Compounds for the treatment of kinase-dependent disorders

Abstract

A compound of chemical formula I is disclosed here. I Compounds of Formula I inhibit, regulate, and / or modulate kinase receptors, particularly Axl and Mer signaling pathways, regarding changes in cell activity as described above, compositions containing these compounds, and methods for using the same to treat kinase-dependent diseases and pathological conditions. The present invention also provides a method for preparing the said compounds and compositions containing these compounds.

Description

Technology Field

[0001] Field of invention

[0002] The present invention relates to compounds that regulate cellular activities such as proliferation, differentiation, programmed cell death, migration, and chemical invasion by regulating protein kinase enzyme activity. More specifically, the present invention relates to compounds that inhibit, regulate, and / or regulate Axl and Mer receptor tyrosine kinases, compositions containing these compounds, methods for treating kinase-dependent diseases and pathologies using these compounds, the synthesis of the compounds, and methods for formulating the compounds for pharmaceutical purposes.

[0003] Cross-reference regarding related applications

[0004] The present application claims priority to U.S. Provisional Application No. 62 / 622,702 filed January 26, 2018 and U.S. Provisional Application No. 62 / 758,321 filed November 9, 2018, the entirety of which is incorporated herein. Background Technology

[0005] Background of the Invention

[0006] Human Axl belongs to the TAM subfamily of receptor tyrosine kinases, which includes Mer. TAM kinases are characterized by an extracellular ligand binding domain composed of two immunoglobulin-like domains and two fibronectin type III domains. Axl is overexpressed in numerous tumor cell types and was initially cloned from patients with chronic myeloid leukemia. When overexpressed, Axl exhibits transformability. Axl signaling is believed to induce tumor growth through the activation of proliferative and anti-apoptotic signaling pathways. Axl is associated with cancers such as lung cancer, myeloid leukemia, uterine cancer, ovarian cancer, glioma, melanoma, thyroid cancer, renal cell carcinoma, osteosarcoma, gastric cancer, prostate cancer, and breast cancer. Overexpression of Axl leads to a poor prognosis in patients with the indicated cancers.

[0007] Activation of Mers, such as Axl, transmits downstream signaling pathways that induce tumor growth and activation. Mers bind to ligands such as the soluble protein Gas-6. Gas-6 binding to Mers induces autophosphorylation of Mers within their intracellular domains, leading to downstream signal activation. Overexpression of Mers in cancer cells increases metastasis, largely mediated by the production of soluble Mer extracellular domain proteins acting as decoy receptors. Tumor cells secrete soluble forms of extracellular Mer receptors, reducing the ability of soluble Gas-6 ligands to activate Mers in endothelial cells, thereby causing cancer progression. Therefore, compounds that inhibit TAM receptor tyrosine kinases, such as Axl and Mers, are required for the treatment of selected cancers.

[0008] Therefore, compounds that inhibit TAM receptor tyrosine kinases, such as Axl and Mer, are required for the treatment of selected cancers.

[0009] Summary of the Invention

[0010] In one aspect, the present invention is a compound of formula I:

[0011]

[0012] I

[0013] or provides a pharmaceutically acceptable salt thereof, where:

[0014] R1 is selected from the group consisting of -H, -CN, -CO-NR5R6, -CO2R7, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C8) cycloalkyl, optionally substituted (C3-C6) heterocycloalkyl, -SO2NR8R9, and -(SO2)-(C1-C6) alkyl;

[0015] Herein, when R1 is selected from the group consisting of -CN, -CO-NR5R6, -CO2R7, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (C3-C8) cycloalkyl, optionally substituted (C3-C6) heterocycloalkyl, -SO2NR8R9, and -(SO2)-(C1-C6) alkyl, R2 is -H, halo, -NR5R6, or optionally substituted (C1-C6) alkoxy;

[0016] Here, when R1 is -H, an optionally substituted (C1-C6) alkyl, or an optionally substituted (C1-C6) alkoxy, R2 is -CO-NR5R6; or -CO2R7;

[0017] Or R1 and R2 bond together with the atoms to which they are attached to form an arbitrarily substituted cycloalkyl or an arbitrarily substituted heterocycloalkyl;

[0018] R3 is -H, arbitrarily substituted (C 1- C6) Selected from the group consisting of alkyl, -CN, and halo;

[0019] R4 is -H or Halo;

[0020] is optionally substituted with a 1, 2, 3, or 4 group independently selected from the group consisting of halos and (C1-C6) alkyls, where " " indicates an attachment point;

[0021] R5 and R6 are each independently -H, an optionally substituted (C1-C6) alkyl, or an optionally substituted (C1-C6) alkoxy;

[0022] R7 is -H or an optionally substituted (C1-C6) alkyl.

[0023] R8 and R9 are each independently -H or optionally substituted (C1-C6) alkyl;

[0024] Or R8 and R9 are connected to form an arbitrarily substituted heterocycle; and

[0025] Y is selected from the group consisting of O, S, SO, SO2, NH, and N-(C1-C6 alkyl).

[0026] Another aspect is the compound of chemical formula A:

[0027]

[0028] A

[0029] or provides a pharmaceutically acceptable salt thereof, wherein

[0030] (i) R1 is (C2-C6) alkenyl, (C2-C6) alkenyl, (C6-C 10 ) Aryl, ( C3-C 10 ) Cycloalkyl, 5-10-membered heteroaryl, 4-10-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)2R 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 , -C(=NR a )NR a R a , -S(O)NR a R a , -S(O)2NR 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)2NR a R a Selected from a group consisting of; and

[0031] R2 is -H, halo, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C 1- C6) haloalkyl, (C 1- C6) Haloalkoxy, (C6-C 10 ) Aril-(C 1- C4) Alkylene-, (C3-C 10 ) Cycloalkyl-(C 1- C4) Alkylene-, (5-14 atom heteroaryl)-(C 1- C4) Alkylene-, (4-14 cyclic heterocycloalkyl)-(C 1- C4) Alkylene-, -CN, -NO2, -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 , -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 Ra , -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)2R a , -NR a S(O)2NR a R a , -S(O)R a , -S(O)NR a R a , -S(O)2R a , -S(O)2NR 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)2NR a R a Selected from, wherein R1 or R2 is a (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C 10 ) Aril-(C 1- C4) Alkylene-, (C3-C 10 ) Cycloalkyl-(C 1- C4) Alkylene-, (5-14 atom heteroaryl)-(C 1- C4) Alkylene-, and (4-14 cyclic heterocycloalkyl)-(C 1- C4) Alkylene-1, 2, 3, 4, or 5 independently selected R b Each is optionally substituted with a substituent, provided that R1 is a 5-7-membered heteroaryl or 5-7-membered heterocycloalkyl and R2 is C1-6 When it is an alkoxy, then the 5-7-membered heteroaryl or 5-7-membered heterocycloalkyl is not connected to the fused phenyl ring of the quinoline moiety ring through the nitrogen atom; or

[0032] (ii) R1 is -H, halo, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C 1- C6) haloalkyl, (C 1- C6) Haloalkoxy, (C6-C 10 ) Aryl, ( C3-C 10 ) Cycloalkyl, 5-14 ecumenical, 4-14 ecumenical heterocycloalkyl, (C6-C 10 ) Aril-(C 1- C4) Alkylene-, (C3-C 10 ) Cycloalkyl-(C 1- C4) Alkylene-, (5-14 atom heteroaryl)-(C 1- C4) Alkylene-, (4-14 cyclic heterocycloalkyl)-(C 1- C4) Alkylene-, -CN, -NO2, -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 , -NR a C(O)R a , -NR a C(=NR a )Ra , -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)2R a , -NR a S(O)2NR a R a , -S(O)R a , -S(O)NR a R a , -S(O)2R a , -S(O)2NR a C(O)R a , -P(O)R a R a , -P(O)(OR a )(OR a ), -B(OH)2, -B(OR a ) 2, 및 -S(O)2NR a R a Selected from, wherein R1 or R2 is a (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C 10 ) Aryl, ( C3-C 10 ) Cycloalkyl, 5-14 ecumenical, 4-14 ecumenical heterocycloalkyl, (C6-C 10 ) Aril-(C1- C4) Alkylene-, (C3-C 10 ) Cycloalkyl-(C 1- C4) Alkylene-, (5-14 atom heteroaryl)-(C 1- C4) Alkylene-, and (4-14 cyclic heterocycloalkyl)-(C 1- C4) Alkylene-1, 2, 3, 4, or 5 independently selected R b Each is arbitrarily substituted with a substituent; and

[0033] R2 is (C2-C6) alkenyl, (C2-C6) alkenyl, -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)2R 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)2NR 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)2NR a R aSelected from the group consisting of, wherein R1 is a 5-7-membered heteroaryl or 5-7-membered heterocycloalkyl and R2 is C 1-6 When it is an alkoxy, then the 5-7-membered heteroaryl or 5-7-membered heterocycloalkyl of R1 is not connected to the fused phenyl ring of the quinoline moiety ring through the nitrogen atom, and

[0034] (iii) R1 and R2 bond together with the atoms to which they are attached to form a fused (C3-C7) cycloalkyl ring or a fused 4- to 10-membered heterocycloalkyl ring, wherein the fused (C 3- C7) The cycloalkyl ring and the fused 4- to 10-membered heterocycloalkyl ring are 1, 2, or 3 independently selected R b Each is optionally substituted with a substituent, provided that the compound is not 1-[2-(4-fluoro-phenyl)-acetyl]-cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododeca[b]naphthalene-4-yloxy)-phenyl]-amide;

[0035] R 10 and R 11 are -H, halo, (C1-C6) alkyl, (C 1- C6) haloalkyl, (C 1- C6) Haloalkoxy, (C6-C 10 ) Aryl, ( C3-C 10 ) Cycloalkyl, 5-14 ecumenical, 4-14 ecumenical heterocycloalkyl, (C6-C 10 ) Aril-(C 1- C4) Alkylene-, (C3-C 10 ) Cycloalkyl-(C 1- C4) Alkylene-, (5-14 atom heteroaryl)-(C 1- C4) Alkylene-, (4-14 cyclic heterocycloalkyl)-(C1- C4) 알킬렌-, -CN, -NO2, -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)2R 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)2R a , -NR a S(O)2NR a R a , -S(O)R a , -S(O)NR a R a , -S(O)2R a, -S(O)2NR 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)2NR a R a Independently selected from the group consisting of, wherein R1 or R2 is a (C1-C6) alkyl, (C6-C 10 ) Aryl, ( C3-C 10 ) Cycloalkyl, 5-14 ecumenical, 4-14 ecumenical heterocycloalkyl, (C6-C 10 ) Aril-(C 1- C4) Alkylene-, (C3-C 10 ) Cycloalkyl-(C 1- C4) Alkylene-, (5-14 atom heteroaryl)-(C 1- C4) Alkylene-, and (4-14 cyclic heterocycloalkyl)-(C 1- C4) Alkylene-1, 2, 3, 4, or 5 independently selected R b Each is arbitrarily substituted with a substituent;

[0036] Each R3 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-C6alkyl)2, and (C3-C6) cycloalkyl, wherein the (C1-C6) alkoxy, -NH(C1-C6)alkyl, -N(C1-C6alkyl)2, and (C3-C6) cycloalkyl of R3 are 1, 2, or 3 independently selected Rs. g Each is arbitrarily substituted with a substituent;

[0037] Each R 14is halo, -OH, -NH2, -CN, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, -COOH, -NH(C1-C6)alkyl, -N(C1-C6alkyl)2, phenyl, phenyl-(C 1- C2) Alkylene, (C 3- C6) cycloalkyl, (C 3- C6) Cycloalkyl-(C 1- C4) Alkylene-, 4- to 6-membered heterocycloalkyl, (4- to 6-membered heterocycloalkyl)-(C 1- C4) Alkylene-, 5- to 6-membered heteroaryl, (5- to 6-membered heteroaryl)-(C 1- C4) Alkylene-, and -OR e Independently selected from a group consisting of, where R 14 of (C1-C6) alkyl, phenyl, phenyl-(C 1- C2) Alkylene, (C 3- C6) cycloalkyl, (C 3- C6) Cycloalkyl-(C 1- C4) Alkylene-, 4- to 6-membered heterocycloalkyl, (4- to 6-membered heterocycloalkyl)-(C 1- C4) alkylene-, 5- to 6-membered heteroaryl, and (5- to 6-membered heteroaryl)-(C 1- C4) Alkylene-1, 2, or 3 independently selected R g Each is arbitrarily substituted with a substituent, and

[0038] R 15 is H or C 1-6 Alkyl;

[0039] Each R4 is -H, halo, -OH, -COOR e , -CONR e R e , -CN, -NH2, -NH((C 1- C6) alkyl), -N((C 1- C6) Alkyl)2, (C 1- C6) alkyl, (C 1-C6) Alkoxy, (C 1- C6) haloalkyl, (C 1- C6) Haloalkoxy, -CONR a R a , -NR a COR a , -NR a CONR a R a , -SO2R a , -NR a S(O)2R a , -NR a S(O)2NR a R a , (C 3- C6) Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, (C 3- C6) Cycloalkyl-(C 1- C4) Alkylene-, (4- to 6-membered heterocycloalkyl)-(C 1- C4) Alkylene-, phenyl-(C 1- C2) alkylene, and (5- or 6-membered heteroaryl)-(C 1- C4) Independently selected from the group consisting of alkylene-, wherein R4's (C 1- C6) alkyl, (C 3- C6) Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, (C 3- C6) Cycloalkyl-(C 1- C4) Alkylene-, (4- to 6-membered heterocycloalkyl)-(C 1- C4) Alkylene-, phenyl-(C 1- C2) alkylene, and (5- or 6-membered heteroaryl)-(C 1- C4) Alkylene-1, 2, or 3 independently selected R f Each is arbitrarily substituted with a substituent;

[0040] Each R a-H, -CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C 10 ) Aryl, ( C3-C 10 ) Cycloalkyl, 5-14 ecumenical, 4-14 ecumenical heterocycloalkyl, (C6-C 10 ) Aril-(C 1- C4) Alkylene-, (C3-C 10 ) Cycloalkyl-(C 1- C4) Alkylene-, (5-14 atom heteroaryl)-(C 1- C4) Alkylene-, and (4-14 cyclic heterocycloalkyl)-(C 1- C4) Independently selected from the group consisting of alkylene-, where R a (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C 10 ) Aryl, ( C3-C 10 ) Cycloalkyl, 5-14 ecumenical, 4-14 ecumenical heterocycloalkyl, (C6-C 10 ) Aril-(C 1- C4) Alkylene-, (C3-C 10 ) Cycloalkyl-(C 1- C4) Alkylene-, (5-14 atom heteroaryl)-(C 1- C4) Alkylene-, and (4-14 cyclic heterocycloalkyl)-(C 1- C4) Alkylene-1, 2, 3, 4, or 5 independently selected R d Each is arbitrarily substituted with a substituent;

[0041] Each R bis halo, oxo, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C6-C 10 ) Aryl, ( C3-C 10 ) Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, (C 6- C 10 ) Aril-(C 1- C4) Alkylene-, (C 3- C 10 ) Cycloalkyl-(C 1- C4) Alkylene-, (5-10 conjugate heteroaryl)-(C 1- C4) Alkylene-, (4-10 cyclic heterocycloalkyl)-(C 1- C4) Alkylene-, -CN, -OH, -NH2, -NO2, -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)2R 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 , -NRc 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)2R c , -NR c S(O)2NR c R c , -S(O)R c , -S(O)NR c R c , -S(O)2R c , -S(O)2NR 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, 및 -S(O)2NR c R c Independently selected from a group consisting of, where R b (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C 10 ) Aryl, ( C3-C 10 ) Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, (C6-C 10 ) Aril-(C 1- C4) Alkylene-, (C 3- C 10 ) Cycloalky-(C 1- C4) Alkylene-, (5-10 conjugate heteroaryl)-(C 1- C4) Alkylene-, and (4-10-membered heterocycloalkyl)-(C1-C4)alkylene- are 1, 2, or 3 independently selected R d Each is additionally and arbitrarily substituted with a substituent;

[0042] Each R c -H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C 10 ) Aryl, ( C3-C 10 ) Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, (C6-C 10 ) Aril-(C 1- C4) Alkylene-, (C3-C 10 ) Cycloalkyl-(C 1- C4) Alkylene-, (5-10 conjugate heteroaryl)-(C 1- C4) Alkylene-, and (4-10 univalent heterocycloalkyl)-(C 1- C4) Independently selected from the group consisting of alkylene-, where R c (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C 10 ) Aryl, ( C3-C 10 ) Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, (C6-C 10 ) Aril-(C 1- C4) Alkylene-, (C3-C 10 ) Cycloalkyl-(C 1- C4) Alkylene-, (5-10 conjugate heteroaryl)-(C 1- C4) Alkylene-, and (4-10 univalent heterocycloalkyl)-(C 1- C4) Alkylene-1, 2, 3, 4, or 5 independently selected R f Each is arbitrarily substituted with a substituent;

[0043] Each R d is (C 1- C6) alkyl, (C 1- C6) haloalkyl, halo, (C 6- C 10 ) Aryl, 5-10 pedigree heteroaryl, (C 3- C 10 ) Cycloalkyl, 4-10 cyclic heterocycloalkyl, (C 6- C 10 ) Aril-(C 1- C4) Alkylene-, (C 3- C 10 ) Cycloalkyl-(C 1- C4) Alkylene-, (5-10 conjugate heteroaryl)-(C 1- C4) Alkylene-, (4-10 cyclic heterocycloalkyl)-(C 1- C4) Alkylene-, -CN, -NH2, -NHOR e , -OR e , -SR e , -C(O)R e , -C(O)NR e R e , -C(O)OR e , -OC(O)R e , -OC(O)NR e R e , -NHR e , -NR e R e , -NR e C(O)R e , -NR e C(O)NR e R e , -NR eC(O)OR e , -C(=NR e )NR e R e , -NR e C(=NR e )NR e R e , -NR e C(=NOH)NR e R e , -NR e C(=NCN)NR e R e , -S(O)R e , -S(O)NR e R e , -S(O)2R e , -NR e S(O)2R e , -NR e S(O)2NR e R e , and -S(O)2NR e R e Independently selected from a group consisting of, where R d of (C 1- C6) alkyl, (C 1- C6) haloalkyl, (C 6- C 10 ) Aryl, 5-10 pedigree heteroaryl, (C 3- C 10 ) Cycloalkyl, 4-10 cyclic heterocycloalkyl, (C 6- C 10 ) Aril-(C 1- C4) Alkylene-, (C 3- C 10 ) Cycloalkyl-(C 1- C4) Alkylene-, (5-10 conjugate heteroaryl)-(C 1- C4) Alkylene-, and (4-10 univalent heterocycloalkyl)-(C 1- C4) Alkylene-1, 2, or 3 independently selected R fEach is arbitrarily substituted with a substituent;

[0044] Each R e is -H, (C 1- C6) alkyl, (C 3- C6) Cycloalkyl, (C 3- C6) Cycloalkyl-(C 1- C4) Alkylene-, (C 6- C 10 ) Aril, (C 6- C 10 ) Aril-(C 1- C4) 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- C4) Alkylene-, (C 1- C6) haloalkyl, (C 1- C6) Haloalkoxy, (C 2- C4) alkenyl, and (C 2- C4) Independently selected from a group consisting of alkynyl groups, where R e of (C 1- C4) alkyl, (C 3- C6) Cycloalkyl, (C 6- C 10 ) Aryl, 5- or 6-membered heteroaryl, 4-7-membered heterocycloalkyl, (C 6- C 10 ) Aril-(C 1- C4) Alkylene-, (5- or 6-membered heteroaryl)-(C 1- C4) Alkylene-, (4-7-membered heterocycloalkyl)-(C 1- C4) Alkylene-, (C 2- C4) alkenyl, and (C 2- C4) Alkynyl groups are 1, 2, or 3 R f Each is arbitrarily substituted with a substituent, and

[0045] or any two R a The substituents form 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl groups with the nitrogen atoms to which they are attached, each of which has 1, 2, or 3 independently selected R atoms. f Arbitrarily substituted with a substituent;

[0046] or any two R c The substituents form 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl groups with the nitrogen atoms to which they are attached, each of which has 1, 2, or 3 independently selected R atoms. f It is arbitrarily substituted with a substituent, and

[0047] or any two R e The substituents form 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl groups with the nitrogen atoms to which they are attached, each of which has 1, 2, or 3 independently selected R atoms. f Arbitrarily substituted with a substituent;

[0048] Each R f is halo, -OH, -CN, -COOH, -NH2, -NH-(C 1- C6) alkyl, -N((C 1- C6) Alki)2, (C 1- C6) Alkyl, (C 1- C6) Alkoxy, (C 1- C6) Alkylthio, (C 1- C6) haloalkyl, (C 1- C6) Haloalkoxy, phenyl, 5-6-membered heteroaryl, 4-6-membered heterocycloalkyl, and (C 3- C6) Independently selected from the group consisting of cycloalkyl, where R f of (C 1- C6) Alkyl, phenyl, (C3- C6) Cycloalkyl, 4-6 member heterocycloalkyl, and 5-6 member heteroaryls are halos, -OH, -CN, -COOH, -NH2, (C 1- C4) Alkyl, (C 1- C4) Alkoxy, (C 1- C4) haloalkyl, (C 1- C4) Haloalkoxy, phenyl, (C 3- C 10 ) Each is optionally substituted with 1, 2, or 3 substituents selected from cycloalkyl, 5-6-membered heteroaryl, and 4-6-membered heterocycloalkyl;

[0049] Each R g is a halo, -OH, -CN, -COOH, -COO-(C 1- C4) Alkyl, -NH2, -NH-(C 1- C6) alkyl, -N((C 1- C6) Alki)2, (C 1- C6) Alkyl, (C 1- C6) Alkoxy, (C 1- C6) Alkylthio, (C 1- C6) haloalkyl, (C 1- C6) Haloalkoxy, phenyl, 5-6-membered heteroaryl, 4-6-membered heterocycloalkyl, and (C 3- C6) Independently selected from a group consisting of cycloalkyls;

[0050] Y is -O-, -S-, -SO-, -SO2-, -NH-, and -N((C 1- Selected from C6) alkyl)-;

[0051] The nitrogen atom in the quinoline moiety phase ring of chemical formula A is optionally oxidized;

[0052] The subscript n is an integer 1, 2, 3, or 4;

[0053] The subscript m is an integer 1, 2, 3, 4, or 5; and

[0054] The subscript p is an integer of 0, 1, 2, 3, or 4.

[0055] Another aspect provides a method of using a compound of Formula I or a pharmaceutically acceptable salt thereof for the treatment of a disease, disorder, or symptom mediated at least partially by the modulation of the in vivo activity of a kinase.

[0056] An additional aspect provides a process for manufacturing a compound of formula A and a compound of formula I.

[0057] These and other aspects and specific examples are described below. Specific details for implementing the invention

[0058] Detailed description of the invention

[0059] Abbreviations and Definitions

[0060] The following abbreviations and terms have the meanings indicated throughout:

[0061]

[0062]

[0063] The symbol "-" signifies a single combination, and "=" signifies a double combination.

[0064] The single forms "a," "an," and "the" used herein include plural references unless the context clearly indicates otherwise.

[0065] When the variable is generally defined, with many possible substituents, each individual radical can be defined with or without bonding. For example, R z If this could be hydrogen, then this is R z of In the definition, it can be represented as "-H" or "H".

[0066] When a chemical structure is illustrated or described, it is assumed that all carbons have hydrogen substitutions to match a valence of 4, unless explicitly stated otherwise. For example, in the structure on the left side of the schematic diagram below, 9 hydrogens are implied. In the structure on the right, 9 hydrogens are illustrated. Often, specific atoms within a structure are described in the chemical formula in the text as having hydrogen or hydrogens (clearly defined hydrogens) as substitutions, for example, as -CH2CH2-. Those skilled in the field understand that the above descriptive descriptions are common in chemistry to provide brevity and simplicity to complex structures.

[0067]

[0068] For example, if the group "R" in the following chemical formula is plotted as a "floating" on a ring system:

[0069]

[0070] Then, unless otherwise defined, the substituent "R" may exist on any atom of the ring system, as long as a stable structure is formed, by implying, suggesting, or explicitly defining the substitution of a hydrogen from one of the ring constituent atoms.

[0071] For example, if the group "R" in the chemical formula is depicted as a "floating" on a fused ring system:

[0072] , and

[0073] Then, unless otherwise defined, the substituent "R" may exist on any atom of the ring system, provided that a stable structure is formed, by presuming the substitution of one of the ring constituent atoms of the illustrated hydrogen (e.g., -NH- in the above formula), implied hydrogen (e.g., in the above formula, where hydrogens are not illustrated but are understood to be present), or explicitly defined hydrogen (e.g., where "Z" in the above formula is =CH-). In the illustrated example, the "R" group may exist on the 5-membered or 6-membered ring of the fused ring system. For example, when the group "R" is illustrated as existing on a ring system containing saturated carbon in the following formula:

[0074]

[0075] In this example, if "y" can be more than one by assuming that it replaces the currently depicted, implied, or explicitly defined hydrogen on the ring; then, unless otherwise defined, the structure generated here is stable and two "R"s can exist on the same carbon. A simple example is that when R is a methyl group, a cosite dimethyl can exist on the depicted ring-shaped carbon ("cyclic" carbon). In another example, two Rs on the same carbon, including that carbon, form a ring and thus can form a spirocyclic ring ("spirocyclyl" group) structure having the depicted ring, for example, as in the following chemical formula:

[0076]

[0077] "Halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0078] Term "C n-m " or "C n -C m " indicates the range including the terminal points, where n and m are integers representing the number of carbons. An example is C 1-4 , C1-C4, C1-6 Includes , C1-C6, etc.

[0079] "Alkyl" refers to branched or straight-chain hydrocarbon chains of 1 to 8 carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl, and heptyl. (C1-C6)alkyls are 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., 1 to 4, 1 to 2, or 1) may be replaced by a moiety as described under “Optional Substitution” below. In some aspects, the alkyl group is unsubstituted or optionally unsubstituted.

[0080] "Alkylene" refers to 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 having an optionally substituted divalent saturated aliphatic radical. When optionally substituted, one or more hydrogen atoms of the alkylene group (e.g., 1 to 4, 1 to 2, or 1) may be replaced by a moiety as described under "Optional Substitution" below. In some aspects, the alkylene group is unsubstituted or optionally unsubstituted. The term "C n-m "Alkylene" refers to an alkylene group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, methylene, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, 2-methyl-propane-1,3-diyl, etc.

[0081] 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. The alkenyl group formally corresponds to an alkene having one CH bond replaced by an attachment site of the alkenyl group in 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 embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Example alkenyl groups are, but not limited to, ethenyl, n -propenyl, isopropenyl, n -Butenyl, sec - Includes butenyl, etc.

[0082] 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. The alkynyl group formally corresponds to an alkyne having one CH bond replaced by an alkyl group attachment site in 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. Examples of alkynyl groups include, but are not limited to, ethinyl, propin-1-yl, propin-2-yl, etc. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0083] "Alkoxy" refers to a moiety of the chemical formula -OR', where R' is a (C1-C6)alkyl moiety as defined here. The term "C n-m "Alkoxy" or (C n -C m ) Alkoxy refers to an alkoxy group, and its alkyl group has n to m carbons. Examples of alkoxy moiety include, but are not limited to, methoxy, ethoxy, isopropoxy, etc.

[0084] The alkoxy group may be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms of the alkoxy group (e.g., 1 to 4, 1 to 2, or 1) may be replaced by a moiety as described under “Optional Substitution” below, provided that the hydrogen atom at the alpha position of the ether oxygen is not replaced by a hydroxyl, amino, or thio group. In some aspects, the alkoxy group is unsubstituted or optionally substituted.

[0085] "Alkoxycarbonyl" refers to the group -C(O)-R', where R' is a (C1-C6)alkoxy as defined here.

[0086] The term "amino" refers to the group of the chemical formula -NH2.

[0087] The term "carbamyl" refers to the group of the chemical formula -C(O)NH2.

[0088] The term "carbonyl," used alone or in combination with other terms, refers to a -C(=O)- group, which can also be written as C(O).

[0089] The term "cyno" or "nitrile" refers to a group of the chemical formula -C≡N, which may also be written as -CN or CN.

[0090] The term "oxo" refers to a group that forms a carbonyl group when attached to a carbon, or a sulfoxide or sulfone group when attached to a heteroatom, or N - Refers to an oxygen atom as a divalent substituent forming an oxide group. In some embodiments, the heterocyclic group may be optionally substituted with a 1 or 2 oxo (=O) substituent.

[0091] The term "sulfide" refers to a sulfur atom as a divalent substituent that forms a thiocarbonyl group (C=S) when attached to a carbon.

[0092] The term "heteroatom" used here means including boron, phosphorus, sulfur, oxygen, and nitrogen.

[0093] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms. The term "C n-m "haloalkyl" or (C n -C m ) The haloalkyl group has n to m carbon atoms and at least one to {2(n to m)+1} halogen atom that may be the same or different. C n-m It refers to an alkyl group. In some embodiments, the halogen atom is a fluoro atom. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms. Examples of haloalkyl groups include CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, etc. In some embodiments, the haloalkyl group is a fluoroalkyl group.

[0094] The term "haloalkoxy," used alone or in combination with other terms, refers to a group of the chemical 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, and its haloalkyl group has n to m carbons. Examples of haloalkoxy groups include trifluoromethoxy, etc. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0095] "Aryl" means a monovalent 6- to 14-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 within the bicyclic ring is aromatic. The term "C n-m Aril" or "(C n -C m"Aryl" refers to an aryl group having n to m ring carbon atoms. In some embodiments, the aryl group has 6 to about 10 carbon atoms. In some embodiments, the aryl group has 6 carbon atoms. In some embodiments, the aryl group has 10 carbon atoms. Unless otherwise noted, the valence of the group may be located on any atom of any ring within the radical as permitted by the valence rule. Representative examples include phenyl, naphthyl, and indanyl, etc.

[0096] The aryl group may be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms of the aryl group (e.g., 1 to 5, 1 to 2, or 1) may be replaced by a moiety as described under “optional substitution” below. In some aspects, the alkoxy group is unsubstituted or optionally substituted.

[0097] "Arylene" means a divalent 6- to 14-membered, mono- or bi-carbocyclic ring, wherein the monocyclic ring is aromatic and at least one of the rings within the bicyclic ring is aromatic. Representative examples include phenylene, naphthylene, and indanylene, etc.

[0098] "Cycloalkyl" refers to cyclic alkyl and alkenyl groups comprising non-aromatic hydrocarbon ring systems (monocyclic, bicyclic, or polycyclic). The term "C n-m "cycloalkyl" or "(C n -C m ") Cycloalkyl" refers to a cycloalkyl having n to m ring member carbon atoms. The cycloalkyl group may include a mono- or polycyclic group (e.g., having 2, 3, or 4 fused rings) and a spirocycle. The cycloalkyl group has 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring-forming carbons (C 3-14It may have ). In some embodiments, 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 embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is C 3-6 It is a monocyclic cycloalkyl group. The ring-forming carbon atom of the cycloalkyl group may optionally be oxidized to form an oxo or sulfido group. The cycloalkyl group also includes cycloalkylidene. In some embodiments, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornelyl, norfinyl, norcarnyl, bicyclo[1.1.1]fentanyl, bicyclo[2.1.1]hexanyl, etc. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the cycloalkyl comprises a monosaturated carbocyclic ring of 3 to 8 ring carbons, e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl may optionally be substituted with one or more substituents, e.g., 1, 2, or 3 substituents. In some embodiments, the cycloalkyl substituent is selected from the group consisting of (C1-C6)alkyl, hydroxy, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, halo, amino, mono- and di(C1-C6)alkylamino, hetero(C1-C6)alkyl, acyl, aryl, and heteroaryl.

