNF) family, or an immunostimulatory oligonucleotide. In some instances, the immunotherapeutic agent is an immune checkpoint modulator (e.g., an immune checkpoint inhibitor e.g. an inhibitor of PD-1 activity, a modulator of PD-L1 activity, a modulator of PD-L2 activity, a modulator of CTLA-4, or a CD40 agonist (e.g., an anti-CD40 antibody molecule), (xi) an OX40 agonist (e.g., an anti-OX40 antibody molecule), or (xii) a CD27 agonist (e.g., an anti-CD27 antibody molecule). In one instance, the immunomodulator is an inhibitor of PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM (e.g., CEACAM-1, -3 and / or -5), VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and / or TGF beta. In one instance, the inhibitor of an immune checkpoint molecule inhibits PD-1, PD-L1, LAG-3, TIM-3, CEACAM (e.g., CEACAM-1, -3 and / or -5), CTLA-4, or any combination thereof.

[0191] Inhibition of an inhibitory molecule can be performed at the DNA, RNA or protein level. In instances, an inhibitory nucleic acid (e.g., a dsRNA, siRNA or shRNA), can be used to inhibit expression of an inhibitory molecule. In other instances, the inhibitor of an inhibitory signal is, a polypeptide e.g., a soluble ligand (e.g., PD-1-Ig or CTLA-4 Ig), or an antibody or antigen-binding fragment thereof,, for example, a monoclonal antibody, a bispecific antibody comprising one or more immune checkpoint antigen binding moieties, a trispecific antibody, or an immune cell-engaging multivalent antibody / fusion protein / construct known in the art that binds to the inhibitory molecule; e.g., an antibody or fragment thereof (also referred to herein as "an antibody molecule") that binds to PD-1, PD-L1, PD-L2, CEACAM (e.g., CEACAM-1, -3 and / or -5), CTLA-4, TIM-3, LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, TGF beta, or a combination thereof.

[0192] In some instances, where the combination comprises a compound of Formula I' and an immunotherapeutic agent, wherein the immunotherapeutic agent is a monoclonal antibody or a bispecific antibody. For example, the monoclonal or bispecific antibody may specifically bind a member of the c-Met pathway and / or an immune checkpoint modulator (e.g., the bispecific antibody binds to both a hepatocyte growth factor receptor (HGFR) and an immune checkpoint modulator described herein, such as an antibody that binds PD-1, PD-L1, PD-L2, or CTLA-4, LAG-3, OX40, 41BB, LIGHT, CD40, GITR, TGF-beta, TIM-3, SIRP-alpha, TIGIT, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS, B7H3, B7H4, FAS, BTNL2 or CD27). In particular instances, the bispecific antibody specifically binds a human HGFR protein and one of PD-1, PD-L1, and CTLA-4.

[0193] In some instances, the immunotherapeutic agent is a cytokine, for example, a chemokine, an interferon, an interleukin, lymphokine, or a member of the tumor necrosis factor family. In some instances, the cytokine is IL-2, IL15, or interferon-gamma.

[0194] In some instances of any of the above aspects or those described elsewhere herein, the cancer is selected from the group consisting of lung cancer, pancreatic cancer, breast cancer, colon cancer, colorectal cancer, melanoma, gastrointestinal cancer, gastric cancer, renal cancer, ovarian cancer, liver cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, neuroblastoma, glioma, glioblastoma, glioblastoma multiforme, cervical cancer, stomach cancer, bladder cancer, head and neck cancer, and hepatoma.

[0195] In some instances of any of the above aspects or those described elsewhere herein, the subject's cancer or tumor does not respond to immune checkpoint inhibition (e.g., to any immune checkpoint inhibitor described herein, such as a PD-1 antagonist or PD-L1 antagonist) or the subject's cancer or tumor has progressed following an initial response to immune checkpoint inhibition (e.g., to any immune checkpoint inhibitor described herein, such as a PD-1 antagonist or PD-L1 antagonist).

[0196] In some instances of any of the above aspects or those described elsewhere herein, the subject is a human.

[0197] A checkpoint inhibitor can be any molecule, agent, treatment and / or method of inhibiting an immune checkpoint, and / or promoting an inhibitor of an immune checkpoint, e.g., by promoting an intrinsic immune checkpoint inhibitor; inhibiting a transcription factor involved in the expression of an immune checkpoint; and / or by acting in concert with some additional extrinsic factor. For example, a checkpoint inhibitor could include a treatment that inhibits transcription factors involved the expression of immune checkpoint genes, or promotes the expression of transcription factors for tumor-suppressor genes, e.g., BACH2 (Luan et al., (2016). Transcription Factors and Checkpoint Inhibitor Expression with Age: Markers of Immunosenescence. Blood, 128(22), 5983). Moreover, a checkpoint inhibitor can inhibit the transcription of immune checkpoint genes; the modification and / or processing of immune checkpoint mRNA; the translation of immune checkpoint proteins; and / or molecules involved in immunity or the immune checkpoint pathway, e.g., PD-1 transcription factors such as HIF-1, STAT3, NF-κB, and AP-1, or the activation of common oncogenic pathways such as JAK / STAT, RAS / ERK, or PI3K / AKT / mTOR (Zerdes et al., Genetic, transcriptional and post-translational regulation of the programmed death protein ligand 1 in cancer: biology and clinical correlations, Oncogenevolume 37, pages4639-4661 (2018)).

[0198] Checkpoint inhibitors can include treatments, molecules, agents, and / or methods that regulate immune checkpoints at the transcriptional level, e.g., using the RNA-interference pathway co-suppression, and / or post-transcriptional gene silencing (PTGS) (e.g., microRNAs, miRNA; silencing-RNA, small-interfering-RNA, or short-interfering-RNA (siRNA). Transcriptional regulation of checkpoint molecules has been shown to involve mir-16, which has been shown to target the 3'UTR of the checkpoint mRNAs CD80, CD274 (PD-L1) and CD40 (Leibowitz et al., Post-transcriptional regulation of immune checkpoint genes by mir-16 in melanoma, Annals of Oncology (2017) 28; v428-v448). Mir-33a has also been shown to be involved in regulating the expression of PD-1 in cases of lung adenocarcinoma (Boldini et al., Role of microRNA-33a in regulating the expression of PD-1 in lung adenocarcinoma, Cancer Cell Int. 2017; 17: 105).

[0199] T-cell-specific aptamer-siRNA chimeras have been suggested as a highly specific method of inhibiting molecules in the immune checkpoint pathway (Hossain et al., The aptamer-siRNA conjugates: reprogramming T cells for cancer therapy, Ther. Deliv. 2015 Jan; 6(1): 1-4).

[0200] Alternatively, members of the immune checkpoint pathway can be inhibited using treatments that affect associated pathways, e.g., metabolism. For example, oversupplying the glycolytic intermediate pyruvate in mitochondria from CAD macrophages promoted expression of PD-L1 via induction of the bone morphogenetic protein 4 / phosphorylated SMAD1 / 5 / IFN regulatory factor 1 (BMP4 / p-SMAD1 / 5 / IRF1) signaling pathway. Accordingly, implementing treatments that modulate the metabolic pathway can result in subsequent modulation of the immunoinhibitory PD-1 / PD-L1 checkpoint pathway (Watanabe et al., Pyruvate controls the checkpoint inhibitor PD-L1 and suppresses T cell immunity, J Clin Invest. 2017 Jun 30; 127(7): 2725-2738).

[0201] Checkpoint immunity can be regulated via oncolytic viruses that selectively replicate within tumor cells and induce acute immune responses in the tumor-microenvironment, i.e., by acting as genetic vectors that carry specific agents (e.g., antibodies, miRNA, siRNA, and the like) to cancer cells and effecting their oncolysis and secretion of cytokines and chemokines to synergize with immune checkpoint inhibition (Shi et al., Cancer Immunotherapy: A Focus on the Regulation of Immune Checkpoints, Int J Mol Sci. 2018 May; 19(5): 1389). Currently, there are clinical trials underway that utilize the following viruses as checkpoint inhibitors: poliovirus, measles virus, adenoviruses, poxviruses, herpes simplex virus (HSV), coxsackieviruses, reovirus, Newcastle disease virus (NDV), T-VEC (a herpes virus encoded with GM-CSF (granulocyte-macrophage colony stimulating factor)), and H101 (Shi et al., supra).

[0202] Checkpoint inhibitors can operate at the translational level of checkpoint immunity. The translation of mRNA into protein represents a key event in the regulation of gene expression, thus inhibition of immune checkpoint translation is a method in which the immune checkpoint pathway can be inhibited.

[0203] Inhibition of the immune checkpoint pathway can occur at any stage of the immune checkpoint translational process. For example, drugs, molecules, agents, treatments, and / or methods can inhibit the initiation process (whereby the 40S ribosomal subunit is recruited to the 5' end of the mRNA and scans the 5'UTR of the mRNA toward its 3' end. Inhibition can occur by targeting the anticodon of the initiator methionyl-transfer RNA (tRNA) (Met-tRNAi), its base-pairing with the start codon, or the recruitment of the 60S subunit to begin elongation and sequential addition of amino acids in the translation of immune-checkpoint-specific genes. Alternatively, a checkpoint inhibitor can inhibit checkpoints at the translational level by preventing the formation of the ternary complex (TC), i.e., eukaryotic initiation factor (eIF)2 (or one or more of its α, β, and γ subunits); GTP; and Met-tRNAi.

[0204] Checkpoint inhibition can occur via destabilization of eIF2α by precluding its phosphorylation via protein kinase R (PKR), PERK, GCN2, or HRI, or by precluding TCs from associating with the 40S ribosome and / or other initiation factors, thus preventing the preinitiation complex (PIC) from forming; inhibiting the eIF4F complex and / or its cap-binding protein eIF4E, the scaffolding protein eIF4G, or eIF4A helicase. Methods discussing the translational control of cancer are discussed in Truitt et al., New frontiers in translational control of the cancer genome, Nat Rev Cancer. 2016 Apr 26; 16(5): 288-304.

[0205] Checkpoint inhibitors can also include treatments, molecules, agents, and / or methods that regulate immune checkpoints at the cellular and / or protein level, e.g., by inhibiting an immune checkpoint receptor. Inhibition of checkpoints can occur via the use of antibodies, antibody fragments, antigen-binding fragments, small-molecules, and / or other drugs, agents, treatments, and / or methods.

[0206] Immune checkpoints refer to inhibitory pathways in the immune system that are responsible for maintaining self-tolerance and modulating the degree of immune system response to minimize peripheral tissue damage. However, tumor cells can also activate immune system checkpoints to decrease the effectiveness of immune response ('block' the immune response) against tumor tissues. In contrast to the majority of anti-cancer agents, checkpoint inhibitors do not target tumor cells directly, but rather target lymphocyte receptors or their ligands in order to enhance the endogenous antitumor activity of the immune system. (Pardoll, 2012, Nature Reviews Cancer 12:252-264).

[0207] Until recently, cancer immunotherapy had focused substantial effort on approaches that enhance anti-tumor immune responses by adoptive-transfer of activated effector cells, immunization against relevant antigens, or providing non-specific immune-stimulatory agents such as cytokines. In the past decade, however, intensive efforts to develop specific immune checkpoint pathway inhibitors have begun to provide new immunotherapeutic approaches for treating cancer, including the development of antibody (Ab), ipilimumab (YERVOY.RTM.), that binds to and inhibits CTLA-4 for the treatment of patients with advanced melanoma (Hodi et al. (2010) N Engl J Med 363:711-23) and the development of antibodies such as nivolumab and pembrolizumab (formerly lambrolizumab; USAN Council Statement (2013) Pembrolizumab: Statement on a nonproprietary name adopted by the USAN Council (ZZ-165), Nov. 27, 2013) that bind specifically to the Programmed Death-1 (PD-1) receptor and block the inhibitory PD-1 / PD-1 ligand pathway (Topalian et al. (2012a) N Engl J Med 366:2443-54; Topalian et al. (2012b) Curr Opin Immunol 24:207-12; Topalian et al. (2014) J Clin Oncol 32(10):1020-30; Hamid et al. (2013) N Engl J Med 369:134-144; Hamid and Carvajal (2013) Expert Opin Biol Ther 13(6):847-61; McDermott and Atkins (2013) Cancer Med 2(5):662-73).

[0208] PD-1 is a key immune checkpoint receptor expressed by activated T and B cells and mediates immunosuppression. Nivolumab (formerly designated 5C4, BMS-936558, MDX-1106, or ONO-4538) is a fully human IgG4 (S228P) PD-1 immune checkpoint inhibitor antibody that selectively prevents interaction with PD-1 ligands (PD-L1 and PD-L2), thereby blocking the down-regulation of antitumor T-cell functions (U.S. Pat. No. 8,008,449; Wang et al. (2014) In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Nivolumab has been approved for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor and for the treatment of squamous non-small cell lung cancer.

