COMPOUND FOR TREATMENT AGAINST KINASE-DEPENDENT DISORDERS AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME

Description

"COMPOUND FOR TREATMENT OF KINASE-DEPENDENT DISORDERS AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME" Split order BR 1120200152013 filed on 01 / 25 / 2019 FIELD OF THE INVENTION

[001] The invention relates to compounds that modulate cellular activities such as proliferation, differentiation, programmed cell death, migration and chemoinvasion by modulating protein kinase enzymatic activity. More specifically, the invention relates to compounds that inhibit, regulate and / or modulate Axl and Mer receptor tyrosine kinases, compositions containing these compounds, methods of using them to treat kinase-dependent diseases and conditions, synthesis of the compounds and processes for formulating the compounds for pharmaceutical purposes. CROSS-REFERENCE TO RELATED REQUESTS

[002] This request claims priority of the Request Provisional Application under Serial Number US62 / 622,702, filed January 26, 2018, and Provisional Application under Serial Number US62 / 758,321, filed November 9, 2018, the contents of which are incorporated herein in their entirety. BACKGROUND OF THE INVENTION

[003] Human Axl belongs to the TAM subfamily of receptor tyrosine kinases, which includes Mer. TAM kinases are characterized by an extracellular ligand-binding domain consisting of two immunoglobulin-like domains and two fibronectin type III domains. Axl is overexpressed in numerous tumor cell types and was initially cloned from patients with leukemia. Petition 870230091982, dated 10 / 17 / 2023, page 9 / 422 2 / 378 chronic myelogenous leukemia. When overexpressed, Axl exhibits transformative potential. Axl signaling is believed to induce tumor growth through activation of proliferative and anti-apoptotic signaling pathways. Axl has been associated with cancers such as lung cancer, myeloid leukemia, uterine cancer, ovarian cancer, gliomas, melanoma, thyroid cancer, renal cell carcinoma, osteosarcoma, gastric cancer, prostate cancer, and breast cancer. Overexpression of Axl results in a poor prognosis for patients with the indicated cancers.

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

[005] Therefore, there remains a need for compounds that inhibit TAM receptor tyrosine kinases such as Axl and Mer for the treatment of selected cancers. SUMMARY OF THE INVENTION

[006] In one aspect, the present invention provides a compound of formula I: Petition 870230091982, dated 10 / 17 / 2023, p. 10 / 422 3 / 378 I or a pharmaceutically acceptable salt thereof, where: Ri is selected from the group consisting of -H, -CN, -CO-NR5R6, -CO2R7, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (C1-C8) alkyl, optionally substituted (C3-C8) cycloalkyl, optionally substituted (C3-C8) heterocycloalkyl, -SO2NR8R9 and -(SO2)-(C1-C8) alkyl; wherein Ri 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-C1e) alkyl, R2 is -H, halo, -NR5R6 or optionally substituted (C1-C1e) alkoxy; where Ri is -H, optionally substituted (Ci-Ce) alkyl or optionally substituted (Ci-Ce) alkoxy, R2 is -CO-NR5Re; or -CO2R7; or R1 and R2 obtained together with the atoms to which they are attached form optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; R3 is selected from the group consisting of -H, optionally substituted (Ci-Ce) alkyl, -CN, and halo; R4 is -H or halo; is optionally replaced by one, two, three Petition 870230091982, dated 10 / 17 / 2023, p. 11 / 422 4 / 378 or four groups selected independently from the group consisting of halo and (C1-C6) alkyl, where χ / wv' indicate attachment points; R5 and R6 are each independently -H, optionally substituted (C1-C6) alkyl or optionally substituted (C1-C6) alkoxy; R7 is -H or optionally substituted (C1-C6) alkyl R8 and R9 are each independently -H or optionally substituted (C1-C6) alkyl; or R8 and R9 can connect to form an optionally substituted heterocycle; and Y is selected from the group consisting of O, S, SO, SO2, NH and N-(C1-C6 alkyl).