[0099] The cycloalkyl group may be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms of the cycloalkyl group (e.g., 1 to 4, 1 to 2, or 1) may be replaced by a moiety as described under “Optional Substitution” below. In some aspects, the substituted cycloalkyl group may comprise an exo- or endocyclic alkene (e.g., cyclohex-2-en-1-yl). In some aspects, the cycloalkyl group is unsubstituted or optionally unsubstituted.

[0100] "Cycloalkyloxycarbonyl" means the group -C(O)-OR', where R' is a (C3-C6) cycloalkyl as defined here.

[0101] "Phenyloxycarbonyl" refers to the -C(O)-O phenyl group.

[0102] "Heteroaryl" is -O-, -S(O) n- (n is 0, 1, or 2), -N-, and -N(R')- represent a monocyclic, fused bicyclic, or fused tricyclic, monovalent radical of 5 to 14 ring constituents containing one or more, preferably 1, 2, 3, or 4 ring heteroatoms independently selected from, and the remaining ring constituent atoms being carbon, wherein the ring containing the monocyclic radical is aromatic and at least one of the fused rings containing the bicyclic or tricyclic radical is aromatic. One or two ring carbon atoms of any non-aromatic ring containing the bicyclic or tricyclic radical may be replaced with -C(O)-, -C(S)-, or -C(=NH)- groups. R' is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl. Unless otherwise noted, the valence point may be located on any atom of any ring of the heteroaryl group permitted by the valence rule. In particular, when the valence point is located on the nitrogen, no additional nitrogen substituents exist. In particular, the term heteroaryl is, but is not limited to, 1,2,4-triazolyl, 1,3,5-triazolyl, phthalimidyl, pyridinyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro-1 H -Indolyl (e.g., 2,3-dihydro-1 H -Indole-2-yl or 2,3-dihydro-1 H-Indole-5-yl, including etc.), isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, benzodioxo-1-4-yl, benzofuranyl, cinnolinyl, indolinil, naphthiridin-3-yl, phthalazine-3-yl, phthalazine-4-yl, pteridinyl, furinyl, quinazolinyl, quinoxalinyl, tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isooxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl (e.g., tetrahydroisoquinoline-4-yl or tetrahydroisoquinoline-6-yl, including etc.), pyrrolo[3,2-c]pyridinyl (e.g., (including pyrrolo[3,2-c]pyridin-2-yl or pyrrolo[3,2-c]pyridin-7-yl, etc.), benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl, benzothienyl, and derivatives thereof, and N - It includes oxide or a protected derivative thereof.

[0103] A 5-membered heteroaryl ring is a heteroaryl group having 5 ring members, wherein one or more (e.g., 1, 2, 3, or 4) ring members are independently selected from N, O, and S. Exemplary 5-membered heteroaryls include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

[0104] A 6-membered heteroaryl ring is a heteroaryl group having 6 ring members, where one or more (e.g., 1, 2, 3, or 4) ring members are independently selected from N, O, and S. Exemplary 6-membered heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

[0105] "Heteroarylene" is -O-, -S(O) n - (n is 0, 1, or 2), -N-, and -N(R 19 )- means a monocyclic, fused bicyclic, or fused tricyclic, divalent radical of 5 to 14 ring constituents containing one or more, preferably 1, 2, 3, or 4 ring heteroatoms independently selected from ), and the remaining ring constituent atoms being carbon, wherein the ring containing the monocyclic radical is aromatic and at least one of the fused rings containing the bicyclic or tricyclic radical is aromatic. One or two ring carbon atoms of any non-aromatic ring containing the bicyclic or tricyclic radical may be replaced with -C(O)-, -C(S)-, or -C(=NH)- groups. R 19 is hydrogen, alkyl, or alkenyl. Unless otherwise noted, the valence point may be located on any atom of any ring of the heteroarylene group permitted by the valence rule. In particular, when the valence point is located on nitrogen, no additional nitrogen substituents exist. In particular, the term heteroaryl is, but is not limited to, thiene-diyl, benzo[ d ]Isoksajol-Dil, Benjo[ d ]Isothiazol-diyl, 1 H -Indazole-diyl (R at the N1 position 19 Arbitrarily substituted as), benzo[ d ]Oxazole-diyl, benzo[ d ]Thiazol-Diyl, 1 H -Benzo[ d ]Imidazole-diyl (R at the N1 position 19 arbitrarily substituted as), 1 H -Benzo[ d ][1,2,3]triazole-diyl (R at N1 position 19 arbitrarily substituted as), imidazo[1,2- aIncludes ]pyridine-diyl, cinnoline-diyl, quinoline-diyl, pyridine-diyl, 1-oxide-pyridine-diyl, [1,2,4]triazolo[4,3-a]pyridine-diyl, and 2,3-dihydroimideazo[1,2-a]pyridine-diyl, etc.

[0106] As used herein, “heterocycloalkyl” or “heterocyclo” refers to a non-aromatic ring or ring system, which may optionally contain a ring structure as part of one or more alkenylene groups and has at least one heteroatom ring member independently selected from boron, nitrogen, sulfur, oxygen, and phosphorus, which has a 4-14 ring member, a 4-10 ring member, a 4-7 ring member, or a 4-6 ring member. Monocyclic 4-, 5-, 6-, and 7-membered heterocycloalkyl groups are included within the term “heterocycloalkyl”. The heterocycloalkyl group may comprise a mono- or bicyclic or polycyclic (e.g., having two or three fused or cross-linked rings) ring system or a spirocycle. In some embodiments, the heterocycloalkyl group is a monocyclic group having one, two, or three heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring-forming carbon atom and the heteroatom of the heterocycloalkyl group may optionally be 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, etc.), or the nitrogen atom may be quaternized. The heterocycloalkyl group may be attached via the ring-forming carbon atom or the ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Moiety having one or more aromatic rings fused to the heterocycloalkyl ring (i.e., having a common bond), e.g., benzo or thienyl derivatives of piperidine, morpholine, azepine, etc., is also included within the definition of heterocycloalkyl. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom containing a ring-forming atom of the fused aromatic ring.Examples of heterocycloalkyl groups include azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, morpholino, 3-oxa-9-azapiro[5.5]undecanyl, 1-oxa-8-azapiro[4.5]decanyl, piperidinyl, piperazinyl, oxopiperajinyl, pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, trophanyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, and thiomophorino.

[0107] "Heterocycloalkyl" or "heterocyclo" may be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms of the group (e.g., 1 to 4, 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, the substituted heterocyclyl group may comprise an exo- or endocyclic alkene (e.g., cyclohex-2-en-1-yl). In some aspects, the heterocyclyl group is unsubstituted or optionally unsubstituted.

[0108] Arbitrary substitution

[0109] The group is optionally substituted here unless clearly provided otherwise. The term “optional substitution” refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, carbocycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted. “Optional substitution” refers to a group that may be substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” cycloalkyl, “substituted” or “unsubstituted” heterocycloalkyl, “substituted” or “unsubstituted” aryl, or “substituted” or “unsubstituted” heteroaryl group). Generally, the term “substituted” means that at least one hydrogen present in the group is replaced by an acceptable substituent, for example, a substituent that results in a compound that is stable upon substitution, for example, a compound that does not undergo spontaneous modification by rearrangement, cyclization, elimination, or other reactions. Unless otherwise indicated, the “substituted” group has substituents at one or more substitutable positions of the group, and if more than one position is substituted in any given structure, the substituents are the same or different at each position. The term “substituted” is considered to include all acceptable substituents of an organic compound and, for example, substitution with any substituent described herein that results in the formation of a stable compound. The present invention considers any such combination to arrive at a stable compound. For the purposes of the present invention, a heteroatom such as nitrogen may have any suitable substituent described herein that satisfies the hydrogen substituent and / or the valence of the heteroatom and results in the formation of a stable moiety. The present invention is not intended to be limited in any way to the exemplary substituents described herein.

[0110] Exemplary carbon atom substituents are, without limitation, halogens (halo), -CN, -NO2, -N3, -SO2H, -SO3H, -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 , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb)2, -NR bb C(=O)R aa , -NR bb CO2R 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 SO2R aa , -NR bb SO2R aa , -SO2N(R bb )2, -SO2R aa , -SO2OR aa , -OSO2R 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)2R aa , -OP(=O)2R aa , -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb)2, -OP(=O)2N(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, (C3-C 10 ) Carbocycloalkyl, 3-14 valent heterocycloalkyl, (C6-C 14 ) comprising aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is 0, 1, 2, 3, 4, or 5 R dd Independently replaced by gi;

[0111] Or, two identical hydrogens on a carbon atom are =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc Replaced by;

[0112] R aa Each case of (C1-C 10 ) alkyl, (C1-C 10 ) perhaloalkyl, (C2-C 10 ) alkenyl, (C2-C 10 ) alkynyl, (C3-C 10 ) cycloalkyl, 3-14 cyclic heterocycloalkyl, (C6-C 14Independently selected from aryls, and 5-14-membered heteroaryls, or two R aa The groups combine to form a 3-14 member heterocycloalkyl or 5-14 member heteroaryl ring, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is 0, 1, 2, 3, 4, or 5 R dd Independently replaced by gi;

[0113] R bb In each case, hydrogen, (C1-C 10 ) perhaloalkyl, (C2-C 10 ) alkenyl, (C2-C 10 ) alkynyl, (C3-C 10 ) Cycloalkyl, C 6-14 Independently selected from aryls, and 5-14-membered heteroaryls, or two Rs bb The groups combine to form a 3-14 member heterocycloalkyl or 5-14 member heteroaryl ring, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is 0, 1, 2, 3, 4, or 5 R dd Independently replaced by gi;

[0114] R cc In each case, hydrogen, (C1-C 10 ) alkyl, (C1-C 10 ) perhaloalkyl, (C2-C 10 ) alkenyl, (C2-C 10 ) alkynyl, (C3-C 10 ) cycloalkyl, 3-14 cyclic heterocycloalkyl, (C6-C 14 Independently selected from aryls, and 5-14-membered heteroaryls, or two R cc The groups combine to form a 3-14 member heterocycloalkyl or 5-14 member heteroaryl ring, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is 0, 1, 2, 3, 4, or 5 R ddIndependently replaced by gi;

[0115] R dd Each of the cases involves halogen, -CN, -NO2, -SO2H, -SO3H, -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 , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R 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 SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R 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)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, (C1-C 10) Alkyl, (C1-C 10 ) perhaloalkyl, (C2-C 10 ) alkenyl, (C2-C 10 ) alkynyl, (C3-C 10 ) cycloalkyl, 3-10 cyclic heterocycloalkyl, (C6-C 10 ) independently selected from aryls, 5-10-membered heteroaryls, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is 0, 1, 2, 3, 4, or 5 R gg Independently substituted with gi, or two identical position R dd Substituents can combine to form =O or =S;

[0116] R ee Each of the cases is (C1-C6) alkyl, (C1-C6) perhaloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C 10 ) cycloalkyl, (C6-C 10 ) independently selected from aryl, 3-10-membered heterocycloalkyl, and 3-10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is 0, 1, 2, 3, 4, or 5 R gg Independently replaced by gi;

[0117] R ff Each of the cases involves hydrogen, (C1-C6) alkyl, (C1-C6) perhaloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C 10 ) cycloalkyl, (C6-C10 Independently selected from aryls, and 5-10-membered heteroaryls, or two R ff The groups combine to form a 3-10-membered heterocycloalkyl or 5-10-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is 0, 1, 2, 3, 4, or 5 R gg It is independently replaced by gi; and

[0118] R gg Each case independently includes halogen, -CN, -NO2, -SO2H, -SO3H, -OH, and -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 -, -NH2(C 1-6 alkyl) + X -, -NH3 + 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), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 Alkyl), -C(=O)NH2, -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), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -NHC(=O)NH(C1-6 alkyl), -NHC(=O)NH2, -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)NH2, -OC(=NH)N(C 1-6 Alkyl)2, -OC(NH)NH(C 1-6 Alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 Alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 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)NH2, -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, (C1-C6) alkyl, (C1-C6) perhaloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C 10 ) cycloalkyl, (C6-C 10 ) aryl, 3-10-membered heterocycloalkyl, 5-10-membered heteroaryl; or two identical sites R gg Substituents can combine to form =O or =S; where X - is a counterion.

[0119] As described above, the nitrogen atoms may be substituted or unsubstituted as the valence of the nitrogen atoms allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents are, without limitation, hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, (C1-C 10 ) alkyl, (C1-C 10 ) perhaloalkyl, (C2-C 10 ) alkenyl, (C2-C 10 ) alkynyl, (C3-C 10 ) cycloalkyl, 3-14 cyclic heterocycloalkyl, (C6-C 14 ) aryl, and including 5-14 atom heteroaryls, or two R cc The N atom attached to the group bonds to form a 3-14 member heterocycloalkyl or 5-14 member heteroaryl ring, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is 0, 1, 2, 3, 4, or 5 R ddIt is independently substituted with , where R aa , R bb , R cc and R dd is as defined above.

[0120] In a specific embodiment, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protection devices are, without limitation, -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , (C1-C 10 ) alkyl (e.g., aralkyl, heteroaralkyl), (C2-C 10 ) alkenyl, (C2-C 10 ) alkynyl, (C3-C 10 ) cycloalkyl, 3-14 cyclic heterocycloalkyl, (C6-C 14 ) comprising aryl, and 5-14 valent heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, aryl, and heteroaryl is 0, 1, 2, 3, 4, or 5 R dd It is independently substituted with , where R aa , R bb , R cc , and R dd...is as defined herein. Nitrogen protection devices are widely known in the industry and are included herein by reference. Protective Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd Includes what is described in detail in edition, John Wiley & Sons, 1999.

[0121] For example, a nitrogen-protecting group, such as an amide group ( For example, -C(=O)R aa ) is, non-limitingly, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N -Benzoylphenylalanyl derivatives, benzamides, 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 -Phenylazophenoxypropanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o - Nitrocinnamide, N -Acetylmethionine derivative, o- Nitrobenzamide, and o- It contains (benzoyloxymethyl)benzamide.

[0122] Nitrogen-protecting group, for example, a carbamate group (e.g., -C(=O)OR aa ) is, without limitation, methyl carbamate, ethyl carbamate, 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-tetrahydrothioxantyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamandyl)-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-adamandyl 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, alkyldithiocarbamate, 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-Anthylmethyl 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-triphenylphosphoniisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cynoethyl 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- Cynobenzyl 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, Isobornyl 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 - Includes butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0123] Nitrogen-protecting group, e.g., sulfonamide group (e.g., -S(=O)2R aa ) is, unrestrictively, 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, Includes 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0124] Other nitrogen protecting groups are, to a non-limiting extent, phenothiazinyl-(10)-acyl derivatives, N' - p -Toluenesulfonylaminoacyl derivative, N' -Phenylaminothioacyl derivative, N -Benzoylphenylalanyl derivatives, 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-tetramethyldisylazcyclopentane adduct (STA base), 5-substituted 1,3-dimethyl-1,3,5-triazcyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazcyclohexan-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 salt, 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, Np -Methoxybenzylideneamine, N -Diphenylmethyleneamine, N -[(2-pyridyl)methyl]methyleneamine, N -( N' , N' -dimethylaminomethylene)amine, N , N' - Isopropylidenediamine, Np - Nitrobenzylideneamine, N -Salicylideneamine, N- 5-chlorosalicylideneamine, N -(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N -Cyclohexyllideneamine, N -(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N - Boran derivative, N-Diphenylboric acid derivative, N -[phenyl(pentaacylchromium- or tungsten)acyl]amine, N - Copper chelate, N - Zinc chelate, N - Nitroamine, N - Nitrosamine, amine N- Oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidate, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o - Includes nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

[0125] In a specific embodiment, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). Oxygen protectors, without limitation, - R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R 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 , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3, -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bbIncludes )2, where R aa , R bb , and R cc is as defined here. Oxygen protectors are widely known in the industry and are included herein by reference. Protective Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd Includes what is described in detail in edition, John Wiley & Sons, 1999.

[0126] Exemplary oxygen protectors, to the non-limiting extent, methyl, methoxymethyl (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), Tetrahydropyranil (THP), 3-Bromotetrahydropyranil, Tetrahydrothiopyranil, 1-Methoxycyclohexyl, 4-Methoxytetrahydropyranil (MTHP), 4-Methoxytetrahydrothiopyranil, 4-Methoxytetrahydrothiopyranil S,S-Dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-Methoxypiperidin-4-yl (CTMP), 1,4-Dioxane-2-yl, Tetrahydrofuranil, Tetrahydrothiopyranil, 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 -Siinobenzyl, p -Phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N -Oxide, diphenylmethyl, p , p' -Dinitrobenzhydryl, 5-Dibenzosuberyl, Triphenylmethyl, α-Naphthyldiphenylmethyl, p -Methoxyphenyldiphenylmethyl, di( p -methoxyphenyl)phenylmethyl, tri( p -methoxyphenyl)methyl, 4-(4'-bromopenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″-tris(benzoyloxyphenyl)methyl, 3-(imidazole-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), dimethylhexylsilyl, t -Butyldimethylsilyl (TBDMS), t -Butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri- p - Xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t -Butylmethoxyphenylsilyl (TBMPS), formate, benzoyl formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p- Chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldioacetal), pivaloate, adamanthoate, crotonate, 4-methoxycrotonate, benzoate, p -Phenylbenzoate, 2,4,6-trimethylbenzoate (methitoate), 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-naphthyl 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, alkylN - Includes phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0127] In a specific embodiment, the substituent present on the sulfur atom is a sulfur protecting group (also referred to herein as a "thiol protecting group"). Sulfur protection devices, without restriction, - R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R 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 , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3, -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bb Includes )2, where R aa , R bb , and R cc is as defined here. Sulfur protectors are widely known in the industry and are included herein by reference. Protective Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd Includes what is described in detail in edition, John Wiley & Sons, 1999.

[0128] As used herein, "leaving group" (LG) is an industry-understood term referring to a molecular fragment that leaves along with an electron pair during heterolysis bond dissolution, wherein the molecular fragment is an anion or a neutral molecule. As used herein, the leaving group may be an atom or group replaceable by a nucleophile. For example, Smith, March Advanced Organic Chemistry See 6th ed. (501-502). Exemplary leaving groups are, non-limitingly, halo (e.g., chloro, bromo, iodo), -OR aa (When O is attached to a carbonyl group, here R aa is as defined here), -O(C=O)R LG , or -O(SO)2R LG Includes (e.g., tosil, mesil, besil), where R LG is an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl. In certain embodiments, the leaving group is a halogen.

[0129] The terms defined above are exemplified particularly in the examples.

[0130] The "yield" for each reaction described here is expressed as a percentage of the theoretical yield.

[0131] For the purposes of the present invention, the “patient” includes humans and any other animals, particularly mammals, and other organisms. Accordingly, the present method is applicable to both human treatment and animal use. In a preferred embodiment, the patient is a mammal, and in a most preferred embodiment, the patient is a human. Examples of preferred mammals include mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, and primates.

[0132] "Kinase-dependent disease or condition" refers to a pathological condition that depends on the activity of one or more kinases. Kinases directly or indirectly bind to signaling pathways of various cellular activities, including proliferation, adhesion, migration, differentiation, and invasion. Diseases associated with kinase activity include cancer growth that supports solid tumor growth and pathological angiogenesis associated with other diseases, where excessive focal angiogenesis is accompanied by, for example, ophthalmic diseases (diabetic nephropathy, age-related macular degeneration, etc.) and inflammation (psoriasis, rheumatoid arthritis, etc.).

[0133] "Therapeutically effective amount" is an amount of the compound of the present invention that alleviates disease symptoms when administered to a patient. The amount of the compound of the present invention constituting the "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the age of the patient to be treated, etc. The therapeutically effective amount can be determined by a person skilled in the art with knowledge of and with respect to the present disclosure.

[0134] "Cancer" refers, without limitation, to cell-proliferative disease conditions including the following: heart : Sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Head and Neck: Squamous cell carcinoma of the head and neck, laryngeal and hypopharyngeal cancer, nasal and paranasal sinus cancer, nasopharyngeal cancer, salivary gland cancer, oral and oropharyngeal cancer; lung : Bronchial carcinoma (squamous epithelial, undifferentiated small cell, undifferentiated large cell, adenocarcinoma, non-small cell lung cancer), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, hamartoma, mesothelioma; colon: Colon cancer, adenocarcinoma, gastrointestinal stromal cancer, lymphoma, carcinoid, Turcot syndrome; gastrointestinal tract: Gastric cancer, gastroesophageal junction adenocarcinoma, esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid, non-formoma), small intestine (adenocarcinoma, lymphoma, carcinoid, Kaposi sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (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; urogenital tract : Kidney (adenocarcinoma, Wilms' carcinoma [nephroblastoma], lymphoma, leukemia, renal cell carcinoma), bladder and urethra (squamous cell carcinoma, metastatic cell carcinoma, adenocarcinoma, urothelial carcinoma), prostate (adenocarcinoma, sarcoma, castration-resistant prostate cancer), testis (semiticoma, teratoma, embryonic carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous carcinoma, lipoma), clear cell carcinoma, papillary carcinoma; liver : Hepatocellular carcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bone : Osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell carcinoma chordoma, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromyfibroma, osteoid osteoma, and giant cell carcinoma; thyroid: Medullary thyroid cancer, differentiated thyroid cancer, papillary thyroid cancer, follicular thyroid cancer, Hürtle cell carcinoma, and anaplastic thyroid cancer; nervous system : Skull (bone cancer, hemangioma, granuloma, xanthomas, osteitis degenerative), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, myeloblastoma, glioma, cerebral cortex-covering cytology, germ cell tumor [pineal tumor], glioblastoma pleomorphic, oligodendrocyte glioma, schwannoma, retinoblastoma, congenital cancer), spinal neurofibroma, meningioma, glioma, sarcoma); Gynecology: Uterus (endometrial cancer), cervix (cervical carcinoma, precancerous cervical dysplasia), ovary (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosauric follicle-cell carcinoma, Sertoli-Leydig cell carcinoma, ovarian testicoma, malignant teratoma), vulva (squamous cell carcinoma, epithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, staphylocortic sarcoma [embryonic rhabdomyosarcoma]), fallopian tube (carcinoma); hematology : Blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin lymphoma [malignant lymphoma]; skin : Malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, atypical pigmented nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and check : Neuroblastoma. Accordingly, the term "cancerous cell" provided herein includes a cell afflicted with any of the aforementioned pathological conditions.

[0135] "Pharmaceuticalally acceptable salts" include "pharmaceutically acceptable acid addition salts" and "pharmaceutically acceptable base addition salts." "Pharmaceutically acceptable acid addition salts" refer to salts formed by inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvate, oxalic acid, maleic acid, malonsine, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc., which possess the biological effects of a free base and are not biologically or otherwise undesirable.

[0136] "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, etc. Exemplary salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, naturally occurring substituted amines, cyclic amines, and salts of primary, secondary, and tertiary amines and substituted amines, including basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamin, choline, betaine, ethylenediamine, glucosamine, methylglucarmin, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, for example, SM Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19, incorporated herein by reference.)

[0137] As used herein, the term "compound" includes all stereoisomers, geometric isomers, tautomers, and isotopes of the described structure. The term also refers to the compounds of the present invention regardless of the method by which they are prepared, for example, by synthesis, by biological processes (e.g., metabolism or enzymatic conversion), or a combination thereof.

[0138] The compounds of the present invention may also include all isotopes of atoms occurring within the intermediate or final compound. Isotopes include atoms having the same number of atoms but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0139] Any one of the process steps or sequences disclosed and / or claimed herein may be carried out under an inert gas atmosphere, particularly under argon or nitrogen. Additionally, the method of the present invention may be carried out as a semi-continuous or continuous process, more preferably as a continuous process.

[0140] In addition, many of the process steps and sequences described here can be shortened.

[0141] In general, the nomenclature used in this application is based on the nomenclature rules adopted by the International Union of Pure and Applied Chemistry (IUPAC). The chemical structures depicted herein were fabricated using CHEMDRAW®. Here, open valence appearing on carbon, oxygen, or nitrogen atoms within the structure indicates the presence of a hydrogen atom.

[0142] Specific examples of the present invention

[0143] One aspect is a compound of chemical formula A:

[0144]

[0145] A

[0146] Or provide a pharmaceutically acceptable salt thereof, wherein the variables and substituents in Formula A are as defined in the summary of the present invention.

[0147] In one specific example of this aspect, the compound of formula A is the compound of formula A-1.

[0148]

[0149] A-1

[0150] In another specific example of this aspect, the compound of formula A is the compound of formula A-2.

[0151]

[0152] A-2

[0153] In a further embodiment of this aspect, the compound of formula A is the compound of formula A-3:

[0154]

[0155] A-3

[0156] Here, R a1 is -H or (C 1- C6) It is an alkyl.

[0157] In an additional embodiment, R1 in the compound of formula A-3 is -H.

[0158] In a further embodiment of this aspect, the compound of formula A is the compound of formula A-4:

[0159]

[0160] A-4

[0161] Here, ring A is a 5- to 14-membered heteroaryl; and subscript r is 1, 2, 3, or 4.

[0162] In this specific example, R2 is -H.

[0163] In additional embodiments, r in chemical formula A-4 is 1 or 2.

[0164] In a further embodiment of Formula A: R1 is -H, optionally substituted (C1-C6) alkyl, halo, -OR a , -NO2, -NH2, -NHR a , -NR a R a , -SR a , -SOR a , or -S(O)2R a And, R2 is (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C 10 ) Aryl, ( C3-C 10 ) Cycloalkyl, -CN, -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)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(=NOR a )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)2R a , -NR a S(O)2NR a R a , -S(O)R a , -S(O)NR a R a , -S(O)2R a , -S(O)2NR a C(O)R a , -P(O)R a R a , -P(O)(OR a )(OR a ), -B(OH)2, -B(OR a )2, 및 -S(O)2NR a R aIt is selected from a group consisting of.

[0165] In one embodiment of this embodiment, R1 is -H.

[0166] In additional embodiments: R1 is (C2-C6) alkenyl, (C2-C6) alkenyl, (C6-C 10 ) Aryl, ( C3-C 10 ) Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, -CN, -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)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(=NOR a )R 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 , -NRa S(O)2R a , -NR a S(O)2NR a R a , -S(O)R a , -S(O)NR a R a , -S(O)2R a , -S(O)2NR a C(O)R a , -P(O)R a R a , -P(O)(OR a )(OR a ), -B(OH)2, -B(OR a ) 2, 및 -S(O)2NR a R a Selected from a group consisting of; and

[0167] R2 is -H, optionally substituted (C1-C6) alkyl, halo, -OR a , -NO2, -NH2, -NHR a , -NR a R a , -SR a , -SOR a , or -S(O)2R a am.

[0168] In one embodiment of this specific example, R2 is -H.

[0169] In another specific example:

[0170] R1 is (C2-C6) alkenyl, (C2-C6) alkenyl, (C6-C 10 ) Aryl, ( C3-C 10 ) Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, -CN, -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)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(=NOR a )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)2R a , -NR a S(O)2NR a R a , -S(O)R a , -S(O)NR a R a , -S(O)2R a , -S(O)2NR a C(O)R a , -P(O)R a R a , -P(O)(OR a )(OR a ), -B(OH)2, -B(OR a )2, 또는 -S(O)2NR a R a ; 그리고

[0171] R2 is -H, halo, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C 1- C6) haloalkyl, (C 1- C6) Haloalkoxy, (C6-C 10 ) Aril-(C 1- C4) Alkylene-, (C3-C 10 ) Cycloalkyl-(C 1- C4) Alkylene-, (5-14 atom heteroaryl)-(C 1- C4) Alkylene-, (4-14 cyclic heterocycloalkyl)-(C 1- C4) Alkylene-, -CN, -NO2, -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 , -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(=NOR a )R a , -C(=NCN)NRa 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)2R a , -NR a S(O)2NR a R a , -S(O)R a , -S(O)NR a R a , -S(O)2R a , -S(O)2NR 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)2NR a R a It is selected from a group consisting of.

[0172] In one embodiment of this specific example, R2 is -H.

[0173] In another specific example:

[0174] R1 is -H, halo, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C 1- C6) haloalkyl, (C 1- C6) Haloalkoxy, (C6-C 10 ) Aryl, ( C3-C 10 ) Cycloalkyl, 5-14 ecumenical, 4-14 ecumenical heterocycloalkyl, (C6-C 10 ) Aril-(C1- C4) Alkylene-, (C3-C 10 ) Cycloalkyl-(C 1- C4) Alkylene-, (5-14 atom heteroaryl)-(C 1- C4) Alkylene-, (4-14 cyclic heterocycloalkyl)-(C 1- C4) Alkylene-, -CN, -NO2, -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 , -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(=NOR a )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(=NRa )NR a R a , -NR a S(O)R a , -NR a S(O)2R a , -NR a S(O)2NR a R a , -S(O)R a , -S(O)NR a R a , -S(O)2R a , -S(O)2NR 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)2NR a R a Selected from a group consisting of; and

[0175] In one embodiment of this embodiment, R1 is -H.

[0176] In another additional specific example:

[0177] R1 and R2 bond together with the atoms to which they are attached to form a fused (C3-C7) cycloalkyl ring or a fused 4- to 10-membered heterocycloalkyl ring; wherein the fused (C 3- C7) The cycloalkyl ring or fused 4- to 10-membered heterocycloalkyl ring is one, two, or three independently selected R b Each is optionally substituted with a substituent, provided that the compound is not 1-[2-(4-fluoro-phenyl)-acetyl]-cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododeca[b]naphthalene-4-yloxy)-phenyl]-amide.

[0178] In additional embodiments: R1 and R2 bond together with the atoms to which they are attached to form a fused (C3-C7) cycloalkyl ring or a fused 4- to 10-membered heterocycloalkyl ring, wherein the fused (C 3- C7) The cycloalkyl ring or fused 4- to 10-membered heterocycloalkyl ring is one, two, or three independently selected R b Each is arbitrarily substituted with a substituent, provided that the above compounds are not compounds having the following chemical formula:

[0179]

[0180] Here, ring E is a fused 4- to 10-membered heterocycloalkyl.

[0181] In another embodiment, R1 in the compound of formula A, A-1, or A-3, or A-4 is -H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -C(=NO-(C 1- C6) Alkyl)R a , -CN, -C(O)OR a , -C(O)NR a R a , -C(O)NHOR a , -S(O)2NR a R a , phenyl, 5- to 6-membered heteroaryl, (C 3- C6) Selected from the group consisting of cycloalkyl, and 4- to 6-membered heterocycloalkyl.

[0182] In another embodiment, R1 is -H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -C(=NO-(C 1- C6) Alkyl)R a , -CN, -C(O)OR a , -C(O)NR a R a , -C(O)NHOR a , -S(O)2NR a R a, phenyl, 5- to 6-membered heteroaryl, (C 3- C6) Selected from the group consisting of cycloalkyl, and 4- to 6-membered heterocycloalkyl; and

[0183] R2 is H, an optionally substituted (C1-C6) alkyl, halo, -OR a , -NO2, -NH2, -NHR a , -NR a R a , -SR a , -SOR a , or -S(O)2R a am.