[0209] Recent data suggest a secondary mechanism of anti-CTLA-4 antibodies, which could occur within the tumor itself. CTLA-4 has been found to be expressed in tumors at higher levels on regulatory T-cells (also referred to herein as "Treg cells") as compared with intra-tumoral effector T-cells (also referred to herein as "Teff cells"), resulting in the hypothesis of anti-CTLA-4 preferentially impacting the Treg cell. "Therapeutic use of anti-CTLA-4 antibodies", Christian U. Blank and Alexander Enk, International Immunology, Vol. 27, No. 1, pp. 3-10. A recent study of a PD-1 and CTLA-4 combination show that the combination blockade of the CTLA-4 and PD-1 pathways also cooperates to increase the ratio of Teff cells to both regulatory T-cells and MDSCs, thereby reducing suppression and promoting inflammation in the tumor microenvironment. "Combination of CTLA-4 and PD-1 blockade expands infiltrating T-cells and reduces regulatory T and myeloid cells within B16 melanoma tumors", Curran et al., PNAS|Mar. 2, 2010; vol. 107 (no. 9); pp. 4275-4280. The combination of a checkpoint inhibitor and another therapeutic agent(s) may enhance or prolong anti-tumor response of the checkpoint inhibitor and / or effects of the therapeutic agent. In this regard, WO 2015 / 069770 discloses a combination treatment based on activating the adaptive immune response, in particular the combination of CTLA-4 and PD-1 inhibitors, for the treatment of cancer.

[0210] One mechanism by which the checkpoint blockade anti-CTLA-4 antibodies mediate anti-tumor effect is by decreasing regulatory T-cells. Due to the distinct mechanism of action of anti-CTLA-4 antibodies, they can successfully combine with the anti-PD1 checkpoint blockade antibodies which work to release the suppressive signaling conferred to effector T-cells. Dual blockade with these antibodies combine to improve anti-tumor response both preclinically (Proc Natl Acad Sci USA 2010, 107, 4275-4280) and in the clinic (N Engl J Med 2013, 369, 122-133; N Engl J Med 2015, 372, 2006-2017).

[0211] CTLA-4 attenuates the early activation of naïve and memory T cells through interactions with its ligands B7-1 (CD80) and B7-2 (CD86) (Fig. 1A). PD-1 is an receptor expressed on the surface of activated mature T cells, activated NK cells, B cells, monocytes and multiple normal tissues and plays a crucial role in the maintenance of peripheral tolerance [20-21] (Fig. 1A). In contrast to CTLA-4, PD-1 acts via interactions with its ligands PD-L1 (also known as B7-H1 or CD274) and is involved mainly in T cell activity modulation in peripheral tissues as well as providing a major immune resistance mechanism within the tumor microenvironment.

[0212] In some instances, the immunotherapeutic agent is a modulator of PD-1 activity, a modulator of PD-L1 activity, a modulator of PD-L2 activity, a modulator of CTLA-4 activity, a modulator of CD28 activity, a modulator of CD80 activity, a modulator of CD86 activity, a modulator of 4-1BB activity, an modulator of OX40 activity, a modulator of KIR activity, a modulator of Tim-3 activity, a modulator of LAG3 activity, a modulator of CD27 activity, a modulator of CD40 activity, a modulator of GITR activity, a modulator of TIGIT activity, a modulator of CD20 activity, a modulator of CD96 activity, a modulator of IDO1 activity, a cytokine, a chemokine, an interferon, an interleukin, a lymphokine, a member of the tumor necrosis factor (TNF) family, or an immunostimulatory oligonucleotide. In some instances, the immune checkpoint modulator, i.e. is an inhibitor or antagonist, or is an activator or agonist, for example, a CD28 modulator, a 4-1BB modulator, an OX40 modulator, a CD27 modulator, a CD80 modulator, a CD86 modulator, a CD40 modulator, or a GITR modulator, a Lag-3 modulator, a 41BB modulator, a LIGHT modulator, a CD40 modulator, a GITR modulator, a TGF-beta modulator, a TIM-3 modulator, a SIRP-alpha modulator, a TIGIT modulator, a VSIG8 modulator, a BTLA modulator, a SIGLEC7 modulator, a SIGLEC9 modulator, a ICOS modulator, a B7H3 modulator, a B7H4 modulator, a FAS modulator, and / or a BTNL2 modulator. In some instances, the immunotherapeutic agent is an immune checkpoint modulator as described above (e.g., an immune checkpoint modulator antibody, which can be in the form of a monoclonal antibody, a bispecific antibody comprising one or more immune checkpoint antigen binding moieties, a trispecific antibody, or an immune cell-engaging multivalent antibody / fusion protein / construct known in the art).

[0213] Combination treatments with immune checkpoint inhibitor immunotherapeutic agent may include antibodies that specifically target immune system checkpoints such as CTLA4, PD1 and PD-L1 are one of the most promising new avenues of immunotherapy for cancer and other diseases. Additional checkpoint targets, such as TIM-3, LAG-3, various B-7 ligands, CHK 1 and CHK2 kinases, BTLA, A2aR, and others, are also under investigation. Currently, three checkpoint inhibitors have received rapid approval from the U.S. Food and Drug Administration for cancer treatment, including ipilimumab (Yervoy ®< ), a CTLA-4 inhibitor, and pembrolizumab (Keytruda ®< ) and nivolumab (Opdivo ®< ), both PD-1 inhibitors. In addition, several checkpoint inhibitor agents are in clinical trials.

[0214] Programmed Cell Death Protein 1, (PD-1 or CD279), a 55-kD type 1 transmembrane protein, is a member of the CD28 family of T cell co-stimulatory receptors that include immunoglobulin superfamily member CD28, CTLA-4, inducible co-stimulator (ICOS), and BTLA. PD-1 is highly expressed on activated T cells and B cells. PD-1 expression can also be detected on memory T-cell subsets with variable levels of expression. Two ligands specific for PD-1 have been identified: programmed death-ligand 1 (PD-L1, also known as B7-H1 or CD274) and PD-L2 (also known as B7-DC or CD273). PD-L1 and PD-L2 have been shown to down-regulate T cell activation upon binding to PD-1 in both mouse and human systems (Okazaki et al., Int Immunol., 2007; 19: 813-824). The interaction of PD-1 with its ligands, PD-L1 and PD-L2, which are expressed on antigen-presenting cells (APCs) and dendritic cells (DCs), transmits negative regulatory stimuli to down-modulate the activated T cell immune response. Blockade of PD-1 suppresses this negative signal and amplifies T cell responses.

[0215] Numerous studies indicate that the cancer microenvironment manipulates the PD-L1- / PD-1 signaling pathway and that induction of PD-L1 expression is associated with inhibition of immune responses against cancer, thus permitting cancer progression and metastasis. The PD-L1 / PD-1 signaling pathway is a primary mechanism of cancer immune evasion for several reasons. First, and most importantly, this pathway is involved in negative regulation of immune responses of activated T effector cells, found in the periphery. Second, PD-L1 is up-regulated in cancer microenvironments, while PD-1 is also up-regulated on activated tumor infiltrating T cells, thus possibly potentiating a vicious cycle of inhibition. Third, this pathway is intricately involved in both innate and adaptive immune regulation through bi-directional signaling. These factors make the PD-1 / PD-L1 complex a central point through which cancer can manipulate immune responses and promote its own progression.

[0216] CTLA-4 (also known as Cytotoxic T-lymphocyte-associated protein 4, CTLA4, CTLA-4, CD152, cluster of differentiation 152; ALPS5, CD, CELIAC3, GRD4, GSE, and IDDM12). CTLA-4 is a ~24.6-kDa single-pass type I membrane protein that plays an inhibitory role in T-cell function. CTLA-4 was originally identified by differential screening of a murine cytolytic T cell cDNA library, See Brunet et al., A new member of the immunoglobulin superfamily--CTLA-4, Nature. 1987 Jul 16-22;328(6127):267-70. CTLA- has been shown to interact with the b7 family ligands CD80 (also known as Cluster of differentiation 80, and B7-1); and CD86 (also known as Cluster of Differentiation 86 or B7-2). See Linsley et al., CTLA-4 is a second receptor for the B cell activation antigen B7, J Exp Med. 1991 Sep 1;174(3):561-9. Sequence comparison between the human CTLA-4 DNA encoding region, and that of CD28, reveals significant homology between both sequences, with the greatest similarity between juxtamembrane and cytoplasmic regions; accordingly, CTLA-4 is implicated in abrogating / reducing T-cell activity, and opposes the activity of CD28. CTLA-4 deficient mice have been shown to exhibit massive lymphoproliferation. Chambers et al., Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells, Immunity. 1997 Dec;7(6):885-95. It has been reported that CTLA-4 blockade augments T-cell responses both in vitro and in vivo, enhances an induced autoimmune disease, and exacerbates antitumor immunity. (See Luhder, J. Exp. Med. 1998; 187:427-432; Walunas et al., Immunity. 1994; 1:405-413; Keamey, J. Immunol. 1995; 155:1032-1036); Leach, Science 1996; 271:1734-1736). CTLA-4 has also been reported as having alternative and / or additional impact on the initial character of the T-cell immune response (Chambers, Curr. Opin. Immunol. 1997; 9:396-404; Bluestone, J. Immunol. 1997; 158:1989-1993; Thompson, Immunity 1997; 7:445-450).

[0217] The first immune-checkpoint inhibitor to be tested in a clinical trial was ipilimumab (Yervoy, Bristol-Myers Squibb), an CTLA-4 mAb. CTLA-4 belongs to the immunoglobulin superfamily of receptors, which also includes PD-1, BTLA, TIM-3, and V-domain immunoglobulin suppressor of T cell activation (VISTA). Anti-CTLA-4 mAb is a powerful checkpoint inhibitor which removes "the break" from both naive and antigen-experienced cells. Therapy enhances the antitumor function of CD8+ T cells, increases the ratio of CD8+ T cells to Foxp3+ T regulatory cells, and inhibits the suppressive function of T regulatory cells. The major drawback to anti-CTLA-4 mAb therapy is the generation of autoimmune toxicities due to on-target effects of an over-exuberant immune system which has lost the ability to turn itself down. It has been reported that up to 25% of patients treated with ipilimumab developed serious grade 3-4 adverse events / autoimmune-type side effects including dermatitis, enterocolitis, hepatitis, endocrinopathies (including hypophysitis, thyroiditis, and adrenalitis), arthritis, uveitis, nephritis, and aseptic meningitis. In contrast to the anti-CTLA-4 experience, anti-PD-1 therapy appears to be better-tolerated and induces a relatively lower rate of autoimmune-type side effects.

[0218] In some instances, the immunotherapeutic agent is an agent that inhibits the activity of PD-1. In some instances, the immunotherapeutic agent is an agent that inhibits the activity of PD-L1 and / or PD-L2. In some instances, the immunotherapeutic agent is an agent that inhibits the activity of CTLA-4. In some instances, the immunotherapeutic agent is an agent that inhibits the activity of CD80 and / or CD86. In some instances, the immunotherapeutic agent is an agent that inhibits the activity of TIGIT. In some instances, the immunotherapeutic agent is an agent that inhibits the activity of KIR. In some instances, the immunotherapeutic agent is an agent that enhances or stimulates the activity of activating immune checkpoint receptors.

[0219] In some of the instances of the methods described herein, the immunotherapeutic agent is a PD-1 antagonist, a PD-L1 antagonist, a PD-L2 antagonist, a CTLA-4 antagonist, a CD80 antagonist, a CD86 antagonist, a KIR antagonist, a Tim-3 antagonist, a LAG3 antagonist, a TIGIT antagonist, a CD20 antagonist, a CD96 antagonist, or an IDO1 antagonist.

[0220] In some instances, the PD-1 antagonist is an antibody that specifically binds PD-1. In some instances, the antibody that binds PD-1 is pembrolizumab (KEYTRUDA ®< , MK-3475; Merck), pidilizumab (CT-011; Curetech Ltd.), nivolumab (OPDIVO ®< , BMS-936558, MDX-1106; Bristol Myer Squibb), MEDI0680 (AMP-514; AstraZenenca / MedImmune), REGN2810 (Regeneron Pharmaceuticals), BGB-A317 (BeiGene Ltd.), PDR-001 (Novartis), or STI-A1110 (Sorrento Therapeutics). In some instances, the antibody that binds PD-1 is described in PCT Publication WO 2014 / 179664, for example, an antibody identified as APE2058, APE1922, APE1923, APE1924, APE 1950, or APE1963 (Anaptysbio), or an antibody containing the CDR regions of any of these antibodies. In other instances, the PD-1 antagonist is a fusion protein that includes the extracellular domain of PD-L1 or PD-L2, for example, AMP-224 (AstraZeneca / MedImmune). In other instances, the PD-1 antagonist is a peptide inhibitor, for example, AUNP-12 (Aurigene).