[007] Another aspect provides a compound of formula A: Rn A or a pharmaceutically acceptable salt thereof, wherein (i) R1 is selected from the group consisting of (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C10) aryl, (C3-C10) cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, -CN,-NHOH, -C(O)Ra, C(O)NRaRa, -C(O)NHORa, -C(O)ORa, -C(O)NRaS(O)2Ra, -OC(O)NRaRa, C(=NRa)Ra, -C(=NOH)Ra, -C(=NOH)NRa, -C(=NCN)NRaRa, C(=NRa)NRaRa, -S(O)NRaRa, -S(O)2NRaC(O)Ra, -P(O)RaRa, Petition 870230091982, of 10 / 17 / 2023, p. 12 / 422 5 / 378 P(O)(ORa)(ORa), -B(OH)2, -B(ORa)2, and S(O)2NRaRa; and R2 is selected from -H, halo, (C1-Ce) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-Ce) haloalkyl, (C1Ce) haloalkoxy, (C6-C10) aryl-(C1-C4) alkylene-, (C3-C10) cycloalkyl-(C1-C4) alkylene-, (5- to 14-membered heteroaryl)-(C1-C4) alkylene-, (4- to 14-membered heterocycloalkyl)-(C1-C4) alkylene-, -CN, -NO2, -ORa, -SRa, -NHORa, C(O)Ra, -C(O)NRaRa, -C(O)NHORa, -C(O)ORa, -C(O)NRaS(O)2Ra, OC(O)Ra, -OC(O)NRaRa, -NHRa, -NRaRa, -NRaC(O)Ra, -NRaC(=NRa)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -C(=NRa)Ra, -C(=NOH)Ra,C(=NOH)NRa, -C(=NCN)NRaRa, -NRaC(=NCN)NRaRa, -C(=NRa)NRaRa,NRaC(=NRa)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa,S(O)Ra, -S(O)NRaRa, -S(O)2Ra, -S(O)2NRaC(O)Ra, -P(O)RaRa,P(O)(ORa)(ORa), -B(OH)2, -B(ORa)2, and -S(O)2NRaRa, where (C1Ce) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C10)aryl-(C1-C4)alkylene-, (C3-C10)cycloalkyl-(C1-C4)alkylene-, (5- to 14-membered heteroaryl)-(C1-C4)alkylene-, and (4- to 14-membered heterocycloalkyl)-(C1-C4)alkylene- of R1 or R2 are optionally substituted, each, by 1, 2, 3, 4 or 5 Rb substituents independently selected, provided that when R1 is a 5- to 7-membered heteroaryl or 5- to 7-membered heterocycloalkyl and R2 is a C1-6 alkoxy, then the 5- to 7-membered heteroaryl or 5- to 7-membered heterocycloalkyl does not connect to the fused phenyl ring of the quinoline chemical portion through a ring nitrogen atom;or (ii) R1 is selected from -H, halo, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-Ce) haloalkyl, (C1-Ce) haloalkoxy, (C6-C10) aryl, (C3-C10) cycloalkyl, heteroaryl with 5 to 14 members; Petition 870230091982, dated 10 / 17 / 2023, page 13 / 422 6 / 378 heterocycloalkyl with 4 to 14 members, (C6-C10) aryl-(C1-C4) alkylene-, (C3-C10) cycloalkyl-(C1-C4) alkylene-, (heteroaryl with 5 to 14 members)-(C1-C4) alkylene-, (heterocycloalkyl with 4 to 14 members)-(C1-C4) alkylene-, CN, -NO2, -ORa, -SRa, -NHORa, -C(O)Ra, -C(O)NRaRa, -C(O)NHORa, -C(O)ORa, -C(O)NRaS(O)2Ra, -OC(O)Ra, -OC(O)NRaRa, -NHRa,NRaRa, -NRaC(O)Ra, -NRaC(=NRa)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa,C(=NRa)Ra, -C(=NOH)Ra, -C(=NOH)NRa, -C(=NCN)NRaRa,NRaC(=NCN)NRaRa, -C(=NRa)NRaRa, -NRaC(=NRa)NRaRa, -NRaS(O)Ra,NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra,S(O)2NRaC(O)Ra, -P(O)RaRa, -P(O)(ORa)(ORa), -B(OH)2, -B(ORa)2, and -S(O)2NRaRa, where (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C10) aryl, (C3-C10) cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, (C6-C10) aryl-(C1-C4) alkylene-, (C3-C10) cycloalkyl-(C1-C4) alkylene-, (5-14 membered heteroaryl)-(C1-C4) alkylene-,and (heterocycloalkyl with 4 to 14 members)-(C1-C4)alkylene- of R1 or R2 are optionally replaced, each, by 1, 2, 3, 4 or 5 independently selected Rb substituents; and, R2 is selected from the group consisting of (C2C6) alkenyl, (C2-C6) alkynyl, -CN, -NHOH, -C(O)Ra, C(O)NRaRa, -C(O)NHORa, -C(O)ORa, -C(O)NRaS(O)2Ra, -OC(O)NRaRa, C(=NRa)Ra, -C(=NOH)Ra, -C(=NOH)NRa, -C(=NCN)NRaRa, NRaC(=NCN)NRaRa, -C(=NRa)NRaRa, -S(O)NRaRa, -S(O)2NRaC(O)Ra, P(O)RaRa, -P(O)(ORa)(ORa), -B(OH)2, -B(ORa)2, and S(O)2NRaRa, provided that when R1 is a 5- to 7-membered heteroaryl or 5-membered