[0184] In another embodiment, R1 is -H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -C(=NO-(C 1- C6) Alkyl)R a , -CN, -C(O)OR a , -C(O)NR a R a , -C(O)NHOR a , -S(O)2NR a R a , phenyl, 5- to 6-membered heteroaryl, (C 3- C6) Cycloalkyl: selected from the group consisting of 4- to 6-membered heterocycloalkyls; and

[0185] R2 is -H, halo, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C 1- C6) haloalkyl, (C 1- C6) Haloalkoxy, (C6-C 10 ) Aryl, ( C3-C 10 ) Cycloalkyl, (C6-C 10 ) Aril-(C 1- C4) Alkylene-, (C3-C 10 ) Cycloalkyl-(C 1- C4) Alkylene-, (5-14 atom heteroaryl)-(C 1- C4) Alkylene-, (4-14 cyclic heterocycloalkyl)-(C 1- C4) Alkylene-, -CN, -NO2, -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 , -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(=NOR a )R 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)2Ra , -NR a S(O)2NR a R a , -S(O)R a , -S(O)NR a R a , -S(O)2R a , -S(O)2NR a C(O)R a , -P(O)R a R a , -P(O)(OR a )(OR a ), -B(OH)2, -B(OR a ) 2; 그리고 -S(O)2NR a R a It is selected from a group consisting of.

[0186] In another embodiment, R1 is -H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -C(=NO-(C 1- C6) Alkyl)R a , -CN, -C(O)OR a , -C(O)NR a R a , -C(O)NHOR a , -S(O)2NR a R a , phenyl, 5- to 6-membered heteroaryl, -(C 3- C6) Selected from the group consisting of cycloalkyl, and 4- to 6-membered heterocycloalkyl; and

[0187] R2 is (C2-C6) alkenyl, (C2-C6) alkenyl, -CN, -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)NR a R a , -NR a C(O)Ra , -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(=NOR a )R 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)2R a , -NR a S(O)2NR a R a , -S(O)R a , -S(O)NR a R a , -S(O)2R a , -S(O)2NR a C(O)R a , -P(O)R a R a , -P(O)(OR a )(OR a ), -B(OH)2, -B(OR a )2, or -S(O)2NR a R a am.

[0188] In an additional embodiment, R1 is -H, R a NHC(O)-, R a OC(O)-, (C 1- C6) Alkyl, (C 1- C6) Alkoxy, or -C(=NO-CH3)R a And, R2 is selected from 2-methoxyethylamino, azetidine-1-yl, methylamino, 3-morpholinopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, propoxy, 2-hydroxypropoxy, methoxycarbonyl, carboxy, carbamoyl, methylcarbamoyl, (2-hydroxyethoxy)carbamoyl, (2,2-dihydroxyethoxy)carbamoyl, (oxetane-3-yloxy)carbamoyl, methoxycarbamoyl, 2-trimethylsilylethynyl, ethinyl, sulfamoyl, acetyl, and -C(=NOCH3)CH3.

[0189] In additional embodiments of chemical formulas A and A-2, and R2 is -H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -C(=NO-(C 1- C6) Alkyl)R a , -CN, -C(O)OR a , -C(O)NR a R a , -C(O)NHOR a , and -S(O)2NR a R a It is selected from a group consisting of.

[0190] In additional embodiments, R1 is -H, optionally substituted (C1-C6) alkyl, halo, -OR a , -NO2, -NH2, -NHR a , -NR a R a , -SR a , -SOR a , or S(O)2R a And,

[0191] R2 is -H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -C(=NO-(C 1- C6) Alkyl)R a , -CN, -C(O)OR a , -C(O)NR a R a, -C(O)NHOR a , -S(O)2NR a R a , phenyl, and (C 3- C6) Selected from the group consisting of cycloalkyl groups.

[0192] In additional embodiments, R1 is -H, optionally substituted (C1-C6) alkyl, halo, -OR a , -NO2, -NH2, -NHR a , -NR a R a , -SR a , -SOR a , and -S(O)2R a Selected from a group consisting of,

[0193] R2 is -H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -C(=NO-(C 1- C6) Alkyl)R a , -CN, -C(O)OR a , -C(O)NR a R a , -C(O)NHOR a , -S(O)2NR a R a It is selected from a group consisting of.

[0194] In additional embodiments, R1 is a (C2-C6) alkenyl, (C2-C6) alkenyl, (C6-C 10 ) Aryl, ( C3-C 10 ) Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, -CN, -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)NR a R a , -NRa 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(=NOR a )R 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)2R a , -NR a S(O)2NR a R a , -S(O)R a , -S(O)NR a R a , -S(O)2R a , -S(O)2NR a C(O)R a , -P(O)R a R a , -P(O)(OR a )(OR a ), -B(OH)2, -B(OR a ) 2, 및 -S(O)2NR a R a Selected from a group consisting of; and

[0195] R2 is -H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -C(=NO-(C 1- C6) Alkyl)R a , -CN, -C(O)OR a , -C(O)NR a R a , -C(O)NHOR a , -S(O)2NR a R a It is selected from a group consisting of.

[0196] In additional embodiments, R1 is -H, halo, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C 1- C6) haloalkyl, (C 1- C6) Haloalkoxy, (C6-C 10 ) Aryl, ( C3-C 10 ) Cycloalkyl, 5-14 ecumenical, 4-14 ecumenical heterocycloalkyl, (C6-C 10 ) Aril-(C 1- C4) Alkylene-, (C3-C 10 ) Cycloalkyl-(C 1- C4) Alkylene-, (5-14 atom heteroaryl)-(C 1- C4) Alkylene-, (4-14 cyclic heterocycloalkyl)-(C 1- C4) Alkylene-, -CN, -NO2, -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)NRa 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(=NOR a )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)2R a , -NR a S(O)2NR a R a , -S(O)R a , -S(O)NR a R a , -S(O)2R a , -S(O)2NR a C(O)R a , -P(O)R a R a , -P(O)(OR a )(OR a ), -B(OH)2, -B(OR a ) 2, 및 -S(O)2NR a R aSelected from a group consisting of; and

[0197] R2 is -H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -C(=NO-(C 1- C6) Alkyl)R a , -CN, -C(O)OR a , -C(O)NR a R a , -C(O)NHOR a , -S(O)2NR a R a It is selected from a group consisting of.

[0198] In additional embodiments, R1 is 2-methoxyethylamino, azetidine-1-yl, methylamino, 3-morpholinopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, propoxy, 2-hydroxypropoxy, methoxycarbonyl, carboxy, carbamoyl, methylcarbamoyl, 2-oxazolyl, pyrazole-3-yl, pyrazole-4-yl, 4-isoxazolyl, 3,5-dimethylisoxazol-4-yl, 1-methyl-pyrazole-4-yl, 2-methyl-pyrazole-3-yl, 2-ethyl-pyrazole-3-yl, 2-(2-hydroxyethyl)-pyrazole-3-yl, 2-(2,2,2-trifluoroethyl)-pyrazole-3-yl, 2-(2-fluoroethyl)-pyrazole-3-yl, Selected from the group consisting of 2-(2,2-difluoroethyl)-pyrazole-3-yl, 2-trifluoromethyl-pyrazole-3-yl, 2-difluoromethyl-pyrazole-3-yl, 1-methyl-imidazole-4-yl, 1-methyl-imidazole-2-yl, 1H-imidazole-2-yl, (2-hydroxyethoxy)carbamoyl, (2,2-dihydroxyethoxy)carbamoyl, (oxetane-3-yloxy)carbamoyl, methoxycarbamoyl, 2-trimethylsilylethynyl, ethinyl, 1,3,4-oxadiazole-3-yl, 1H-1,2,3-triazole-5-yl, sulfamoyl, acetyl, and -C(=NOCH3)CH3; and

[0199] R2 is -H, -R a NHC(O)-, -R a OC(O)-, (C 1- C6) Alkyl, (C 1- C6) Alkoxy, or -C(=NO-CH3)R a am.

[0200] In an additional embodiment of chemical formula A-4, the subscript r is 1 or 2.

[0201] In additional embodiments of the above aspects and embodiments, R 10 and R 11 are each -H.

[0202] In the additional embodiments of the above aspects and embodiments, the subscript n is 1.

[0203] In the additional embodiments of the above aspects and embodiments, the subscript m is 1.

[0204] In the additional embodiments of the above aspects and embodiments, the subscript p is 1.

[0205] Another specific example, the compound of formula A is the compound of formula B:

[0206]

[0207] B

[0208] or its pharmaceutically acceptable salt, where R1 and R2 are as defined in (i), (ii), or (iii) of Formula A; and R3, R 10 , R 11 , R 14 , R4, n, p, m, and Y are defined as follows:

[0209] Each R3 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-C6alkyl)2, and (C3-C6) cycloalkyl, wherein the (C3-C6) cycloalkyl is optionally substituted;

[0210] Each R10 and R 11 is independently selected from the group consisting of -H, (C1-C6) alkyl, (C1-C6) alkoxy, and (C1-C6) haloalkoxy;

[0211] Each R 14 -halo, -OH, -NH2, -CN, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -COOH, -NH(C1-C6)alkyl, -N(C1-C6alkyl)2, phenyl, phenyl-(C 1- C2) Alkylene, (C 3- C6) cycloalkyl, (C 3- C6) Cycloalkyl-(C 1- C4) Alkylene-, 4- to 6-membered heterocycloalkyl, (4- to 6-membered heterocycloalkyl)-(C 1- C4) Alkylene-, 5- to 6-membered heteroaryl, (5- to 6-membered heteroaryl)-(C 1- C4) Alkylene-, and -OR e Independently selected from a group consisting of, where R 14 of (C1-C6) alkyl, phenyl, phenyl-(C 1- C2) Alkylene, (C 3- C6) cycloalkyl, (C 3- C6) Cycloalkyl-(C 1- C4) Alkylene-, 4- to 6-membered heterocycloalkyl, (4- to 6-membered heterocycloalkyl)-(C 1- C4) alkylene-, 5- to 6-membered heteroaryl, and (5- to 6-membered heteroaryl)-(C 1- C4) Alkylene- are each optionally substituted;

[0212] Each R4 is independently selected from -H, halo, -OH, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, and (C1-C6) haloalkoxy, wherein the (C1-C6) alkyl is each independently optionally substituted with (C1-C6) alkoxy, (C1-C6) haloalkyl, and (C1-C6) haloalkoxy.

[0213] Each R a -H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C6-C 10 ) Aryl, ( C3-C 10 ) Cycloalkyl, 5-14 ecumenical, 4-14 ecumenical heterocycloalkyl, (C6-C 10 ) Aril-(C 1- C4) Alkylene-, (C3-C 10 ) Cycloalkyl-(C 1- C4) Alkylene-, (5-14 atom heteroaryl)-(C 1- C4) Alkylene-, and (4-14 valent heterocycloalkyl)-(C 1- C4) Independently selected from alkylene-, wherein (C1-C6) alkyl, (C1-C6) haloalkyl, (C6-C 10 ) Aryl, ( C3-C 10 ) Cycloalkyl, 5-14 ecumenical, 4-14 ecumenical heterocycloalkyl, (C6-C 10 ) Aril-(C 1- C4) Alkylene-, (C3-C 10 ) Cycloalkyl-(C 1- C4) Alkylene-, (5-14 atom heteroaryl)-(C 1- C4) Alkylene-, and (4-14 valent heterocycloalkyl)-(C 1-C4) Alkylene- are each independently and arbitrarily substituted;

[0214] n, p, and m are each independently integers from 0 to 3; and

[0215] Y is -O-, -S-, -SO-, -SO2-, -NH-, and -N((C 1- It is selected from C6) alkyl)-.

[0216] In one embodiment of chemical formulas A and B:

[0217] (i) R1 is selected from the following groups:

[0218] (C2-C6) alkenyl, (C2-C6) alkenyl, (C6-C 10 ) Aryl, ( C3-C 10 ) Cycloalkyl, 5-10-membered heteroaryl, and 4-10-membered heterocycloalkyl, where (C2-C6) alkenyl, (C2-C6) alkenyl, (C6-C 10 ) Aryl, ( C3-C 10 ) Cycloalkyl, 5-10-membered heteroaryl, and 4-10-membered heterocycloalkyl are each independently and optionally substituted,

[0219] -CN, -P(O)R a R a , P(O)(OR a )2, B(OH)2, B(OR a )2,

[0220] X2R a , where X2 is -NHO-, -NH-S(O)-, -N-(C1-C6)alkyl-S(O)-, -NH-S(O)2-, -N-(C1-C6)alkyl-S(O)2R a -, -NH-S(O)-NH-, -N-(C1-C6) alkyl-S(O)NH-, -NH-S(O)2NH-, -N-(C1-C6) alkyl-S(O)2NH-, -S(O)2NHC(O)-, and

[0221] Here " " indicates the attachment point, where:

[0222] Y1 is absent, or -NH-, -N-(C1-C6) alkyl-, or -O-,

[0223] Y2 is absent, or -O-, -NH-, -NHO-, -N-(C1-C6) alkyl-, -N2H2-, -NH-S(O)-, or -NH-S(O)2-; or

[0224] Y2 is arbitrarily substituted, where " " indicates an attachment point, where ring A is a 3, 4, 5, 6, or 7-circle ring; and

[0225] Z 1 ≠ O, NH, N-(C1-C6) alkyl, NOH, NO-(C1-C6) alkyl, or NCN; and

[0226] R2 is:

[0227] - A gi selected from the group consisting of -H or the following:

[0228] (C1-C6) Alkyl, Halo, -NO 2, and X1R a , where X1 is -O-, -S-, -SO-, -SO2-, -SO2NH-, -SO2NR a -, -NH-, and -N-(C1-C6) alkyl-, where the (C1-C6) alkyl is optionally substituted.

[0229] In another specific example of A and B:

[0230] (ii) R1 is selected from the following groups:

[0231] (C2-C6) alkenyl, (C2-C6) alkenyl, (C6-C 10 ) Aryl, ( C3-C 10 ) Cycloalkyl, 5-10-membered heteroaryl, and 4-10-membered heterocycloalkyl, where (C2-C6) alkenyl, (C2-C6) alkenyl, (C6-C 10 ) Aryl, ( C3-C 10 ) The cycloalkyl, 5-14-membered heteroaryl, and 4-14-membered heterocycloalkyl are each independently and optionally substituted;

[0232] P(O)R a R a , P(O)(OR a )(OR a ), B(OH)2, B(OR a )2, CN,

[0233] X2R a , where X2 is -NHO-, -NH-S(O)-, -N-(C1-C6)alkyl-S(O)-, -NH-S(O)2-, -N-(C1-C6)alkyl-S(O)2R a -, -NH-S(O)-NH-, -N-(C1-C6) alkyl-S(O)NH-, -NH-S(O)2NH-, -N-(C1-C6) alkyl-S(O)2NH-, -S(O)-, -S(O)2-, -S(O)2NHC(O), and

[0234] , here:

[0235] Y1 is absent, or -NH-, -N-(C1-C6) alkyl-, or -O-,

[0236] Y2 is absent, or -O-, -NH-, -NHO-, -N-(C1-C6) alkyl-, -N2H2-, -NH-S(O)-, or -NH-S(O)2, or

[0237] Y2 is arbitrarily substituted , here " " indicates an attachment point, where ring A is a 3, 4, 5, 6, or 7-circle ring;

[0238] Z 1-O-, -NH-, -N-(C1-C6) alkyl-, -NOH-, -NO-(C1-C6) alkyl-, or -NCN-; and

[0239] R2 is selected from the following group:

[0240] H, halo, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C 1- C6) haloalkyl, (C 1- C6) Haloalkoxy, (C6-C 10 ) Aril-(C 1- C4) Alkylene-, (C3-C 10 ) Cycloalkyl-(C 1- C4) Alkylene-, (5-14 atom heteroaryl)-(C 1- C4) Alkylene-, and (4-14 cyclic heterocycloalkyl)-(C 1- C4) Alkylene-, where (C2-C6) alkenyl, (C2-C6) alkenyl, (C 1- C6) haloalkyl, (C 1- C6) Haloalkoxy, (C6-C 10 ) Aryl, ( C3-C 10 ) Cycloalkyl, (C6-C 10 ) Aril-(C 1- C4) Alkylene-, (C3-C 10 ) Cycloalkyl-(C 1- C4) Alkylene-, (5-14 atom heteroaryl)-(C 1- C4) Alkylene-, and (4-14 cyclic heterocycloalkyl)-(C 1- C4) Alkylene- are each independently and arbitrarily substituted,

[0241] CN, NO2, P(O)R aR a , P(O)(OR a )(OR a ), B(OH)2, B(OR a )2,

[0242] X1R a , where X1 is -O-, -S-, -NH-, or -N-(C1-C6)-, -NHO-, -NH-S(O)-, -N-(C1-C6)alkyl-S(O)-, -NH-S(O)2-, -N-(C1-C6)alkyl-S(O)2-, -NH-S(O)-NH-, -N-(C1-C6)alkyl-S(O)NH-, -NH-S(O)2NH-, -N-(C1-C6)alkyl-S(O)2NH-, -S(O)2NHC(O)-, -NH-S(O)R a -, -N-(C1-C6) alkyl-S(O)R a -, -NH-S(O)2R a -, -N-(C1-C6) alkyl-S(O)2R a -, and

[0243] , here:

[0244] Y1 is absent or -NH-, -N-(C1-C6) alkyl-, or -O-;

[0245] Y2 is absent or -O-, -NH-, -NHO-, -N-(C1-C6) alkyl-, -N2H2-, -NH-S(O)-, or -NH-S(O)2-, or

[0246] Y2 is arbitrarily substituted , where ring A is a 3, 4, 5, 6, or 7-one ring and here " " indicates the attachment point; and

[0247] Z 1 is O, NH, N-(C1-C6) alkyl, NOH, NO-(C1-C6) alkyl, or NCN.

[0248] In another specific example of A and B:

[0249] (iii) R1 and R2 bond together with the atoms to which they are attached to form a 4- to 10-membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of halo, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, -CN, -OH, -NH2, provided that the compound is not 1-[2-(4-fluoro-phenyl)-acetyl]-cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododeca[b]naphthalene-4-yloxy)-phenyl]-amide.

[0250] In additional embodiments of compounds of chemical formulas A and B:

[0251] R1 is -H, -CN, (C1-C6) alkyl, (C3-C 10 ) Cycloalkyl, (C6-C 10 ) Aryl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, -S(O)2NHR a , -P(O)R a R a , -OR a , or

[0252] , here " " indicates the attachment point, where:

[0253] Y1 is absent or -NH-, -N-(C1-C6) alkyl-, or -O-;

[0254] Y2 is absent or -O-, -NH-, -NHO-, -N-(C1-C6) alkyl-, -NH-NH-, -NH-S(O)-, or NH-S(O)2; and

[0255] Z 1 is -O, -NH, -N-(C1-C6) alkyl, -N-OH, or -NO(C1-C6)alkyl.

[0256] In another embodiment of chemical formulas A and B:

[0257] R2 is -H, Halo, -X1R a , (C2-C6) alkenyl, (C2-C6) alkenyl, or

[0258] Here " " indicates the attachment point, where:

[0259] Y1 is absent or NH, N-(C1-C6) alkyl, or O;

[0260] Y2 is absent or O, NH, NHO, N-(C1-C6) alkyl, N2H2, NH-S(O), or NH-S(O)2; and

[0261] Z 1 is -O, -NH, -N-(C1-C6) alkyl, -NOH-, or -NO(C1-C6)alkyl.

[0262] In another specific example of A and B, R3 is -H or halo.

[0263] In another specific example of A and B, R4 is -H or halo.

[0264] In another embodiment of A and B, where R 14 is -H or halo.

[0265] In another specific example of A and B, Y is -O-.

[0266] In another embodiment, the compound of B is a compound of the chemical formula B-1 or B-2:

[0267]

[0268] B-1

[0269]

[0270] B-2

[0271] also is his pharmaceutically acceptable salt.

[0272] In one embodiment of chemical formula B-1:

[0273] Ra1 is an optionally substituted (C1-C6) alkyl;

[0274] R1 is -H, -CN, optionally substituted 3-6 member cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 member heterocycloalkyl, optionally substituted 5-6 member heteroaryl, -SO2-(C1-C6) alkyl, -SO2NH2, -SO2-NH(C1-C6) alkyl, P(O)((C1-C6) alkyl)2, or

[0275] Here " " indicates the attachment point, where:

[0276] Y1 is absent;

[0277] Y2 is absent or -O-, -NH-, -NHO-, -NH-NH-, -N-(C1-C6) alkyl-; or

[0278] Y2 is arbitrarily substituted , where ring A is a 3, 4, 5, 6, or 7-one ring, where " " indicates the attachment point;

[0279] Z 1 is O, NH, N-(C1-C6) alkyl, NHO, or NO-(C1-C6) alkyl; and

[0280] R a -H, -(C1-C6) alkyl, 4-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, -(C2-C6) alkylene-OH, -CH2CHOH-(C2-C6) alkylene-OH, -(C2-C6) alkylene-NH2, -(C2-C6) alkylene-NH(C1-C6), -(C2-C6) alkylene-N(C1-C6)2, or -(C2-C6) alkylene-N-(4-6-membered heterocycloalkyl);

[0281] In another specific example of chemical formula B-1:

[0282] R a1 (C1-C6) alkyl;

[0283] R1 is - H, -CN, optionally substituted cyclopropyl, optionally substituted phenyl, optionally substituted 4-6 azetidinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted oxetanyl, optionally substituted oxazolyl, optionally substituted pyridinyl, optionally substituted imidazolyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted pyrazolyl, optionally substituted oxadiazolyl, -SO2-(C1-C6) alkyl, -SO2NH2, -SO2-NH(C1-C6) alkyl, or P(O)((C1-C6) alkyl)2; or

[0284] R1 is , here:

[0285] Y1 is absent;

[0286] Y2 is O, NH, NHO, NH-NH, or N-(C1-C6) alkyl; or

[0287] Y2 is arbitrarily substituted azetidinyl;

[0288] Z 1 is O, NH, or N-(C1-C6) alkyl; and

[0289] R a is H, (C1-C6) alkyl, -(C2-C6) alkylene-OH, -CH2CHOH-(C2-C6) alkylene-OH, -(C2-C6) alkylene-NH2, -(C2-C6) alkylene-NH(C1-C6) alkyl, -(C2-C6) alkylene-N((C1-C6) alkyl)2, -(C2-C6) alkylene-heterocycloalkyl), or 4-6 heterocycloalkyl, where the heterocycloalkyl is optionally substituted.

[0290] In one embodiment of chemical formula B-2:

[0291] R a2 is an optionally substituted (C1-C6) alkyl;

[0292] R2 is Here " " indicates the attachment point, where:

[0293] Y1 is absent;

[0294] Y2 is absent or -O- or -NH-; and

[0295] Z 1 is O; and

[0296] R a is -H or -(C1-C6) alkyl.

[0297] In another specific example of chemical formula B-2:

[0298] R a2 (C1-C6) alkyl;

[0299] R2 is , here " " indicates the attachment point, where:

[0300] Y1 is absent;

[0301] Y2 is absent or -O- or -NH-; and

[0302] Z 1 ⅓O or NO-(C1-C6) alkyl; and

[0303] R a is -H or -(C1-C6) alkyl.

[0304] In another embodiment of chemical formula B-1, R a1 It is methoxy.

[0305] In another specific example of chemical formula B-2, R a2 It is methoxy.

[0306] In another embodiment, the compound of formula B is a compound of formula B-3 or B-4:

[0307]

[0308] B-3

[0309]

[0310] B-4

[0311] Or it is his pharmaceutically acceptable salt.

[0312] In one embodiment of chemical formula B-3:

[0313] R1 is -H or (C1-C6) alkyl; and

[0314] Y1 is absent;

[0315] Y2 is absent or -O-, -NHO-, or -NH-; and

[0316] Z 1 ⅓O or NO-(C1-C6) alkyl; and

[0317] R a is -H or -(C1-C6) alkyl.

[0318] In another specific example of chemical formula B-3:

[0319] R1 is -H or methyl;

[0320] Y1 is absent;

[0321] Y2 is absent or -O-, -NHO-, or -NH-; and

[0322] Z 1 is O or NO-Me; and

[0323] R a is -H or Me.

[0324] In another specific example of chemical formula B-3:

[0325] R1 and R a is, together with the atoms to which they are attached,

[0326] It forms a 4-6 member heterocycloalkyl ring, (C1-C6) alkyl, or (C1-C6) haloalkyl optionally substituted with a halo.

[0327] In one embodiment of chemical formula B-4:

[0328] Y1 is absent;

[0329] Y2 is O, NH, NHO, NH-NH, or N-(C1-C6) alkyl; or

[0330] Y2 is arbitrarily substituted azetidinyl;

[0331] Z1 is O, NH, NO-(C1-C6) alkyl, or N-(C1-C6) alkyl; and

[0332] R a is H, (C1-C6) alkyl, -(C2-C6) alkylene-OH, -CH2CHOH-(C2-C6) alkylene-OH, -(C2-C6) alkylene-NH2, -(C2-C6) alkylene-NH(C1-C6) alkyl, -(C2-C6) alkylene-N((C1-C6) alkyl)2, -(C2-C6) alkylene-optional substituted 4-6 heterocycloalkyl), or optionally substituted 4-6 heterocycloalkyl;

[0333] R2 is -H, -F, -Cl, -Br, -(C1-C6)alkoxy, -O-(C2-C6)alkylene-OH, -O-(C2-C6)alkylene-O-(C1-C6alkyl), (C2-C6)alkylene-O-(C1-C6)alkyl, -NH2, -NH-(C1-C6alkyl), -NH-(C1-C6)alkylene-(optionally substituted 4-6 heterocycloalkyl), or -NH-(C2-C6)alkylene-O-(C1-C6alkyl).

[0334] In another specific example of chemical formula B-4:

[0335] Y1 is absent;

[0336] Y2 is O, NH, NHO, NH-NH, or N-(C1-C6) alkyl; or

[0337] Y2 is arbitrarily substituted azetidinyl;

[0338] Z 1 It is O, NH, NO-(C1-C6) alkyl, N-(C1-C6) alkyl; and

[0339] R a-H, methyl, ethyl, -(C2-C6)alkylene-OH, -CH2CHOH-(C2-C6)alkylene-OH, -(C2-C6)alkylene-NH2, -(C2-C6)alkylene-NHMe, -(C2-C6)alkylene-N(Me)2, -(C1-C6)alkylene-morpholinyl), -(C1-C6)alkylene-piperidinyl), (C1-C6)alkylene-(optionally substituted pyrrolidinyl), optionally substituted azetidinyl, or optionally substituted oxetanyl;

[0340] R2 is -H, -F, -Cl, -Br, methoxy, -O-(C2-C6)alkylene-OH, -O-(C2-C6)alkylene-OMe, -NH2, -NH-(C1-C6alkyl), -NH-(C2-C6)alkylene-OMe, -NH-(C2-C6)alkylene-(optionally substituted morpholinyl), or -NH-(C2-C6)alkylene-O-(C1-C6alkyl).

[0341] In another specific example of chemical formula B-4:

[0342] R2 and R a They form a 4-6 member heterocycloalkyl ring, (C1-C6) alkyl, or (C1-C6) haloalkyl that is optionally substituted with a halo, together with the atoms to which they are attached.

[0343] In another embodiment, the compound of formula B is the compound of formula B-5:

[0344]

[0345] B-5

[0346] or its pharmaceutically acceptable salt, wherein ring A in formula B-5 is an optionally substituted 5-6 member heteroaryl or aryl.

[0347] In one embodiment of chemical formula B-5:

[0348] Ring A is arbitrarily substituted (C6-C 10 ) Aryl, arbitrarily substituted (C3-C 10 ) Cycloalkyl, optionally substituted 5-10-membered heteroaryl, or optionally substituted 4-10-membered heterocycloalkyl; and

[0349] R2 is H, or (C1-C6)alkoxy.

[0350] In another specific example of chemical formula B-5:

[0351] Ring A is optionally substituted phenyl, optionally substituted cyclopropyl, optionally substituted pyridyl, optionally substituted imidazolyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, optionally substituted azetidinyl, or optionally substituted oxetanyl; and

[0352] R2 is H, or methoxy.

[0353] Another specific example of the compounds of chemical formulas A and B is the compound of chemical formula C:

[0354]

[0355] C

[0356] or his pharmaceutically acceptable salt, where:

[0357] Y1 is absent;

[0358] Y2 is O, NH, NHO, NH-NH, or N-(C1-C6) alkyl; or

[0359] Y2 is arbitrarily substituted azetidinyl;

[0360] Z is O, NH, NO-(C1-C6) alkyl, or N-(C1-C6) alkyl;

[0361] R a-H, (C1-C6) alkyl, -(C2-C6) alkylene-OH, -CH2CHOH-(C2-C6) alkylene-OH, -(C2-C6) alkylene-NH2, -(C2-C6) alkylene-NH(C1-C6) alkyl, -(C2-C6) alkylene-N((C1-C6) alkyl)2, -(C2-C6) alkylene-optional substituted 4-6 heterocycloalkyl), or optionally substituted 4-6 heterocycloalkyl;

[0362] R2 is -H, -F, -Cl, -Br, -(C1-C6)alkoxy, -O-(C2-C6)alkylene-OH, -O-(C2-C6)alkylene-O-(C1-C6alkyl), (C2-C6)alkylene-O-(C1-C6)alkyl, -NH2, -NH-(C1-C6alkyl), -NH-(C1-C6)alkylene-(optionally substituted 4-6 heterocycloalkyl), -NH-(C2-C6)alkylene-O-(C1-C6alkyl); and

[0363] n and m are each independently integers from 0 to 3.

[0364] In another specific example of chemical formula C:

[0365] Y1 is absent;

[0366] Y2 is O, NH, NHO, NH-NH, or N-(C1-C6) alkyl; or

[0367] Y2 is arbitrarily substituted azetidinyl;

[0368] Z 1 O, NH, NO-(C1-C6) alkyl, or N-(C1-C6) alkyl;

[0369] R a -H, methyl, ethyl, -(C2-C6)alkylene-OH, -CH2CHOH-(C2-C6)alkylene-OH, -(C2-C6)alkylene-NH2, -(C2-C6)alkylene-NHMe, -(C2-C6)alkylene-N(Me)2, -(C1-C6)alkylene-morpholinyl), -(C1-C6)alkylene-piperidinyl), (C1-C6)alkylene-(optionally substituted pyrrolidinyl), optionally substituted azetidinyl, or optionally substituted oxetanyl;

[0370] R2 is -H, -F, -Cl, -Br, methoxy, -O-(C2-C6)alkylene-OH, -O-(C2-C6)alkylene-OMe, -NH2, -NH-(C1-C6alkyl), -NH-(C2-C6)alkylene-OMe, -NH-(C2-C6)alkylene-(optionally substituted morpholinyl), or -NH-(C2-C6)alkylene-O-(C1-C6alkyl); and

[0371] and n and m are 0 or 1, respectively.

[0372] In another specific example of chemical formula C:

[0373] R2 and R a is, together with the atoms to which they are attached,

[0374] Forming a 4-6 member heterocycloalkyl ring optionally substituted with a halo, (C1-C6) alkyl, and (C1-C6) haloalkyl; and

[0375] n and m are each independently integers from 0 to 3.

[0376] Another specific example of chemical formula C is a compound of chemical formula C-1.