[0221] In some instances, the PD-L1 antagonist is an antibody that specifically binds PD-L1. In some instances, the antibody that binds PD-L1 is atezolizumab (RG7446, MPDL3280A; Genentech), MEDI4736 (AstraZeneca / MedImmune), BMS-936559 (MDX-1105; Bristol Myers Squibb), avelumab (MSB0010718C; Merck KGaA), KD033 (Kadmon), the antibody portion of KD033, or STI-A1014 (Sorrento Therapeutics). In some instances, the antibody that binds PD-L1 is described in PCT Publication WO 2014 / 055897, for example, Ab-14, Ab-16, Ab-30, Ab-31, Ab-42, Ab-50, Ab-52, or Ab-55, or an antibody that contains the CDR regions of any of these antibodies.

[0222] In some instances, the CTLA-4 antagonist is an antibody that specifically binds CTLA-4. In some instances, the antibody that binds CTLA-4 is ipilimumab (YERVOY ®< ; Bristol Myer Squibb) or tremelimumab (CP-675,206; Pfizer). In some instances, the CTLA-4 antagonist a CTLA-4 fusion protein or soluble CTLA-4 receptor, for example, KARR-102 (Kahr Medical Ltd.).

[0223] In some instances, the LAG3 antagonist is an antibody that specifically binds LAG3. In some instances, the antibody that binds LAG3 is IMP701 (Prima BioMed), IMP731 (Prima BioMed / GlaxoSmithKline), BMS-986016 (Bristol Myer Squibb), LAG525 (Novartis), and GSK2831781 (GlaxoSmithKline). In some instances, the LAG3 antagonist includes a soluble LAG3 receptor, for example, IMP321 (Prima BioMed).

[0224] In some instances, the KIR antagonist is an antibody that specifically binds KIR. In some instances, the antibody that binds KIR is lirilumab (Bristol Myer Squibb / Innate Pharma).

[0225] In some instances, the immunotherapeutic agent used in the combinations disclosed herein (e.g., in combination with a compound of Formula I') is an activator or agonist of a costimulatory molecule. In one instance, the agonist of the costimulatory molecule is chosen from an agonist (e.g., an agonistic antibody or antigen-binding fragment thereof, or a soluble fusion) of OX40, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, or CD83 ligand.

[0226] In some instances, the OX40 agonist includes OX40 ligand, or an OX40-binding portion thereof. For example, the OX40 agonist may be MEDI6383 (AstraZeneca). In some instances, the OX40 agonist is an antibody that specifically binds OX40. In some instances, the antibody that binds OX40 is MEDI6469 (AstraZeneca / MedImmune), MEDI0562 (AstraZeneca / MedImmune), or MOXR0916 (RG7888; Genentech). In some instances, the OX40 agonist is a vector (e.g., an expression vector or virus, such as an adenovirus) capable of expressing OX40 ligand. In some instances the OX40-expressing vector is Delta-24-RGDOX (DNAtrix) or DNX2401 (DNAtrix).

[0227] In some instances, the 4-1BB (CD137) agonist is a binding molecule, such as an anticalin. In some instances, the anticalin is PRS-343 (Pieris AG). In some instances, the 4-1BB agonist is an antibody that specifically binds 4-1BB. In some instances, antibody that binds 4-1BB is PF-2566 (PF-05082566; Pfizer) or urelumab (BMS-663513; Bristol Myer Squibb).

[0228] In some instances, the CD27 agonist is an antibody that specifically binds CD27. In some instances, the antibody that binds CD27 is varlilumab (CDX-1127; Celldex).

[0229] In some instances, the GITR agonist comprises GITR ligand or a GITR-binding portion thereof. In some instances, the GITR agonist is an antibody that specifically binds GITR. In some instances, the antibody that binds GITR is TRX518 (GITR, Inc.), MK-4166 (Merck), or INBRX-110 (Five Prime Therapeutics / Inhibrx).

[0230] TIM-3 has been identified as another important inhibitory receptor expressed by exhausted CD8+ T cells. In mouse models of cancer, it has been shown that the most dysfunctional tumor-infiltrating CD8+ T cells actually co-express PD-1 and TIM-3.

[0231] LAG-3 is another recently identified inhibitory receptor that acts to limit effector T-cell function and augment the suppressive activity of T regulatory cells. It has recently been revealed that PD-1 and LAG-3 are extensively co-expressed by tumor-infiltrating T cells in mice, and that combined blockade of PD-1 and LAG-3 provokes potent synergistic antitumor immune responses in mouse models of cancer.

[0232] PD-1 pathway blockade can be combined with vaccines or other a compound of Formula I' antibodies for improved therapeutic efficacy (Hirano, F. et al, Cancer Res., 65(3): 1089-1096 (2005); Li, B. et al, Clin. Cancer Res., 15: 1507-1509 (2009); and Curran, M. A. et al, Proc. Natl. Acad. Set, 107(9):4275-4280 (2010)).

[0233] In some instances, immunotherapeutic agents useful in the compositions and methods described herein may include a monoclonal antibody, a bispecific antibody comprising one or more immune checkpoint antigen binding moieties, a trispecific antibody, or an immune cell-engaging multivalent antibody / fusion protein / construct known in the art that target specifically both PD-1 and ligand PD-L1.

[0234] PD-1 (also known as Programmed Death 1, CD279, PDCD1) is a cell surface receptor with a critical role in regulating the balance between stimulatory and inhibitory signals in the immune system and maintaining peripheral tolerance (Ishida, Y et al. 1992 EMBO J. 11 3887; Kier, Mary E et al. 2008 Annu Rev Immunol 26 677-704; Okazaki, Taku et al. 2007 International Immunology 19 813-824). PD-1 is an inhibitory member of the immunoglobulin super-family with homology to CD28. The structure of PD-1 is a monomeric type 1 transmembrane protein, consisting of one immunoglobulin variable-like extracellular domain and a cytoplasmic domain containing an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM). Expression of PD-1 is inducible on T cells, B cells, natural killer (NK) cells and monocytes, for example upon lymphocyte activation via T cell receptor (TCR) or B cell receptor (BCR) signalling (Kier, Mary E et al. 2008 Annu Rev Immunol 26 677-704; Agata, Y et al 1996 Int Immunol 8 765-72). PD-1 is a receptor for the ligands CD80, CD86, PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273), which are cell surface expressed members of the B7 family (Freeman, Gordon et al. 2000 J Exp Med 192 1027; Latchman, Y et al. 2001 Nat Immunol 2 261). Upon ligand engagement, PD-1 recruits phosphatases such as SHP-1 and SHP-2 to its intracellular tyrosine motifs which subsequently dephosphorylate effector molecules activated by TCR or BCR signalling (Chemnitz, J et al. 2004 J Immunol 173 945-954; Riley, James L 2009 Immunological Reviews 229 114-125) In this way, PD-1 transduces inhibitory signals into T and B cells only when it is engaged simultaneously with the TCR or BCR.

[0235] PD-1 has been demonstrated to down-regulate effector T cell responses via both cell-intrinsic and cell-extrinsic functional mechanisms. Inhibitory signaling through PD-1 induces a state of unresponsiveness in T cells, resulting in the cells being unable to clonally expand or produce optimal levels of effector cytokines. PD-1 may also induce apoptosis in T cells via its ability to inhibit survival signals from co-stimulation, which leads to reduced expression of key anti-apoptotic molecules such as Bcl-XL (Kier, Mary E et al. 2008 Annu Rev Immunol 26 677-704). In addition to these direct effects, recent publications have implicated PD-1 as being involved in the suppression of effector cells by promoting the induction and maintenance of regulatory T cells (TREG). For example, PD-L1 expressed on dendritic cells was shown to act in synergy with TGF-β to promote the induction of CD4+ FoxP3+TREG with enhanced suppressor function (Francisco, Loise M et al. 2009 J Exp Med 206 3015-3029).

[0236] TIM-3 (also known as T-cell immunoglobulin and mucin-domain containing-3, TIM-3, Hepatitis A virus cellular receptor 2, HAVCR2, HAVcr-2, KIM-3, TIMD-3, TIMD3, Tim-3, and CD366) is a ~33.4-kDa single-pass type I membrane protein involved in immune responses (Sanchez-Fueyo et al., Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance, Nat. Immunol. 4:1093-1101(2003)).

[0237] TIM-3 is selectively expressed on Th1-cells, and phagocytic cells (e.g., macrophages and dendritic cells). The use of siRNA or a blocking antibody to reduce the expression of human resulted in increased secretion of interferon γ (IFN-γ) from CD4 positive T-cells, implicating the inhibitory role of TIM-3 in human T cells. Analysis of clinical samples from autoimmune disease patients showed no expression of TIM-3 in CD4 positive cells. In particular, expression level of TIM-3 is lower and secretion of IFN-γ is higher in T cell clones derived from the cerebrospinal fluid of patients with multiple sclerosis than those in clones derived from normal healthy persons (Koguchi K et al., J Exp Med. 203:1413-8. (2006)).

[0238] TIM-3 is the receptor for the ligands Galectin-9, which is a member of galectin family, molecules ubiquitously expressed on a variety of cell types and which binds β-galactoside; Phospatidyl serine (PtdSer) (DeKryff et al., T cell / transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells, J Immunol. 2010 Feb 15;184(4):1918-30); High Mobility Group Protein 1 (also known as HMGB1, HMG1, HMG3, SBP-1, HMG-1, and high mobility group box 1) Chiba et al., Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1, Nat Immunol. 2012 Sep;13(9):832-42); and Carcinoembryonic Antigen Related Cell Adhesion Molecule 1 (also known as CEACAM1, BGP, BGP1, BGPI, carcinoembryonic antigen related cell adhesion molecule 1) (Huang et al., CEACAM1 regulates TIM-3-mediated tolerance and exhaustion, Nature. 2015 Jan 15;517(7534):386-90).

[0239] BTLA (also known as B- and T-lymphocyte attenuator, BTLA1, CD272, and B and T lymphocyte associated) is a ~27.3-kDa single-pass type I membrane protein involved in lymphocyte inhibition during immune response. BTLA is constitutively expressed in both B and T cells. BTLA interacts with HVEM (herpes virus-entry mediator), a member of the tumor-necrosis factor receptor (TNFR) family (Gonzalez et al., Proc. Natl. Acad. Sci. USA, 2005, 102: 1116-21). The interaction of BTLA, which belongs to the CD28 family of the immunoglobulin superfamily, and HVEM, a costimulatory tumor-necrosis factor (TNF) receptor (TNFR), is unique in that it defines a cross talk between these two families of receptors. BTLA contains a membrane proximal immunoreceptor tyrosine-based inhibitory motif (ITIM) and membrane distal immunoreceptor tyrosine-based switch motif (ITSM). Disruption of either the ITIM or ITSM abrogated the ability of BTLA to recruit either SHP1 or SHP2, suggesting that BTLA recruits SHP1 and SHP2 in a manner distinct from PD-1 and both tyrosine motifs are required to block T cell activation. The BTLA cytoplasmic tail also contains a third conserved tyrosine-containing motif within the cytoplasmic domain, similar in sequence to a Grb-2 recruitment site (YXN). Also, a phosphorylated peptide containing this BTLA N-terminal tyrosine motif can interact with GRB2 and the p85 subunit of PI3K in vitro, although the functional effects of this interaction remain unexplored in vivo (Gavrieli et al., Bioochem. Biophysi Res Commun, 2003, 312, 1236-43). BTLA is the receptor for the ligands PTPN6 / SHP-1; PTPN11 / SHP-2; TNFRSF14 / HVEM; and B7H4.

[0240] VISTA (also known as V-domain Ig suppressor of T cell activation VSIR, B7-H5, B7H5, GI24, PP2135, SISP1, DD1alpha, VISTA, C10orf54, chromosome 10 open reading frame 54, PD-1H, and V-set immunoregulatory receptor) is a ~33.9-kDa single-pass type I membrane protein involved in T-cell inhibitory response, embryonic stem cells differentiation via BMP4 signaling inhibition, and MMP14-mediated MMP2 activation (Yoon et al., Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53, Science. 2015 Jul 31; 349(6247): 1261669). VISTA interacts with the ligand VSIG-3 (Wang et al., VSIG-3 as a ligand of VISTA inhibits human T-cell function, Immunology. 2019 Jan;156(1):74-85)

[0241] LAG-3 (also known as Lymphocyte-activation gene 3, LAG3, CD223, and lymphocyte activating 3) is a ~57.4-kDa single-pass type I membrane protein involved in lymphocyte activation that also binds to HLA class-II antigens. LAG-3 is a member of the immunoglobulin supergene family, and is expressed on activated T cells (Huard et al., 1994, Immunogenetics 39:213), NK cells (Triebel et al., 1990, J. Exp. Med. 171:1393-1405), regulatory T cells (Huang et al., 2004, Immunity 21:503-513; Camisaschi et al., 2010, J Immunol. 184:6545-6551; Gagliani et al., 2013, Nat Med 19:739-746), and plasmacytoid dendritic cells (DCs) (Workman et al.,2009, J Immunol 182:1885-1891). LAG-3 is a membrane protein encoded by a gene located on chromosome 12, and is structurally and genetically related to CD4. Similar to CD4, LAG-3 can interact with MHC class II molecules on the cell surface (Baixeras et al., 1992, J. Exp. Med. 176:327-337; Huard et al., 1996, Eur. J. Immunol. 26:1180-1186). It has been suggested that the direct binding of LAG-3 to MHC class II plays a role in down-regulating antigen-dependent stimulation of CD4+ T lymphocytes (Huard et al., 1994, Eur. J. Immunol. 24:3216-3221) and LAG-3 blockade has also been shown to reinvigorate CD8+ lymphocytes in both tumor or self-antigen (Gross et al., 2007, J Clin Invest. 117:3383-3392) and viral models (Blackburn et al., 2009, Nat. Immunol. 10:29-37). Further, the intra-cytoplasmic region of LAG-3 can interact with LAP (LAG-3-associated protein), which is a signal transduction molecule involved in the downregulation of the CD3 / TCR activation pathway (Iouzalen et al., 2001, Eur. J. Immunol. 31:2885-2891). Moreover, CD4+CD25+ regulatory T cells (Treg) have been shown to express LAG-3 upon activation, which contributes to the suppressor activity of Treg cells (Huang, C. et al., 2004, Immunity 21:503-513). LAG-3 can also negatively regulate T cell homeostasis by Treg cells in both T cell-dependent and independent mechanisms (Workman, C. J. and Vignali, D. A., 2005, J. Immunol. 174:688-695).