heterocycloalkyl If the 7-membered group R1 is C1-6 alkoxy and R2 is a C1-6 alkoxy, then the 5- to 7-membered heteroaryl or 5- to 7-membered heterocycloalkyl group with R1 does not connect to the phenyl ring. Petition 870230091982, dated 10 / 17 / 2023, p. 14 / 422 7 / 378 fused from the quinoline chemical portion through a ring nitrogen atom, (iii) Ri and R2, obtained near the atoms to which they are attached, form a fused (C3-C7)cycloalkyl ring or a fused 4- to 10-membered heterocycloalkyl ring, wherein the fused (C3-C7)cycloalkyl ring and the fused 4- to 10-membered heterocycloalkyl ring are optionally substituted, each, by 1, 2 or 3 independently selected Rb substituents, provided that the compound is not 1-[2-(4-Fluorophenyl)acetyl]cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododeca[b]naphthalen-4yloxy)-phenyl]-amide; R10 and R11 are each selected independently from the group consisting of -H, halo, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C6-C10) aryl, (C3C10) cycloalkyl, 5- to 14-membered heteroaryl, 4- to 14-membered heterocycloalkyl, (C6-C10) aryl-(C1-C4) alkylene-, (C3-C10) cycloalkyl-(C1-C4) alkylene-, (5- to 14-membered heteroaryl)-(C1-C4) alkylene-, (4- to 14-membered heterocycloalkyl)-(C1-C4) alkylene-, CN, -NO2, -ORa, -SRa, -NHORa, -C(O)Ra, -C(O)NRaRa, -C(O)ORa,C(O)NRaS(O)2Ra, -OC(O)Ra, -OC(O)NRaRa, -NHRa, -NRaRa,NRaC(O)Ra, -NRaC(=NRa)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa,C(=NRa)Ra, -C(=NOH)Ra, -C(=NOH)NRa, -C(=NCN)NRaRa,NRaC(=NCN)NRaRa, -C(=NRa)NRaRa, -NRaC(=NRa)NRaRa, -NRaS(O)Ra,NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra,S(O)2NRaC(O)Ra, -P(O)RaRa, -P(O)(ORa)(ORa), -B(OH)2, -B(ORa)2, and S(O)2NRaRa, wherein (C1-C6) alkyl, (C6-C10) aryl, (C3-C10) cycloalkyl, heteroaryl with 5 to 14 members, Petition 870230091982, dated 10 / 17 / 2023, page 15 / 422 8 / 378 4- to 14-membered heterocycloalkyl, (C6-C10)aryl-(C1-C4)alkylene-, (C3-C10)cycloalkyl-(C1-C4)alkylene-, (5- to 14-membered heteroaryl)-(C1-C4)alkylene-, and (4- to 14-membered heterocycloalkyl)-(C1-C4)alkylene- of R1 or R2 are optionally each replaced by 1, 2, 4 or 5 independently selected Rb substituents; 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-Ce)alkyl, -N(C1-C6 alkyl)2, and (C3-C6) cycloalkyl, wherein the (C1-C6) alkoxy, -NH(C1-Ce)alkyl, -N(C1-C6 alkyl)2, and (C3-C6) cycloalkyl of R3 are optionally substituted, each, by 1, 2, or 3 independently selected Rg substituents; Each R14 is selected independently from the group consisting of halo, -OH, -NH2, -CN, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, COOH, -NH(C1-C6) alkyl, -N(C1-C6 alkyl)2, phenyl, phenyl-(C1-C2) alkylene, (C3-C6) cycloalkyl, (C3-C6) cycloalkyl-(C1-C4) alkylene-, 4- to 6-membered heterocycloalkyl, (4- to 6-membered heterocycloalkyl)-(C1-C4) alkylene-, 5- to 6-membered heteroaryl, (5- to 6-membered heteroaryl)-(C1-C4) alkylene-, and -ORe, wherein the (C1-C6) alkyl, The phenyl, phenyl-(C1-C2)alkylene, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C4)alkylene-, 4- to 6-membered heterocycloalkyl, (4- to 6-membered heterocycloalkyl)-(C1-C4)alkylene-, 5- to 6-membered heteroaryl, and (5- to 6-membered heteroaryl)-(C1-C4)alkylene- groups of R14 are optionally substituted, each by 1, 2, or 3 independently selected Rg substituents. Petition 870230091982, dated 10 / 17 / 2023, page 16 / 422 9 / 378 R15 is H or C1-6 alkyl; Each R4 is selected independently from the group consisting of -H, halo, -OH, -COORe, -CONReRe, -CN, -NH2, -NH((C1-Ce) alkyl), -N((C1-Ce) alkyl)2, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, CONRaRa, -NRaCORa, -NRaCONRaRa, -SO2Ra, -NRaS(O)2Ra,NRaS(O)2NRaRa, (C3-C6) cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, (C3-C6) cycloalkyl-(C1-C4) alkylene-, (4- to 