[0377]

[0378] C-1

[0379] or his pharmaceutically acceptable salt, where:

[0380] Y2 is O, NH, NHO, NH-NH, or N-(C1-C6) alkyl; or

[0381] Y2 is arbitrarily substituted azetidinyl;

[0382] Z 1 O, NH, NO-(C1-C6) alkyl, or N-(C1-C6) alkyl;

[0383] R a-H, methyl, ethyl, -(C2-C6)alkylene-OH, -CH2CHOH-(C2-C6)alkylene-OH, -(C2-C6)alkylene-NH2, -(C2-C6)alkylene-NHMe, -(C2-C6)alkylene-N(Me)2, -(C1-C6)alkylene-morpholinyl), -(C1-C6)alkylene-piperidinyl), (C1-C6)alkylene-(optionally substituted pyrrolidinyl), optionally substituted azetidinyl, or optionally substituted oxetanyl;

[0384] R2 is -H, -F, -Cl, -Br, methoxy, -O-(C2-C6)alkylene-OH, -O-(C2-C6)alkylene-OMe, -NH2, -NH-(C1-C6alkyl), -NH-(C2-C6)alkylene-OMe, -NH-(C2-C6)alkylene-(optionally substituted morpholinyl), or -NH-(C2-C6)alkylene-O-(C1-C6alkyl); and

[0385] and n and m are each independently 0 or 1.

[0386] Another specific example of chemical formulas A and B is a compound of chemical formula D:

[0387]

[0388] D

[0389] In one embodiment of chemical formula D:

[0390] R1 is -H or (C1-C6) alkyl; and

[0391] Y1 is absent;

[0392] Y2 is absent or -O-, -NHO-, or -NH-; and

[0393] Z 1 Silver O or NO-(C1-C6) alkyl;

[0394] R a is -H or -(C1-C6) alkyl; and

[0395] n and m are each independently integers from 0 to 3.

[0396] In another specific example of chemical formula D:

[0397] R1 is -H or methyl;

[0398] Y1 is absent;

[0399] Y2 is absent or -O-, -NHO-, or -NH-; and

[0400] Z 1 is O or NO-Me; and

[0401] R a is -H, or -Me.

[0402] n and m are each independently integers from 0 to 1.

[0403] In another specific example of chemical formula D:

[0404] R1 and R a is, together with the atoms to which they are attached,

[0405] A 4-6 alkyl ring optionally substituted with a halo, (C1-C6) alkyl, or (C1-C6) haloalkyl; and

[0406] n and m are each independently integers from 0 to 1.

[0407] Another specific example of chemical formula D is the compound of chemical formula D-1.

[0408]

[0409] D-1

[0410] Another specific example of chemical formulas A and B is a compound of chemical formula E:

[0411]

[0412] E

[0413] or his pharmaceutically acceptable salt, where:

[0414] Ring A is arbitrarily substituted (C6-C 10 ) Aryl, arbitrarily substituted (C3-C 10 ) Cycloalkyl, optionally substituted 5-10-membered heteroaryl, or optionally substituted 4-10-membered heterocycloalkyl; and

[0415] R2 is H or (C1-C6)alkoxy.

[0416] In another specific example of chemical formula E:

[0417] Ring A is optionally substituted phenyl, optionally substituted cyclopropyl, optionally substituted pyridyl, optionally substituted imidazolyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, optionally substituted azetidinyl, or optionally substituted oxetanyl; and

[0418] R2 is H or methoxy.

[0419] Another specific example of chemical formulas A and B is a compound of chemical formula F:

[0420]

[0421] F

[0422] or its pharmaceutically acceptable salt, where

[0423] R a1 is an optionally substituted (C1-C6) alkyl;

[0424] R1 is -H, -CN, optionally substituted 3-6 member cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 member heterocycloalkyl, optionally substituted 5-6 member heteroaryl, -SO2-(C1-C6) alkyl, -SO2NH2, -SO2-NH(C1-C6) alkyl, or P(O)((C1-C6) alkyl)2, or

[0425] Here " " indicates the attachment point, where:

[0426] Y1 is absent;

[0427] Y2 is absent or -O-, -NH-, -NHO-, -NH-NH-, -N-(C1-C6) alkyl-; or

[0428] Y2 is arbitrarily substituted , where ring A is a 3, 4, 5, 6, or 7-one ring, where " " indicates the attachment point;

[0429] Z 1 is O, NH, N-(C1-C6) alkyl, NHO, or NO-(C1-C6) alkyl; and

[0430] R a -H, -(C1-C6) alkyl, 4-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, -(C2-C6) alkylene-OH, -CH2CHOH-(C2-C6) alkylene-OH, -(C2-C6) alkylene-NH2, -(C2-C6) alkylene-NH(C1-C6), -(C2-C6) alkylene-N(C1-C6)2, -(C2-C6) alkylene-N-(4-6-membered heterocycloalkyl);

[0431] In another specific example of chemical formula F:

[0432] R a1 methyl;

[0433] R1 is - H, -CN, optionally substituted cyclopropyl, optionally substituted phenyl, optionally substituted 4-6 azetidinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted oxetanyl, optionally substituted oxazolyl, optionally substituted pyridinyl, optionally substituted imidazolyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted pyrazolyl, optionally substituted oxadiazolyl, -SO2-(C1-C6) alkyl, -SO2NH2, -SO2-NH(C1-C6) alkyl, or P(O)((C1-C6) alkyl)2; or

[0434] R1 is , here:

[0435] Y1 is absent;

[0436] Y2 is O, NH, NHO, NH-NH, or N-(C1-C6) alkyl; or

[0437] Y2 is arbitrarily substituted azetidinyl;

[0438] Z 1 is O, NH, or N-(C1-C6) alkyl; and

[0439] R a is H, (C1-C6) alkyl, -(C2-C6) alkylene-OH, -CH2CHOH-(C2-C6) alkylene-OH, -(C2-C6) alkylene-NH2, -(C2-C6) alkylene-NH(C1-C6) alkyl, -(C2-C6) alkylene-N((C1-C6) alkyl)2, -(C2-C6) alkylene-heterocycloalkyl), and 4-6 heterocycloalkyl, where the heterocycloalkyl is optionally substituted.

[0440] Another specific example of chemical formulas A and B is a compound of chemical formula G:

[0441]

[0442] G

[0443] or his pharmaceutically acceptable salt, where:

[0444] R a1 is an optionally substituted (C1-C6) alkyl;

[0445] R2 is , here " " indicates the attachment point, where:

[0446] Y1 is absent;

[0447] Y2 is absent or -O-, or -NH-; and

[0448] Z 1 is O; and

[0449] R a is -H or -(C1-C6) alkyl.

[0450] In another specific example of chemical formula G:

[0451] R a2 methyl;

[0452] R2 is , here " " indicates the attachment point, where:

[0453] Y1 is absent;

[0454] Y2 is absent or -O-, or -NH-; and

[0455] Z 1 ⅓O or NO-(C1-C6) alkyl; and

[0456] R a is -H, or -(C1-C6) alkyl.

[0457] Another embodiment of chemical formulas A and B is a compound for controlling kinase activity according to chemical formula H:

[0458]

[0459] H

[0460] or his pharmaceutically acceptable salt, where:

[0461] R1 is selected from the group consisting of -H, -CN, -CO-NR5R6, -CO2R7, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C8) cycloalkyl, optionally substituted (C3-C6) heterocycloalkyl, -SO2NR8R9, or -(SO2)(C1-C6) alkyl;

[0462] Herein, when R1 is selected from the group consisting of -CN, -CO-NR5R6, -CO2R7, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (C3-C8) cycloalkyl, optionally substituted (C3-C6) heterocycloalkyl, -SO2NR8R9, and -(SO2)-(C1-C6) alkyl, R2 is H, halo, NR5R6, or optionally substituted (C1-C6) alkoxy;

[0463] Here, when R1 is -H, an optionally substituted (C1-C6) alkyl, or an optionally substituted (C1-C6) alkoxy, R2 is -CO-NR5R6 or -CO2R7;

[0464] Or R1 and R2 bond together with the atoms to which they are attached to form an arbitrarily substituted cycloalkyl or an arbitrarily substituted heterocycloalkyl;

[0465] R3 is -H, arbitrarily substituted (C 1- C6) Selected from the group consisting of alkyl, -CN, and halo;

[0466] R4 is -H or Halo;

[0467] is optionally substituted with a 1, 2, 3, or 4 group independently selected from the group consisting of halos and (C1-C6) alkyls, where " " indicates an attachment point;

[0468] R5 and R6 are each independently -H; an optionally substituted (C1-C6) alkyl; or an optionally substituted C1-C6 alkoxy;

[0469] R7 is -H or optionally substituted (C1-C6) alkyl;

[0470] R8 and R9 are each independently -H or optionally substituted (C1-C6) alkyl; or

[0471] R8 and R9 can be connected to form an arbitrarily substituted heterocycle; and

[0472] Y is selected from the group consisting of O, S, SO, SO2, NH, and N-((C1-C6) alkyl).

[0473] In one embodiment of the compound of chemical formula I, Y is O.

[0474] In another specific example, R3 is -H.

[0475] In another specific example, is not substituted.

[0476] In another specific example, R4 is a halo.

[0477] In another specific example, R4 is parafluoro.

[0478] In another embodiment, R2 is -H, halo, or an optionally substituted (C1-C6)-alkoxy.

[0479] In another specific example, R1 is -CN.

[0480] In another specific example, R1 is -CO2H.

[0481] In another specific example, R1 is -CO2-Me.

[0482] In another specific example, R1 is -CO-NHR6.

[0483] In another specific example, R1 is -CO-NH2.

[0484] In another specific example, R1 is -CO-NMeR6.

[0485] In another specific example, R3 is -H or halo.

[0486] In another specific example, R1 is -CN, -(SO2)NH2, -OMe, -(SO2)CH3 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and Selected from a group consisting of, where " " is an attachment point.

[0487] In another specific example, R1 is , , , , , , , , , and Selected from a group consisting of, where " " is an attachment point.

[0488] In another specific example, R1 is , , , , , , , , , , , , Selected from a group consisting of, where " " is an attachment point.

[0489] In another specific example, R2 is -H, -CN, -Br, -F, -Cl, -OMe, -CH3, , , , , -CH2NH2, NH2, NHMe, , , , and Selected from a group consisting of, where " " is an attachment point.

[0490] In another embodiment, R1 is -H, methyl, or methoxy.

[0491] In another specific example, R2 is -CO2H.

[0492] In another specific example, R1 is -CO2-Me.

[0493] In another specific example, R1 is -CO-NHR6.

[0494] In another specific example, R1 is -CO-NH2.

[0495] In another specific example, R1 is -CO-NMeR6.

[0496] In another specific example, R1 is , , , and It is selected from a group consisting of.

[0497] In another embodiment, R1 and R2 are combined together formed.

[0498] In an additional embodiment, the compound of formula I is the compound of formula I-1:

[0499]

[0500] I-1

[0501] Here, R6 is (C 1- C6) alkyl, R2 is (C 1- C6) Alkoxy, R3 is -H or halo, and R4 is halo.

[0502] In another aspect, the present invention provided a compound of formula A or AI provided in Table 1 below.

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527] or his pharmaceutically acceptable salt.

[0528] General administration

[0529] The compound of the present invention, or a pharmaceutically acceptable salt thereof, in its pure form or as a suitable pharmaceutical composition, may be administered via any route of administration or substance to produce similar utility. Thus, it may be administered, for example orally, intranasally, parenterally (intravenously, intramuscularly, or subcutaneously), topically, transdermally, vaginally, intravesically, saccharically, or rectally, in the form of a solid, semi-solid, lyophilized powder, or liquid dosage form, e.g., tablets, suppositories, pills, soft and hard gelatin capsules, powders, solutions, suspensions, aerosols, etc., preferably in the form of a unit dosage suitable for simple administration of an accurate dosage.

[0530] The composition may include a conventional pharmaceutical carrier or excipient and the compound of the present invention as the active substance, and may also include other medicinal substances, pharmaceutical substances, carriers, adjuvants, etc. The composition of the present invention may be used in combination with anticancer agents or other substances generally administered to patients undergoing cancer treatment. Adjuvants include preservatives, humectants, suspending agents, sweeteners, flavoring agents, fragrances, emulsifiers, and dispersants. Prevention of microbial action may be ensured by various antibacterial and antifungal agents, e.g., parabens, chlorobutanol, phenol, sorbic acid, etc. Additionally, it may be preferable to include isotonic agents, e.g., sugars, syl chlorides, etc. Prolongation of absorption in the injectable pharmaceutical form may be achieved by absorption retardants, e.g., aluminum monostearate and gelatin.

[0531] If necessary, the pharmaceutical composition of the present invention may also contain a small amount of auxiliary substances, such as humectants or emulsifiers, pH buffers, antioxidants, etc., such as citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.

[0532] Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters, such as ethyl oleate. Suitable fluidity may be maintained by the use of a coating, such as lecithin, for example, by maintaining the required particle size in the case of dispersions, and by the use of a surfactant.

[0533] One preferred route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the severity of the disease condition to be treated.

[0534] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound comprises one or more inert functional excipients (or carriers), such as sodium citrate or dicalcium phosphate, or (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as cellulose derivatives, starch, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia; (c) humectants, such as glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, sodium croscarmellose, complex silicates, and sodium carbonate; (e) dissolution retardants, such as paraffin; (f) absorption promoters, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate, magnesium stearate, etc.; (h) adsorbents, such as kaolin and bentonite; and (i) It is mixed with a lubricant, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or a mixture thereof. In the case of capsules, tablets, and pills, the dosage form may also include a buffer.

[0535] Solid formulations as described above may be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. These may contain sedatives and may also be compositions that release an active compound or compounds in a delayed manner in specific parts of the intestine. Examples of embedded compositions that may be used are polymeric materials and waxes. The active compound may also be in a microencapsulated form with one or more of the excipients, where appropriate.

[0536] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. These dosage forms are prepared by forming solutions or suspensions by dissolving, dispersing, etc., in a carrier, e.g., water, saline solution, aqueous dextrose, glycerol, ethanol, etc., of a compound of the present invention or a pharmaceutically acceptable salt thereof, and any pharmaceutical adjuvant; solubilizing agents and emulsifiers, e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, and dimethylformamide; oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, fatty acid esters of glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan; or in a mixture of these substances.

[0537] In addition to the active compound, the suspension may contain a suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacant, or a mixture thereof.

[0538] A composition for rectal administration is a suppository that can be prepared by mixing, for example, the compound of the present invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at room temperature but liquid at body temperature and melts within a suitable body cavity to release the active ingredient.

[0539] Forms of administration for topical administration of the compounds of the present invention include ointments, powders, sprays, and inhalants. The active ingredient is mixed with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary under sterile conditions. Ophthalmic formulations, ophthalmic ointments, powders, and solutions are also considered to be within the scope of the present invention.

[0540] Generally, depending on the intended mode of administration, a pharmaceutically acceptable composition will contain about 1 weight % to about 99 weight % of the compound of the present invention or a pharmaceutically acceptable salt thereof, and 99 to 1 weight % of a suitable pharmaceutical excipient. In one example, the composition is about 5 weight % to about 75 weight % of the compound of the present invention or a pharmaceutically acceptable salt thereof, and the remainder is a suitable pharmaceutical excipient.

[0541] Actual methods for preparing such dosage forms will be known or obvious to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, 18th Ed. (Mack Publishing Company, Easton, Pa., 1990). The composition to be administered will, in any case, contain a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof for the treatment of a diseased condition according to the teaching of the present invention.

[0542] The compound of the present invention or its pharmaceutically acceptable salt is administered at a therapeutically effective dose that may vary depending on various factors, including the activity of the specific compound used, metabolic stability and the duration of action of the compound, age, body weight, general health, gender, diet, form and time of administration, excretion rate, drug combination, severity of the specific disease state, and the subject receiving the treatment. The compound of the present invention may be administered to a patient at a dosage ranging from about 0.1 to about 1,000 mg per day. For a normal human adult with a body weight of about 70 kilograms, a dosage of about 0.01 to about 100 mg per kilogram of body weight per day is an example. However, the specific dosage used may vary. For example, the dosage may depend on a number of factors, including the patient's requirements, the severity of the condition being treated, and the pharmacological activity of the compound used. The determination of the optimal dosage for a specific patient is widely known to those skilled in the art. The determination of the optimal dosage for a specific patient is widely known to those skilled in the art.

[0543] Combination therapy

[0544] Compounds as disclosed herein may be administered (“co-administered”) as a monotherapy or in combination with one or more additional therapies for the treatment of diseases or disorders, e.g., diseases or disorders related to proliferation such as cancer. Therapies that may be used in combination with compounds disclosed herein include: (i) surgery; (ii) radiation therapy (e.g., gamma radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and whole-body radioisotope therapy); (iii) endocrine therapy; (iv) adjuvant therapy, immunotherapy, CAR T-cell therapy; and (v) other chemotherapy agents.

[0545] The term "co-administered" ("co-administration") refers to the simultaneous administration or any individual sequential administration of a compound of formula I' or its salt, and additional active pharmaceutical components, including cytotoxic agents and radiation therapy. If administration is not simultaneous, the compounds are administered at times close to each other. Furthermore, it is not important whether the compounds are administered in the same dosage form; for example, one compound may be administered topically and the other orally.

[0546] Typically, any substance active against the disease or condition being treated may be co-administered. Examples of such cancer treatments are, for instance, https: / / www.cancer.gov / about-cancer / treatment / drugs (last accessed January 22, 2019) and Cancer Principles and Practice of Oncology by VT Devita and S. Hellman (editors), 11 th It can be found in open sources such as the edition (2018), Lippincott Williams & Wilkins Publishers. Those skilled in the art will be able to identify which combination of formulations is useful based on the specific characteristics of the drugs and the associated disease.

[0547] In one embodiment, a treatment method comprises the combination of a compound or a pharmaceutically acceptable salt thereof as disclosed herein and one or more immunotherapies. Immunotherapy (also known as biological response modulation therapy, biological therapy, biotherapy, immunotherapy, or biological therapy) is a therapy that uses a part of the immune system to fight disease. Immunotherapy can help the immune system recognize cancer cells or enhance the response to cancer cells. Immunotherapy includes active and passive immunotherapy. Active immunotherapy stimulates the body's immune system, whereas passive immunotherapy generally uses immune system components generated outside the body.

[0548] Examples of active immunotherapy include, but are not limited to, 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) vaccines, including interleukin-2 (IL-2) or lymphokine-activating killer (LAK) cell therapy.

[0549] Examples of passive immunotherapy include, but are not limited to, targeted therapies containing monoclonal antibodies and toxins. Monoclonal antibodies include naked antibodies and conjugated monoclonal antibodies (also known as tags, labels, or loaded antibodies). Naked monoclonal antibodies do not have drugs or radioactive materials attached to them, whereas conjugated monoclonal antibodies are bound to, for example, chemotherapy drugs (chemical labels), radioactive particles (radiolabels), or toxins (immunotoxins). Examples of such naked monoclonal antibody drugs are, for example, rituximab (Rituxan), an antibody against the CD20 antigen used to treat B-cell non-Hodgkin lymphoma; trastuzumab (Herceptin), an antibody against the HER2 protein used to treat advanced breast cancer; and alemtuzumab (Campath), an antibody against the CD52 antigen used to treat B-cell chronic lymphocytic leukemia (B-CLL). Examples include cetuximab (Erbitux), an antibody against EGFR protein used in combination with irinotecan to treat advanced colorectal and head and neck cancers; and bevacizumab (Avastin), an anti-angiogenic therapy acting against VEGF protein used in combination with chemotherapy to treat metastatic colorectal cancer. Examples of conjugated monoclonal antibodies include the radiolabeled antibody ibritumomab tuxetan (Zevalin), which delivers radioactivity directly to cancerous B lymphocytes without restriction and is used to treat, for example, B-cell non-Hodgkin lymphoma; the radiolabeled antibody tocitumomab (Bexxar), which is used to treat, for example, certain types of non-Hodgkin lymphoma; and the immunotoxin gemtuzumab ozogamicin (Mylotarg), which contains caliceamicin and is used to treat, for example, acute myeloid leukemia (AML).BL22 is, for example, a conjugated monoclonal antibody for treating hair cell leukemia, an immunotoxin for treating leukemia, lymphoma, and brain tumors, and, for example, a radiolabeled antibody such as OncoScint for colorectal and ovarian cancer, and ProstaScint for prostate cancer.

[0550] Additional examples of therapeutic antibodies that may be used include, but are not limited to: HERCEPTIN™ (trastuzumab) (Genentech, Calif.), a humanized anti-HER2 monoclonal antibody for the treatment of patients with metastatic breast cancer; REOPRO.RTM. (abxiximab) (Centocor), an anti-glycoprotein IIb / IIIa receptor on platelets to prevent clot formation; ZENAPAX™ (daclizumab) (Roche Pharmaceuticals, Switzerland), an immunosuppressive, humanized anti-CD25 monoclonal antibody for the prevention of acute renal allograft rejection; PANOREX™ (Glaxo Wellcome / Centocor), a murine anti-17-IA cell surface antigen IgG2a antibody; BEC2, a murine anti-ideotype (GD3 epitope) IgG antibody (ImClone System); and IMC-C225 (ImClone System), a chimeric anti-EGFR IgG antibody. VITAXIN™ (Applied Molecular Evolution / Medlmmune), a humanized anti-alpha V beta 3 integrin antibody; Campath 1H / LDP-03, a humanized anti-CD52 IgG1 antibody (Leukosite); Smart M195 (Protein Design Lab / Kanebo), a humanized anti-CD33 IgG antibody; RITUXAN™ (IDEC Pharm / Genentech, Roche / Zettyaku), a chimeric anti-CD20 IgG1 antibody; LYMPHOCIDE™ (Immunomedics), a humanized anti-CD22 IgG antibody; LYMPHOCIDE™ Y-90 (Immunomedics); Lymphoscan (Tc-99m-labeled; radiographics; Immunomedics); Nuvion (compared to CD3; Protein Design Labs); CM3 is a humanized anti-ICAM3 antibody (ICOS Pharm); IDEC-114 is a primate-modified anti-CD80 antibody (IDEC Pharm / Mitsubishi);ZEVALIN™ is a radiolabeled murine anti-CD20 antibody (IDEC / Schering AG); IDEC-131 is a humanized anti-CD40L antibody (IDEC / Eisai); IDEC-151 is a primate-modified anti-CD4 antibody (IDEC); IDEC-152 is a primate-modified 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 primate-modified anti-CD4 IgG1 antibody (IDEC Pharm / SmithKline Beecham); MDX-CD4 is a human anti-CD4 IgG antibody (Medarex / Eisai / Genmab); CD20-Threptadabinin (+ Biotin-Yttrium 90; NeoRx); CDP571 is a humanized anti-TNF-alpha IgG4 antibody (Celltech); LDP-02 is a humanized anti-alpha 4 beta 7 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 subsequent paragraphs.

[0551] Immunotherapy that may be used in combination with compounds as disclosed herein includes adjuvant immunotherapy. Examples include cytokines, e.g., granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte-colony-stimulating factor (G-CSF), macrophage inflammatory protein (MIP)-1-alpha, interleukins (IL-1, IL-2, IL-4, IL-6, IL-7, IL-12, IL-15, IL-18, IL-21, and IL-27), tumor necrosis factor (including TNF-alpha), and interferons (including IFN-alpha, IFN-beta, and IFN-gamma); aluminum hydroxide (alum); basyl calmet-guerin (BCG); keyhole limpet hemocyanin (KLH); incomplete Freund adjuvant (IFA); QS-21; detoxification; levamisole; And includes dinitrophenyl (DNP), and combinations thereof, for example, combinations of interleukin, for example IL-2, and other cytokines, for example IFN-alpha.

[0552] In various embodiments, immunotherapy or immunotherapy may include one or more of the following: adoptive cell transfer, angiogenesis inhibitors, Bacillus Calmette-Guerin therapy, biochemotherapy, cancer vaccine, chimeric antigen receptor (CAR) T-cell therapy, cytokine therapy, gene therapy, immune checkpoint modulators, immunoconjugates, radioconjugates, oncolytic virus therapy, or targeted drug therapy. One or more of the functions or functions of immunotherapy or immunotherapeutic agents are collectively referred to herein as "immunotherapeutic agents."

[0553] The present disclosure provides a method for preventing, treating, reducing, inhibiting, or controlling neoplasms, tumors, or cancer in subjects requiring such treatment, comprising administering a combination comprising a therapeutically effective amount of a compound of formula I' and an immunotherapeutic agent. In one non-limiting embodiment, the method comprises the step of administering a therapeutically effective amount of a combination comprising a compound of formula I' together with an immunotherapeutic agent. In various embodiments, the combination provides a synergistic effect, an additive effect, or a synergistic effect that reduces the number of cancer cells when treated with the combination compared to each treatment alone. In some embodiments, administration of a therapeutically effective amount of a combination comprising a compound of formula I' and an immunotherapeutic agent results in a synergistic anti-tumor activity and / or anti-tumor activity that is more potent than the additive effect of administering the compound of formula I' or the immunotherapeutic agent alone.

[0554] Human cancers possess numerous genetic and acquired modifications that generate neoantigens potentially recognizable by the immune system (Sjoblom et al. (2006) Science 314:268-74). The adaptive immune system, composed of T and B lymphocytes, possesses potent anticancer potential and exhibits a broad spectrum of responses to various tumor antigens, as well as sophisticated specificity. Furthermore, the immune system demonstrates significant plasticity and memory components. The successful utilization of all these properties of the adaptive immune system makes immunotherapy unique among all cancer treatment methods.

[0555] The present disclosure provides a combination of a compound of Formula I' and an immunotherapeutic agent. Such exemplified combinations may be used to treat subjects with cancer. In various embodiments, the immunotherapeutic agent finding utility in the compositions, formulations, and methods of the present invention may comprise one or more substances or therapies including: adoptive cell delivery, angiogenesis inhibitors, Bacillus calmet-Guerin therapy, biochemotherapy, cancer vaccines, chimeric antigen receptor (CAR) T-cell therapy, cytokine therapy, gene therapy, immune checkpoint modulators, e.g., immune checkpoint inhibitors, immunoconjugates, radioconjugates, oncolytic virus therapy, or targeted drug therapy.

[0556] In specific embodiments of the present disclosure, the therapeutically effective combination comprises a compound of formula I' and an immunotherapeutic agent. In various related embodiments, the compound of formula I' enhances the activity of the immunotherapeutic agent.

[0557] In each specific embodiment of the aspects mentioned above, as well as in other aspects and embodiments described elsewhere in this invention, the immunotherapeutic agent enhances the activity of a compound of formula I'.

[0558] In specific embodiments of each of the aforementioned aspects, and in other aspects and embodiments described elsewhere in this invention, the compound of Formula I' and the immunotherapeutic agent act synergistically. In various embodiments described herein, the exemplary immunotherapeutic agent is an immune cell selected from the agonist or activator of the co-stimulatory molecule (e.g., T-cells, dendritic cells, natural killer cells, etc.) and is a modulator, wherein the modulator is a monoclonal antibody, a bispecific antibody containing one or more immune checkpoint antigen-binding portions, a trispecific antibody, or an immune cell-binding polyvalent antibody / fusion protein / structure known in the art. In some embodiments, the immunotherapeutic agent may be an antibody that modulates the co-stimulatory molecule or binds to an antigen on the surface of an immune cell or cancer cell. In each of these different embodiments, the antibody modifier may be a monoclonal antibody, a polyclonal antibody, a bispecific antibody, a trispecific or multispecific format antibody, a fusion protein or a fragment thereof, e.g., a diabody, a single-stranded (sc)-diabody (scFv) 2, a miniantibody, a minibody, Barnase-barstar, scFv-Fc, sc (Fab) 2, a trimeric antibody construct, a trimeric antibody construct, a trimeric antibody construct, a trimeric antibody construct, a collagen antibody construct, a (scFv-TNFa) 3 or F (ab) 3 / DNL antibody construct.

[0559] In specific embodiments of each of the aforementioned aspects, and in other aspects and embodiments described elsewhere in this invention, the immunotherapeutic agent is an agent that modulates the immune response, e.g., a checkpoint inhibitor or a checkpoint agent. In some embodiments, the immunotherapeutic agent is a substance that enhances the anti-tumor immune response. In some embodiments, the immunotherapeutic agent is a substance that increases cell-mediated immunity. In some embodiments, the immunotherapeutic agent is a substance that increases T-cell activity. In some embodiments, the immunotherapeutic agent is a substance that increases cytolytic T-cell (CTL) activity. In some embodiments, the immunotherapeutic agent is an antibody modulator targeting 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 embodiments, the immunotherapeutic agent is a substance that increases natural killer (NK) cell activity. In some embodiments, the immunotherapeutic agent is a substance that inhibits the suppression of an immune response. In some embodiments, the immunotherapeutic agent is a substance that inhibits suppressor cells or suppressor cell activity. In some embodiments, the immunotherapeutic agent is a substance or therapy that inhibits Treg activity. In some embodiments, the immunotherapeutic agent is a substance that inhibits the activity of suppressive immune checkpoint receptors. In some embodiments, the combination of the present disclosure comprises a compound of formula I' and an immunotherapeutic agent, wherein the immunotherapeutic agent comprises a T cell modulator selected from agonists or activators of co-stimulatory molecules.In one embodiment, the agonist of the co-stimulatory molecule is selected from 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 agonists (e.g., agonist antibodies or their antigen-binding fragments, or soluble fusions). In another embodiment, the effector cell combination comprises a bispecific T cell junction (e.g., CD3 binding to a bispecific antibody molecule) and an oncogene (e.g., particularly EGFR, PSCA, PSMA, EpCAM, HER2).

[0560] In some embodiments, 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, a 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, and FAS The immunotherapeutic agent is a modulator of 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 immunostimulating oligonucleotide. In some embodiments, the immunotherapeutic agent is an immune checkpoint modulator (e.g., immune checkpoint inhibitor, e.g., inhibitor of PD-1 activity, modulator of PD-L1 activity, modulator of PD-L2 activity, 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 embodiment, 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 embodiment, an 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.

[0561] Inhibition of the inhibitory molecule may be performed at the DNA, RNA, or protein level. In a specific embodiment, an inhibitory nucleic acid (e.g., dsRNA, siRNA, or shRNA) may be used to inhibit the expression of the inhibitory molecule. In another embodiment, the inhibitor of the inhibitory signal is a polypeptide, e.g., a soluble ligand (e.g., PD-1-Ig or CTLA-4 Ig), or an antibody or its antigen-binding fragment, e.g., one or more immune checkpoint antigen-binding moieties comprising a monoclonal antibody, a bispecific antibody, a trispecific antibody, or an immune cell-binding multivalent antibody / fusion protein / composition known in the art that binds to the inhibitory molecule; For example, an antibody or fragment thereof (also referred to herein as "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.

[0562] In some embodiments, 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 bind particularly to a member of the c-Met pathway and / or immune checkpoint modulator (for example, the bispecific antibody binds to both the hepatocyte growth factor receptor (HGFR) described herein and the immune checkpoint modulator, e.g., 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 a specific embodiment, the bispecific antibody binds specifically to the human HGFR protein and one of PD-1, PD-L1, and CTLA-4.

[0563] In some embodiments, the immunotherapeutic agent is a cytokine, e.g., a chemokine, interferon, interleukin, lymphokine, or a member of the tumor necrosis factor family. In some embodiments, the cytokine is IL-2, IL15, or interferon-gamma.