[0242] LAG-3 has been shown to interact with MHC class II molecules (Huard et al., CD4 / major histocompatibility complex class II interaction analyzed with CD4- and lymphocyte activation gene-3 (LAG-3)-Ig fusion proteins, Eur J Immunol. 1995 Sep;25(9):2718-21).

[0243] Additionally, several kinases are known to be checkpoint inhibitors. For example, CHEK-1, CHEK-2, and A2aR.

[0244] CHEK-1 (also known as CHK 1 kinase, CHK1, and checkpoint kinase 1) is a ~54.4-kDa serine / threonine-protein kinase that is involved with checkpoint-mediated cell cycle arrest, and the activation of DNA repair in response to the DNA damage and / or unreplicated DNA.

[0245] CHEK-2 (also known as CHK2 kinase, CDS1, CHK2, HuCds1, LFS2, PP1425, RAD53, hCds1, and checkpoint kinase 2) is a ~ 60.9-kDa. serine / threonine-protein kinase involved in checkpoint-mediated cell cycle arrest, DNA-repair activation, and double-strand break-mediated apoptosis.

[0246] A2aR (also known as adenosine A2A receptor, ADORA2A, adenosine A2a receptor, A2aR, ADORA2, and RDC8) is a ~44.7-kDa multi-pass membrane receptor for adenosine and other ligands.

[0247] In various instances, the immunotherapeutic agent can comprise an antibody or an antigen binding fragment thereof. Within this definition, immune checkpoint inhibitors include bispecific antibodies and immune cell-engaging multivalent antibody / fusion protein / constructs known in the art. In some instances, immunotherapeutic agents which comprise bispecific antibodies may include bispecific antibodies that are bivalent and bind either the same epitope of the immune checkpoint molecule, two different epitopes of the same immune checkpoint molecule or different epitopes of two different immune checkpoints.

[0248] Persons of ordinary skill in the art can implement several bispecific antibody formats known in the field to target one or more of CTLA4, PD1, PD-L1 TIM-3, LAG-3, various B-7 ligands, B7H3, B7H4, CHK 1 and CHK2 kinases, BTLA, A2aR, OX40, 41BB, LIGHT, CD40, GITR, TGF-beta, SIRP-alpha, TIGIT, VSIG8, SIGLEC7, SIGLEC9, ICOS, FAS, BTNL2 and other for use in the combination described herein.

[0249] In various instances, the immunotherapeutic agent can include am immune cell-engaging multivalent antibody / fusion protein / construct.

[0250] In an instance of the disclosure, the checkpoint inhibitor, in combination with a compound of Formula I', is used to reduce or inhibit metastasis of a primary tumor or cancer to other sites, or the formation or establishment of metastatic tumors or cancers at other sites distal from the primary tumor or cancer thereby inhibiting or reducing tumor or cancer relapse or tumor or cancer progression.

[0251] In a further instance of the disclosure, there is provided a combination therapy for treating cancer, comprising a compound of Formula I' and blockade of checkpoint inhibitors with the potential to elicit potent and durable immune responses with enhanced therapeutic benefit and more manageable toxicity.

[0252] In a further instance of the disclosure, there is provided a combination therapy for treating cancer, comprising a compound of Formula I' and an immune checkpoint inhibitor. In an instance of the disclosure is provided a method for treating cancer and / or preventing the establishment of metastases by employing a checkpoint inhibitor which act synergistically with a compound of Formula I'.

[0253] In further instances, methods of the disclosure include, one or more of the following: 1) reducing or inhibiting growth, proliferation, mobility or invasiveness of tumor or cancer cells that potentially or do develop metastases, 2) reducing or inhibiting formation or establishment of metastases arising from a primary tumor or cancer to one or more other sites, locations or regions distinct from the primary tumor or cancer; 3) reducing or inhibiting growth or proliferation of a metastasis at one or more other sites, locations or regions distinct from the primary tumor or cancer after a metastasis has formed or has been established, 4) reducing or inhibiting formation or establishment of additional metastasis after the metastasis has been formed or established, 5) prolonged overall survival, 6) prolonged progression free survival, or 7) disease stabilization.

[0254] In an instance of the disclosure, administration of the immunotherapeutic agent, in combination therapy with a compound of Formula I', provides a detectable or measurable improvement in a condition of a given subject, such as alleviating or ameliorating one or more adverse (physical) symptoms or consequences associated with the presence of a cell proliferative or cellular hyperproliferative disorder, neoplasia, tumor or cancer, or metastasis, i e., a therapeutic benefit or a beneficial effect.

[0255] A therapeutic benefit or beneficial effect is any objective or subjective, transient, temporary, or long-term improvement in the condition or pathology, or a reduction in onset, severity, duration or frequency of adverse symptom associated with or caused by cell proliferation or a cellular hyperproliferative disorder such as a neoplasia, tumor or cancer, or metastasis. It may lead to improved survival. A satisfactory clinical endpoint of a treatment method in accordance with the disclosure is achieved, for example, when there is an incremental or a partial reduction in severity, duration or frequency of one or more associated pathologies, adverse symptoms or complications, or inhibition or reversal of one or more of the physiological, biochemical or cellular manifestations or characteristics of cell proliferation or a cellular hyperproliferative disorder such as a neoplasia, tumor or cancer, or metastasis. A therapeutic benefit or improvement therefore may be, but is not limited to destruction of target proliferating cells (e.g., neoplasia, tumor or cancer, or metastasis) or ablation of one or more, most or all pathologies, adverse symptoms or complications associated with or caused by cell proliferation or the cellular hyperproliferative disorder such as a neoplasia, tumor or cancer, or metastasis. However, a therapeutic benefit or improvement need not be a cure or complete destruction of all target proliferating cells (e.g., neoplasia, tumor or cancer, or metastasis) or ablation of all pathologies, adverse symptoms or complications associated with or caused by cell proliferation or the cellular hyperproliferative disorder such as a neoplasia, tumor or cancer, or metastasis. For example, partial destruction of a tumor or cancer cell mass, or a stabilization of the tumor or cancer mass, size or cell numbers by inhibiting progression or worsening of the tumor or cancer, can reduce mortality and prolong lifespan even if only for a few days, weeks or months, even though a portion or the bulk of the tumor or cancer mass, size or cells remain.

[0256] Specific non-limiting examples of therapeutic benefit include a reduction in neoplasia, tumor or cancer, or metastasis volume (size or cell mass) or numbers of cells, inhibiting or preventing an increase in neoplasia, tumor or cancer volume (e.g., stabilizing), slowing or inhibiting neoplasia, tumor or cancer progression, worsening or metastasis, or inhibiting neoplasia, tumor or cancer proliferation, growth or metastasis.

[0257] In an instance of the disclosure, administration of the immunotherapeutic agent, in combination therapy with a compound of Formula I', provides a detectable or measurable improvement or overall response according to the irRC (as derived from time-point response assessments and based on tumor burden), including one of more of the following: (i) irCRcomplete disappearance of all lesions, whether measurable or not, and no new lesions (confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented), (ii) irPR--decrease in tumor burden .gtoreq.50% relative to baseline (confirmed by a consecutive assessment at least 4 weeks after first documentation).

[0258] Optionally, any method described herein may not take effect immediately. For example, treatment may be followed by an increase in the neoplasia, tumor or cancer cell numbers or mass, but over time eventual stabilization or reduction in tumor cell mass, size or numbers of cells in a given subject may subsequently occur.

[0259] Additional adverse symptoms and complications associated with neoplasia, tumor, cancer and metastasis that can be inhibited, reduced, decreased, delayed or prevented include, for example, nausea, lack of appetite, lethargy, pain and discomfort. Thus, a partial or complete decrease or reduction in the severity, duration or frequency of adverse symptom or complication associated with or caused by a cellular hyperproliferative disorder, an improvement in the subjects quality of life and / or well-being, such as increased energy, appetite, psychological well-being, are all particular non-limiting examples of therapeutic benefit.

[0260] A therapeutic benefit or improvement therefore can also include a subjective improvement in the quality of life of a treated subject. In an additional instance, a method prolongs or extends lifespan (survival) of the subject. In a further instance, a method improves the quality of life of the subject.

[0261] In one instance, administration of the immunotherapeutic agent, in combination therapy with a compound of Formula I', results in a clinically relevant improvement in one or more markers of disease status and progression selected from one or more of the following: (i): overall survival, (ii): progression-free survival, (iii): overall response rate, (iv): reduction in metastatic disease, (v): circulating levels of tumor antigens such as carbohydrate antigen 19.9 (CA19.9) and carcinembryonic antigen (CEA) or others depending on tumor, (vii) nutritional status (weight, appetite, serum albumin), (viii): pain control or analgesic use, (ix): CRP / albumin ratio.

[0262] Treatment with a compound of Formula I' in combination with an immunotherapeutic agent gives rise to more complex immunity including not only the development of innate immunity and type-1 immunity, but also immunoregulation which more efficiently restores appropriate immune functions.

[0263] In various exemplary methods, a checkpoint inhibitor antibody (monoclonal or polyclonal, bispecific, trispecific, or an immune cell-engaging multivalent antibody / fusion protein / construct) directed to a checkpoint molecule of interest (e.g., PD-1) may be sequenced and the polynucleotide sequence may then be cloned into a vector for expression or propagation. The sequence encoding the antibody or antigen-binding fragment thereof of interest may be maintained in vector in a host cell and the host cell can then be expanded and frozen for future use. Production of recombinant monoclonal antibodies in cell culture can be carried out through cloning of antibody genes from B cells by means known in the art. See, e.g. Tiller et al., 2008, J. Immunol. Methods 329, 112; U.S. Pat. No. 7,314,622.

[0264] In some instances, methods for producing the recombinant antibodies can include the steps of culturing a host cell containing isolated nucleic acid(s) encoding the antibodies of the present disclosure. Methods for culturing a host cell containing isolated nucleic acid(s) encoding the antibodies of the present disclosure can be done in a variety of ways, depending on the nature of the antibody. In some instances, in the case where the antibodies of the disclosure are full length traditional antibodies, for example, a heavy chain variable region and a light chain variable region under conditions such that an antibody is produced and can be isolated.

[0265] In general, nucleic acids are provided that encode the antibodies or antigen-binding fragments thereof of the present disclosure. Such polynucleotides encode for both the variable and constant regions of each of the heavy and light chains, although other combinations are also contemplated by the present disclosure. The present disclosure also contemplates oligonucleotide fragments derived from the disclosed polynucleotides and nucleic acid sequences complementary to these polynucleotides.

[0266] The polynucleotides can be in the form of RNA, DNA, cDNA, genomic DNA, nucleic acid analogs, and synthetic DNA. The DNA may be double-stranded or single-stranded, and if single stranded, may be the coding (sense) strand or non-coding (anti-sense) strand. The coding sequence that encodes the polypeptide may be identical to the coding sequence or may be a different coding sequence, which sequence, as a result of the redundancy or degeneracy of the genetic code, encodes the same polypeptides.

[0267] In some instances, nucleic acid(s) encoding the antibodies of the present disclosure are incorporated into expression vectors, which can be extrachromosomal or designed to integrate into the genome of the host cell into which it is introduced. Expression vectors can contain any number of appropriate regulatory sequences (including, but not limited to, transcriptional and translational control sequences, promoters, ribosomal binding sites, enhancers, origins of replication, and the like) or other components (selection genes, and the like), all of which are operably linked as is well known in the art. In some cases two nucleic acids are used and each put into a different expression vector (e.g. heavy chain in a first expression vector, light chain in a second expression vector), or alternatively they can be put in the same expression vector. It will be appreciated by those skilled in the art that the design of the expression vector(s), including the selection of regulatory sequences may depend on such factors as the choice of the host cell, the level of expression of protein desired, and the like.