6-membered heterocycloalkyl)-(C1-C4) alkylene-, phenyl-(C1-C2) alkylene, and (5- to 6-membered heteroaryl)-(C1-C4) alkylene-, where (C1-C6) alkyl, (C3-C6) cycloalkyl, 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, (C3- C6)cycloalkyl-(C1-C4)alkylene-, (4- to 6-membered heterocycloalkyl)-(C1-C4)alkylene-, phenyl-(C1-C2)alkylene, and (5- to 6-membered heteroaryl)-(C1-C4)alkylene- of R4 are optionally substituted, each, by 1, 2, or 3 independently selected Rf substituents; Each Rae is independently selected from the group consisting of -H, -CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C10) aryl, (C3-C10) cycloalkyl, 5- to 14-membered heteroaryl, 4- to 14-membered heterocycloalkyl, (C6-C10) aryl-(C1-C4) alkylene, (C3-C10) cycloalkyl-(C1-C4) alkylene, (5- to 14-membered heteroaryl)-(C1-C4) alkylene, and (4- to 14-membered heterocycloalkyl)-(C1-C4) alkylene, wherein the (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C10) aryl, (C3-C10) cycloalkyl, 5- to 14-membered heteroaryl, 4- to 14-membered heterocycloalkyl, (C6-C10) aryl-(C1-C4) Petition 870230091982, dated 10 / 17 / 2023, page 17 / 422 10 / 378 alkylene-, (C3-C10)cycloalkyl-(C1-C4)alkylene-, (5- to 14-membered heteroaryl)-(C1-C4)alkylene-, and (4- to 14-membered heterocycloalkyl)-(C1-C4)alkylene- of Rasão optionally substituted, each, by 1, 2, 3, 4 or 5 R-substituents independently selected; each Rbé selected independently from the group consisting of halo, oxo, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C6-C10) aryl, (C3-C10) cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, (C6-C10) aryl-(C1-C4) alkylene-, (C3-C10) cycloalkyl-(C1-C4) alkylene-, (5- to 10-membered heteroaryl)-(C1-C4) alkylene-, (4- to 10-membered heterocycloalkyl)-(C1-C4) alkylene-, -CN, -OH, -NH2, -NO2, -NHORc, -ORc, -SRc, -C(O)Rc, -C(O)NRcRc, -C(O)ORc, -C(O)NRcS(O)2Rc, -OC(O)Rc, -OC(O)NRcRc, -C(=NOH)Rc, -C(=NOH)NRc, -C(=NCN)NRcRc, -NRcC(=NCN)NRcRc,C(=NRc)NRcRc, -NRcC(=NRc)NRcRc, -NHRc, -NRcRc, -NRcC(O)Rc,NRcC(=NRc)Rc, -NRcC(O)ORc, -NRcC(O)NRcRc, -NRcS(O)Rc,NRcS(O)2Rc, -NRcS(O)2NRcRc, -S(O)Rc, -S(O)NRcRc, -S(O)2Rc,S(O)2NRcC(O)Rc, -Si(Rc)3, -P(O)RcRc, -P(O)(ORc)(ORc), -B(OH)2, -B(ORc)2, and -S(O)2NRcRc, wherein (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C10) aryl, (C3-C10) cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, (C6-C10) aryl-(C1-C4) alkylene-, (C3-C10) cycloalkyl-(C1-C4) alkylene-, (5- to 10-membered heteroaryl)-(C1-C4) alkylene-, and (4- to 10-membered heterocycloalkyl)-(C1C4) alkylene- of Rb are optionally further substituted, each by 1, 2 or 3 substituents of Rdindependently selected; Petition 870230091982, dated 10 / 17 / 2023, page 18 / 422 11 / 378 each Rcé selected independently from the group consisting of -H, (Ci-Ce) alkyl, (C1-Ce) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C10) aryl, (C3-C10) cycloalkyl, heteroaryl with 5 to 10 members, heterocycloalkyl with 4 to 10 members, (C6-C10) aryl-(C1-C4) alkylene-, (C3-C10) cycloalkyl-(C1-C4) alkylene-, (5- to 10-membered heteroaryl)-(C1-C4) alkylene-, and (4 to 10-membered heterocycloalkyl)-(C1-C4) alkylene-, wherein the (C1-Ce) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C10) aryl, (C3-C10) cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, (C6-C10) aryl(C1-C4) alkylene-, (C3-C10) cycloalkyl-(C1-C4) alkylene-, (5- to 10-membered heteroaryl)-(C1-C4) alkylene-, and (4- to 10-membered heterocycloalkyl)-(C1-C4) alkylene- of Rc are optionally substituted, each, by 1, 2, 3, 4 or 5 independently selected Rf substituents; each Rdé selected independently from the group consisting of (C1-Ce) alkyl, (C1-Ce) haloalkyl, halo, (C6-C10) aryl, 5- to 10-membered heteroaryl, (C3-C10) cycloalkyl, 4- to 10-membered