[0564] In any of the above aspects or in some embodiments of those described elsewhere in this invention, cancer is selected from the group consisting of lung cancer, pancreatic cancer, breast cancer, colon cancer, colorectal cancer, melanoma, gastric cancer, stomach cancer, kidney cancer, ovarian cancer, liver cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, neuroblastoma, glioma, glioblastoma, pleomorphic glioblastoma, cervical cancer, stomach cancer, bladder cancer, head and neck cancer, and liver cancer.

[0565] In any of the above aspects or in some embodiments of those described elsewhere in this invention, the cancer or tumor of the subject does not respond to any immune checkpoint inhibitor described herein, such as an immune checkpoint inhibitor (e.g., a PD-1 antagonist or a PD-L1 antagonist), or the cancer or tumor of the subject progresses after an initial response to immune checkpoint inhibitor (e.g., any immune checkpoint inhibitor described herein, such as a PD-1 antagonist or a PD-L1 antagonist).

[0566] In any of the above aspects or in some specific embodiments of those described elsewhere in this invention, the subject is a human.

[0567] A checkpoint inhibitor may be any molecule, substance, treatment, and / or method that inhibits immune checkpoints and / or promotes immune checkpoint inhibitors by, for example, promoting an intrinsic immune checkpoint inhibitor; inhibiting transcription factors involved in the expression of immune checkpoints; and / or acting in cooperation with some additional external factors. For example, a checkpoint inhibitor may include a treatment that inhibits transcription factors associated with 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). Additionally, a checkpoint inhibitor may include the transcription of immune checkpoint genes; modification and / or processing of immune checkpoint mRNA; translation of immune checkpoint proteins; and / or molecules involved in immune or immune checkpoint pathways, e.g., PD-1 transcription factors, e.g., HIF-1, STAT3, NF-κB, and AP-1, or general oncogenic pathways, e.g., JAK / STAT, RAS / ERK, or PI3K / AKT / mTOR, may be inhibited (Zerdes et al., Genetic, transcriptional and post-translational regulation of the programmed death protein ligand 1 in cancer: biology and clinical correlations, Oncogenevolume 37, pages 4639-4661 (2018), the entire disclosure thereof is incorporated herein by reference).

[0568] Checkpoint inhibitors may include therapies, molecules, substances, and / or methods that regulate immune checkpoints at the transcriptional level using, for example, co-inhibition of RNA-interference pathways and / or post-transcriptional gene silencing (PTGS) (e.g., microRNA, miRNA; silencing RNA, small interfering RNA, or short interfering RNA (siRNA). Transcriptional regulation of checkpoint molecules has been shown to involve mir-16, which was found to target the 3'UTR of 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 the regulation of PD-1 expression in 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, the entire disclosure thereof incorporated herein by reference).

[0569] T-cell-specific aptamer-siRNA chimeras have been proposed as a highly specific method for inhibiting molecules in immune checkpoint pathways (Hossain et al., The aptamer-siRNA conjugates: reprogramming T cells for cancer therapy, Ther. Deliv. 2015 Jan; 6(1): 1-4, the full text of which is incorporated herein by reference).

[0570] Alternatively, members of the immune checkpoint pathway can be inhibited using treatments that affect related pathways, e.g., metabolism. For example, an oversupply of the corresponding mitochondrial intermediate pyruvate from CAD macrophages promoted PD-L1 expression through the induction of the bone morphogenetic protein 4 / phosphorylated SMAD1 / 5 / IFN regulatory factor 1 (BMP4 / p-SMAD1 / 5 / IRF1) signaling pathway. Therefore, administering treatments that modulate metabolic pathways can lead to subsequent regulation of the immunosuppressive 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).

[0571] Checkpoint immunity can be regulated by oncolytic viruses that selectively replicate within tumor cells and induce an acute immune response in the tumor microenvironment—that is, by acting as gene vectors containing specific agents against cancer cells (e.g., antibodies, miRNA, siRNA)—and influence the tumor degradation and secretion of cytokines and chemokines, thereby causing synergy 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, clinical trials utilizing the following viruses as checkpoint inhibitors are underway: poliovirus, measles virus, adenovirus, poxvirus, herpes simplex virus (HSV), coxsackievirus, reovirus, Newcastle disease virus (NDV), T-VEC (herpes simplex virus encoded by GM-CSF (granulocyte-macrophage colony-stimulating factor)), and H101 (Shi et al., cit.).

[0572] Checkpoint inhibitors can act on checkpoint immunity at the translation level. Since the translation of mRNA into protein represents a critical event in the regulation of gene expression, inhibiting immune checkpoint translation is a method by which immune checkpoint pathways can be suppressed.

[0573] Inhibition of the immune checkpoint pathway can occur at any stage of the immune checkpoint translation process. For example, drugs, molecules, agents, treatments, and / or methods can inhibit the initiation process (thereby recruiting the 40S ribosomal subunit to the 5' end of the mRNA and scanning the 5'UTR of the mRNA to the 3' end). Inhibition can occur by targeting the anticodon of the initiator methionyl-transfer RNA (tRNA) (Met-tRNAi), base-pairing it with its start codon, or recruiting the 60S subunit to initiate the elongation and sequential addition of amino acids in the translation of immune checkpoint-specific genes. Alternatively, checkpoint inhibitors can inhibit the checkpoint at the translation level by preventing the formation of the ternary complex (TC), namely, eukaryotic initiation factor (eIF) 2 (or one or more of its α, β, and γ subunits); GTP; and Met-tRNAi.

[0574] Checkpoint inhibition may occur by excluding phosphorylation via protein kinase R (PKR), PERK, GCN2, or HRI, or by excluding TC from being associated with the 40S ribosome and / or other initiation factors, thereby preventing the formation of the pre-initiation complex (PIC); or through the destabilization of eIF2α by inhibiting the eIF4F complex and / or its cap-binding protein eIF4E, scaffolding protein eIF4G, or eIF4A helicase. Methods discussing translational control in cancer are disclosed in Truitt et al., New frontiers in translational control of the cancer genome, Nat Rev Cancer. 2016 Apr 26; 16(5): 288-304, the full text of which is incorporated herein by reference.

[0575] Checkpoint inhibitors may also include therapies, molecules, agents, and / or methods that modulate immune checkpoints at the cellular and / or protein level, for example, by inhibiting immune checkpoint receptors. Inhibition of checkpoints may occur through the use of antibodies, antibody fragments, antigen-binding fragments, small molecules, and / or other drugs, agents, therapies, and / or methods.

[0576] Immune checkpoints refer to inhibitory pathways of the immune system responsible for maintaining self-tolerance to minimize peripheral tissue damage and regulating the degree of the immune system response. However, tumor cells can also activate immune tissue checkpoints to reduce the effect of the immune response against tumor tissue (immune response 'blocking'). In contrast to most anticancer drugs, checkpoint inhibitors do not directly target tumor cells but rather target lymphocyte receptors or their ligands to enhance the endogenous antitumor activity of the immune system (Pardoll, 2012, Nature Reviews Cancer 12:252-264).

[0577] Until recently, cancer immunotherapy has focused significant efforts on approaches to enhance anti-tumor immune responses by adoptive delivery of activated effector cells, immunization against relevant antigens, or the provision of non-specific immunostimulators such as cytokines. However, over the past decade, intensive efforts to develop specific immune checkpoint pathway inhibitors have begun to provide new immunotherapeutic approaches for treating cancer, including: antibodies (Abs) that bind to and inhibit CTLA-4 for the treatment of patients with advanced melanoma, ipilimumab (YERVOY.RTM.) (Hodi et al. (2010) N Engl J Med 363: 711-23), and antibodies that specifically bind to receptors and block inhibitory PD-1 / PD-1 ligand pathways, such as nivolumab and pembrolizumab (formerly ramrolizumab; development of pembrolizumab: specifically binds to the Programmed Death-1 (PD-1) receptor and blocks the PD-1 / PD-1 ligand pathway, a non-proprietary name adopted by the USAN Council (ZZ-165), Nov. 27, 2013). Statement (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.

[0578] PD-1 is a major immune checkpoint receptor expressed by activated T and B cells and mediates immunosuppression. Nivolumab (formerly 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) and thereby blocks the downregulation of anti-tumor T-cell function (U.S. Patent 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 after ipilimumab, and for the treatment of squamous non-small cell lung cancer with BRAF inhibitors in cases positive for BRAF V600 mutations.

[0579] Recent data suggest a secondary mechanism of anti-CTLA-4 antibodies that may occur within the tumor itself. CTLA-4 has been found to be expressed at higher levels in regulatory T-cells (also referred to herein as "Treg cells") compared to effector T-cells (also known herein as "Teff cells") within the tumor, leading to the hypothesis that anti-CTLA-4 preferentially affects Treg cells. "Therapeutic use of anti-CTLA-4 antibodies", Christian U. Blank and Alexander Enk, International Immunology, Vol. 27, No. 1, pp. 3-10. Recent studies on the combination of PD-1 and CTLA-4 show that combined blockade of the CTLA-4 and PD-1 pathways also increases the ratio of Teff cells to both regulatory T-cells and MDSCs, thereby reducing inhibition in the tumor microenvironment and promoting inflammation. "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 entirety of which is incorporated herein by reference. A combination of a checkpoint inhibitor and other therapeutic(s) may enhance or prolong the anti-tumor response of the checkpoint inhibitor and / or the effect of the therapeutic(s). In this regard, WO 2015 / 069770 discloses combination therapy based on activating an adaptive immune response for the treatment of cancer, in particular a combination of CTLA-4 and PD-1 inhibitors. The entirety of which is incorporated herein by reference.

[0580] One mechanism by which checkpoint-blocking anti-CTLA-4 antibodies mediate the anti-tumor effect is the reduction of regulatory T-cells. Due to the distinct mechanism of action of anti-CTLA-4 antibodies, they can be successfully combined with anti-PD1 checkpoint-blocking antibodies that act to release inhibitory signaling conferred to effector T-cells. Dual blockade using these antibodies is combined to enhance anti-tumor responses in both preclinical (Proc Natl Acad Sci USA 2010, 107, 4275-4280) and clinical (N Engl J Med 2013, 369, 122-133; N Engl J Med 2015, 372, 2006-2017).

[0581] CTLA-4 attenuates the initial activation of naive and memory T cells through interactions with its ligands B7-1 (CD80) and B7-2 (CD86) (Fig. 1A). PD-1 is a receptor expressed on the surface of activated mature T cells, activated NK cells, B cells, monocytes, and many normal tissues and plays an important role in maintaining peripheral tolerance [20-21] (Fig. 1A). In contrast to CTLA-4, PD-1 acts through interactions with its ligand PD-L1 (also known as B7-H1 or CD274) and is primarily involved in regulating T cell activity in peripheral tissues as well as providing major immune resistance mechanisms within the tumor microenvironment.

[0582] In some embodiments, 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, a 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 immunostimulating oligonucleotide. In some embodiments, immune checkpoint modulators, i.e., inhibitors or antagonists, or activators or agonists, are, for example, CD28 modulators, 4-1BB modulators, OX40 modulators, CD27 modulators, CD80 modulators, CD86 modulators, CD40 modulators, or GITR modulators, Lag-3 modulators, 41BB modulators, bright modulators, CD40 modulators, GITR modulators, TGF-beta modulators, TIM-3 modulators, SIRP-alpha modulators, TIGIT modulators, VSIG8 modulators, BTLA modulators, SIGLEC7 modulators, SIGLEC9 modulators, ICOS modulators, B7H3 modulators, B7H4 modulators, FAS modulators, and / or BTNL2 modulators. In some embodiments, the immunotherapeutic agent is an immune checkpoint modulator as described above (e.g., one or more immune checkpoint antigen-binding moiety comprising a monoclonal antibody, a bispecific antibody, a trispecific antibody, or an immune checkpoint modulator antibody that may be in the form of an immune cell-binding multivalent antibody / fusion protein / composition known in the art).

[0583] Combination therapy with immune checkpoint inhibitors, which may include antibodies specifically targeting immune system checkpoints such as CTLA4, PD1, and PD-L1, is one of the most promising new approaches to immunotherapy for cancer and other diseases. Additional checkpoint targets, such as TIM-3, LAG-3, various B-7 ligands, CHK1 and CHK2 kinases, BTLA, and A2aR, are also under investigation. Currently, three checkpoint inhibitors have received expedited approval from the U.S. Food and Drug Administration for cancer treatment, including the CTLA-4 inhibitor ipilimumab (Yervoy®) and both PD-1 inhibitors, pembrolizumab (Keytruda®) and nivolumab (Opdivo®). Additionally, several checkpoint inhibitors are currently in clinical trials.

[0584] 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, which includes immunoglobulin superfamily members CD28, CTLA-4, inducible co-stimulators (ICOS), and BTLA. PD-1 is highly expressed in activated T cells and B cells. PD-1 expression can also be detected in memory T-cell subsets with varying expression levels. Two ligands specific to PD-1 have been identified: programmed death-ligand 1 (also known as PD-L1, B7-H1, or CD274) and PD-L2 (also known as B7-DC or CD273). PD-L1 and PD-L2 have been shown to downregulate T cell activation upon binding to PD-1 in both mouse and human systems (Okazaki et al., Int Immunol., 2007; 19: 813-824). Interactions between PD-1 and its ligands, PD-L1 and PD-L2, expressed on antigen-presenting cells (APCs) and dendritic cells (DCs), deliver negative regulatory stimuli to downregulate activated T cell immune responses. Blockade of PD-1 inhibits this negative signal and amplifies the T cell response.

[0585] Numerous studies indicate that the tumor microenvironment manipulates the PD-L1 / PD-1 signaling pathway, and that the induction of PD-L1 expression is associated with the suppression of the immune response against cancer, thereby allowing cancer progression and metastasis. The PD-L1 / PD-1 signaling pathway is a major mechanism of cancer immune evasion for several reasons. First, and most importantly, this pathway is involved in the negative regulation of the immune response of activated T effector cells found in the periphery. Second, while PD-L1 is upregulated in the tumor microenvironment, PD-1 is also upregulated by activated tumor-infiltrating T cells, enabling a vicious cycle of suppression. Third, this pathway is intricately involved in innate and adaptive immune regulation through bidirectional signaling. These factors center the PD-1 / PD-L1 complex, through which cancer can manipulate the immune response and promote its own progression.

[0586] CTLA-4 (also known as cytotoxic T-lymphocyte-associated protein 4, CTLA4, CTLA-4, CD152, differentiation cluster 152; also known as 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 murine cell lysed T cell cDNA libraries, see Brunet et al., A new member of the immunoglobulin superfamily--CTLA-4, Nature. 1987 Jul 16-22;328(6127):267-70. CTLA-4 was shown to interact with the b7 family ligands CD80 (also known as differentiation cluster 80 and B7-1); and CD86 (also known as differentiation cluster 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 of the human CTLA-4 DNA-coding region and CD28 shows significant homology between the two sequences, most similar between the mucosal and cytoplasmic regions; therefore, CTLA-4 is involved in discarding / reducing T-cell activation and opposes the activation of CD28. CTLA-4 deficient mice have been shown to exhibit massive lymphoproliferative proliferation. 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. CTLA-4 blockade has been reported to increase T-cell responses, enhance induced autoimmune diseases, and impair antitumor immunity in both in vitro and in vivo. (Luhder, J.Exp. Med. 1998; 187:427-432; Walunas et al., Immunity. 1994; 1:405-413; Kearney, J. Immunol. 1995; 155:1032-1036); see Leach, Science 1996; 271:1734-1736). CTLA-4 has also been reported to have alternative and / or additional effects on the initial characteristics of T-cell immune responses (Chambers, Curr. Opin. Immunol. 1997; 9:396-404; Bluestone, J. Immunol. 1997; 158:1989-1993; Thompson, Immunity 1997; 7:445-450).

[0587] The first immune checkpoint inhibitor to be tested in clinical trials was ipilimumab (Yervoy, Bristol-Myers Squibb), a CTLA-4 mAb. CTLA-4 belongs to the receptor immunoglobulin superfamily, which also includes V-domain immunoglobulin inhibitors of PD-1, BTLA, TIM-3, and T cell activation (VISTA). Anti-CTLA-4 mAbs are potent checkpoint inhibitors that eliminate "disruption" in both pure cells and antigen-experienced cells. The treatment enhances the anti-tumor function of CD8+ T cells, increases the ratio of CD8+ T cells to Foxp3+ T regulatory cells, and suppresses the inhibitory function of T regulatory cells. A major drawback of anti-CTLA-4 mAb therapy is the generation of autoimmune toxicity due to targeted effects on the overactive immune system, which results in a loss of the ability to self-degrade. It has been reported that up to 25% of patients treated with ipilimumab develop 3-4 serious adverse / autoimmune side effects, including dermatitis, enteritis, hepatitis, endocrine disorders (including pituitary-thyroiditis, thyroiditis, and adrenalitis), arthritis, uveitis, nephritis, and aseptic meningitis. In contrast to the experience with anti-CTLA-4 therapy, anti-PD-1 therapy is better tolerated and induces a relatively low rate of autoimmune side effects.

[0588] In some embodiments, the immunotherapeutic agent is a substance that inhibits the activity of PD-1. In some embodiments, the immunotherapeutic agent is a substance that inhibits the activity of PD-L1 and / or PD-L2. In some embodiments, the immunotherapeutic agent is a substance that inhibits the activity of CTLA-4. In some embodiments, the immunotherapeutic agent is a substance that inhibits the activity of CD80 and / or CD86. In some embodiments, the immunotherapeutic agent is a substance that inhibits the activity of TIGIT. In some embodiments, the immunotherapeutic agent is a substance that inhibits the activity of KIR. In some embodiments, the immunotherapeutic agent is a substance that enhances or stimulates the activity of immune checkpoint receptor activation.

[0589] In some embodiments of the method 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.

[0590] In some embodiments, the PD-1 antagonist is an antibody that specifically binds to PD-1. In some embodiments, the antibody that binds to PD-1 is pembrolizumab (KEYTRUDA®, MK-3475; Merck), fidilizumab (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 embodiments, the antibody binding to PD-1 is an antibody identified, for example, as APE2058, APE1922, APE1923, APE1924, APE 1950, or APE1963 (Anaptysbio), as described in PCT Publication WO 2014 / 179664, or an antibody containing the CDR region of any of these antibodies. In other embodiments, the PD-1 antagonist is a fusion protein containing the extracellular domain of PD-L1 or PD-L2, for example, AMP-224 (AstraZeneca / MedImmune). In other embodiments, the PD-1 antagonist is a peptide inhibitor, for example, AUNP-12 (Aurigene).

[0591] In some embodiments, the PD-L1 antagonist is an antibody that specifically binds to PD-L1. In some embodiments, the antibody that binds to PD-L1 is atezolizumab (RG7446, MPDL3280A; Genentech), MEDI4736 (AstraZeneca / MedImmune), BMS-936559 (MDX-1105; Bristol Myers Squibb), avelumab (MSB0010718C; Merck KGaA), KD033 (Kadmon), or the antibody portion of STI-A1014 (Sorrento Therapeutics). In some embodiments, the antibody binding to PD-L1 is described in PCT Publication WO 2014 / 055897 and is, for example, Ab-14, Ab-16, Ab-30, Ab-31, Ab-42, Ab-50, Ab-52, or Ab-55, or an antibody containing a CDR region of any of these antibodies, the entirety of which is incorporated herein by reference.

[0592] In some embodiments, the CTLA-4 antagonist is an antibody that specifically binds to CTLA-4. In some embodiments, the antibody that binds to CTLA-4 is ipilimumab (YERVOY®; Bristol Myer Squibb) or tremelimumab (CP-675,206; Pfizer). In some embodiments, CTLA-4 antagonizes a CTLA-4 fusion protein or a soluble CTLA-4 receptor, e.g., KARR-102 (Kahr Medical Ltd.).

[0593] In some embodiments, the LAG3 antagonist is an antibody that specifically binds to LAG3. In some embodiments, the antibodies that bind to LAG3 are IMP701 (Prima BioMed), IMP731 (Prima BioMed / GlaxoSmithKline), BMS-986016 (Bristol Myer Squibb), LAG525 (Novartis), and GSK2831781 (GlaxoSmithKline). In some embodiments, the LAG3 antagonist comprises a soluble LAG3 receptor, e.g., IMP321 (Prima BioMed).

[0594] In some embodiments, the KIR antagonist is an antibody that specifically binds to KIR. In some embodiments, the antibody that binds to KIR is ririlumab (Bristol Myer Squibb / Innate Pharma).

[0595] In some embodiments, the immunotherapeutic agent used in the combination disclosed herein (e.g., in combination with a compound of formula I') is an activator or agonist of a co-stimulatory molecule. In one embodiment, the agonist of the co-stimulatory molecule is selected from 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 agonists (e.g., agonist antibodies or antigen-binding fragments thereof, or soluble fusions).

[0596] In some embodiments, the OX40 agonist comprises an OX40 ligand or its OX40-binding portion. For example, the OX40 agonist may be MEDI6383 (AstraZeneca). In some embodiments, the OX40 agonist is an antibody that specifically binds to OX40. In some embodiments, the antibody that binds to OX40 is MEDI6469 (AstraZeneca / MedImmune), MEDI0562 (AstraZeneca / MedImmune), or MOXR0916 (RG7888; Genentech). In some embodiments, the OX40 agonist is an expressible vector (e.g., an expression vector or a virus, e.g., an adenovirus) containing the OX40 ligand. In some embodiments, the OX40-expression vector is Delta-24-RGDOX (DNAtrix) or DNX2401 (DNAtrix).

[0597] In some embodiments, the 4-1BB (CD137) agonist is a binding molecule, e.g., anticalin. In some embodiments, the anticalin is PRS-343 (Pieris AG). In some embodiments, the 4-1BB agonist is an antibody that specifically binds to 4-1BB. In some embodiments, the antibody that binds to 4-1BB is PF-2566 (PF-05082566; Pfizer) or urelumab (BMS-663513; Bristol Myer Squibb).

[0598] In some embodiments, the CD27 agonist is an antibody that specifically binds to CD27. In some embodiments, the antibody that binds to CD27 is varlilumab (CDX-1127; Celldex).

[0599] In some embodiments, the GITR agonist comprises a GITR ligand or its GITR-binding portion. In some embodiments, the GITR agonist is an antibody that specifically binds to GITR. In some embodiments, the antibody that binds to GITR is TRX518 (GITR, Inc.), MK-4166 (Merck), or INBRX-110 (5 Prime Therapeutics / Inhibrx).

[0600] TIM-3 was identified as another important inhibitory receptor expressed by depleted CD8+ T cells. In a mouse model of cancer, it was revealed that most dysfunctional tumor-infiltrating CD8+ T cells actually co-express PD-1 and TIM-3.

[0601] LAG-3 is another recently identified inhibitory receptor that acts to limit effector T-cell function and enhance the inhibitory 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 the combined blockade of PD-1 and LAG-3 induces a potent synergistic anti-tumor immune response in mouse models of cancer.

[0602] PD-1 pathway blockade can be combined with vaccines or compounds of other chemical 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, MA et al, Proc. Natl. Acad. Set, 107(9):4275-4280 (2010)).

[0603] In some embodiments, the immunotherapeutic agent useful in the compositions and methods described herein may comprise a monoclonal antibody, a bispecific antibody comprising one or more immune checkpoint antigen-binding moiety, a trispecific antibody, or an immune cell-binding multivalent antibody / fusion protein / composition known in the art targeting both PD-1 and ligand PD-L1.

[0604] PD-1 (also known as Programmed Death 1, CD279, and PDCD1) is a cell surface receptor that plays an important role in regulating the balance between stimulating 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 superfamily that is homologous 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). PD-1 expression can be induced upon lymphocyte activation via T cell, B cell, natural killer (NK) cell, and monocyte signaling, for example, T cell receptor (TCR) or B cell receptor (BCR) signaling (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 ligands CD80, CD86, PD-L1 (B7-H1, CD274), and PD-L2 (B7-DC, CD273), which are cell surface expression 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 binding, PD-1 recruits phosphatases such as SHP-1 and SHP-2 to intracellular tyrosine motifs and subsequently dephosphorylates effector molecules activated by TCR or BCR signaling (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 an inhibitory signal into T and B cells only when it binds simultaneously with TCR or BCR.

[0605] PD-1 has been shown to downregulate effector T cell responses through both cell-intrinsic and cell-extrinsic functional mechanisms. Inhibitory signaling via PD-1 induces a non-response state in T cells, preventing them from clonal expansion or the production of optimal levels of effector cytokines. PD-1 can also induce apoptosis in T cells through its ability to suppress survival signals from co-stimulation, which reduces the 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 imply that PD-1 is involved in the inhibition of effector cells by promoting the induction and maintenance of regulatory T cells (TREGs). For example, PD-L1 expressed in dendritic cells was shown to act synergistically with TGF-β to promote the induction of CD4+FoxP3+TREG, which has an enhanced inhibitory function (Francisco, Loise M et al. 2009 J Exp Med 206 3015-3029).

[0606] TIM-3 (also known as T-cell immunoglobulin and mucin domain-3, TIM-3, hepatitis A virus cell 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)).

[0607] TIM-3 is selectively expressed in Th1 cells and phagocytes (e.g., macrophages and dendritic cells). The use of siRNA or blocking antibodies to reduce human expression increased the secretion of interferon γ (IFN-γ) from CD4-positive T cells, suggesting a repressive role of TIM-3 in human T cells. Analysis of clinical samples from patients with autoimmune diseases did not show TIM-3 expression in CD4-positive cells. In particular, T cell clones derived from the cerebrospinal fluid of multiple sclerosis patients showed lower expression levels of TIM-3 and higher secretion of IFN-γ compared to clones derived from normal healthy individuals (Koguchi K et al., J Exp Med. 203:1413-8. (2006)).

[0608] TIM-3 is a receptor for the ligand galectin-9, a member of the galectin family, a molecule that is ubiquitously expressed in various cell types and binds to β-galactosides; phosphatidylserine (PtdSer) (DeKryff et al., T cell / membrane-transversal, Ig and mucin-3 allele variants differentially recognize phosphatidylserine and mediate phagocytosis in 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 1) Chiba et al., tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alamin HMGB1, Nat Immunol. 2012 Sep;13(9):832-42); Carcinoembryonic antigen-associated cell adhesion molecule 1 (also known as CEACAM1, BGP, BGP1, BGPI, and carcinoembryonic antigen-associated cell adhesion molecule 1) (Huang et al., CEACAM1 regulates TIM-3-mediated tolerance and exhaustion, Nature. 2015 Jan 15;517(7534):386-90).

[0609] BTLA (also known as B- and T-lymphocyte attenuator, BTLA1, CD272, and associated B and T lymphocytes) is a ~27.3-kDa single-pass type I membrane protein involved in lymphocyte suppression during immune responses. BTLA is constitutively expressed in both B and T cells. BTLA interacts with HVEM (herpes virus entry vector), a member of the tumor necrosis factor receptor (TNFR) family (Gonzalez et al., Proc. Natl. Acad. Sci. USA, 2005, 102: 1116-21). The interaction between BTLA, which belongs to the CD28 family of the immunoglobulin superfamily, and HVEM, a co-stimulating tumor necrosis factor (TNF) receptor (TNFR), is unique in that it defines the reciprocal dialogue between receptors of these two families. BTLA contains a tyrosine-based inhibitory motif (ITIM) for a proximal membrane immune receptor and a tyrosine-based switch motif (ITSM) for a distal membrane immune receptor. Disruption of ITIM or ITSM resulted in the loss of BTLA's ability to recruit SHP1 or SHP2, suggesting that BTLA requires both tyrosine motifs to recruit SHP1 and SHP2 in a manner different from PD-1 and to block T cell activation. The BTLA cytoplasmic tail also contains a third conserved tyrosine-containing motif within its cytoplasmic domain, which is sequence-similar to the Grb-2 recruitment site (YXN). In addition, phosphorylated peptides containing this BTLA N-terminal tyrosine motif can interact with the p85 subunits of GRB2 and PI3K in vitro, but the functional effects of these interactions have not yet been explored in vivo (Gavrieli et al., Bioochem. Biophysi Res Commun, 2003, 312, 1236-43). BTLA is a receptor for the ligands PTPN6 / SHP-1; PTPN11 / SHP-2; TNFRSF14 / HVEM; and B7H4.

[0610] VISTA (also known as a T cell-activating VSIR, B7-H5, B7H5, GI24, PP2135, SISP1, DD1alpha, VISTA, C10orf54, chromosome 10 open reading frame 54, PD-1H, and V-set immunomodulatory receptor V-domain Ig inhibitor) is a ~33.9-kDa single-pass type I membrane protein involved in T-cell suppressive responses, embryonic stem cell differentiation through inhibition of BMP4 signaling, 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)

[0611] LAG-3 (also known as lymphocyte activation gene 3, LAG3, CD223, and lymphocyte activation 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 in 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 plasma dendritic cells (DC) (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 the antigen-dependent stimulation of downregulation of CD4+ T lymphocytes (Huard et al., 1994, Eur. J. Immunol. 24:3216-3221), and LAG-3 blockade has also been shown to reactivate CD8+ lymphocytes in tumor or auto-antigen (Gross et al., 2007, J Clin Invest. 117: 3383-3392) and viral models (Blackburn et al., 2009, Nat. Immunol. 10:29-37).Furthermore, the intracellular cytoplasmic region of LAG-3 can interact with LAP (LAG-3-associated protein), a signaling 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 inhibitory 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 through both T cell-dependent and T cell-independent mechanisms (Workman, CJ and Vignali, DA, 2005, J. Immunol. 174: 688-695).

[0612] 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).

[0613] In addition, some kinases are known to be checkpoint inhibitors. For example, CHEK-1, CHEK-2, and A2aR.

[0614] CHEK-1 (also known as CHK 1 kinase, CHK1, and checkpoint kinase 1) is a ~54.4-kDa serine / threonine-protein kinase involved in checkpoint-mediated cell cycle arrest and the activation of DNA repair in response to DNA damage and / or non-replicated DNA.

[0615] 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 disruption, DNA-repair activation, and double-strand break-mediated atoptosis.

[0616] 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.

[0617] In various embodiments, the immunotherapeutic agent may comprise an antibody or a fragment thereof that binds to an antigen. Within this definition, the immune checkpoint inhibitor comprises a bispecific antibody and an immune cell-binding polyvalent antibody / fusion protein / composition known in the art. In some embodiments, the immunotherapeutic agent comprising a bispecific antibody may comprise a bispecific antibody that is divalent and binds to the same epitope of an immune checkpoint molecule, two different epitopes of the same immune checkpoint molecule, or different epitopes of two different immune checkpoints.

[0618] A person skilled in the art may execute some bispecific antibody formats known in the art 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 others for use in the combinations described herein.

[0619] In various embodiments, the immunotherapeutic agent may include an immune cell-binding multivalent antibody / fusion protein / composition.

[0620] In a specific embodiment of the present disclosure, a checkpoint inhibitor is used in combination with a compound of formula I' to reduce or inhibit metastasis of a primary tumor or cancer to another site, or the formation or establishment of a metastatic tumor or cancer at another site distal from the primary tumor or cancer, and thereby inhibit or reduce tumor or cancer recurrence or tumor or cancer progression.

[0621] In a further embodiment of the disclosure, a combination therapy for treating cancer is provided, comprising a compound of formula I' and a blockade of a checkpoint inhibitor having the potential to induce a potent and sustained immune response with enhanced therapeutic benefits and more manageable toxicity.