[0268] In general, the nucleic acids and / or expression can be introduced into a suitable host cell to create a recombinant host cell using any method appropriate to the host cell selected (e.g., transformation, transfection, electroporation, infection), such that the nucleic acid molecule(s) are operably linked to one or more expression control elements (e.g., in a vector, in a construct created by processes in the cell, integrated into the host cell genome). The resulting recombinant host cell can be maintained under conditions suitable for expression (e.g. in the presence of an inducer, in a suitable non-human animal, in suitable culture media supplemented with appropriate salts, growth factors, antibiotics, nutritional supplements, and the like), whereby the encoded polypeptide(s) are produced. In some cases, the heavy chains are produced in one cell and the light chain in another.

[0269] Mammalian cell lines available as hosts for expression are known in the art and include many immortalized cell lines available from the American Type Culture Collection (ATCC), Manassas, VA USA. including but not limited to Chinese hamster ovary (CHO) cells, HEK 293 cells, NSO cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), and a number of other cell lines. Non-mammalian cells including but not limited to bacterial, yeast, insect, and plants can also be used to express recombinant antibodies. In some instances, the antibodies can be produced in transgenic animals such as cows or chickens.

[0270] Exemplary and illustrative recombinant methods for antibody molecular biology, expression, purification, and screening are described, for example, in Antibody Engineering, edited by Kontermann & Dubel, Springer, Heidelberg, 2001 and 2010 Hayhurst & Georgiou, 2001, Curr. Opin. Chem. Biol. 5:683-689; Maynard & Georgiou, 2000, Annu. Rev. Biomed. Eng. 2:339-76; and Morrison, S. (1985) Science 229:1202.

[0271] In various instances, the polynucleotide sequence encoding the selected variable heavy and light chains may be used for genetic manipulation to humanize the antibody or to improve the affinity, or other characteristics of the antibody. Antibodies may also be customized for use, for example, in dogs, cats, primate, equines and bovines.

[0272] In some instances, fully human antibodies may be obtained by using commercially available mice that have been engineered to express specific human immunoglobulin proteins. Transgenic animals that are designed to produce a more desirable (e.g., fully human antibodies) or more robust immune response may also be used for generation of humanized or human antibodies. Examples of such technology are Xenomouse ™< from Abgenix, Inc. (Fremont, Calif.) and HuMAb-Mouse ®< and TC Mouse ™< from Medarex, Inc. (Princeton, N.J.).

[0273] Immune checkpoint modulator antibodies of the present disclosure can be made recombinantly by first isolating the antibodies and antibody producing cells from host animals, obtaining the gene sequence, and using the gene sequence to express the antibody recombinantly in host cells (e.g., CHO cells). Another method which may be employed is to express the antibody sequence in plants (e.g., tobacco) or in yeast cells (e.g. Pichia pastoris or Sacchromyces cerevisiae. Methods for expressing antibodies recombinantly in plants or yeast have been disclosed. See, for example, Peeters, et al. Vaccine 19:2756, 2001; Lonberg, N. and D. Huszar Int. Rev. Immunol 13:65, 1995; and Horwitz, A. H. et al., Proc. Natl. Acad. Sci. 85:8678-8682. Methods for making derivatives of antibodies, e.g., domain, single chain, and the like are known in the art.

[0274] Immunoassays and flow cytometry sorting techniques such as fluorescence activated cell sorting (FACS) can also be employed to isolate antibodies that are specific for checkpoint molecules.

[0275] In some instances, a polynucleotide comprises a sequence encoding the heavy chain and / or the light chain variable regions of the checkpoint inhibitor antibody or antigen-binding fragment thereof of the present disclosure. The sequence encoding the antibody or antigen-binding fragment thereof of interest may be maintained in a vector in a host cell and the host cell can then be expanded and frozen for future use. Vectors (including expression vectors) and host cells are further described herein.

[0276] The disclosure includes affinity matured checkpoint modulator antibodies. For example, affinity matured antibodies can be produced by procedures known in the art (Marks et al., 1992, Bio / Technology, 10:779-783; Barbas et al., 1994, Proc Nat. Acad. Sci. USA 91:3809-3813. One way of characterizing a CDR of an antibody and / or altering (such as improving) the binding affinity of a polypeptide, such as an antibody, termed "library scanning mutagenesis". An exemplary method for providing affinity matures antibodies and antigen-binding fragments can include replacing one or more amino acid positions in the CDR with two or more (such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) amino acids using art recognized methods. a library of clones are generated, each with a complexity of two or more members (if two or more amino acids are substituted at every position). Generally, the library also includes a clone comprising the native (unsubstituted) amino acid. A small number of clones, e.g., about 20-80 clones (depending on the complexity of the library), from each library are screened for binding affinity to the target polypeptide (or other binding target), and candidates with increased, the same, decreased, or no binding are identified. Methods for determining binding affinity are well-known in the art. Binding affinity may be determined using, for example, Biacore ™< surface plasmon resonance analysis, which detects differences in binding affinity of about 2-fold or greater, Kinexa ®< Biosensor, scintillation proximity assays, ELISA, ORIGEN ®< immunoassay, fluorescence quenching, fluorescence transfer, and / or yeast display. Binding affinity may also be screened using a suitable bioassay. Biacore ™< is particularly useful when the starting antibody already binds with a relatively high affinity, for example a KD of about 10 nM or lower. The library of clones can then be recombinantly introduced into a selection construct using any method known in the art for selection, including phage display, yeast display, and ribosome display.

[0277] The antibodies may also be modified, e.g., in the variable domains of the heavy and / or light chains, e.g., to alter a binding property of the antibody. Changes in the variable region can alter binding affinity and / or specificity. In some instances, no more than one to five conservative amino acid substitutions are made within a CDR domain. In other instances, no more than one to three conservative amino acid substitutions are made within a CDR domain. For example, a mutation may be made in one or more of the CDR regions to increase or decrease the KD of the antibody directed to a checkpoint molecule, to increase or decrease kon or to alter the binding specificity of the antibody. Techniques in site-directed mutagenesis are well-known in the art. See, e.g., Sambrook et al. and Ausubel et al.

[0278] Pharmaceutical compositions containing a compound of Formula I' according to the present disclosure will comprise an effective amount of a compound of Formula I', an immunotherapeutic agent, and / or both, typically dispersed in a pharmaceutically acceptable carrier. The phrases "pharmaceutically or pharmacologically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic or other untoward reaction when administered to animal, such as, for example, a human, as appropriate. The preparation of an pharmaceutical composition that contains a compound of Formula I' will be known to those of skill in the art in light of the present disclosure, as exemplified by Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, Moreover, for animal (e.g., human) administration, it will be understood that preparations should meet sterility, pyrogenicity, general safety and purity standards. A specific example of a pharmacologically acceptable carrier for a combination compositions, containing a compound of Formula I' in admixture with an immunotherapeutic agent as described herein is borate buffer or sterile saline solution (0.9% NaCl).

[0279] Formulations of the an immunotherapeutic agent, for example an immune checkpoint modulator antibody used in accordance with the present disclosure can be prepared for storage by mixing an antibody having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers as amply described and illustrated in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed.

[1980] , in the form of lyophilized formulations or aqueous solutions and / or suspensions. Acceptable carriers, excipients, buffers or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include suitable aqueous and / or non-aqueous excipients that may be employed in the pharmaceutical compositions of the disclosure, for example, water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants, buffers such as phosphate, citrate, and other organic acids. Antioxidants may be included, for example, (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like; preservatives (such as octade-cyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues). Other exemplary pharmaceutically acceptable excipients may include polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and / or non-ionic surfactants such as TWEENTM, PLURONICSTM or polyethylene glycol (PEG).

[0280] In one illustrative instance, the pharmaceutical compositions can optionally contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents and toxicity adjusting agents, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride and sodium lactate. In some instances, the checkpoint inhibitor antibodies or antigen-binding fragments thereof of the present disclosure are formulated for and can be lyophilized for storage and reconstituted in a suitable excipient prior to use according to art-known lyophilization and reconstitution techniques. In one exemplary pharmaceutical composition containing one or more checkpoint inhibitor antibodies or antigen-binding fragment thereof, the composition is formulated as a sterile, preservative-free solution of one or more checkpoint inhibitor antibodies or antigen-binding fragment thereof for intravenous or subcutaneous administration. The formulation can be supplied as either a single-use, prefilled pen, as a single-use, for example containing about 1 mL prefilled glass syringe, or as a single-use institutional use vial. Preferably, the pharmaceutical composition containing the checkpoint inhibitor antibody or antigen-binding fragment thereof is clear and colorless, with a pH of about 6.9-5.0, preferably a pH of 6.5-5.0, and even more preferably a pH ranging from about 6.0 to about 5.0. In various instances, the formulations comprising the pharmaceutical compositions can contain from about 500 mg to about 10 mg, or from about 400 mg to about 20 mg, or from about 300 mg to about 30 mg or from about 200 mg to about 50 mg of the checkpoint inhibitor antibody or antigen-binding fragment thereof per mL of solution when reconstituted and administered to the subject. Exemplary injection or infusion excipients can include mannitol, citric acid monohydrate, dibasic sodium phosphate dihydrate, monobasic sodium phosphate dihydrate, polysorbate 80, sodium chloride, sodium citrate and water for parenteral administration, for example, intravenously, intramuscularly, intraperitoneally, or subcutaneous administration.

[0281] In another exemplary instance, one or more immunotherapeutic agents, or an antigen-binding fragment thereof is formulated for intravenous or subcutaneous administration as a sterile aqueous solution containing 1-75 mg / mL, or more preferably, about 5-60 mg / mL, or yet more preferably, about 10-50 mg / mL, or even more preferably, about 10-40 mg / mL of antibody, with sodium acetate, polysorbate 80, and sodium chloride at a pH ranging from about 5 to 6. Preferably, the intravenous or subcutaneous formulation is a sterile aqueous solution containing 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg / mL of the immunotherapeutic agent, for example, an immune checkpoint inhibitor antibody or an antigen-binding fragment thereof, with 20 mM sodium acetate, 0.2 mg / mL polysorbate 80, and 140 mM sodium chloride at pH 5.5. Further, a solution comprising a checkpoint inhibitor antibody or an antigen-binding fragment thereof, can comprise, among many other compounds, histidine, mannitol, sucrose, trehalose, glycine, poly(ethylene)glycol, EDTA, methionine, and any combination thereof, and many other compounds known in the relevant art.

[0282] In one instance, a pharmaceutical composition of the present disclosure comprises the following components: 5-500 mg of an immunotherapeutic agent or antigen-binding fragment thereof of the present disclosure, 10 mM histidine, 5% sucrose, and 0.01% polysorbate 80 at pH 5.8, with or without a compound of Formula I'. This composition may be provided as a lyophilized powder. When the powder is reconstituted at full volume, the composition retains the same formulation. Alternatively, the powder may be reconstituted at half volume, in which case the composition comprises 10-500 mg of an immunotherapeutic agent or antigen-binding fragment thereof of the present disclosure, 20 mM histidine, 10% sucrose, and 0.02% polysorbate 80 at pH 5.8.

[0283] In one instance, part of the dose is administered by an intravenous bolus and the rest by infusion of the immunotherapeutic agent formulation. For example, from about 0.001 to about 200 mg / kg, for example, from about 0.001 mg / kg to about 100 mg / kg, or from about 0.001 mg / kg to about 50 mg / kg, or from about 0.001 mg / kg to about 10 mg / kg intravenous injection of the immunotherapeutic agent, or antigen-binding fragment thereof, may be given as a bolus, and the rest of the antibody dose may be administered by intravenous injection. A predetermined dose of the immunotherapeutic agent, or antigen-binding fragment thereof, may be administered, for example, over a period of an hour to two hours to five hours.

[0284] In a further instance, part of the dose is administered by a subcutaneous injection and / or infusion in the form of a bolus and the rest by infusion of the immunotherapeutic agent formulation. In some exemplary doses, the immunotherapeutic agent formulation can be administered subcutaneously in a dose ranging from about 0.001 to about 200 mg / kg, for example, from about 0.001 mg / kg to about 100 mg / kg, or from about 0.001 mg / kg to about 50 mg / kg, or from about 0.001 mg / kg to about 10 mg / kg intravenous injection of the immunotherapeutic agent, or antigen-binding fragment thereof. In some instances the dose may be given as a bolus, and the rest of the immunotherapeutic agent dose may be administered by subcutaneous or intravenous injection. A predetermined dose of the immunotherapeutic agent, or antigen-binding fragment thereof, may be administered, for example, over a period of an hour to two hours to five hours.

[0285] The formulation herein may also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. For example, it may be desirable to provide one or more immunotherapeutic agents with other specificities. Alternatively, or in addition, the composition may comprise an anti-inflammatory agent, a chemotherapeutic agent, a cytotoxic agent, a cytokine, a growth inhibitory agent and / or a small molecule antagonist. Such molecules are suitably present in combination in amounts that are effective for the purpose intended.