heterocycloalkyl, (C6-C10) aryl-(C1-C4) alkylene, (C3-C10) cycloalkyl-(C1-C4) alkylene, (5- to 10-membered heteroaryl)-(C1-C4) alkylene, (4- to 10-membered heterocycloalkyl)-(C1-C4) alkylene, CN, -NH2, -NHORe, -ORe, -SRe, -C(O)Re, -C(O)NReRe, -C(O)ORe, OC(O)Re, -OC(O)NReRe, -NHRe, -NReRe, -NReC(O)Re, -NReC(O)NReRe, -NReC(O)ORe, -C(=NRe)NReRe, -NReC(=NRe)NReRe, -NReC(=NOH)NReRe, -NReC(=NCN)NReRe, -S(O)Re, -S(O)NReRe, -S(O)2Re, -NReS(O)2Re, NReS(O)2NReRe, and -S(O)2NReRe, wherein the (C1-Ce) alkyl, (C1-Ce) haloalkyl, (C6-C10) aryl, 5- to 10-membered heteroaryl, (C3-C10) cycloalkyl, 4- to 10-membered heterocycloalkyl, Petition 870230091982, dated 10 / 17 / 2023, page 19 / 422 12 / 378 (C6-C10)aryl-(C1-C4)alkylene-, (C3-C10)cycloalkyl-(C1-C4)alkylene-, (5- to 10-membered heteroaryl)-(C1-C4)alkylene-, and (4- to 10-membered heterocycloalkyl)-(C1-C4)alkylene- of Rd are optionally substituted, each, by 1, 2 or 3 independently selected Rf substituents; Each Re is independently selected from the group consisting of -H, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C3-C6) cycloalkyl-(C1-C4) alkylene-, (C6-C10) aryl, (C6-C10) aryl-(C1-C4) alkylene-, 5- to 6-membered heteroaryl, (5- to 6-membered heteroaryl)-(C1-C4) alkylene-, 4- to 7-membered heterocycloalkyl, (4- to 7-membered heterocycloalkyl)-(C1-C4) alkylene-, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C2-C4) alkenyl, and (C2-C4) alkynyl, wherein the (C1-C4) alkyl, (C3-C6) cycloalkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, (C6-C10) aryl-(C1-C4) alkylene-, (5- to 6-membered heteroaryl)-(C1-C4) alkylene-, (4- to 7-membered heterocycloalkyl)-(C1-C4) alkylene-, (C2-C4) alkenyl, and (C2-C4) alkynyl of Resão, each optionally substituted by 1, 2 or 3 Rf substituents, or any two Rf substituents together with the nitrogen atom to which they are attached, form a 4, 5, 6, 7, 8, 9 or 10-membered heterocycloalkyl groups, each of which is optionally substituted by 1, 2 or 3 independently selected Rf substituents; or any two Rc substituents together with the nitrogen atom to which they are attached form heterocycloalkyl groups with 4, 5, 6, 7, 8, 9 or 10 members, each of which is optionally substituted by 1, 2 or 3 independently. Petition 870230091982, dated 10 / 17 / 2023, p. 20 / 422 13 / 378 selected Rf substituents, or any two Rf substituents together with the nitrogen atom to which they are attached, form a 4, 5, 6, 7, 8, 9 or 10-membered heterocycloalkyl groups, each of which is optionally substituted by 1, 2 or 3 independently selected Rf substituents; Each Rf is independently selected from the group consisting of halo, -OH, -CN, -COOH, -NH2, -NH-(C1Cg)alkyl, -N((C1-Ce)alkyl)2, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, and (C3-C6)cycloalkyl, wherein the (C1-C6)alkyl, phenyl, (C3-C6)cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl of Rf are optionally substituted, each, by 1, 2, or 3 substituents selected from halo, -OH, -CN, -COOH, -NH2, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, phenyl, (C3-C10) cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl; each Rg is selected independently from the group consisting of halo, -OH, -CN, -COOH, -COO-(C1-C4) alkyl, -NH2, -NH-(C1-C6) alkyl, -N((C1-C6) alkyl)2, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkylthio, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, and (C3-C6) cycloalkyl; Y is selected from -O-, -S-, -SO-, -SO2-, -NH, and —N((C1-Cg) alkyl)-; the nitrogen atom of the ring in the chemical portion of Petition 870230091982, dated 10 / 17 / 2023, p. 21 / 422 14 / 378 quinoline in Formula A is optionally oxidized; the subscript n is an integer of 1, 2, 3, or 4; the subscript m is an integer of 1, 2, 3, 4, or 5; and the subscript p is an integer of 0, 1, 2, 3, or 4.