[0622] In a further embodiment of the disclosure, a combination therapy for treating cancer is provided, comprising a compound of formula I' and an immune checkpoint inhibitor. In an embodiment of the disclosure, a method for treating cancer and / or preventing the establishment of metastasis is provided by using a checkpoint inhibitor that acts synergistically with a compound of formula I'.

[0623] In additional embodiments, the method of the present disclosure comprises one or more of the following: 1) reducing or inhibiting the growth, proliferation, motility, or invasiveness of tumor or cancer cells that are potentially or metastatically metastatic; 2) reducing or inhibiting the formation or establishment of metastases occurring from the primary tumor or cancer to one or more other sites, locations, or regions distinct from the primary tumor or cancer; 3) reducing or inhibiting the growth or proliferation of metastases in one or more other sites, locations, or regions distinct from the primary tumor or cancer after metastases have formed or established; 4) reducing or inhibiting the formation or establishment of additional metastases; 5) extended overall survival; 6) extended progression-free survival; or 7) disease stabilization.

[0624] In a specific embodiment of the present disclosure, the administration of an immunotherapeutic agent in combination with a compound of formula I' provides a detectable or measurable improvement, i.e., a therapeutic benefit or beneficial effect, of (physical) symptoms or results associated with the presence of a proliferative or hyperproliferative disorder, neoplasm, tumor or cancer or metastasis, such as alleviating or mitigating one or more side effects of a given subject's pathological condition.

[0625] Therapeutic benefit or beneficial effect is any objective or subjective, transient, temporary or long-term improvement of a condition or pathology, or a reduction in the onset, severity, duration, or frequency of adverse effects associated with or caused by cell proliferation or cellular hyperproliferative disorders, e.g., neoplasms, tumors, or cancers, or metastases. This may improve survival rates. A satisfactory clinical endpoint of the treatment method according to the present disclosure is achieved, for example, when the severity, duration, or frequency of one or more associated pathologies, adverse symptoms, or complications is progressively or partially reduced, or when there is inhibition or reversal of one or more physiological, biochemical, or cellular expression or characteristics of cell proliferation or cellular hyperproliferative disorders such as neoplasms, tumors, or cancers, or metastases. Therefore, therapeutic benefit or improvement may be, without limitation, the destruction of target proliferating cells (e.g., neoplasms, tumors, or cancers, or metastases) or the resection of one or more, most or all, pathologies, side effects, or complications associated with or caused by cell proliferation or hyperproliferative disorders such as neoplasms, tumors, or cancers, or metastases. However, therapeutic benefit or improvement does not need to be the treatment or complete destruction of all target proliferating cells (e.g., neoplasms, tumors, or cancers, or metastases) or the resection of one or more, most or all, pathologies, side effects, or complications associated with or caused by cell proliferation or hyperproliferative disorders such as neoplasms, tumors, or cancers, or metastases. For example, partial destruction of a tumor or cancer cell mass, or stabilization of the tumor or cancer mass, size, or number of cells by inhibiting the progression or deterioration of the tumor or cancer, may reduce mortality and extend life by as few days, weeks, or months, even if some or most of the tumor, cancer mass, size, or cells remain.

[0626] Specific, non-limiting examples of therapeutic benefits include reduction of neoplasms, tumors, or cancers, or reduction of metastatic volume (size or cell mass) or cell number; inhibition or prevention of the increase in volume of neoplasms, tumors, or cancers (e.g., stabilization); slowing or inhibition of the progression of neoplasms, tumors, or cancers; or the exacerbation or inhibition of neoplasms, tumors, or cancer proliferation, growth, or metastasis.

[0627] In one embodiment of the present disclosure, administration of an immunotherapeutic agent in combination therapy with a compound of formula I' provides a detectable or measurable improvement or total response according to irRC (as derived from time-period response evaluation), comprising one of the following: (i) irCR—complete resolution of all lesions and no new lesions, regardless of measurability (confirmed by repeated, continuous evaluations of 4 weeks or more after initial documentation, continuous evaluation of 4 weeks or more) (ii) irPR—a 50% reduction in tumor burden gtoreq. compared to baseline (confirmed by continuous evaluation of 4 weeks or more after initial documentation).

[0628] At any time, any method described herein may not be immediately effective. For example, the number or mass of neoplasms, tumors, or cancer cells may increase after treatment, but a decrease in tumor cell mass, size, or number of cells may subsequently occur in a given subject over time.

[0629] Additional adverse symptoms and complications associated with neoplasms, tumors, cancers, and metastases that may be suppressed, reduced, decreased, delayed, or prevented include, for example, nausea, loss of appetite, lethargy, pain, and discomfort. Thus, partial or complete reduction in the severity, duration, or frequency of adverse effects or complications associated with or resulting from cellular hyperproliferative disorders, and improvement in the subject's quality of life and / or well-being, such as increased energy, appetite, and psychological well-being, are all specific, non-limiting examples of therapeutic benefits.

[0630] Therefore, therapeutic benefits or improvements may also include subjective improvements in the quality of life of the treated subject. In additional embodiments, the method extends or prolongs the subject's lifespan (survival). In other embodiments, the method improves the subject's quality of life.

[0631] In one embodiment, administration of an immunotherapeutic agent in combination therapy with a compound of formula I' results in 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 Carcinoembryonic Antigen (CEA) or other tumor-dependent levels, (vii) nutritional status (body weight, appetite, serum albumin), (viii): pain control or use of analgesics, (ix): CRP / albumin ratio.

[0632] Treatment using a compound of chemical formula I' combined with an immunotherapeutic agent induces a more complex immune response, including the development of innate and type-1 immunity as well as immunomodulation that more efficiently restores appropriate immune function.

[0633] In various exemplary methods, a checkpoint inhibitor antibody (monoclonal or polyclonal, bispecific, trispecific, or immune cell-binding multivalent antibody / fusion protein / composition) against a checkpoint molecule of interest (e.g., PD-1) may be sequenced, and the polynucleotide sequence may subsequently be cloned into a vector for expression or propagation. The sequence encoding the antibody of interest or its antigen-binding fragment may be maintained as a vector in host cells, and the host cells may subsequently be expanded and frozen for use. Production of recombinant monoclonal antibodies in cell culture may be carried out by cloning antibody genes from B cells by means known in the art. See, for example, Tiller et al., 2008, J. Immunol. Methods 329, 112; U.S. Patent No. 7,314,622.

[0634] In some embodiments, a method for producing a recombinant antibody may include the step of culturing a host cell containing isolated nucleic acid(s) encoding the antibody of the present disclosure. The method of culturing a host cell containing isolated nucleic acid(s) encoding the antibody of the present disclosure may be performed in various ways depending on the properties of the antibody. In some embodiments, where the antibody of the present disclosure is a full-length conventional antibody, for example, a heavy chain variable region and a light chain variable region exist under conditions in which the antibody can be generated and isolated.

[0635] Generally, nucleic acids encoding the antibody or its antigen-binding fragment of the present disclosure are provided. These polynucleotides encode both variable and constant regions of their respective heavy and light chains, but other combinations are also considered by the present invention. The present invention also considers oligonucleotide fragments derived from the disclosed polynucleotides and nucleic acid sequences complementary to these polynucleotides.

[0636] Polynucleotides can be in the form of RNA, DNA, cDNA, genomic DNA, nucleic acid analogs, and synthetic DNA. DNA can be double-stranded or single-stranded, and if single-stranded, it can be a coding (sense) strand or a non-coding (antisense) strand. The coding sequence encoding a polypeptide can be identical to or different from the coding sequence, and this sequence encodes the same polypeptide as a result of redundancy or degeneration of the genetic code.

[0637] In some embodiments, the nucleic acid(s) encoding the antibody of the present disclosure are introduced into an expression vector that may be designed to be extrachromosomal or incorporated into the genome of the host cell to be introduced. The expression vector may contain any number of appropriate regulatory sequences (transcription and translation control sequences, promoters, ribosome binding sites, enhancers, replication origins, etc.) or other components (selection genes, etc.), all of which are operably linked as known in the art. In some cases, two nucleic acids are used and each may be inserted into different expression vectors (e.g., the heavy chain of the first expression vector and the light chain of the second expression vector) or into the same expression vector. Those skilled in the art will understand that the design of the expression vector(s), including the selection of regulatory sequences, may depend on factors such as the selection of the host cell, the expression level of the desired protein, etc.

[0638] Generally, nucleic acids and / or expressions can be introduced into suitable host cells to generate recombinant host cells using any method suitable for the selected host cells (e.g., transformation, transfection, electroporation, infection), so that the nucleic acid molecule(s) are operably linked to one or more expression control elements (e.g., vectors, incorporation into the host cell genome from constructs generated by processes in the cells). The generated recombinant host cells can be maintained under conditions suitable for expression (e.g., in the presence of an inducer, in suitable non-human animals, in a suitable culture medium supplemented with appropriate salts, growth factors, antibiotics, nutritional supplements, etc.), thereby generating the polypeptide(s) encoded therein. In some cases, the heavy chain is generated in one cell and the light chain in another.

[0639] Mammalian cell lines available as hosts for expression, 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 many other cell lines, are known in the art and include many immortalized cell lines available from the American Type Culture Collection (ATCC), Manassas, VA USA. Non-mammalian cells, including but not limited to bacteria, yeast, insects, and plants, may also be used to express recombinant antibodies. In some embodiments, antibodies may be produced in transgenic animals such as cattle or chickens.

[0640] Exemplary and recombinant methods for antibody molecular biology, expression, purification and screening are disclosed, for example, in Antibody Engineering 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, the entirety of which is incorporated herein by reference.

[0641] In various embodiments, polynucleotide sequences encoding selected variable heavy and light chains can be used for genetic engineering to humanize antibodies or to improve the affinity or other properties of antibodies. Antibodies can also be customized for use in, for example, dogs, cats, primates, horses, and cattle.

[0642] In some embodiments, fully human antibodies can be obtained using commercially available mice engineered to express specific human immunoglobulin proteins. Transgenic animals designed to produce more desirable (e.g., fully human antibodies) or more potent immune responses may also be used for the production of humanized or human antibodies. Examples of such technologies are Xenomouse™ from Abgenix, Inc. (Fremont, Calif.) and HuMAb-Mouse® and TC Mouse™ from Medarex, Inc. (Princeton, NJ).

[0643] The immune checkpoint modulator antibody of the present disclosure can be recombinantly produced by first isolating the antibody and antibody-producing cells from a host animal, obtaining the gene sequence, and using the gene sequence to recombinantly express the antibody in host cells (e.g., CHO cells). Another method that can be used is to express antibody sequences in plants (e.g., tobacco) or yeast cells (e.g., Pichia pastoris or Sacchromyces cerevisiae). Methods for recombinantly expressing antibodies in plants or yeast have been disclosed. For example, Peeters, et al., Vaccine 19:2756, 2001; Lonberg, N. and D. Huszar, Int. Rev. Immunol 13:65, 1995; and Horwitz, AH et al., Proc. Natl. Acad. Sci. 85:8678-8682; the entire contents of which are incorporated herein by reference. Methods for preparing antibody derivatives, e.g., domains, single chains, etc., are known in the art.

[0644] Immunoassay methods such as fluorescence-activated cell sorting (FACS) and flow cytometry sorting methods can also be used to isolate antibodies specific to checkpoint molecules.

[0645] In some embodiments, the polynucleotide comprises a sequence encoding a variable region of the heavy chain and / or light chain of the checkpoint inhibitor antibody of the present disclosure or its antigen-binding fragment. The sequence encoding the antibody of interest or its antigen-binding fragment may be maintained as a vector in a host cell, and the host cell may then be expanded and frozen for subsequent use. Vectors (including expression vectors) and host cells are further described herein.

[0646] The present disclosure includes an affinity maturation checkpoint regulator antibody. For example, affinity-matured antibodies may be generated 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 method for characterizing the CDR of an antibody and / or altering (e.g., improving) the binding affinity of a polypeptide such as an antibody, referred to as "library scanning mutagenesis." An exemplary method providing an affinity-matured antibody and an antigen-binding fragment is to mature the antibody and, using methods recognized in the art, divide one or more amino acid positions in the CDR into two or more amino acids (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20). This may include substitutions. Clonal libraries are generated, each having a complexity of two or more members (where two or more amino acids are substituted at all positions). Typically, the libraries also include clones containing natural (unsubstituted) amino acids. A small number of clones, for example, about 20–80 clones (libraries), are screened from each library for binding affinity to a target polypeptide (or other binding target), and candidates with increased, equal, decreased, or no binding are identified. Methods for determining binding affinity are well known in the art. Binding affinity can be measured using Kinexa® biosensors, scintillation proximity assays, ELISA, ORIGEN® immunoassays, fluorescence extinction, fluorescence transition, and / or Biacore™ surface plasmon resonance assays to detect binding affinity differences of about twofold or more. Binding affinity can also be screened using suitable bioassays.Biacore™ is particularly useful when the starting antibody already binds to a relatively high affinity, for example, about 10 nM or less of KD. Subsequently, the clone library can be recombinantly introduced into a selected construct using any method known in the art for selection, including phage display, yeast display, and ribosome display.

[0647] Antibodies may also be modified, for example, in variable domains of heavy and / or light chains to alter the binding properties of the antibody. Changes in the variable domain may alter binding affinity and / or specificity. In some embodiments, one to five or fewer conservative amino acid substitutions are made within the CDR domain. In other embodiments, one to three or fewer conservative amino acid substitutions are made within the CDR domain. For example, mutations may be made in one or more CDR regions to increase or decrease the KD of the antibody against a checkpoint molecule, to increase or decrease the kon, or to alter the binding specificity of the antibody. Techniques for site-directed mutagenesis are well known in the art. See, for example, Sambrook et al. and Ausubel et al.

[0648] A pharmaceutical composition containing a compound of Formula I' according to the present disclosure will disperse an effective amount of the compound of Formula I', an immunotherapeutic agent, and / or both in a typically pharmaceutically acceptable carrier. The phrase “pharmaceutically or pharmacologically acceptable” means a molecular entity and composition that does not cause abnormal, allergic, or other involuntary reactions when administered to animals, e.g., humans. The preparation of a pharmaceutical composition containing a compound of Formula I' is known to those skilled in the art in light of the present invention, as illustrated in 18th Ed. Mack Printing Company, 1990, and it will also be understood that, in the case of administration to animals (e.g., humans), the formulation must meet standards of sterility, pyrogenicity, general safety, and purity. Specific examples of pharmacologically acceptable carriers for combination compositions containing a compound of Formula I' mixed with the immunotherapeutic agent described herein are borate buffers or sterile saline solutions (0.9% NaCl).

[0649] Immunotherapeutic agents, for example, formulations of immune checkpoint modulator antibodies used according to the present disclosure, may be prepared for storage in the form of lyophilized formulations or aqueous solutions and / or suspensions by sufficiently mixing antibodies of desired purity with any pharmaceutically acceptable carriers, excipients, or stabilizers described and exemplified in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed.

[1980] . Acceptable carriers, excipients, buffers, or stabilizers are non-toxic to the recipient at the dose and concentration used and include suitable aqueous and / or non-aqueous excipients that can be used in the pharmaceutical compositions of the present invention, such as water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by the use of coating materials such as lecithin, the maintenance of the required particle size in the case of dispersions, and the use of buffers such as surfactants, phosphates, and citrates, and other organic acids.Antioxidants include, for example, (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) fat-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, etc.; and (3) metal chelating agents such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.; Preservatives (e.g., octadecyldimethylbenzylammonium 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); may include low molecular weight (less than about 10 residues). Other exemplary pharmaceutically acceptable excipients include polypeptides; proteins such as serum albumin, gelatin, or immunoglobulin; hydrophilic polymers, e.g., polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrin; chelating agents, e.g., EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; It may include salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants, such as TWEEN™, PLURONICS™, or polyethylene glycol (PEG).

[0650] In one exemplary embodiment, the pharmaceutical composition may optionally contain pharmaceutically acceptable auxiliary substances, such as pH adjusters and buffers and toxicity-modifying substances, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, and sodium lactate, to approximate physiological conditions as needed. In some embodiments, the checkpoint inhibitor antibody or its antigen-binding fragment of the present disclosure may be formulated for storage and reconstitution with a suitable excipient before use and lyophilized according to known lyophilization and reconstitution techniques. In one exemplary pharmaceutical composition containing one or more checkpoint inhibitor antibodies or their antigen-binding fragments, the composition is formulated as a sterile, preservative-free solution of one or more checkpoint inhibitor antibodies or their antigen-binding fragments for intravenous or subcutaneous administration. The formulation may be supplied as a single-use, pre-filled pen containing, for example, about 1 mL of a pre-filled glass syringe, or as a single-use or single-use institutional vial. Preferably, the pharmaceutical composition containing a checkpoint inhibitor antibody or an antigen-binding fragment thereof is clear and colorless with a pH of about 6.9 to 5.0, preferably 6.5 to 5.0, and more preferably in the range of about 6.0 to about 5.0 pH. In various embodiments, a formulation comprising the pharmaceutical composition may contain about 500 mg to about 10 mg, or about 400 mg to about 20 mg, or about 300 mg to about 30 mg, or about 200 mg to about 50 mg of the checkpoint inhibitor antibody or its antigen-binding fragment per 1 mL of solution when reconstituted and administered to a subject. Exemplary injection or infusion excipients may include mannitol, citrate monohydrate, dibasic sodium phosphate dihydrate, monobasic sodium phosphate dihydrate, polysorbate 80, sodium chloride, sodium citrate, and water for parenteral administration, e.g., intravenously, intramuscularly, intraperitoneally, or subcutaneously.

[0651] In another exemplary embodiment, one or more immunotherapeutic agents or antigen-binding fragments thereof are 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 also more preferably, about 10-50 mg / mL, or even more preferably, about 10-40 mg / mL of antibody at a pH in the range of about 5 to 6 with sodium acetate, polysorbate 80, and sodium chloride. 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 an immunotherapeutic agent, e.g., an immune checkpoint inhibitor antibody or its antigen-binding fragment, in 20 mM sodium acetate, 0.2 mg / mL polysorbate 80, and 140 mM sodium chloride at pH 5.5. Additionally, the solution containing the checkpoint inhibitor antibody or its antigen-binding fragment may include, 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 art.

[0652] In one embodiment, the pharmaceutical composition of the present disclosure comprises the following components: 5-500 mg of the immunotherapeutic agent of the present disclosure or its antigen-binding fragment at pH 5.8 with or without a compound of formula I', 10 mM histidine, 5% sucrose, and 0.01% polysorbate 80. The composition may be provided as a lyophilized powder. When the powder is reconstituted in full volume, the composition has the same formulation. Alternatively, the powder may be reconstituted in half volume, in which case the composition comprises 10-500 mg of the immunotherapeutic agent of the present disclosure or its antigen-binding fragment at pH 5.8, 20 mM histidine, 10% sucrose, and 0.02% polysorbate 80.

[0653] In one embodiment, a portion of the dose is administered as an intravenous bolus and the remainder as an infusion of an immunotherapeutic agent. For example, an immunotherapeutic agent or its antigen-binding fragment in an intravenous injection of about 0.001 to about 200 mg / kg, for example, about 0.001 mg / kg to about 100 mg / kg, or about 0.001 mg / kg to about 50 mg / kg, or about 0.001 mg / kg to about 10 mg / kg, may be given as a bolus, and the remainder of the antibody dose may be administered as an intravenous injection. A preliminary dose of the immunotherapeutic agent or its antigen-binding fragment may be administered over a period of, for example, 2 to 5 hours.

[0654] In additional embodiments, a portion of the dose is administered by subcutaneous injection and / or by infusion in the form of a bolus, and the remainder is administered by infusion of an immunotherapeutic agent. In some exemplary doses, the immunotherapeutic agent may be administered subcutaneously in an intravenous injection dose range of about 0.001 to about 200 mg / kg, e.g., about 0.001 mg / kg to about 100 mg / kg, or about 0.001 mg / kg to about 50 mg / kg, or about 0.001 mg / kg to about 10 mg / kg of the immunotherapeutic agent, or its antigen-binding fragment. In some embodiments, the dose may be given as a given bolus, and the remainder of the immunotherapeutic agent dose may be administered subcutaneously or by intravenous injection. A preliminary dose of the immunotherapeutic agent, or its antigen-binding fragment, may be administered over a period of, for example, 2 to 5 hours.

[0655] The formulations of the present invention may also contain one or more active compounds necessary for the specific indication being treated, preferably compounds having complementary activities that do not have adverse effects on each other. For example, it may be desirable to provide one or more immunotherapies having different specificities. Alternatively, or additionally, the composition may include anti-inflammatory agents, chemotherapy agents, cytotoxic agents, cytokines, growth inhibitors, and / or small molecule antagonists. These molecules are suitably present in combination in amounts effective for the intended purpose.

[0656] Preparations used for in vivo administration must be sterile or nearly sterile. This is easily achieved by filtration through a sterile filter membrane.

[0657] In various embodiments, exemplary formulations of the pharmaceutical compositions described herein may be prepared using methods widely known in the field of pharmaceutical formulations. Generally, such preparation methods may include the step of associating an active ingredient with a carrier or one or more other auxiliary ingredients, and then, if preferred, packaging the product into desired single- or multiple-dose units.

[0658] In some embodiments, a composition comprising a compound of formula I' may also be delivered in a vesicle, and an immunotherapeutic agent may be delivered in the same liposomal formulation or in a separate formulation compatible with a liposomal formulation containing a compound of formula I', and in some exemplary examples, a liposome containing one or more liposomal surface portions, e.g., polyethylene glycol, an antibody and a fragment of the antibody thereof, which targets a desired tumor surface antigen, receptor, growth factor, glycoprotein, glycolipid, or neoantigen, which is selectively transported to a specific cell or organ to enhance targeted drug delivery.

[0659] In another embodiment, the compound of formula I' can be delivered within vesicles, particularly liposomes (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, NY, pp. 353-365 (1989); see Lopez-Berestein, ibid., pp. 317-327; generally see ibid.).

[0660] Also in another embodiment, a composition containing a compound of formula I' or a combination thereof, or a composition containing an immunotherapeutic agent, may be delivered to a controlled release system. In one embodiment, a pump may 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 embodiment, the controlled release of a compound of formula I' may comprise a polymeric material that provides delayed, intermediate, periodic, or alternating release (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-emission systems discussed in the review by Langer (Science 249:1527-1533 (1990)) can be used.

[0661] The optimal concentration of the active ingredient(s) in the selected medium can be determined experimentally according to procedures widely known to those skilled in the art and will vary depending on the desired final pharmaceutical formulation and the intended use.

[0662] The present invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the components of the pharmaceutical composition of the present invention, which will comprise at least a compound of Formula I' as described herein and one or more checkpoint inhibitor antibodies or their antigen-binding fragments. In other embodiments, the kit may contain one or more additional containers providing pharmaceutically acceptable excipients, e.g., diluents. In one embodiment, the kit may comprise one or more containers, which may comprise a compound of Formula I', a checkpoint inhibitor antibody, or their antigen-binding fragments. The kit may also include a set of instructions for preparing a final pharmaceutical composition and administering it to a subject in need for the treatment of a checkpoint molecular-mediated disease or disorder.

[0663] In some embodiments of the present disclosure, the immunotherapeutic agent is a population of immune cells, which may be administered in combination with a compound of Formula I' to treat a subject having cancer. In some embodiments, the immunotherapeutic agent is a population of immune cells, such as leukocytes (nuclear leukocytes), that possess (e.g., express) a receptor that binds to an antigen of interest. The leukocytes of the present disclosure may be, for example, neutrophils, eosinophils, basophils, lymphocytes, or monocytes. In some embodiments, the leukocytes are lymphocytes. Examples of lymphocytes include T cells, B cells, natural killer (NK) cells, or NKT cells. In some embodiments, the T cells are CD4+ Th (T helper) cells, CD8+ cytotoxic T cells, γδT cells, or regulatory (inhibitor) T cells. In some embodiments, the immune cells are dendritic cells.

[0664] In some embodiments, the immune cells of the present disclosure are genetically engineered to express antigen-binding receptors. Cells containing the engineered (exogenous) nucleic acid are considered to be "engineered." The engineered nucleic acid of the present disclosure may be introduced into the cell by any known (e.g., conventional) method. For example, engineered nucleic acids can be transfected by electroporation (e.g., see Heiser WC Transcription Factor Protocols: Methods in Molecular Biology.™. 2000; 130: 117-134), chemicals (e.g., calcium phosphate or lipids), transfection (e.g., see Lewis WH, 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 (e.g., see Schaffner W. Proc Natl Acad Sci USA. 1980 April; 77 (4): 2163-7), direct microinjection of purified DNA into the cell nucleus (e.g., see Capecchi MR Cell. 1980 November; 22 (2 Pt 2): 479-88), or retroviral transfection. It can be introduced into cells by introduction.

[0665] Some aspects of the present disclosure provide an “adoptive cell” approach involving isolating immune cells (e.g., T-cells) from a subject having cancer, genetically modifying the immune cells (e.g., to express an antigen-coupled receptor such as a chimeric antigen receptor), expanding the cells in vitro, and then reintroducing the immune cells to the subject. This method generates a greater number of modified immune cells in the subject compared to what can be achieved by conventional gene transfer and vaccination methods. In some embodiments, the immune cells are isolated from the subject, expanded in vitro without genetic modification, and then reintroduced to the subject.

[0666] The immune cells of the present disclosure comprise receptors that bind to antigens such as antigens encoded by exogenously delivered nucleic acids as provided herein. In some embodiments, leukocytes are modified (e.g., genetically modified) to express receptors that bind to antigens. In some embodiments, the receptors may be naturally occurring antigen receptors (generally expressed in immune cells), recombinant antigen receptors (not normally expressed in immune cells), or chimeric antigen receptors (CARs). Naturally occurring and recombinant antigen receptors included in the present invention include T cell receptors, B cell receptors, NK cell receptors, NKT cell receptors, and dendritic cell receptors. "Chimeric antigen receptor" refers to an artificial immune cell receptor engineered to recognize and bind to an antigen expressed by a tumor cell. Generally, CARs are designed for T cells and are chimeras of the signaling domain of the T-cell receptor (TcR) complex and the antigen-recognition domain (e.g., a single-chain fragment (scFv) of an antibody) (Enblad et al., Human Gene Therapy. 2015; 26(8):498-505), the entirety of which is incorporated herein by reference.

[0667] In some embodiments, the antigen-coupled receptor is a chimeric antigen receptor (CAR). T cells expressing a CAR are referred to as "CAR T cells." In some embodiments, the CAR T cell receptor comprises a signaling domain of a T-cell receptor (TcR) complex and an antigen-recognition domain (e.g., a single-chain fragment of an antibody (scFv)) (Enblad et al., Human Gene Therapy. 2015; 26 (8): 498-505). The entire disclosure thereof is incorporated herein by reference.

[0668] There are four generations of CARs, each containing different components. First-generation CARs bind antibody-derived scFvs to the CD3 zeta (zeta or z) intracellular signaling domain of the T-cell receptor via hinge and transmembrane domains. Second-generation CARs incorporate additional domains, e.g., CD28, 4-1BB (41BB), or ICOS, to deliver co-stimulatory signals. Third-generation CARs contain two co-stimulatory domains fused to the TcR CD3-zeta chain. The third-generation co-stimulatory domains may include, for example, a combination of CD3z, CD27, CD28, 4-1BB, ICOS, or OX40. In some embodiments, CAR contains an ectodomain (e.g., CD3) generally derived from a single-chain variable fragment (scFv), a hinge, a transmembrane domain, and an endodomain having one (first generation), two (second generation), or three (third generation) signaling domains derived from CD3Z and / or a co-stimulator (Maude et al., Blood. 2015; 125 (26): 4017-4023; Kakarla and Gottschalk, Cancer J. 2014; 20 (2): 151-155). The disclosure thereof is incorporated herein by reference in its entirety.

[0669] In some embodiments, the chimeric antigen receptor (CAR) is a T-cell directed toward universal cytokine apoptosis (TRUCK), also known as a fourth-generation CAR. TRUCK is a CAR-directed T-cell used as a vehicle to generate and release transgenic cytokines that accumulate in targeted tissues, e.g., targeted tumor tissues. Transgenic cytokines are released upon binding of the CAR to the target. TRUCK cells can deposit various therapeutic cytokines at the target. This results in therapeutic concentrations at the target site and can avoid systemic toxicity.

[0670] CARs typically differ in their functional characteristics. When combined, the CD3 zeta signaling domain of the T-cell receptor activates T-cells and induces proliferation, but it can induce anaphylacticity (which leads to the direct induction of peripheral lymphocyte tolerance due to a lack of response by the body's defense mechanisms). Lymphocytes are considered allergic if they do not respond to a specific antigen. The addition of a co-stimulatory domain to second-generation CARs improved the replication ability and persistence of modified T-cells. While similar antitumor effects are observed in vitro with CD28 or 4-1BB CARs, preclinical in vivo studies suggest that 4-1BB CARs can generate superior proliferation and / or persistence. Clinical trials suggest that while both of these second-generation CARs can induce substantial T-cell proliferation in vivo, CARs containing the 4-1BB co-stimulatory domain appear to be more sustained. Third-generation CARs enhance efficacy by combining multiple signaling domains (co-stimulators). Fourth-generation CARs are further modified with constitutive or inducible expression cassettes for transforming cytokines released by CAR T-cells to modulate T-cell responses. 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, the entire disclosure of which is incorporated herein by reference.

[0671] In some embodiments, the exemplary immunotherapeutic agent is a first-generation chimeric antigen receptor CAR. In some embodiments, the chimeric antigen receptor is a third-generation CAR. In some embodiments, the chimeric antigen receptor is a second-generation CAR. In some embodiments, the chimeric antigen receptor is a third-generation CAR. In some embodiments, the chimeric antigen receptor (CAR) is a fourth-generation CAR or a T-cell directed toward universal cytokine apoptosis (TRUCK).

[0672] In some embodiments, the chimeric antigen receptor (CAR) comprises an extracellular domain containing an antigen-binding domain, a transmembrane domain, and a cytoplasmic domain. In some embodiments, the CAR is entirely human. In some embodiments, the antigen-binding domain of the CAR is specific to one or more antigens. In some embodiments, a “spacer” domain or “hinge” domain is located between the extracellular domain (containing the antigen-binding domain) and the transmembrane domain of the CAR, or between the cytoplasmic domain and the transmembrane domain of the CAR. The “spacer domain” refers to any oligopeptide or polypeptide that functions to connect the transmembrane domain to the extracellular domain and / or cytoplasmic domain within the polypeptide chain. The “hinge domain” refers to any oligopeptide or polypeptide that functions to provide flexibility to the CAR or its domain, or to prevent steric interference of the CAR or its domain. In some embodiments, the spacer domain or hinge domain may contain up to 300 amino acids (e.g., 10 to 100 amino acids, or 5 to 20 amino acids). In some embodiments, one or more spacer domain(s) may be included within other regions of the CAR.

[0673] In some embodiments, the CAR of the present disclosure comprises an antigen-binding domain specific to a tumor antigen, such as a single-stranded Fv (scFv). The selection of the binding domain depends on the type and number of ligands defining the surface of the target cell. For example, the antigen-binding domain may be selected to recognize ligands that act as cell surface markers on target cells associated with specific disease states, such as cancer or autoimmune diseases. 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 disease cells. In some embodiments, the CAR is engineered to target a tumor antigen of interest by 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.