[0286] The formulations to be used for in vivo administration should be sterile, or nearly so. This is readily accomplished by filtration through sterile filtration membranes.

[0287] In various instances, illustrative formulations of the pharmaceutical compositions described herein can be prepared using methods widely known in the field of pharmaceutical formulations. In general, such preparatory methods can include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if desirable, packaging the product into a desired single-or multi-dose unit.

[0288] In some instances, the composition comprising a compound of Formula I' can be also delivered in a vesicle, and the immunotherapeutic agent can be delivered in the same liposome formulation, or in a separate formulation that is compatible with the liposomal formulation containing the compound of Formula I', In some illustrative examples, a liposome containing one or more liposomal surface moieties for example, polyethylene glycol, antibodies and antibody fragments thereof that target a desired tumor surface antigen, receptor, growth factor, glycoprotein, glycolipid or neoantigen, which are selectively transported into specific cells or organs, thus enhance targeted drug delivery.

[0289] In another instance, a compound of Formula I' can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990); Treat et al., in LIPOSOMES IN THE THERAPY OF INFECTIOUS DISEASE AND CANCER, Lopez-Berestein and Fidler (eds.), Liss, N.Y., pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid.).

[0290] In yet another instance, a compound of Formula I', or the composition containing the combination, or a composition containing the immunotherapeutic agent, can be delivered in a controlled release system. In one instance, a pump can be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In another instance, controlled relaease of the compound of Formula I' can comprise polymeric materials to provide sustained, intermediate, pulsatile, or alternate release (see MEDICAL APPLICATIONS OF CONTROLLED RELEASE, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); CONTROLLED DRUG BIOAVAILABILITY, DRUG PRODUCT DESIGN AND PERFORMANCE, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); see also Levy et al., Science 228:190 (1985); During et al., Ann. Neurol. 25:351(1989); Howard et al., J. Neurosurg. 71:105 (1989)). Other controlled-release systems discussed in the review by Langer (Science 249:1527-1533 (1990)) can be used.

[0291] The optimum concentration of the active ingredient(s) in the chosen medium can be determined empirically, according to procedures well known to the skilled artisan, and will depend on the ultimate pharmaceutical formulation desired and the use to be employed.

[0292] The present disclosure also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the disclosure, which at minimum will include a compound of Formula I' and one or more checkpoint inhibitor antibodies or antigen-binding fragment thereof as described herein. In other instances, the kit may contain one or more further containers providing a pharmaceutically acceptable excipient, for example a diluent. In one instance a kit may comprise at least one container, wherein the container can include a compound of Formula I', a checkpoint inhibitor antibody or an antigen-binding fragment thereof of the present disclosure,. The kit may also include a set of instructions for preparing and administering the final pharmaceutical composition to the subject in need thereof, for the treatment of a checkpoint molecule-mediated disease or disorder.

[0293] Some instances of the present disclosure, the immunotherapeutic agent is a population of immune cells, which can be administered in combination with a compound of Formula I' to treat a subject with cancer. In some instances, the immunotherapeutic agent is a population of immune cells, such as leukocytes (nucleated white blood cells), comprising (e.g., expressing) a receptor that binds to an antigen of interest. A leukocyte of the present disclosure may be, for example, a neutrophil, eosinophil, basophil, lymphocyte or a monocyte. In some instances, a leukocyte is a lymphocyte. Examples of lymphocytes include T cells, B cells, Natural Killer (NK) cells or NKT cells. In some instances, a T-cell is a CD4+ Th (T helper) cell, a CD8+ cytotoxic T cell, a γδT cell or a regulatory (suppressor) T cell. In some instances, an immune cell is a dendritic cell.

[0294] Immune cells of the present disclosure, in some instances, are genetically engineered to express an antigen-binding receptor. A cell is considered "engineered" if it contains an engineered (exogenous) nucleic acid. Engineered nucleic acids of the present disclosure may be introduced into a cell by any known (e.g., conventional) method. For example, an engineered nucleic acid may be introduced into a cell by electroporation (see, e.g., Heiser W. C. Transcription Factor Protocols: Methods in Molecular Biology.TM. 2000; 130: 117-134), chemical (e.g., calcium phosphate or lipid), transfection (see, e.g., Lewis W. H., et al., Somatic Cell Genet. 1980 May; 6(3): 333-47; Chen C., et al., Mol Cell Biol. 1987 August; 7(8): 2745-2752), fusion with bacterial protoplasts containing recombinant plasmids (see, e.g., Schaffner W. Proc Natl Acad Sci USA. 1980 April; 77(4): 2163-7), microinjection of purified DNA directly into the nucleus of the cell (see, e.g., Capecchi M. R. Cell. 1980 November; 22(2 Pt 2): 479-88), or retrovirus transduction.

[0295] Some aspects of the present disclosure provide an "adoptive cell" approach, which involves isolating immune cells (e.g., T-cells) from a subject with cancer, genetically engineering the immune cells (e.g., to express an antigen-binding receptor, such as a chimeric antigen receptor), expanding the cells ex vivo, and then re-introducing the immune cells into the subject. This method results in a greater number of engineered immune cells in the subject relative to what could be achieved by conventional gene delivery and vaccination methods. In some instances, immune cells are isolated from a subject, expanded ex vivo without genetic modification, and then re-introduced into the subject.

[0296] Immune cells of the present disclosure comprise receptors that bind to antigens, such as an antigen encoded by an exogenously delivered nucleic acid, as provided herein. In some instances, a leukocyte is modified (e.g., genetically modified) to express a receptor that binds to an antigen. The receptor may be, in some instances, a naturally-occurring antigen receptor (normally expressed on the immune cell), recombinant antigen receptor (not normally expressed on the immune cell) or a chimeric antigen receptor (CAR). Naturally-occurring and recombinant antigen receptors encompassed by the present disclosure include T cell receptors, B cell receptors, NK cell receptors, NKT cell receptors and dendritic cell receptors. A "chimeric antigen receptor" refers to an artificial immune cell receptor that is engineered to recognize and bind to an antigen expressed by tumor cells. Generally, a CAR is designed for a T cell and is a chimera of a signaling domain of the T-cell receptor (TcR) complex and an antigen-recognizing domain (e.g., a single chain fragment (scFv) of an antibody) (Enblad et al., Human Gene Therapy. 2015; 26(8):498-505.

[0297] In some instances, an antigen binding receptor is a chimeric antigen receptor (CAR). A T cell that expressed a CAR is referred to as a "CAR T cell." A CAR T cell receptor, in some instances, comprises a signaling domain of the T-cell receptor (TcR) complex and an antigen-recognizing domain (e.g., a single chain fragment (scFv) of an antibody) (Enblad et al., Human Gene Therapy. 2015; 26(8):498-505).

[0298] There are four generations of CARs, each of which contains different components. First generation CARs join an antibody-derived scFv to the CD3zeta (zeta. or z) intracellular signaling domain of the T-cell receptor through hinge and transmembrane domains. Second generation CARs incorporate an additional domain, e.g., CD28, 4-1BB (41BB), or ICOS, to supply a costimulatory signal. Third-generation CARs contain two costimulatory domains fused with the TcR CD3-zeta chain. Third-generation costimulatory domains may include, e.g., a combination of CD3z, CD27, CD28, 4-1BB, ICOS, or OX40. CARs, in some instances, contain an ectodomain (e.g., CD3), commonly derived from a single chain variable fragment (scFv), a hinge, a transmembrane domain, and an endodomain with one (first generation), two (second generation), or three (third generation) signaling domains derived from CD3Z and / or co-stimulatory molecules (Maude et al., Blood. 2015; 125(26):4017-4023; Kakarla and Gottschalk, Cancer J. 2014; 20(2):151-155).

[0299] In some instances, the chimeric antigen receptor (CAR) is a T-cell redirected for universal cytokine killing (TRUCK), also known as a fourth generation CAR. TRUCKs are CAR-redirected T-cells used as vehicles to produce and release a transgenic cytokine that accumulates in the targeted tissue, e.g., a targeted tumor tissue. The transgenic cytokine is released upon CAR engagement of the target. TRUCK cells may deposit a variety of therapeutic cytokines in the target. This may result in therapeutic concentrations at the targeted site and avoid systemic toxicity.

[0300] CARs typically differ in their functional properties. The CD3zeta signaling domain of the T-cell receptor, when engaged, will activate and induce proliferation of T-cells but can lead to anergy (a lack of reaction by the body's defense mechanisms, resulting in direct induction of peripheral lymphocyte tolerance). Lymphocytes are considered anergic when they fail to respond to a specific antigen. The addition of a costimulatory domain in second-generation CARs improved replicative capacity and persistence of modified T-cells. Similar antitumor effects are observed in vitro with CD28 or 4-1BB CARs, but preclinical in vivo studies suggest that 4-1BB CARs may produce superior proliferation and / or persistence. Clinical trials suggest that both of these second-generation CARs are capable of inducing substantial T-cell proliferation in vivo, but CARs containing the 4-1BB costimulatory domain appear to persist longer. Third generation CARs combine multiple signaling domains (costimulatory) to augment potency. Fourth generation CARs are additionally modified with a constitutive or inducible expression cassette for a transgenic cytokine, which is released by the CAR T-cell to modulate the T-cell response. See, for example, Enblad et al., Human Gene Therapy. 2015; 26(8):498-505; Chmielewski and Hinrich, Expert Opinion on Biological Therapy. 2015; 15(8): 1145-1154.

[0301] In some instances, an illustrative immunotherapeutic agent is a first generation chimeric antigen receptor CAR. In some instances, a chimeric antigen receptor is a third generation CAR. In some instances, a chimeric antigen receptor is a second generation CAR. In some instances, a chimeric antigen receptor is a third generation CAR. In some instances, the chimeric antigen receptor is a fourth generation CAR or a T-cell redirected for universal cytokine killing (TRUCK).

[0302] In some instances, a chimeric antigen receptor (CAR) comprises an extracellular domain comprising an antigen binding domain, a transmembrane domain, and a cytoplasmic domain. In some instances, a CAR is fully human. In some instances, the antigen binding domain of a CAR is specific for one or more antigens. In some instances, a "spacer" domain or "hinge" domain is located between an extracellular domain (comprising the antigen binding domain) and a transmembrane domain of a CAR, or between a cytoplasmic domain and a transmembrane domain of the CAR. A "spacer domain" refers to any oligopeptide or polypeptide that functions to link the transmembrane domain to the extracellular domain and / or the cytoplasmic domain in the polypeptide chain. A "hinge domain" refers to any oligopeptide or polypeptide that functions to provide flexibility to the CAR, or domains thereof, or to prevent steric hindrance of the CAR, or domains thereof. In some instances, a spacer domain or hinge domain may comprise up to 300 amino acids (e.g., 10 to 100 amino acids, or 5 to 20 amino acids). In some instances, one or more spacer domain(s) may be included in other regions of a CAR.

[0303] In some instances, a CAR of the disclosure comprises an antigen binding domain, such as a single chain Fv (scFv) specific for a tumor antigen. The choice of binding domain depends upon the type and number of ligands that define the surface of a target cell. For example, the antigen binding domain may be chosen to recognize a ligand that acts as a cell surface marker on target cells associated with a particular disease state, such as cancer or an autoimmune disease. Thus, examples of cell surface markers that may act as ligands for the antigen binding domain in the CAR of the present disclosure include those associated with cancer cells and / or other forms of diseased cells. In some instances, a CAR is engineered to target a tumor antigen of interest by way of engineering a desired antigen binding domain that specifically binds to an antigen on a tumor cell encoded by an engineered nucleic acid, as provided herein.

[0304] An antigen binding domain (e.g., an scFv) that "specifically binds" to a target or an epitope is a term understood in the art, and methods to determine such specific binding are also known in the art. A molecule is said to exhibit "specific binding" if it reacts or associates more frequently, more rapidly, with greater duration and / or with greater affinity with a particular target antigen than it does with alternative targets. An antigen binding domain (e.g., an scFv) that specifically binds to a first target antigen may or may not specifically bind to a second target antigen. As such, "specific binding" does not necessarily require (although it can include) exclusive binding.

[0305] In some instances, immune cells expressing a CAR are genetically modified to recognize multiple targets or antigens, which permits the recognition of unique target or antigen expression patterns on tumor cells. Examples of CARs that can bind multiple targets include: "split signal CARs," which limit complete immune cell activation to tumors expressing multiple antigens; "tandem CARs" (TanCARs), which contain ectodomains having two scFvs; and "universal ectodomain CARs," which incorporate avidin or a fluorescein isothiocyanate (FITC)-specific scFv to recognize tumor cells that have been incubated with tagged monoclonal antibodies (Mabs).