[008] Another aspect provides methods of using compounds of formula I or a pharmaceutically acceptable salt thereof for the treatment of a disease, disorder or syndrome mediated at least in part by modulation of the in vivo activity of a protein kinase.

[009] An additional aspect provides processes for producing compounds of formula A and formula I.

[010] These and other aspects and modalities are described below. DETAILED DESCRIPTION OF THE INVENTION ABBREVIATIONS AND DEFINITIONS

[011] The following abbreviations and terms have the meanings shown below: Abbreviation Meaning Ac Acetyl anhydride Anhydrous Aq Aqueous Ar Argon Boc tert-Butoxycarbonyl Br Broad °C Degrees Celsius c- Cyclocalcd Calculated CBZ CarboBenzoxy = benzyloxycarbonyl d Doublet dd Doublet of doublets ddd Doublet of doublets of doublets Petition 870230091982, dated 10 / 17 / 2023, p. 22 / 422 15 / 378 Abbreviation Meaning dt Triplet doublet DCM Dichloromethane DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide Dppf 1,1'-bis(diphenylphosphane)ferrocene EA Elemental Analysis EI Electron Impact Ionization eq or equiv Equivalent Fmoc Fluorenylmethyloxycarbonyl g Gram(s) h or hr Hour(s) HPLC High-performance liquid chromatography H2 Hydrogen L Liter(s) LiHMDS Lithium bis(trimethylsilyl)azide M Molar or molarity m Multiplet MHz Megahertz (frequency) Min. Minute (or Minutes) ml Milliliter(s) Mp Melting point m / z Mass-to-charge ratio μΐ Microliter(s) Mol Mol(s) MS Mass spectral analysis N2 Nitrogen N Normal or normality nM Nanomolar NMR Nuclear magnetic resonance spectroscopy Pd / C Palladium in carbon Q Quartet TA Room temperature s Singlet Petition 870230091982, dated 10 / 17 / 2023, page 23 / 422 16 / 378 Abbreviation Meaning soln Solution S / C Substrate / catalyst ratio t or tr Triplet THF Tetrahydrofuran TLC Thin-layer chromatography v / v Volume to volume

[012] The symbol -” means a single bond, and = means a double bond.

[013] As used in this document, the singular forms “um”, “uma”, “o” and “a” include plural reference unless the context clearly indicates otherwise.