[0674] An antigen-binding domain (e.g., scFv) that "specifically binds" to a target or epitope is a term understood in the art, and methods for determining such specific binding are also known in the art. A molecule is said to exhibit "specific binding" if it reacts with a specific target antigen with a greater duration and / or greater affinity than with an alternative target, or if it reacts more frequently and more rapidly. An antigen-binding domain (e.g., scFv) that specifically binds to a first target antigen may or may not specifically bind to a second target antigen. Therefore, "specific binding" does not necessarily require exclusive binding (although it may include it).

[0675] In some embodiments, immune cells expressing the CAR are genetically modified to recognize multiple targets or antigens, allowing for the recognition of unique target or antigen expression patterns on tumor cells. Examples of CARs capable of binding to multiple targets include: a "split signal CAR" that limits complete immune cell activation against tumors expressing multiple antigens; a "tandem CAR" (TanCAR) containing an ectodomain with two scFvs; and a "universal ectodomain CAR" containing an avidin or fluorescein isothiocyanate (FITC)-specific scFv to recognize tumor cells cultured with tagged monoclonal antibodies (Mabs).

[0676] A CAR is considered "bispecific" if it recognizes two distinct antigens (having two distinct antigen recognition domains). In some embodiments, a bispecific CAR consists of two distinct antigen recognition domains existing in tandem on a single transgenic receptor (referred to as TanCAR; see, e.g., Grada Z et al. Molecular Therapy Nucleic Acids 2013; 2: e105, the whole of which is incorporated herein by reference). Accordingly, in some embodiments, a method comprises delivering a combination comprising a compound of formula I' and an immunotherapeutic agent to a tumor, wherein the immunotherapeutic agent is an engineered nucleic acid encoding an antigen, or delivering an engineered nucleic acid that induces the expression of a self-antigen to the tumor, and delivering an immune cell expressing a bispecific CAR that binds to two antigens to the tumor, one of which is encoded by the engineered nucleic acid.

[0677] In some embodiments, the CAR is an antigen-specific inhibitory CAR (iCAR) that can be used, for example, to avoid extratumor toxicity (Fedorov, VD et al., Sci. Transl. Med. Published Online Dec., 11, 2013, the full contents of which are incorporated herein by reference). The iCAR contains an antigen-specific inhibitory receptor to block, for example, non-specific immunosuppression, which may occur through additional tumor target expression. The iCAR may be based, for example, on the inhibitory molecules CTLA-4 or PD-1. In some embodiments, these iCARs block the T cell response from their endogenous T cell receptor or from T cells activated by the activating CAR. In some embodiments, this inhibitory effect is transient.

[0678] In some embodiments, CARs may be used for adoptive cell delivery, wherein immune cells are removed from a subject and modified to express receptors specific to antigens, e.g., tumor-specific antigens. The modified immune cells, capable of recognizing and killing 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, each of which is incorporated herein by reference in its entirety).

[0679] According to another aspect of the present disclosure, the tumor antigen component in the vaccine of the present invention is any natural or synthetic tumor-associated protein or peptide or a combination of tumor-associated protein and / or peptide or glycoprotein or glycopeptide. In another aspect, the antigenic component may be patient-specific or common to many or most patients with a specific type of cancer. According to one aspect, the antigenic component consists of a cell lysate derived from tumor tissue removed from a patient being treated. In another aspect, the lysate may 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 tumor cell lines.

[0680] In various embodiments, the exemplary immunotherapeutic agent comprises one or more cancer vaccines for use in combination with a compound of Formula I'. The tumor-associated antigen components of the vaccine may be prepared by any various known techniques. For individual protein components, the antigenic proteins are isolated from tumor tissue or tumor cell lines by standard chromatographic means, such as high-pressure liquid chromatography or affinity chromatography, or synthesized by standard recombinant DNA techniques in a suitable expression system, such as E. coli, yeast, or plants. Subsequently, the tumor-associated antigenic proteins are purified from the expression system by standard chromatographic means. For peptide antigen components, they are generally prepared by standard automated synthesis. Proteins and peptides may be modified by adding amino acids, lipids, and other agents to improve incorporation into the vaccine's delivery system (e.g., multilamellar liposomes). The tumor-associated antigen components derived from the patient's own tumor, or tumors from other individuals or cell lines, tumor tissue, or single-cell suspensions derived from tumor tissue are typically homogenized in a suitable buffer. The homogenate can also be fractionated by centrifugation to separate specific cellular components, such as cell membranes or soluble substances. Tumor material can be used directly, or tumor-associated antigens can be extracted to be incorporated into a vaccine using a buffer containing a low concentration of a suitable agent, such as a detergent. An example of a detergent suitable for extracting antigen proteins from tumor tissue, tumor cells, and tumor cell membranes is diheptanoyl phosphatidylcholine. Exosomes derived from tumor tissue or tumor cells, whether autologous or xenogeneic, can be used as starting materials for the extraction of antigen components or tumor-associated antigens to be included in a vaccine.

[0681] In some embodiments of the present disclosure, a cancer vaccine, wherein the cancer vaccine comprises one or more tumor-associated antigens, one or more immunostimulators, and optionally one or more cell-based immunotherapies. In some embodiments, the immunostimulator component of the cancer vaccine of the present disclosure is any biological response modifier (BRM) capable of enhancing the efficacy of the therapeutic cancer vaccine by inducing humoral and cellular immune responses against the patient's cancer cells. According to one aspect, the immunostimulator is a cytokine or a combination of cytokines. Examples of such cytokines include interferons, e.g., IFN-gamma; interleukins, e.g., IL-2, IL-15, and IL-23; colony-stimulating factors, e.g., M-CSF and GM-CSF; and tumor necrosis factor. According to another aspect, the immunostimulator component of the disclosed cancer vaccine comprises one or more adjuvant-type immunostimulators, such as APC Toll-like receptor agonists or co-stimulatory / cell adhesion membrane proteins, in the presence or absence of immunostimulatory cytokines. Examples of Toll-like receptor agonists include lipids A and CpG, and co-stimulatory / adhesion proteins, such as CD80, CD86, and ICAM-1.

[0682] In some embodiments, the immunostimulator 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, T effector cells modified with a chimeric antigen receptor for the patient's tumor type, B lymphocytes, natural killer cells, myeloid cells, and any other cells of the patient's immune system, or combinations thereof. In one aspect, the cancer vaccine immunostimulator comprises one or more cytokines, such as interleukin 2 (IL-2), GM-CSF, M-CSF, and interferon-gamma (IFN-γ), 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 co-stimulating membrane proteins and / or cell adhesion proteins, such as CD80, CD86, and ICAM-1, or all combinations of the above. In one aspect, the cancer vaccine comprises an immunostimulator that is a cytokine selected from the group consisting of interleukin 2 (IL-2), GM-CSF, M-CSF, and interferon-gamma (IFN-γ). In another aspect, the cancer vaccine comprises an immunostimulator 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 conjugates and double-stranded RNA. Also in another aspect, the cancer vaccine comprises an immunostimulator that is a co-stimulating membrane protein and / or cell adhesion protein selected from the group consisting of CD80, CD86, and ICAM-1.

[0683] In various embodiments, the immunotherapeutic agent may comprise a cancer vaccine, wherein the cancer vaccine comprises any cancer antigen that can potentially be used to produce a fusion protein according to the present invention, and particularly comprises the following:

[0684] (a) Cancer-testicular antigens including NY-ESO-1, SSX2, SCP1, as well as RAGE, BAGE, GAGE, and MAGE family polypeptides, e.g., GAGE-1, GAGE-2, MAGE-1, MAGE-2, MAGE-3, MAGE-4, MAGE-5, MAGE-6, and MAGE-12, which may be used to treat, e.g., melanoma, lung, head and neck, NSCLC, breast, gastrointestinal, and bladder cancers; (b) various solid cancers, e.g., p53 associated with colon, lung, head and neck cancers; e.g., p21 / Ras associated with melanoma, pancreatic cancer, and colon cancer; e.g., CDK4 associated with melanoma; e.g., MUM1 associated with melanoma; e.g., casp-8 associated with head and neck cancer; e.g., CIA 0205 associated with bladder cancer; (c) Mutant antigens including HLA-A2-R1701, e.g., beta-catenin associated with melanoma; e.g., TCR associated with T-cell non-Hodgkin lymphoma; e.g., BCR-abl associated with chronic myeloid leukemia; triosephosphate isomerase; KIA 0205; CDC-27, and LDLR-FUT; (c) Galectin 4 associated with colorectal cancer; e.g., Galectin 9 associated with Hodgkin's disease; e.g., proteinase 3 associated with chronic myeloid leukemia; e.g., WT 1 associated with various leukemias; e.g., carbonic anhydrase associated with renal cancer; e.g., aldolase A associated with lung cancer; e.g., PRAME associated with melanoma; e.g., HER-2 / neu associated with breast, colon, lung, and ovarian cancers; mammaglobin, e.g., alpha-fetoprotein associated with hepatoma; For example, KSA associated with colorectal cancer; for example, Gastrin associated with pancreatic and gastric cancer; telomerase catalytic proteins, for example, MUC-1 associated with breast and ovarian cancer; for example, G-250 associated with renal cell carcinoma; for example, p53 associated with breast and colorectal cancer;And, for example, overexpressed antigens including carcinoembryonic antigens associated with breast cancer, lung cancer and gastrointestinal cancer, e.g., colorectal cancer; (d) melanoma-melanocyte differentiation antigens such as MART-1 / Melan A; gpl00; MC1R; melanocyte-stimulating hormone receptor; tyrosinase; covalent antigens including, for example, melanoma-associated tyrosinase-associated protein-1 / TRP1 and tyrosinase-associated protein-2 / TRP2; (e) prostate-associated antigens including, for example, prostate cancer, PAP, PSA, PSMA, PSH-P1, PSM-P1, PSM-P2; (f) immunoglobulin genotypes associated with myeloma and B-cell lymphoma. In a specific embodiment, one or more TAAs are human papillomavirus (HPV) antigens including pi 5, Hom / Mel-40, H-Ras, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Epstein-Barr virus antigen, EBNA, E6 and E7, hepatitis B and C virus antigens, human T-cell lymphotropic virus antigen, TSP-180, pl85erbB2, pl80erbB-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 It may be selected from 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 / cyclophyllin C-related protein), TAAL6, TAG72, TLP, TPS, or any combination thereof.;

[0685] In some embodiments, the cancer vaccine of the present disclosure for use in combination with a compound of formula I' may comprise a whole amino acid sequence containing a cancer antigen, a portion thereof, or a specific immunogenic epitope of one of the following human proteins: TCTN1 (Genetic ID: ENSG00000204852), TCTN2 (Genetic ID: ENSG00000168778), TCTN3 (Genetic ID: ENSG00000119977), HIGD2A (Genetic ID: ENSG00000146066), HIGD2B (Genetic ID: ENSG00000175202), C4ORF32 (Genetic ID: ENSG00000174749), FAM62A (E-SYT1, Genetic ID: ENSG00000139641), COLEC11 (Genetic 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 a combination thereof. These cancer antigens are disclosed in WO2010 / 086162, WO2010 / 086163, WO2011 / 051278, WO2011 / 051276, WO2011 / 051277, WO2011 / 051280, WO2011 / 051271, WO2011 / 135068, and WO2014 / 198919, the contents of which are incorporated herein by reference in their entirety.

[0686] In various embodiments, the exemplary immunotherapeutic agent may comprise mRNA capable of encoding any one or more of the aforementioned cancer antigens useful for synthesizing a cancer vaccine. In some exemplary embodiments, the mRNA-based cancer vaccine may have one or more of the following characteristics: a) the mRNA encoding each cancer antigen is interspersed by cleavage-sensitive sites; b) the mRNA encoding each cancer antigen is directly linked to each other without a linker; c) the mRNA encoding each cancer antigen is linked to each other by a single nucleotide linker; d) each cancer antigen contains 20-40 amino acids and contains a centrally located SNP mutation; e) at least 40% of the cancer antigens have the highest affinity for class I MHC molecules from the subject; f) at least 40% of the cancer antigens have the highest affinity for class II MHC molecules from the subject; g) at least 40% of the cancer antigens have a predicted binding affinity of IC > 500 nM for HLA-A, HLA-B, and / or DRB1; h) mRNA encodes 1 to 15 cancer antigens; i) 10-60% of the cancer antigens have binding affinities for class I MHC, and 10-60% of the cancer antigens have binding affinities for class II MHC; and / or j) mRNA encoding the cancer antigens is arranged so that the cancer antigens are aligned to minimize pseudo-epitopes.

[0687] In various embodiments, combinations comprising the compound of Formula I' disclosed herein and a cancer vaccine immunotherapeutic agent may be used to induce an immune response in a subject to a cancer antigen. The method comprises the step of administering to a subject an RNA vaccine comprising one or more RNA polynucleotides having an open reading frame encoding one or more antigen polypeptides or immunogenic fragments thereof, or administering the compound of Formula I' in the same composition or in separate compositions, or administering simultaneously or sequentially, and inducing an immune response specific to the antigen polypeptide or immunogenic fragment in the subject, wherein the anti-antigen polypeptide antibody titer in the subject increases after vaccination compared to the anti-antigen polypeptide antibody titer in a subject vaccinated with a conventional vaccine of a prophylactically effective dose against cancer. "Anti-antigen polypeptide antibody" is a serum antibody that specifically binds to the antigen polypeptide.

[0688] The prophylactic effective dose is a therapeutic effective dose that prevents the progression of cancer at a clinically acceptable level. In some embodiments, the therapeutic effective dose is the dose listed in the package insert of the vaccine. As used herein, the term "prior vaccine" refers to a vaccine other than the mRNA vaccine of the present invention. For example, prior vaccines include, but are not limited to, live microbial vaccines, inactivated microbial vaccines, subunit vaccines, protein antigen vaccines, DNA vaccines, etc. In exemplary embodiments, prior vaccines are vaccines that have obtained regulatory approval and / or are registered by a national drug regulatory agency, e.g., the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA).

[0689] In some embodiments, the anti-antigen polypeptide antibody titer in subjects increases by 1 log to 10 log after vaccination compared to the anti-antigen polypeptide titer in subjects vaccinated with a prophylactic effective amount of a traditional vaccine for cancer. In some embodiments, the anti-antigen polypeptide antibody titer in subjects increases by 1 log after vaccination compared to the anti-antigen polypeptide titer in subjects vaccinated with a prophylactic effective amount of a traditional vaccine for cancer. In some embodiments, the anti-antigen polypeptide antibody titer in subjects increases by 2 log after vaccination compared to the anti-antigen polypeptide titer in subjects vaccinated with a prophylactic effective amount of a traditional vaccine for cancer.

[0690] An aspect of the present invention provides a nucleic acid vaccine comprising one or more RNA polynucleotides having an open read frame encoding a first antigen polypeptide, wherein the RNA polynucleotides are present in a formulation for in vivo administration to a host, which imparts an antibody titer superior to the standard for serum protection against the first antigen for an acceptable percentage of human subjects. In some embodiments, the antibody titer produced by the mRNA vaccine of the present invention is a neutralizing antibody titer. In some embodiments, the neutralizing antibody titer is greater than that of the protein vaccine. In other embodiments, the neutralizing antibody titer produced by the mRNA vaccine of the present invention is greater than that of the auxiliary protein vaccine. In another embodiment, the neutralizing antibody titer generated by the mRNA vaccine of the present invention is 1,000-10,000, 1,200-10,000, 1,400-10,000, 1,500-10,000, 1,000-5,000, 1,000-4,000, 1,800-10,000, 2000-10,000, 2,000-5,000, 2,000-3,000, 2,000-4,000, 3,000-5,000, 3,000-4,000, or 2,000-2,500. The neutralizing titer is typically expressed as the highest serum dilution required to achieve a 50% reduction in the number of plaques.

[0691] In a preferred embodiment, the RNA vaccine immunotherapeutic agent of the present disclosure (e.g., mRNA vaccine) produces a prophylactic and / or therapeutically effective level, concentration, and / or titer of antigen-specific antibodies in the blood or serum of a vaccinated subject. As defined herein, the term antibody titer refers to the amount of antigen-specific antibodies produced in a subject, e.g., a human subject. In exemplary embodiments, the antibody titer is expressed as the reciprocal of the maximum dilution (as a series of dilutions) that still yields a positive result. In exemplary embodiments, the antibody titer is determined or measured by an enzyme-linked immunosorbent assay (ELISA). In exemplary embodiments, the antibody titer is determined or measured by a neutralization assay, e.g., a micro-neutralization assay. In certain embodiments, antibody titer measurements are expressed in ratios such as 1:40, 1:100, etc. In certain embodiments, antibody titer measurements are expressed in ratios such as 1:40, 1:100, etc.

[0692] In an exemplary embodiment of the present invention, the effective vaccine produces antibody titers greater than 1:40, greater than 1:100, greater than 1:400, greater than 1:1000, greater than 1:2000, greater than 1:3000, greater than 1:4000, greater than 1:500, greater than 1:6000, greater than 1:7500, and greater than 1:10000. In an exemplary embodiment, antibody titers are produced or reached by 10 days after vaccination, 20 days after vaccination, 30 days after vaccination, 40 days after vaccination, or 50 days or more after vaccination. In an exemplary embodiment, titers are produced or reached according to a single dose of vaccine administered to the subject. In another embodiment, titers are produced or reached after multiple doses, e.g., a first and second dose (e.g., a booster dose). In an exemplary aspect of the present invention, antigen-specific antibodies are measured in units of g / ml or in IU / L (International Unit per liter) or mIU / ml (ml per milliliter). In an exemplary embodiment of the present invention, an effective vaccine produces >0.5 μg / mL, >0.1 μg / mL, >0.2 μg / mL, >0.35 μg / mL, >0.5 μg / mL, >1 μg / mL, >2 μg / mL, >5 μg / mL, or >10 μg / mL. In an exemplary embodiment of the present invention, an effective vaccine produces >10 mIU / mL, >20 mIU / mL, >50 mIU / mL, >100 mIU / mL, >200 mIU / mL, >500 mIU / ml, or >1000 mIU / ml. In an exemplary embodiment, the antibody level or concentration is generated or reached by 10 days after vaccination, 20 days after vaccination, 30 days after vaccination, 40 days after vaccination, or 50 days or more after vaccination. In an exemplary embodiment, the level or concentration is generated or reached according to a single dose of vaccine administered to the subject.In other embodiments, the level or concentration is generated or reached after multiple doses, e.g., a first and second dose (e.g., a booster dose). In exemplary embodiments, the antibody level or concentration is determined or measured by an enzyme-linked immunosorbent assay (ELISA). In exemplary embodiments, the antibody level or concentration is determined or measured by a neutralization assay, e.g., a microneutralization assay. Additionally, a nucleic acid vaccine is provided comprising one or more RNA polynucleotides having an open read frame encoding a first antigenic polypeptide or a sequence-identical polypeptide, wherein the RNA polynucleotides have a stabilizing element or are formulated with an adjuvant and are present in a formulation for in vivo administration to induce high antibody titers that persist longer than the antibody titers induced by an mRNA vaccine encoding the first antigenic polypeptide. In some embodiments, the RNA polynucleotides are formulated to generate neutralizing antibodies within one week of a single administration. In some embodiments, the adjuvant is selected from cationic peptides and immunostimulating nucleic acids. In some embodiments, the cationic peptide is protamine.

[0693] Immunotherapeutic agent comprising a nucleic acid vaccine comprising one or more RNA polynucleotides having an open reading frame that does not include one or more chemical modifications or optionally nucleotide modifications, wherein the open reading frame encodes a first antigen polypeptide or a sequence-identical polypeptide, the RNA polynucleotides are present in a formulation for in vivo administration to a host such that the antigen expression level in the host is formed with a stabilizing element or adjuvant and significantly exceeds the antigen expression level produced by an mRNA vaccine encoding the first antigenic polypeptide.

[0694] Another aspect provides a nucleic acid vaccine comprising one or more RNA polynucleotides having an open reading frame that includes at least one chemical modification or optionally does not include a nucleotide modification, said open reading frame encoding a first antigen polypeptide or a sequence-identical polypeptide, wherein the vaccine has at least 10 times fewer RNA polynucleotides than is required for an unmodified mRNA vaccine to produce an equivalent antibody titer. In some embodiments, the RNA polynucleotides are present at a dose of 25 to 100 micrograms.

[0695] An aspect of the present invention also provides a unit vaccine for use formulated for delivery to a human subject, comprising 10 to 400 μg of one or more RNA polynucleotides having an open reading frame that includes one or more chemical modifications or optionally does not include nucleotide modifications, and a pharmaceutically acceptable carrier or excipient, wherein the open reading frame encodes a first antigen polypeptide or a sequence-identical polypeptide. In some embodiments, the vaccine further comprises cationic lipid nanoparticles.

[0696] An aspect of the present invention provides a method for generating, maintaining, or restoring antigenic memory in a tumor in an individual or population, comprising the step of administering to an individual or population an antigenic memory booster nucleic acid vaccine comprising (a) at least one RNA polynucleotide, said polynucleotide having no one or more chemical modifications or optionally nucleotide modifications and comprising two or more codon-optimized open reading frames, said open reading frames encoding a series of reference antigen polypeptides, and (b) optionally a pharmaceutically acceptable carrier or excipient. In some embodiments, the vaccine is administered to the individual via a route selected from the group consisting of intramuscular administration, intradermal administration, and subcutaneous administration. In some embodiments, the administration step comprises bringing the muscle tissue of the subject into contact with a device suitable for injection of the composition. In some embodiments, the administration step comprises bringing the muscle tissue of the subject into contact with a device suitable for injection of the composition in combination with electroporation.

[0697] An aspect of the present invention provides a method for vaccinating a subject comprising administering to the subject a single dose of a nucleic acid vaccine comprising 25 μg / kg to 400 μg / kg, the dose comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide or a sequence-identical polypeptide, an effective amount for vaccinating the subject.

[0698] Another aspect provides a nucleic acid vaccine comprising one or more RNA polynucleotides having an open read frame comprising one or more chemical modifications, wherein the open read frame encodes a first antigen polypeptide or a sequence-identical polypeptide, wherein the vaccine has at least 10 times fewer RNA polynucleotides than is required for an unmodified mRNA vaccine to produce an equivalent antibody titer. In some embodiments, the RNA polynucleotides are present at a dose of 25 to 100 micrograms.

[0699] In some embodiments, the exemplary immunotherapeutic agent may comprise one or more interfering RNAs that can be administered in combination with a compound of formula I'. As used herein, "RNA interfering agent" is defined as any agent that interferes with or inhibits the expression of a target biomarker gene by RNA interference (RNAi). Such RNA interfering agents inhibit the expression of a target biomarker nucleic acid by nucleic acid molecules comprising RNA molecules homologous to the target biomarker gene of the present invention, or fragments thereof, short interfering RNA (siRNA), and / or RNA interference (RNAi). Short interfering RNA (siRNA), also referred to herein as “small interfering RNA,” is defined as an agent that functions to inhibit the expression of target biomarker nucleic acids, for example, by RNAi. siRNA can be chemically synthesized or generated within a host cell. In one embodiment, the siRNA is a double-stranded RNA (dsRNA) molecule having a length of about 15 to about 40 nucleotides, preferably about 15 to about 28 nucleotides, more preferably about 19 to about 25 nucleotides, more preferably about 19, 20, 21, or 22 nucleotides, and may include a 3' and / or 5' overhang on each strand having a length of about 0, 1, 2, 3, 4, or 5 nucleotides. The length of the overhang is independent between the two strands, that is, the overhang length of one strand does not depend on the overhang length of the second strand. Preferably, the siRNA is for the degradation of target messenger RNA (mRNA) or RNA interference can be promoted through specific post-transcriptional gene silencing (PTGS).

[0700] Antisense oligonucleotides may be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 or more nucleotides in length. Antisense nucleic acids may be constructed using chemical synthesis and enzymatic ligation reactions using procedures known in the art. For example, antisense nucleic acids (e.g., antisense oligonucleotides) may be chemically synthesized using naturally occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecule or increase the physical stability of the dimer formed between the antisense and sense nucleic acids, for example, phosphorothioate derivatives and acridine-substituted nucleotides may be used. Examples of modified nucleotides that can be used to produce antisense nucleic acids are 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxymethyl)uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosin, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, Includes 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosin, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetate (v), ybutoxosin, pseudouracil, queosin, 2-thiocytosin, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetate methyl ester, uracil-5-oxyacetate (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl)uracil, (acp3)w, and 2,6-diaminopurine.Alternatively, antisense nucleic acids can be biologically produced using an expression vector in which the nucleic acid is subcloned with an antisense orientation (i.e., the RNA transcribed from the inserted nucleic acid will be antisense oriented toward the target nucleic acid, which is described in detail in the following subsection).

[0701] The antisense nucleic acid molecules of the present invention are typically administered to a target or generated in situ so that they hybridize or bind to cellular mRNA and / or genomic DNA encoding a polypeptide corresponding to a selected marker of the present invention, thereby inhibiting the expression of the marker, for example, by inhibiting transcription and / or translation. Hybridization may form a stable dimer by conventional nucleotide complementarity, or, in the case of the antisense nucleic acid molecule, bind to a DNA dimer through specific interactions, for example, in the major groove of the double helix. Examples of routes of administration of the antisense nucleic acid molecules of the present invention include direct injection into a tissue site or infusion of the antisense nucleic acid into blood or bone marrow-related fluids. Alternatively, the antisense nucleic acid molecules may be systemically administered after being modified to target selected cells. For example, in the case of systemic administration, the antisense molecules may be modified to specifically bind to a receptor or antigen expressed on the surface of a selected cell, for example, by linking the antisense nucleic acid molecule to a peptide or antibody that binds to a cell surface receptor or antigen. The antisense nucleic acid molecules may also be delivered to cells using the vectors described herein. To achieve a sufficient intracellular concentration of the antisense molecule, a vector construct in which the antisense nucleic acid molecule is placed under the control of a strong pol II or pol III promoter is preferred.

[0702] The antigen that can be targeted to synthesize the corresponding antisense RNA molecule may include any antigen specific to one or more tumors, for example, the antigen exemplified above in relation to a cancer vaccine.

[0703] In some embodiments, the combination of an immunotherapeutic agent and a compound of formula I' may comprise a bispecific antibody immunotherapeutic agent. The bispecific antibody may comprise a protein construct having a first antigen-binding portion and a second antigen-binding site that binds to cytotoxic immune cells. The first antigen-binding site may bind to a tumor antigen specifically treated by the combination of the present invention. For example, the first antigen-binding moiety may bind to non-restrictive examples of cancer antigens selected from the following: in particular EGFR, HGFR, Her2, Ep-CAM, CD20, CD30, CD33, CD47, CD52, CD133, CEA, gpA33, Mucins, TAG-72, CIX, PSMA, folate-binding protein, GD2, GD3, GM2, VEGF. VEGFR, Integrin αVβ3, Integrin α5β1, MUC1, ERBB2, ERBB3, MET, IGF1R, EPHA3, TRAILR1, TRAILR2, RANKL, FAP, and Tenascin. In some embodiments, the first antigen-binding portion is specific to a protein or peptide that is overexpressed in tumor cells compared to corresponding non-tumor cells. In some embodiments, the first antigen-binding portion is specific to a protein that is overexpressed in tumor cells compared to corresponding non-tumor cells. As used herein, "corresponding non-tumor cells" refers to non-tumor cells of the same cell type as the origin of the tumor cells. It should be noted that these proteins are not necessarily different from the tumor antigens.Non-limiting examples include the Carcinocyte Embryonic Antigen (CEA), which is overexpressed in most colorectal, rectal, breast, lung, pancreatic, and gastrointestinal carcinomas; the Heregulin receptor (HER-2, neu, or c-erbB-2), which is overexpressed in breast, ovarian, colon, lung, prostate, and cervical cancers; the Epidermal Growth Factor Receptor (EGFR), which is highly expressed in various solid tumors, including tumors of the breast, head and neck, non-small cell lung, and prostate; the Asian glycoprotein receptor; the Transferrin receptor; the Serpinase Complex receptor, which is expressed in hepatocytes; the Fibroblast Growth Factor Receptor (FGFR), which is overexpressed in pancreatic ductal adenocarcinoma cells; the Vascular Endothelial Growth Factor Receptor (VEGFR) for anti-angiogenic gene therapy; the Folate receptor, which is selectively overexpressed in 90% of non-point-carcinogenic ovarian carcinomas; cell surface glycocalyxes; carbohydrate receptors; and polymeric immunoglobulin receptors.

[0704] The second antigen-binding moiety is any molecule that specifically binds to an antigen, protein, or polypeptide expressed on the surface of a cytotoxic immune cell (CIK cell). Exemplary non-restriction antigens expressed on the surface of cytotoxic immune cells suitable for use in the present disclosure may include CD2, CD3, CD4, CD5, CD8, CD11a, CD11b, CD14, CD16a, CD27, CD28, CD45, CD45RA, CD56, CD62L, Fc receptor, LFA, LFA-1, TCRαβ, CCR7, macrophage inflammatory protein 1a, perforin, 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, CD27 and Fas ligands. In some embodiments, the second antigen-binding portion binds to CD3 of cytotoxic immune cells, e.g., CIK cells. In some embodiments, the second antigen-binding portion binds to CD56 of cytotoxic immune cells. In some embodiments, the second antigen-binding portion binds to the Fc receptor of cytotoxic immune cells. In some embodiments, the Fc region of the bispecific antibody binds to the Fc receptor of cytotoxic immune cells. In some embodiments, the second antigen-binding moiety is any molecule that specifically binds to an antigen expressed on the surface of a cytotoxic immune cell (e.g., CIK cell). The second antigen-binding portion is specific to the antigen on the cytotoxic immune cell. Exemplary cytotoxic immune cells include, but are not limited to, CIK cells, T-cells, CD8+ T cells, activated T-cells, monocytes, natural killer (NK) cells, NK T cells, lymphokine-activated killer (LAK) cells, macrophages, and dendritic cells.The second antigen-binding portion specifically binds to antigens expressed on the surface of cytotoxic immune cells. Exemplary non-restriction antigens expressed on the surface of cytotoxic immune cells suitable for control in the present disclosure may include CD2, CD3, CD4, CD5, CD8, CD11a, CD11b, CD14, CD16a, CD27, CD28, CD45, CD45RA, CD56, CD62L, Fc receptor, LFA, LFA-1, TCRαβ, CCR7, macrophage inflammatory protein 1a, perforin, 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, CD27 and Fas ligands. In another embodiment, the bispecific antibody modulator is an activator of a co-stimulatory molecule (e.g., an OX40 agonist). In one embodiment, the OX40 agonist is a bispecific antibody molecule against OX40 and another cancer antigen or co-stimulatory antigen. The OX40 agonist may be administered alone or in combination with other immunomodulators, for example, in combination with inhibitors of PD-1, PD-L1, CTLA-4, CEACAM (e.g., CEACAM-1, -3 and / or -5), TIM-3, or LAG-3 (e.g., antibody constructs). In some embodiments, the anti-OX40 antibody molecule is a bispecific antibody that binds to GITR and PD-1, PD-L1, CTLA-4, CEACAM (e.g., CEACAM-1, -3 and / or -5), TIM-3, or LAG-3. In one exemplary embodiment, an OX40 antibody molecule is administered in combination with an anti-PD-1 antibody molecule (e.g., an anti-PD-1 molecule as described herein). The OX40 antibody molecule and the anti-PD-1 antibody molecule may be in the form of separate antibody compositions or as bispecific antibody molecules.In other embodiments, the OX40 agonist may be administered in combination with other co-stimulatory molecules, e.g., GITR, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, or CD83 ligand agonists. In some embodiments, it is a second antigen-binding moiety that binds to an Fc receptor on cytotoxic immune cells, e.g., CIK cells.