[0306] A CAR is considered "bispecific" if it recognizes two distinct antigens (has two distinct antigen recognition domains). In some instances, a bispecific CAR is comprised of two distinct antigen recognition domains present in tandem on a single transgenic receptor (referred to as a TanCAR; see, e.g., Grada Z et al. Molecular Therapy Nucleic Acids 2013; 2:e105). Thus, methods, in some instances, comprise delivering to a tumor a combination comprising a compound of Formula I' and an immunotherapeutic agent, wherein the immunotherapeutic agent is an engineered nucleic acid that encodes an antigen, or delivering to a tumor an engineered nucleic acid that induces expression of a self-antigen, and delivering to the tumor an immune cell expressing a bispecific CAR that binds to two antigens, one of which is encoded by the engineered nucleic acid.

[0307] In some instances, a CAR is an antigen-specific inhibitory CAR (iCAR), which may be used, for example, to avoid off-tumor toxicity (Fedorov, V D et al. Sci. Transl. Med. published online Dec. 11, 2013). iCARs contain an antigen-specific inhibitory receptor, for example, to block nonspecific immunosuppression, which may result from extra tumor target expression. iCARs may be based, for example, on inhibitory molecules CTLA-4 or PD-1. In some instances, these iCARs block T cell responses from T cells activated by either their endogenous T cell receptor or an activating CAR. In some instances, this inhibiting effect is temporary.

[0308] In some instances, CARs may be used in adoptive cell transfer, wherein immune cells are removed from a subject and modified so that they express receptors specific to an antigen, e.g., a tumor-specific antigen. The modified immune cells, which may then recognize and kill the cancer cells, are reintroduced into the subject (Pule, et al., Cytotherapy. 2003; 5(3): 211-226; Maude et al., Blood. 2015; 125(26): 4017-4023).

[0309] According to other aspects of the disclosure, the tumor antigenic component in the vaccine of the disclosure is any natural or synthetic tumor-associated protein or peptide or combination of tumor-associated proteins and / or peptides or glycoproteins or glycopeptides. In still yet other aspects, the antigenic component can be patient-specific or common to many or most patients with a particular type of cancer. According to one aspect, the antigenic component consists of a cell lysate derived from tumor tissue removed from the patient being treated. In another aspect, the lysate can be engineered or synthesized from exosomes derived from tumor tissue. In yet another aspect, the antigenic component consists of a cell lysate derived from tumor tissue extracted from one or more unrelated individuals or from tumor-cell lines.

[0310] In various instances, an illustrative immunotherapeutic agent comprises one or more cancer vaccines, for use in combination with a compound of Formula I'. The tumor-associated antigen component of the vaccine may be manufactured by any of a variety of well-known techniques. For individual protein components, the antigenic protein is isolated from tumor tissue or a tumor-cell line by standard chromatographic means such as highpressure liquid chromatography or affinity chromatography or, alternatively, it is synthesized by standard recombinant DNA technology in a suitable expression system, such as E. coli, yeast or plants. The tumor-associated antigenic protein is then purified from the expression system by standard chromatographic means. In the case of peptide antigenic components, these are generally prepared by standard automated synthesis. Proteins and peptides can be modified by addition of amino acids, lipids and other agents to improve their incorporation into the delivery system of the vaccine (such as a multilamellar liposome). For a tumor-associated antigenic component derived from the patient's own tumor, or tumors from other individuals, or cell lines, the tumor tissue, or a single cell suspension derived from the tumor tissue, is typically homogenized in a suitable buffer. The homogenate can also be fractionated, such as by centrifugation, to isolate particular cellular components such as cell membranes or soluble material. The tumor material can be used directly or tumor-associated antigens can be extracted for incorporation in the vaccine using a buffer containing a low concentration of a suitable agent such as a detergent. An example of a suitable detergent for extracting antigenic proteins from tumor tissue, tumor cells, and tumor-cell membranes is diheptanoyl phosphatidylcholine. Exosomes derived from tumor tissue or tumor cells, whether autologous or heterologous to the patient, can be used for the antigenic component for incorporation in the vaccine or as a starting material for extraction of tumor-associated antigens.

[0311] In some instances of the present disclosure, a cancer vaccine, wherein the cancer vaccine includes at least one tumor-associated antigen, at least one immunostimulant, and optionally, at least one cell-based immunotherapeutic agent. in some instances, the immunostimulant component in the cancer vaccine of the disclosure is any Biological Response Modifier (BRM) with the ability to enhance the therapeutic cancer vaccine's effectiveness to induce humoral and cellular immune responses against cancer cells in a patient. According to one aspect, the immunostimulant is a cytokine or combination of cytokines. Examples of such cytokines include the interferons, such as IFN-gamma, the interleukins, such as IL-2, IL-15 and IL-23, the colony stimulating factors, such as M-CSF and GM-CSF, and tumor necrosis factor. According to another aspect, the immunostimulant component of the disclosed cancer vaccine includes one or more adjuvant-type immunostimulatory agents such as APC Toll-like Receptor agonists or costimulatory / cell adhesion membrane proteins, with or without immunostimulatory cytokines. Examples of Toll-like Receptor agonists include lipid A and CpG, and costimulatory / adhesion proteins such as CD80, CD86, and ICAM-1.

[0312] In some instances, the immunostimulant is selected from the group consisting of IFN-gamma (IFN-γ), IL-2, IL-15, IL-23, M-CSF, GM-CSF, tumor necrosis factor, lipid A, CpG, CD80, CD86, and ICAM-1, or combinations thereof. According to other aspects, the cell-based immunotherapeutic agent is selected from the group consisting of dendritic cells, tumor-infiltrating T lymphocytes, chimeric antigen receptor-modified T effector cells directed to the patient's tumor type, B lymphocytes, natural killer cells, bone marrow cells, and any other cell of a patient's immune system, or combinations thereof. In one aspect, the cancer vaccine immunostimulant includes one or more cytokines, such as interleukin 2 (IL-2), GM-CSF, M-CSF, and interferon-gamma (IFN-y), one or more Toll-like Receptor agonists and / or adjuvants, such as monophosphoryl lipid A, lipid A, muramyl dipeptide (MDP) lipid conjugate and double stranded RNA, or one or more costimulatory membrane proteins and / or cell adhesion proteins, such CD80, CD86 and ICAM-1, or any combination of the above. In one aspect, the cancer vaccine includes an immunostimulant that is a cytokine selected from the group consisting of interleukin 2 (IL-2), GM-CSF, M-CSF, and interferon-gamma (IFN-y). In another aspect, the cancer vaccine includes an immunostimulant that is a Toll-like Receptor agonist and / or adjuvant selected from the group consisting of monophosphoryl lipid A, lipid A, and muramyl dipeptide (MDP) lipid conjugate and double stranded RNA. In yet another aspect, the cancer vaccine includes an immunostimulant that is a costimulatory membrane protein and / or cell adhesion protein selected from the group consisting of CD80, CD86, and ICAM-1.

[0313] In various instances, an immunotherapeutic agent can include a cancer vaccine, wherein the cancer vaccine incorporates any tumor antigen that can be potentially used to construct a fusion protein according to the disclosure and particularly the following:

[0314] (a) cancer-testis antigens including NY-ESO-1, SSX2, SCP1 as well as RAGE, BAGE, GAGE and MAGE family polypeptides, for example, GAGE-1, GAGE-2, MAGE-1 MAGE-2, MAGE-3, MAGE-4, MAGE-5, MAGE-6, and MAGE-12, which can be used, for example, to address melanoma, lung, head and neck, NSCLC, breast, gastrointestinal, and bladder tumors; (b) mutated antigens, including p53, associated with various solid tumors, e.g., colorectal, lung, head and neck cancer; p21 / Ras associated with, e.g., melanoma, pancreatic cancer and colorectal cancer; CDK4, associated with, e.g., melanoma; MUM1 associated with, e.g., melanoma; caspase-8 associated with, e.g., head and neck cancer; CIA 0205 associated with, e.g., bladder cancer; HLA-A2-R1701, beta catenin associated with, e.g., melanoma; TCR associated with, e.g., T-cell non-Hodgkin lymphoma; BCR-abl associated with, e.g., chronic myelogenous leukemia; triosephosphate isomerase; KIA 0205; CDC-27, and LDLR-FUT; (c) over-expressed antigens, including, Galectin 4 associated with, e.g., colorectal cancer; Galectin 9 associated with, e.g., Hodgkin's disease; proteinase 3 associated with, e.g., chronic myelogenous leukemia; WT 1 associated with, e.g., various leukemias; carbonic anhydrase associated with, e.g., renal cancer; aldolase A associated with, e.g., lung cancer; PRAME associated with, e.g., melanoma; HER-2 / neu associated with, e.g., breast, colon, lung and ovarian cancer; mammaglobin, alpha-fetoprotein associated with, e.g., hepatoma; KSA associated with, e.g., colorectal cancer; gastrin associated with, e.g., pancreatic and gastric cancer; telomerase catalytic protein, MUC-1 associated with, e.g., breast and ovarian cancer; G-250 associated with, e.g., renal cell carcinoma; p53 associated with, e.g., breast, colon cancer; and carcinoembryonic antigen associated with, e.g., breast cancer, lung cancer, and cancers of the gastrointestinal tract such as colorectal cancer; (d) shared antigens, including melanoma-melanocyte differentiation antigens such as MART-1 / Melan A; gpl00; MC1R; melanocyte-stimulating hormone receptor; tyrosinase; tyrosinase related protein-1 / TRP1 and tyrosinase related protein-2 / TRP2 associated with, e.g., melanoma; (e) prostate associated antigens including PAP, PSA, PSMA, PSH-P1, PSM-P1, PSM-P2, associated with e.g., prostate cancer; (f) immunoglobulin idiotypes associated with myeloma and B cell lymphomas. In certain instances, the one or more TAA can be selected from pi 5, Hom / Mel-40, H-Ras, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Epstein Barr virus antigens, EBNA, human papillomavirus (HPV) antigens, including E6 and E7, hepatitis B and C virus antigens, human T-cell lymphotropic virus antigens, TSP-180, pl85erbB2, pl 80erbB-3, c-met, mn-23H1, TAG-72-4, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras, pi 6, TAGE, PSCA, CT7, 43-9F, 5T4, 791 Tgp72, beta-HCG, BCA225, BTAA, CA 125, CA 15-3 (CA 27.29\BCAA), CA 195, CA 242, CA-50, CAM43, CD68\KP1, CO-029, FGF-5, Ga733 (EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB / 70K, NY-CO-1, RCAS1, SDCCAG16, TA-90 (Mac-2 binding protein / cyclophilin C-associated protein), TAAL6, TAG72, TLP, TPS or any combinations thereof.

[0315] In some instances, cancer vaccines of the present disclosure for use in combination with a compound of Formula I' can include a tumor antigen comprising the entire amino acid sequence, a portion of it, or specific immunogenic epitopes of one of the following human proteins: TCTN1 (Gene ID: ENSG00000204852), TCTN2 (Gene ID: ENSG00000168778), TCTN3 (Gene ID: ENSG00000119977), HIGD2A (Gene ID: ENSG00000146066), HIGD2B (Gene ID: ENSG00000175202), C4ORF32 (Gene ID: ENSG00000174749), FAM62A (E-SYT1, Gene ID: ENSG00000139641), COLEC11 (Gene ID: ENSG00000118004), FSTL5 (Gene ID: ENSG00000168843), FAM82A2 (Gene ID: ENSG00000137824), SCARA5 (Gene ID: ENSG00000168079), VSTM1 (Gene ID: ENSG00000189068), RNF5 (Gene ID: ENSG00000183574), UNQ6126 (Gene ID: gi|169216088), DPY19L3 (Gene ID: ENSG00000178904), SLC39A10 (gene ID: ENSG00000196950), GPR107 (Gene ID: ENSG00000148358), COL20A1 (Gene ID: ENSG00000101203), GLT25D2 (Gene ID: ENSG00000198756), SYTL3 (Gene ID: ENSG00000164674), DENND1B (Gene ID: ENSG00000162701), C6orf98 (Gene ID: EG: 387079), FAM69B (Gene ID: ENSG00000165716), EMID1 (Gene ID: OTTHUMG00000030824), KLRG2 (GENE ID: ENSG00000188883), ERMP1 (GENE ID: ENSG00000099219), VMO1 (Gene ID: ENSG00000182853), C9orf46 (Gene ID: ENSG00000107020), F1137107 (Gene ID: ENSG00000177990), YIPF2 (Gene ID: ENSG00000130733), TRYX3 (PRSS58, ENSG00000258223.2), C14orf135 (Gene ID: ENSG00000126773), ANGPTL7 (Gene ID: ENSG00000171819), TPCN2 (Gene ID: ENSG00000162341), C18orf19 (Gene ID: ENSG00000177150), OLFML1 (Gene ID: ENSG00000183801), LYPD4 (Gene ID: ENSG00000101203), MEGF8 (Gene ID: ENSG00000105429), F1142986 (Gene ID: ENSG00000196460), SLC46A1 (Gene ID: ENSG00000076351), FAM180A (Gene ID: ENSG00000189320), CRISP-3 (GENE ID: ENSG00000096006), or combinations thereof. These tumor antigens are disclosed in WO2010 / 086162, WO2010 / 086163, WO2011 / 051278, WO2011 / 051276, WO2011 / 051277, WO2011 / 051280, WO2011 / 051271, WO2011 / 135068, WO2014 / 198919.