[014] When a variable is defined generically, with numerous possible substituents, each individual radical can be defined with or without the bond. For example, if Rz can be hydrogen, this can be indicated as -H” or H” in the definition of Rz.

[015] When chemical structures are depicted or described, unless explicitly stated otherwise, all carbons are considered to have hydrogen substitution to conform to a valence of four. For example, in the structure on the left side of the schematic diagram below, there are nine hydrogens. The nine hydrogens are depicted in the structure on the right. Sometimes a particular atom in the structure is described in textual formula as having a hydrogen or hydrogens as substitution (hydrogen expressly defined), for example, -CH2CH2-. It is understood by an element of common knowledge in the art that descriptive techniques Petition 870230091982, dated 10 / 17 / 2023, page 24 / 422 17 / 378 mentioned above are common in chemical techniques to provide brevity and simplicity in describing otherwise complex structures.

[016] If a group R is depicted as floating in a ring system, for example, in the formula: Therefore, unless otherwise defined, a substituent R may reside on any atom of the ring system, considering the substitution of a depicted, implied, or expressly defined hydrogen of one of the ring atoms, provided that a stable structure is formed.

[017] If a group R is depicted as floating in a fused ring system as, for example, in the formulas: Therefore, unless otherwise defined, a substituent R may reside on any atom of the fused ring system, considering the substitution of a depicted hydrogen (e.g., the -NH- in the formula above), implied hydrogen (e.g., in the formula above, where hydrogens are not shown but understood to be present), or expressly defined hydrogen (e.g., where in the formula above, Z equals =CH-) of one of the ring atoms, provided that a stable structure is formed. In the example Petition 870230091982, dated 10 / 17 / 2023, page 25 / 422 18 / 378 depicted, the R group can reside in the 5-membered or 6-membered ring of the fused ring system. When an R group is depicted as existing in a ring system containing saturated carbons, for example, in the formula: (R) / ^^ where, in this example, y can be more than one, considering that each one replaces a hydrogen currently depicted, implied, or expressly defined in the ring; then, unless defined otherwise, where the resulting structure is stable, two Rs can reside on the same carbon. A simple example is when R is a methyl group, there can be a geminal dimethyl on a carbon of the depicted ring (an annular carbon). In another example, two Rs on the same carbon, including this carbon, can form a ring, thus creating a spirocyclic ring structure (a spirocyclyl group) with the depicted ring as, for example, in the formula:

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

[019] The term Cn-m or Cn-Cm indicates a range that includes endpoints, where neither are whole numbers and indicate the number of carbons. Examples include C1-4, C1-C4, C1-6, C1-C6, and similar.

[020] Alkyl refers to a branched or linear hydrocarbon chain of one to eight carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl and Petition 870230091982, dated 10 / 17 / 2023, p. 26 / 422 19 / 378 heptyl. (C1-Ce)alkyl is preferred. The term “Cn-m alkyl” or (Cn-Cm) alkyl refers to an alkyl group that has nam 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 substituted by a chemical moiety as described below in “Optional Substitution”. In some respects, the alkyl group is unsubstituted or not optionally substituted.

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

[022] The term “alkenyl” refers to a linear or branched chain hydrocarbon group that corresponds to an alkyl group having one or more carbon-carbon double bonds. An alkenyl group formally corresponds to an alkene with a CH bond substituted by the alkenyl group's attachment point to the rest of the compound. The term “Cn-m alkenyl” or (Cn-Cm) alkenyl refers to a Petition 870230091982, dated 10 / 17 / 2023, p. 27 / 422 20 / 378 alkenyl group which has m carbons. In some embodiments, the alkenyl chemical moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Exemplary alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[023] The term alkynyl refers to a linear or branched chain hydrocarbon group that corresponds to an alkyl group having one or more carbon-carbon triple bonds. An alkynyl group formally corresponds to an alkyne with a CH bond substituted by the point of attachment of the alkynyl group to the rest of the compound. The term Cn-m alkynyl or (Cn-Cm) alkynyl refers to an alkynyl group that has nam carbons. Exemplary alkynyl groups include, but are not limited to, ethinyl, propyn-1-yl, propyn-2-yl and the like. In some embodiments, the alkynyl chemical moiety contains 2 to 6, 2 to 4 or 2 to 3 carbon atoms.