[0705] In some embodiments, the bispecific antibody immunotherapeutic agent has specificity for tumor antigens and CIK cells, which brings tumor antigen-expressing tumor cells into proximity to CIK cells and eliminates the tumor cells through the anti-tumor cytotoxicity of CIK cells. In some embodiments, the bispecific antibody has specificity for tumor antigens but not for CIK cells, but the Fc region of the bispecific antibody can bind to the Fc receptor of CIK cells, which ultimately brings the tumor cells into proximity to CIK cells and eliminates the tumor cells through the anti-tumor cytotoxicity of CIK cells. In some embodiments, the bispecific antibody has specificity for CIK cells but not for tumor cells, but the Fc region of the bispecific antibody can bind to the Fc receptor of tumor cells, which ultimately brings the tumor cells into proximity to CIK cells and eliminates the tumor cells through the anti-tumor cytotoxicity of CIK cells.

[0706] In some embodiments, the combination of the immunotherapeutic agent and the compound of Formula I' may comprise an immune cell-binding multivalent antibody / fusion protein / composite immunotherapeutic agent. In various embodiments, the exemplary immunotherapeutic agent may comprise an immune cell-binding multivalent antibody / fusion protein / composite agent that may include a recombinant structure, e.g., any engineered antibody that does not mimic the original IgG structure. Here, different strategies are used to multimerize the antibody fragments. For example, shortening the peptide linker between the V domains causes scFv to self-couple into a dimer (diabodies; 55 kDa). Bispecific diabodies are formed by the non-covalent bonding of two VHA-VLB and VHB-VLA fragments expressed in the same cell. This results in the formation of a heterodimer having two different binding sites. Single-stranded diabodies (sc-diabodies) are bispecific molecules in which the VHA-VLB and VHB-VLA fragments are linked together by an additional third linker. Tandem-diabodies (Tandabs) are tetravalent bispecific antibodies produced by two scDiabodies.

[0707] D-diabodies known in the art are also included. This 130-kDa molecule is formed by fusing the diabody to the N-terminus of the CH3 domain of IgG to create an IgG-like structure. Additional diabody derivatives are triabadies and tetrabodies, which fold into trimer and tetramer fragments by shortening the linker to <5 or 0-2 residues. Also exemplified is the (scFv)2 construct known as the 'Bispecific T Cell Binder' (BITE). BITE is a bispecific single-stranded antibody consisting of two scFv antibody fragments linked via a flexible linker and directed against surface antigens on target cells and CD3 on T cells. Divalent (Fab)2 and trivalent (Fab)3 antibody forms are also exemplified. Minibodies and trimers derived from scFvs are also exemplified. Exemplary constructs useful for targeting antibody tumor antigens may include one or more of the following: diabody, single-chain (sc)-diabody (scFv)2, miniantibody, minibody, Barnase-barstar, scFv-Fc, sc(Fab)2, trimeric antibody construct, triabody antibody construct, trimeric body antibody construct, tribody antibody construct, collabody antibody construct, (scFv-TNFa)3, F(ab)3 / DNL. In each of these exemplary constructs, one or more binding moieties may bind to an antigen or protein or polypeptide expressed on the surface of a cytotoxic immune cell, and one or more binding moieties will specifically bind to an antigen on the cytotoxic immune cell. Exemplary cytotoxic immune cells include, but are not limited to, CIK cells, T-cells, CD8+ T cells, activated T-cells, monocytes, natural killer (NK) cells, NK T cells, lymphokine-activated killer (LAK) cells, macrophages, and dendritic cells.

[0708] In some embodiments, the combination of an immunotherapeutic agent and a compound of formula I' may include a radioconjugate immunotherapeutic agent.

[0709] In various embodiments, the radioconjugate is a polypeptide, antibody, or antibody fragment thereof that is bound to or otherwise attached to a radionuclide or a plurality of radionuclides such that binding to a small molecule or a macromolecule (referred herein as "cell targeting agent"), for example, a target of the radionuclide (a protein or molecule on or within the cancer cell), may result in death or morbidity of said cancer cell. In various embodiments, the radioconjugate may be a cell targeting agent labeled with a radionuclide, or the cell targeting agent may be coupled to or otherwise attached to a particle, or a microparticle, or a nanoparticle containing a plurality of radionuclides, wherein the radionuclides may be the same or different. Methods for synthesizing the radioconjugate are known in the art and may comprise an immunoglobulin or an antigen-binding portion thereof conjugated to a toxic radionuclide.

[0710] In some embodiments, molecules that bind to cancer cells may be known as “cell targeting agents.” Exemplary cell targeting agents used herein may allow drug-containing nanoparticles or radionuclides to target specific types of cells of interest. Examples of cell targeting agents include, but are not limited to, small molecules (e.g., folates, adenosine, purines) and large molecules (e.g., peptides or antibodies) that bind to or target tumor-associated antigens. Examples of tumor-associated antigens include, but are not limited to, adenosine receptor, alpha v beta 3, aminopeptidase P, alpha fetoprotein, cancer antigen 125, carcinoembryonic antigen, c caveolin-1, chemokine receptor, clusterin, oncofetogenic antigen, CD20, epithelial tumor antigen, melanoma-associated antigen, Ras, p53, Her2 / Neu, ErbB2, ErbB3, ErbB4, folate receptor, prostate-specific membrane antigen, prostate-specific antigen, purine receptor, radiation-induced cell surface receptor, serpine B3, serpine B4, squamous cell carcinoma antigen, thrombospondin, tumor antigen 4, tumor-associated glycoprotein 72, thiosinase, and tyrosine kinase. In some embodiments, the cell targeting agent is a folate or folate derivative that specifically binds to the folate receptor (FR). In some embodiments, the cell targeting agent is an antibody, bispecific antibody, trispecific antibody, or antigen-binding construct thereof that specifically binds to a cancer antigen selected from the following: EGFR, HGFR, Her2, Ep-CAM, CD20, CD30, CD33, CD47, CD52, CD133, CEA, gpA33, Mucins, TAG-72, CIX, PSMA, folate-binding protein, GD2, GD3, GM2, VEGF, VEGFR, Integrin αVβ3, Integrin α5β1, MUC1, ERBB2, ERBB3, MET, IGF1R, EPHA3, TRAILR1, TRAILR2, RANKL, FAP, and Tenascin, in particular.

[0711] The use of folic acid as a targeting agent in radioconjugates also enables targeting for the destruction of both tumor cells and regulatory T (Treg) cells. It is well known that numerous Treg cells suppress tumor immunity. Specifically, Treg cells suppress (foreign and self) reactive T cells without killing them through contact-dependent or cytokine secretion (e.g., IL-10, TGF-β, etc.). FR4 is selectively upregulated in Treg cells. Antibody blockade of FR4 has been shown to deplete Treg cells and induce tumor immunity in tumor-bearing mice. Therefore, folic acid-coated PBM nanoparticles containing cytotoxic agents will take FR-expressing cells for their rupture, which will inhibit tumor progression directly (i.e., BrCa cells) and indirectly (i.e., breast tumor-associated and peripheral Treg cells).

[0712] In another additional embodiment, the targeting agent is, without limitation, an antibody or peptide capable of binding to cancer-associated antigens, or an immune cell-binding polyvalent antibody / fusion protein / composition comprising: adenosine receptor, alpha v beta 3, aminopeptidase P, alpha-fetoprotein, cancer antigen 125, carcinoembryonic antigen, caveolin-1, chemokine receptor, clusterin, oncofetogenic antigen, CD20, human growth factor receptor (HGFR), epithelial carcinoma antigen, melanoma-associated antigen, MUC1, Ras, p53, Her2 / Neu, ErbB2, ErbB3, ErbB4, folate receptor, prostate-specific membrane antigen, prostate-specific antigen, purine receptor, radiation-induced cell surface receptor, serpine B3, serpine B4, squamous cell carcinoma antigen, thrombospondin, cancer antigen 4, cancer-associated glycoprotein 72, tyrosinase, tyrosine kinase, etc.

[0713] In one embodiment, the treatment method comprises the combination of a compound or a pharmaceutically acceptable salt thereof as disclosed herein and one or more cytotoxic agents. As used herein, the term “cytotoxic agent” refers to a substance that inhibits or prevents cell function and / or causes apoptosis or destruction. Cytotoxic agents are, without limitation, radioisotopes (e.g., At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 radioisotopes of Lu); chemotherapy agents; growth inhibitors; enzymes such as nucleases and fragments thereof; and toxins such as small molecule toxins or enzyme-active toxins of bacterial, fungal, plant, or animal origin containing fragments and / or variants thereof.

[0714] Exemplary cytotoxic agents may be selected from anti-microtubules, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signaling pathway inhibitors, non-receptor tyrosine kinases, angiogenesis inhibitors, immunotherapies, synaptic agents, LDH-A inhibitors; fatty acid biosynthesis inhibitors; cell cycle signaling inhibitors; HDAC inhibitors, proteasome inhibitors; and cancer metabolism inhibitors.

[0715] "Chemotherapy agents" include chemical compounds useful for treating cancer. Examples of chemotherapy agents include: erlotinib (TARCEVA®, Genentech / OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate hydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), suntinib (SUTENT®, Pfizer / Sugen), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), pinasunate (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, and rapamycin (Sirolimus, RAPAMUNE®, Wyeth). Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), lonafemib (SCH 66336), sorafenib (NEXAVAR®, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), AG1478; alkylating agents such as thiotepa and CYTOXAN®; cyclophosphamide; alkyl sulfonates, e.g., busulfan, improsulfan, and piposulfan; aziridines, e.g., benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylmelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylomellamine; acetogenins (particularly, bulatacin and bulatacinone); camptothecins (including topotecan and irinotecan); bryostatin; calistatin; CC-1065 (including synthetic analogs of adozelesin, caselesin, and non-caselesin); cryptopicin (specifically, cryptopicin 1 and cryptopicin 8); adrenocorticosteroids (including prednisone and prednisolone); cyproterone acetate; five alpha-reductases including finasteride and dutasteride);Volinostat, Romitepsin, Panobinostat, Valproic Acid, Mostinostat, Dolastatin; Aldesleukin, Talc, Duocarmycin (including synthetic analogs, KW-2189 and CB1-TM1); Eleutherobin; Pancratistatin; Sarcodictine; Spunstatin; Nitrogen mustards such as Chlorambucil, Clomapazine, Chlorophosphamide, Estramustine, Ifosfamide, Mechloretamine, Mechloretamine Hydrochloride, Melphalan, Novembitine, Fenesterine, Prednimustine, Trophosphamide, and Uracil Mustard; Nitrosoureas such as Carmustine, Chlorozotocin, Potemustine, Lomustine, Nimustine, and Raninustine; Antibiotics such as endigenic antibiotics (e.g., caliceamycin, particularly caliceamycin gamma 1I and caliceamycin omega 1I (Angew Chem. Intl. Ed. Engl. 1994 33: 183-186); dynemycin (including dynemycin A); bisphosphonates such as cloninate; esperamycin; as well as neocasinostatin chromophores and related chromophore proteins enedien antibiotic chromophores), aclassinosin, actinomycin, othricin, azacerin, bleomycin, camtinomycin, carabicin, kaminomycin, casinophylline, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, Cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin); epirubicin, isorubicin, idarubicin, marcelomycin, mitomycin such as mitomycin C, mycophenolic acid, nogalamycin, olibomycin, peflomycin, porpyromycin, furomycin, curamycin, rhodorubicin, streptonigreen, streptozosin, tubercidin, uvenimex, genostatin, rhodorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, e.g., denopterin, methotrexate, pteropterin, trimetrexate; Purine analogs such as fludarabine, 6-mercaptopurine, thiamiphrine, and thioguanine;Pyrimidine analogs, e.g., ancitabine, azacitidine, 6-azauridine, camofur, cytarabine, dideoxyudine, doxyfluridine, enositabine, floroxridine; androgens, e.g., calosterone, dromostanolone propionate, epithiostanol, mepitiostan, testolactone; anti-adrenal agents such as amyglitimide, mitotine, and trirostaine; folic acid supplements, e.g., proline acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; enylacyl; amsacrin; vestrabusil; arsentren; edatrexate; difopamin; demecolsin; diaziquone; l-formitin; elliptinium acetate; epotillone; etogluside; gallium nitrate; hydroxyurea; lentina; Ronidinine metansinoids, e.g., metansine and ansamitosine; mitoguazone; mitoxantrone; mophidamnol; nitraerin; pentostatin; fenamet; pyrarubicin; rosoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Ore.); razaoxane; lyzosine; sizofuran; spiromaninium; tenuasonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes (particularly T-2 toxin, berlaculin A, loridin A, and anguidin); urethanes; vindecin; dacarbazine; mannomustine; mitobronitol; mitolactol; fibobroman; cisitosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; Taxoids, e.g., TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE® (cremopore-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE® (docetaxel; sanofi-Aventis); chlorambucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurines; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16);Ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); Novantron; tenifoside; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethyllomitine (DMFO); retinoids, e.g., retinoic acid; and pharmaceutically acceptable salts, acids, and derivatives of any of the above.;

[0716] Chemotherapy agents also include the following: (i) anti-hormonal agents that act to modulate or inhibit hormonal action against tumors, such as anti-estrogens and selective estrogen receptor modulators (SERMs), e.g., tamoxifen (NOLVADEX®; including tamoxifen citrate), raloxene, droloxifene, iodooxyfen, 4-hydroxytamoxifen, trioxyfen, keoxyfen, LY117018, onapristone, and FARESTON®; (ii) For example, 4(5)-imidazole, aminoglutechimide, aromatase inhibitors that inhibit the enzyme aromatase regulating estrogen production in the adrenal glands, such as MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestani, feidrozol, RIVISOR® (borozol), FEMARA® (letrozol; Novartis), and ARIMIDEX® (anastrozol; AstraZeneca); (iii) anti-androgens, e.g., flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; buserelin, trypterin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all transrethionic acids, fenretinide, and troxacitabine (1,3-dioxolane nucleoside cytosine analogs); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides that inhibit the expression of genes in signaling pathways associated with abnormal cell proliferation, e.g., PKC-alpha, Ralf, and H-Ras; (vii) ribozymes, e.g., VEGF expression inhibitors (e.g., ANGIOZYME® and HER2 expression inhibitors); (viii) vaccines, e.g., gene therapy vaccines, e.g., ALLOVECTIN®, LEUVECTIN® and VAXID®; PROLEUKIN®, rIL-2; topoisomerase 1 inhibitors, e.g., LURTOTECAN®; ABARELIX®; and (ix) pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0717] Chemotherapy agents also include alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech / Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tocitumomab (Bexxar, Corixia), antibody-drug conjugates, gemtuzumab ozogamicin (MYLOTARG®, Wyeth), and antibodies as described above. Additional humanized monoclonal antibodies having therapeutic potential as therapeutic agents as formulations combined with compounds of the present invention comprise: apolizumab, azelizumab, atlizumab, bapineuzumab, vivatuzumab mertansine, cantuzumab mertansine, cedelizumab, sertolizumab pegol, sidfucituzumab, sidtuzumab, daclizumab, eculizumab, epalizumab, efratuzumab, erizumab, felbizumab, pontolizumab, gemtuzumab, ozogamicin, inotuzumab ozogamicin, ipilimumab, rabetuzumab, lintuzumab, matuzumab, mepolizumab, motabizumab, motobizumab, natalizumab, nimotuzumab, nivolumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, Pascolizumab, pectuzumab, pectuzumab, pexelizumab, lalivizumab, ranibizumab, reslibizumab, reslibizumab, lecibizumab, lovelizumab, luplizumab, cibrotuzumab, ciplizumab, sontuzumab, tacatuzumab, tetraxetane, tadosizumab, talizumab, tepivazumab, tocilizumab, toralizumab, tucotuzumab, selmolukene, tucucituzumab, umavizumab, urtoxazumab, ustekinumab, bicilizumab, and anti-interleukin-12 antibodies that are recombinant, exclusively human sequence full-length IgG.sub.1.lamda. antibodies genetically modified to recognize the interleukin-12 p40 protein (ABT-8744695, Wyeth Research and Abbott Laboratories).

[0718] Chemotherapy agents also include the following: "tyrosine kinase inhibitors," including EGFR inhibitors; small molecule HER2 tyrosine kinase inhibitors, e.g., Mubritonib (TAK165, Takeda); CP-724.714 (Arx Medchem BV, an oral selective inhibitor of ErbB2 receptor tyrosine kinase); dual-HER inhibitors such as EKB-569 (available from Wyeth), which binds preferentially to EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016; available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors, e.g., canertinib (CI-1033; Pharmacia); Raf-1 inhibitors that inhibit Raf-1 signaling, such as the antisense agent ISIS-5132 available from ISIS Pharmaceuticals; non-HER targeted TK inhibitors, e.g., imatinib mesylate (available from GLEEVEC®, Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors, e.g., sunitinib (available from SUTENT®, Pfizer); VEGF receptor tyrosine kinase inhibitors, e.g., batalanib (PTK787 / ZK222584, available from Novartis / Schering AG); MAPK extracellular regulatory kinase 1 inhibitor CI-1040 (available from Pharmacia); quinazolin, e.g., PD 153035,4-(3-chloroanilino)quinazolin; pyridopirimidine; pyrimidopirimidine; Pyrrolopyrimidines, e.g., CGP 59326, CGP 60261, and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidine; curcumin (diferuloyl methane, 4,5-bis(4-fluoroanilino)phthalimide); tripostines containing nitrothiophene residues; antisense molecules (e.g., those binding to HER-coding nucleic acids);Quinoxaline (U.S. Patent No. 5,804,396); Trifostin (U.S. Patent No. 5,804,396); Afinitac (ISIS 3521; Isis / Lilly); PKI166 (Novartis); Cemaxinib (Pfizer); INC-1C11 (Imclone), Rapamycin (sirolimus, RAPAMUNE®); or as described in any of the following patent publications: U.S. Patent No. 5,804,396; WO 1999 / 09016 (American Cyanamid); WO 1998 / 43960 (American Cyanamid); WO 1997 / 38983 (Warner Lambert); WO 1999 / 06378 (Warner Lambert); WO 1999 / 06396 (Warner Lambert); WO 1996 / 30347 (Pfizer, Inc); WO 1996 / 33978 (Zeneca); WO 1996 / 3397 (Zeneca) and WO 1996 / 33980 (Zeneca). Tyrosine kinase inhibitors also include the following: erlotinib (Tarceva®), gefitinib (Iressa®), dasatinib (Sprycel®), nilotinib (Tasigna®), crizotinib (Xalkori®), ruxolitinib (Jakafi®), vemurafenib (Zelboraf®), vandetanib (Caprelsa®), pazopanib (Votrient®), afatinib, allicertip, amuratinib, axitinib, bosutinib, brivanib, canertinib, cabozantinib, cediranib, crenolanib, dabrafenib, dacomitinib, dannusertib, dovitinib, foretinib, ganetespib, ibrutinib, iniparib, lenvatinib, linifanib, lincitinib, macitinib, momelotinib, motesanib, neratinib, niraparib, ofrozomib, Olaparib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, saracatinib, saridezip, tandutinib, tasocitibinib, telatinib, tivantinib, tibozanib, tofacitinib, trametinib, veliparib, bismodezip, volaseritib, cobimetinib (Cotellic®), and others.;

[0719] Chemotherapy agents also include the following: dexamethasone, interferon, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacuzimab, bexarotene, cladribine, cloparibine, darbepoetin alpha, denileukin, dexrazoxane, epoetin alpha, eltinib, filgrastim, histroline acetate, ibritumomab, interferon alpha-2a, interferon alpha-2b, lenalidomide, levamisole, mesnar, methoxalen, nandrolone, nerarabin, nofetumamab, ofrelvekin, palcifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, Plicamycin, porfimer sodium, quinacrine, rasburicase, sargranostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valubicin, zoledronate and zoledronic acid, and their pharmaceutically acceptable salts.

[0720] Chemotherapy agents also include the following: hydrocortisone, hydrocortisone acetate, cortisone acetate, thixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amminide, budesonide, desonide, fluorononide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclomethasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetazole-17-propionate, fluocortolone caproate, Fluocortolone pivalate and fluprednidin acetate; immunoselective anti-inflammatory peptides (ImSAIDs) such as phenylalanine-glutamine-glycine (FEG) and its D-isomer form (feG) (IMULAN BioTherapeutics, LLC); Anti-rheumatic drugs, such as azathioprine, cyclosporine (cyclosporine A), D-penicillamine, gold salt, hydroxychloroquine, leflunominocycline, sulfasalazine, tumor necrosis factor alpha (TNF alpha) blockers, e.g. interleukin 1 (IL-1) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (1-Iumira), sertolizumab pegol (Cimzia), golimumab (Simponi), and anakinra (Kineret), T-cell co-stimulation blockers such as abatacept (Orencia), interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA®); interleukin 13 (IL-13) blockers such as lebrikizumab; interferon alpha (IFN) blockers such as lontalizumab; Beta-7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as Anti-M1 prime; secreted homotrimeric LTa3 and membrane-bound heterotrimeric LTa1 / 132 blockers, e.g., anti-lymphotoxin alpha (LTa);Other study substances such as thioplatin, PS-341, phenyl butyrate, ET-18-OCH3, or parmesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, picatanol, epigallocatechin gallate, theaflavin, flavanol, procyanidin, betulinic acid, and their derivatives; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (Dronabinol, MARINOL®); beta-lapachone; lapachol; colchicine; betulinic acid; acetylcamptothecin, scoporectin, and 9-aminocamptothecin); podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN®); Bisphosphonates such as clodronate (e.g., BONEFOS® or OSTAC®), etithtronate (DIDROCAL®), NE-58095, zoledronate / zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); and epidermal growth factor receptor (EGF-R); vaccines such as THERATOPE® vaccine; perifosin, COX-2 inhibitors (e.g., celecoxib or etoricoxib), proteosome inhibitors (e.g., PS341); CCI-779; tipifanib (R11577); oranib, ABT510; Bcl-2 inhibitors such as oblimarsen sodium (GENASENSE) and picantron; Farnesyl transferase inhibitors, e.g., lonafamib (SCH 6636, SARASAR™); and pharmaceutically acceptable salts, acids, or derivatives of any of the above; combinations of two or more of the above, such as CHOP, an abbreviation for combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; and FOLFOX, an abbreviation for therapeutic regimen using oxaliplatin (ELOXATIN™) in combination with 5-FU and leucovorin.;

[0721] Chemotherapy agents also include the following: Poly ADP Ribose Polymerase (PARP) inhibitors: Olaparib (Lynparza®), Rucabrif (Rubraca®), Niraparib (Zejula®), Talzoparib (Talzenna®).

[0722] Effective combinations of the compound of Formula I' described herein or other agents of any other formula may be confirmed through preclinical and clinical trials of the combination and will depend on many factors, including the type and stage of the disease, the overall health status of the patient, and the toxicity and side effects of the drug.

[0723] In some embodiments, compounds as disclosed herein may be used in combination therapy with any kinase inhibitor disclosed herein for the treatment of diseases...

Claims

Claim 1 Compound of chemical formula B-1 or its pharmaceutically acceptable salt: B-1R a1 is an optionally substituted (C1-C6) alkyl; R1 is -CN, optionally substituted phenyl, optionally substituted 4-6-membered heterocycloalkyl, optionally substituted 5-6-membered heteroaryl, -SO2-(C1-C6) alkyl, -SO2NH2, -SO2-NH(C1-C6) alkyl, or -P(O)((C1-C6) alkyl)2; or R1 is and, here " " indicates an attachment site, where: Y1 is a member; Y2 is a member, or -O-, -NH-, -NHO-, -NH-NH-, or -N-(C1-C6) alkyl-; or Y2 is optionally substituted and, where ring A is a 3, 4, 5, 6, or 7-one ring, and here " " indicates the attachment point, and Z 1 is O; and R a is -H, -(C1-C6) alkyl, 4-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, -(C2-C6) alkylene-OH, -CH2CHOH-(C2-C6) alkylene-OH, -(C2-C6) alkylene-NH2, -(C2-C6) alkylene-NH(C1-C6)alkyl, -(C2-C6) alkylene-N((C1-C6)alkyl)2, or -(C2-C6) alkylene-N-(4-6-membered heterocycloalkyl), where the heterocycloalkyl is optionally substituted; each R3 is independently -H or halo; each R4 is independently -H, halo, (C 1- C6) alkyl, (C 1- C6) Alkoxy, or (C 1- C6) haloalkyl and;R 14 is -H; Y is -O-; subscript n is an integer 1, 2, 3, or 4; subscript m is an integer 1, 2, 3, 4, or 5; and subscript p is an integer 0, 1, 2, 3, or 4; where "arbitrarily substituted" in each occurrence is unsubstituted, or halogen, -CN, -OH, -OR aa , -COOR aa , (C1-C 10 ) alkyl, (C3-C 10 ) Carbocycloalkyl, 3-14-membered heterocycloalkyl, (C6-C 14 It means substituted with a substituent selected from aryls, and 5-14-membered heteroaryls, where R aa is (C1-C 10 ) alkyl; the compound is not 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide or its pharmaceutically acceptable salt. Claim 2 In paragraph 1, R a1 is (C1-C6) alkyl; R1 is -CN, optionally substituted phenyl, optionally substituted azetidinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted oxetanyl, optionally substituted oxazolyl, optionally substituted pyridinyl, optionally substituted imidazolyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted pyrazolyl, optionally substituted oxadiazolyl, -SO2-(C1-C6) alkyl, -SO2NH2, -SO2-NH(C1-C6) alkyl, or P(O)((C1-C6) alkyl)2; or R1 is and, where Y2 is O, NH, NHO, NH-NH, or N-(C1-C6) alkyl; or Y2 is optionally substituted azetidinyl; and R a is a compound or a pharmaceutically acceptable salt thereof, wherein the compound is H, (C1-C6) alkyl, -(C2-C6) alkylene-OH, -CH2CHOH-(C2-C6) alkylene-OH, -(C2-C6) alkylene-NH2, -(C2-C6) alkylene-NH(C1-C6) alkyl, -(C2-C6) alkylene-N((C1-C6) alkyl)2, -(C2-C6) alkylene-N-(4-6-membered heterocycloalkyl), or 4-6-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted. Claim 3 In paragraph 2, R a1 A compound that is methyl or its pharmaceutically acceptable salt. Claim 4 In claim 1, a compound of formula C or a pharmaceutically acceptable salt thereof: C Here:Y2 is O, NH, NHO, NH-NH, or N-(C1-C6) alkyl; or Y2 is optionally substituted azetidinyl; and R a is H, (C1-C6) alkyl, -(C2-C6) alkylene-OH, -CH2CHOH-(C2-C6) alkylene-OH, -(C2-C6) alkylene-NH2, -(C2-C6) alkylene-NH(C1-C6) alkyl, -(C2-C6) alkylene-N((C1-C6) alkyl)2, -(C2-C6) alkylene-N-(optionally substituted 4-6-membered heterocycloalkyl), or optionally substituted 4-6-membered heterocycloalkyl; and R2 is a (C1-C6) alkoxy. Claim 5 In paragraph 4, R a A compound or a pharmaceutically acceptable salt thereof that is -H, methyl, ethyl, -(C2-C6)alkylene-OH, -CH2CHOH-(C2-C6)alkylene-OH, -(C2-C6)alkylene-NH2, -(C2-C6)alkylene-NHMe, -(C2-C6)alkylene-N(Me)2, optionally substituted azetidinyl, or optionally substituted oxetanyl. Claim 6 In paragraph 4 or 5, a compound of formula C-1 or a pharmaceutically acceptable salt thereof: C-1 . Claim 7 In claim 1, a compound of formula E or a pharmaceutically acceptable salt thereof: E Here: ring A is optionally substituted phenyl, optionally substituted pyridyl, optionally substituted imidazolyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, optionally substituted azetidinyl or optionally substituted oxetanyl; and R2 is methoxy. Claim 8 In claim 1, a compound of formula F or a pharmaceutically acceptable salt thereof: F. Claim 9 In paragraph 8, R a1 is methyl; R1 is -CN, optionally substituted phenyl, optionally substituted azetidinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted oxetanyl, optionally substituted oxazolyl, optionally substituted pyridinyl, optionally substituted imidazolyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted pyrazolyl, optionally substituted oxadiazolyl, -SO2-(C1-C6) alkyl, -SO2NH2, -SO2-NH(C1-C6) alkyl, or P(O)((C1-C6) alkyl)2; or R1 is and, where: Y2 is O, NH, NHO, NH-NH, or N-(C1-C6) alkyl; or Y2 is optionally substituted azetidinyl; and R a -H, (C1-C6) alkyl, -(C2-C6) alkylene-OH, -CH2CHOH-(C2-C6) alkylene-OH, -(C2-C6) alkylene-NH2, -(C2-C6) alkylene-NH(C1-C6) alkyl, -(C2-C6) alkylene-N((C1-C6) alkyl)2, -(C2-C6) alkylene-N-(4-6-membered heterocycloalkyl), or 4-6-membered heterocycloalkyl, wherein heterocycloalkyl is optionally substituted; a compound or a pharmaceutically acceptable salt thereof. Claim 10 Compound of chemical formula H or its pharmaceutically acceptable salt: H where: Y is -O-; R1 is selected from -CN, -CO-NR5R6, -CO2R7, phenyl, 5-6-one heteroaryl, 4-6-one heterocycloalkyl, -SO2NR8R9, and -(SO2)-(C1-C6) alkyl; R2 is a C1-C6 alkoxy; R3 is -H or halo; R4 is -H or halo; R5 and R6 are each independently -H or C1-C6 alkyl; R7 is -H or C1-C6 alkyl; And R8 and R9 are each independently -H or C1-C6 alkyl; the compound is not 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide or its pharmaceutically acceptable salt. Claim 11 In paragraph 10, R3 is a compound that is H or its pharmaceutically acceptable salt. Claim 12 In Clause 10, R4 is a haloin compound or a pharmaceutically acceptable salt thereof. Claim 13 In paragraph 10, R1 is a compound that is -CN, -CO2H, -CO2Me, -CO-NHR6, -CO-NH2, or -CO-NMeR6, or a pharmaceutically acceptable salt thereof. Claim 14 In paragraph 1, R1 is -CN, -(SO2)NH2, -(SO2)CH3, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and A compound selected from or its pharmaceutically acceptable salt. Claim 15 In Clause 10, R1 is , , , and A compound selected from or its pharmaceutically acceptable salt. Claim 16 Compound of chemical formula IA or its pharmaceutically acceptable salt: IA Here, R6 is (C 1- C6) alkyl, and R2 is (C 1- C6) alkoxy, R3 is -H or halo, and R4 is halo, and the compound is not 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide or its pharmaceutically acceptable salt. Claim 17 A compound selected from the following or a pharmaceutically acceptable salt thereof: . Claim 18 A pharmaceutical composition for treating cancer comprising a compound of any one of claims 1, 10, 16, and 17 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Claim 19 delete Claim 20 delete Claim 21 delete Claim 22 delete Claim 23 delete Claim 24 delete Claim 25 delete Claim 26 delete Claim 27 delete Claim 28 delete Claim 29 delete Claim 30 delete Claim 31 delete Claim 32 delete Claim 33 delete Claim 34 delete Claim 35 delete Claim 36 delete Claim 37 delete Claim 38 delete Claim 39 delete Claim 40 delete

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