[0316] In various instances, an illustrative immunotherapeutic agent may include an mRNA operable to encode any one or more of the aforementioned cancer antigens useful for synthesizing a cancer vaccine. In some illustrative instances, the mRNA based cancer vaccine may have one or more of the following properties: a) the mRNA encoding each cancer antigen is interspersed by cleavage sensitive sites; b) the mRNA encoding each cancer antigen is linked directly to one another without a linker; c) the mRNA encoding each cancer antigen is linked to one another with a single nucleotide linker; d) each cancer antigen comprises a 20-40 amino acids and includes a centrally located SNP mutation; e) at least 40% of the cancer antigens have a highest affinity for class I MHC molecules from the subject; f) at least 40% of the cancer antigens have a highest affinity f...

Claims

1. A compound of Formula I': or a pharmaceutically acceptable salt thereof, wherein: Y is selected from O, S, SO, SO2, NH, and -N(C1-6 alkyl)-; ring A is wherein R18 and R19 are each independently selected from H, halo, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C6-C10) aryl, (C3-C10) cycloalkyl, 4-14 membered heterocycloalkyl, phenyl, 5-14 membered heteroaryl, -CN, -NO2, -ORa, -SRa, -C(O)Ra, - C(O)NRaRa, -C(O)ORa, -NHRa, -NRaRa, and -NRaC(O)Ra, wherein the (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C6-C10) aryl, (C3-C10) cycloalkyl, 4-14 membered heterocycloalkyl, phenyl, and 5-14 membered heteroaryl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, (C1-C6) alkyl, -CN, and -OH; or R18 and R19 taken together with the atoms to which they are attached form a fused C3-7 cycloalkyl ring or a fused 4- to 10-membered heterocycloalkyl ring; R10 and R11 are -H; each R13 is independently selected from the group consisting of -H; halo; -OH; -CN; optionally substituted (C1-C6) alkyl; (C1-C6) alkoxy; (C1-C6) haloalkoxy; -NH2; --NH(C1-C6)alkyl; -N(C1-C6 alkyl)2; and (C3-C6) cycloalkyl; each R14 is independently selected from the group consisting of -H, halo, and (C1-C6) alkyl; R15 is H; each R12 is independently selected from the group consisting of -H and halo; each Ra is independently selected from the group consisting of -H, (C1-C6) alkyl, (C3-C10) cycloalkyl, 4-14 membered heterocycloalkyl, and (4-14 membered heterocycloalkyl)-(C1-C4) alkylene-, wherein the (C1-C6) alkyl, (C3-C10) cycloalkyl, 4-14 membered heterocycloalkyl, and (4-14 membered heterocycloalkyl)-(C1-C4) alkylene- of Ra are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from (C1-C6) alkyl, (C1-C6) alkoxy, and -C(O)O(C1-C4) alkyl; the subscript n is an integer of 1, 2, 3, or 4; the subscript m is an integer of 1, 2, 3, 4, or 5; the subscript p is an integer of 0, 1, 2, 3, or 4; and X is N or CH.

2. The compound of claim 1, having Formula I'b or I'd:

3. The compound of claim 1 or 2, having Formula (I'b-1):

4. The compound of claim 1 or 2, having Formula (I'b-2):

5. The compound of claim 1 or 2, having Formula (I'd-1):

6. The compound of claim 1 or 2, having Formula (I'd-2):

7. The compound of any of claims 3-6, wherein R18 and R19 are each independently selected from -H, halo, (C1-C6) alkyl, phenyl, (C3-C10) cycloalkyl, 4-14 membered heterocycloalkyl, 5-14 membered heteroaryl, -CN, -O(C1-C6) alkyl, -C(O)(C1-C6) alkyl, - C(O)NH2, -C(O)NH(C1-C6) alkyl, -C(O)N((C1-C6) alkyl)2, -C(O)O(C1-C6) alkyl, -NH(C1-C6) alkyl, -N((C1-C6) alkyl)2, -NHC(O)(C1-C6) alkyl, -O(C1-C4 alkylene-(4-14 membered heterocycloalkyl)), O(C1-C6 alkoxy-C1-C6 alkyl)), and -NH2; or wherein R18 and R19 are each independently H, halo, CN, RaNHC(O)-, -ORa or 5- or 6-membered heteroaryl optionally substituted with 1-3 independently selected (C1-C6) alkyl groups.

8. The compound of any of claims 1-7, wherein: the subscript m is 1; and / or the subscript n is 1.

9. The compound of claim 1, having Formula I: wherein: X is selected from N and C-H; Y is O, S, SO, SO2, NH, or N-(C1-C6 alkyl); R13 is selected from -H, halo, -CN, and optionally substituted C1-6 alkyl; R12 is -H or halo; is optionally substituted with one, two, three, or four groups independently selected from the group consisting of halo, and C1-C6 alkyl, wherein "" indicate points of attachment; is selected from the group consisting of wherein R18 and R19 are selected from the group consisting of H, halo, -CN, optionally substituted C1-C6 alkyl, C(O)NR5R6, optionally substituted 5 or 6-membered heteroaryl, and optionally substituted C1-C6 alkoxy; or when is R18 and R19 can be joined together to form a 5 or 6-membered optionally substituted cycloalkyl or heterocycloalkyl; R5 and R6 are selected from the group consisting of H, or optionally substituted C1-6 alkyl, or R5 and R6 taken together with the nitrogen to which they are attached to form a 5- or 6-membered optionally substituted heterocycle; and m and n are each independently 1 or 2.

10. The compound of claim 9, wherein R19 is selected from the group consisting of optionally substituted C1-C6 alkoxy and -CN.

11. The compound of claims 1-8, wherein is 12. The compound of any of claims 9-11, wherein: X is N; and / or R13 is H.

13. The compound of claim 1, wherein the compound is selected from the compounds listed in Table 2: Comp.StructureIUPAC Name7 1-N'-(4-fluorophenyl)-1-N-(4-pyrido[3,2-d]pyrimidin-4-yloxyphenyl)cyclopropane-1,1-dicarboxamide12 1-N-[4-(7-chloropyrido[3,2-d]pyrimidin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide13 1-N-[4-(7-bromopyrido[3,2-d]pyrimidin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide16 1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxypyrido[3,2-d]pyrimidin-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide19 1-N'-[2,5-difluoro-4-(7-methoxypyrido[3,2-d]pyrimidin-4-yl)oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide28 1-N-[4-(6,7-dimethoxypyrido[3,2-d]pyrimidin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide29 1-N'-[3-chloro-4-(6,7-dimethoxypyrido[3,2-d]pyrimidin-4-yl)oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide30 1-N'-[4-(6,7-dimethoxypyrido[3,2-d]pyrimidin-4-yl)oxy-3-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide31 1-N'-[4-(6,7-dimethoxypyrido[3,2-d]pyrimidin-4-yl)oxy-2-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide32 1-N'-[2-chloro-4-(6,7-dimethoxypyrido[3,2-d]pyrimidin-4-yl)oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide33 1-N'-[4-(6,7-dimethoxypyrido[3,2-d]pyrimidin-4-yl)oxy-2-methylphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide34 1-N'-[4-(6,7-dimethoxypyrido[3,2-d]pyrimidin-4-yl)oxy-2,3-difluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide35 1-N'-[4-(6,7-dimethoxypyrido[3,2-d]pyrimidin-4-yl)oxy-2,5-difluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide43 1-N-[4-(6,7-dimethylpyrido[3,2-d]pyrimidin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide52 1-N'-(4-fluorophenyl)-1-N-[4-(6,7,8,9-tetrahydropyrimido[5,4-b]quinolin-4-yloxy)phenyl]cyclopropane-1,1-dicarboxamide57 1-N-[4-(6-cyano-7-methoxypyrido[3,2-d]pyrimidin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide65 1-N'-(4-fluorophenyl)-1-N-[4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide66 1-N'-[3-chloro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide67 1-N'-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide68 1-N-(4-fluorophenyl)-1-N'-[4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxy-3-methylphenyl]cyclopropane-1,1-dicarboxamide69 1-N'-[2-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide70 1-N'-[2-chloro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide71 1-N-(4-fluorophenyl)-1-N'-[4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxy-2-methylphenyl]cyclopropane-1,1-dicarboxamide72 1-N'-[2,5-difluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide73 1-N'-[2,3-difluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide74 1-N-(4-fluorophenyl)-1-N'-[3-methoxy-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide75 1-N'-[3-cyano-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide76 1-N'-[3,5-difluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide78 1-N'-(4-fluorophenyl)-1-N-[4-[6-methoxy-7-(2-methoxyethoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide79 1-N'-[3-fluoro-4-[6-methoxy-7-(2-methoxyethoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide80 1-N'-[3-chloro-4-[6-methoxy-7-(2-methoxyethoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide81 1-N'-[2-fluoro-4-[6-methoxy-7-(2-methoxyethoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide82 1-N'-[2,3-difluoro-4-[6-methoxy-7-(2-methoxyethoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide83 1-N'-[2,5-difluoro-4-[6-methoxy-7-(2-methoxyethoxy)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide85 1-N'-(4-fluorophenyl)-1-N-(4-pyrido[3,4-d]pyrimidin-4-yloxyphenyl)cyclopropane-1,1-dicarboxamide88 1-N-[4-(6-chloropyrido[3,4-d]pyrimidin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide91 1-N'-(4-fluorophenyl)-1-N-[4-(6-methoxypyrido[3,4-d]pyrimidin-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide129 1-N'-(4-fluorophenyl)-1-N-[4-[7-(1-methylpyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide139 1-N-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide140 1-N'-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide141 1-N'-[3-chloro-4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide142 1-N'-[4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-2,5-difluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide149 1-N'-(4-fluorophenyl)-1-N-[4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]cyclopropane-1,1-dicarboxamide150 1-N'-[3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide151 1-N'-[3-chloro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide152 1-N'-[2,5-difluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide153 1-N'-[2,5-difluoro-4-[[6-methoxy-7-(2-morpholin-4-ylethoxy)-1,5-naphthyridin-4-yl]oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide157 1-N-[4-(2,3-dihydro-[1,4]dioxino[2,3-b][1,5]naphthyridin-6-yloxy)phenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide158 1-N'-[4-(2,3-dihydro-[1,4]dioxino[2,3-b][1,5]naphthyridin-6-yloxy)-3-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide159 1-N'-[3-chloro-4-(2,3-dihydro-[1,4]dioxino[2,3-b][1,5]naphthyridin-6-yloxy)phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide164 1-N-[4-[(6-cyano-7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide165 1-N'-[4-[(6-cyano-7-methoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide166 1-N'-[3-chloro-4-[(6-cyano-7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide167 1-N-[4-[(6-carbamoyl-7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide168 1-N'-[4-[(6-carbamoyl-7-methoxy-1,5-naphthyridin-4-yl)oxy]-3-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide169 1-N'-[4-[(6-carbamoyl-7-methoxy-1,5-naphthyridin-4-yl)oxy]-3-chlorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide172 1-N'-(4-fluorophenyl)-1-N-[4-[[7-methoxy-6-(methylcarbamoyl)-1,5-naphthyridin-4-yl]oxy]phenyl]cyclopropane-1,1-dicarboxamide173 1-N'-[3-fluoro-4-[[7-methoxy-6-(methylcarbamoyl)-1,5-naphthyridin-4-yl]oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide174 1-N-[4-[[6-(dimethylcarbamoyl)-7-methoxy-1,5-naphthyridin-4-yl]oxy]phenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide176 1-N'-[2,5-difluoro-4-[(7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide181 1-N-[4-[(6-amino-7-methoxy-1,5-naphthyridin-4-yl)oxy]phenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide182 1-N'-(4-fluorophenyl)-1-N-[4-[[7-methoxy-6-(1-methylpyrazol-4-yl)-1,5-naphthyridin-4-yl]oxy]phenyl]cyclopropane-1,1-dicarboxamide183 1-N'-(4-fluorophenyl)-1-N-[4-[[7-methoxy-6-(1H-pyrazol-4-yl)-1,5-naphthyridin-4-yl]oxy]phenyl]cyclopropane-1,1-dicarboxamide184 1-N'-(4-fluorophenyl)-1-N-[4-[[7-methoxy-6-(2-methylpyrazol-3-yl)-1,5-naphthyridin-4-yl]oxy]phenyl]cyclopropane-1,1-dicarboxamide189 1-N'-(4-fluorophenyl)-1-N-[4-[[6-(1-methylpyrazol-4-yl)-1,5-naphthyridin-4-yl]oxy]phenyl]cyclopropane-1,1-dicarboxamide14. A pharmaceutical composition comprising a compound of any of claims 1-13, and a pharmaceutically acceptable carrier or excipient.

15. A compound of claims 1-13 or a pharmaceutical composition of claim 14, for use in therapy.