[024] Alkoxy refers to a chemical fraction of the formula —OR', where R' is a chemical fraction of (C1-Ce)alkyl as defined in this document. The term Cn-m alkoxy or (Cn-Cm) alkoxy refers to an alkoxy group whose alkyl group has nam carbons. Examples of alkoxy chemical fractions include, but are not limited to, methoxy, ethoxy, isopropoxy and the like.

[025] An 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 substituted by a chemical fraction as described below in Petition 870230091982, dated 10 / 17 / 2023, p. 28 / 422 21 / 378 “Optional Substitution”, provided that no alpha-oxygen atom of ether oxygen is substituted by a hydroxy, amino, or thio group. In some respects, the alkoxy group is unsubstituted or not optionally substituted.

[026] “Alkoxycarbonyl” refers to a -C(O)R' group where R' is (C1-C6)alkoxy as defined herein.

[027] The term “amino” refers to a group with the formula -NH2.

[028] The term “carbamyl” refers to a group of the formula -C(O)NH2.

[029] 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).

[030] The term “cyano” or “nitrile” refers to a group of the formula -C^N, which can also be written as -CN or CN.

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

[032] The term “sulfide” refers to a sulfur atom as a divalent substituent, which forms a thiocarbonyl group (C=S) when bonded to carbon.

[033] The term “heteroatom” used in this document is intended to include boron, phosphorus, sulfur, oxygen and nitrogen.

[034] The term “haloalkyl”, as used in Petition 870230091982, dated 10 / 17 / 2023, page 29 / 422 22 / 378 of this document refers to an alkyl group in which one or more of the hydrogen atoms have been replaced by a halogen atom. The term "Cn-m haloalkyl" or "(Cn-Cm) haloalkyl" refers to a Cn-m alkyl group that has nam carbon atoms and at least one to {2(nam)+1} halogen atoms, which may be the same or different. In some embodiments, the halogen atoms are fluorotoms. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms. Exemplary haloalkyl groups include CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, and the like.

[035] The term “haloalkoxy”, used alone or in combination with other terms, refers to a group of formula -O-haloalkyl, wherein the haloalkyl group is as defined above. The term Cn-m haloalkoxy or (Cn-Cm) haloalkoxy refers to a haloalkoxy group whose haloalkyl group has nam carbons. Exemplary haloalkoxy groups include trifluoromethoxy and the like. In some embodiments, the haloalkoxy group has from 1 to 6, 1 to 4, or 3 carbon atoms.

[036] “Aryl” means a monovalent ring of six to fourteen members, mono- or bicarbocyclic (e.g., having two fused rings), in which the monocyclic ring is aromatic and at least one of the rings in the bicyclic ring is aromatic. The term “Cn-m aryl” or “(Cn-Cm) aryl” refers to an aryl group having nam carbon atoms per ring. In some embodiments, the aryl groups have from 6 to about 10 carbon atoms. In some embodiments, the aryl groups have 6 carbon atoms. In some embodiments, the groups Petition 870230091982, dated 10 / 17 / 2023, p. 30 / 422 23 / 378 aryl groups have 10 carbon atoms. Unless otherwise stated, the valence of the group may be located on any atom of any ring within the radical, when the valence rule permits. Representative examples include phenyl, naphthyl, and indanyl, and the like.

[037] An 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 substituted by a chemical moiety as described below in “Optional Substitution”. In some respects, the alkoxy group is unsubstituted or not optionally substituted.

[038] “Arylene” means a six- to fourteen-membered divalent ring, mono- or bicarbocyclic ring, in which the monocyclic ring is aromatic and at least one of the rings in the bicyclic ring is aromatic. Representative examples include phenylene, naphthylene, indanylene, and the like.

[039] “Cycloalkyl” refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic) including cyclized alkyl and alkenyl groups. The term “Cn-m cycloalkyl” or “(Cn-Cm) cycloalkyl” refers to a cycloalkyl that has nam carbon atom members per ring. Cycloalkyl groups may include mono- or polycyclic spirocyclic groups (e.g., having 2, 3, or 4 fused rings). Cycloalkyl groups may have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring-forming carbons (C3-14). In some embodiments, the cycloalkyl group has 3 to 14 members, 3 to 10 members, 3 to 6 members per ring, 3 to 5 members per ring, or 3 to 4 members per ring. In some embodiments, the group Petition 870230091982, dated 10 / 17 / 2023, p. 31 / 422 24 / 378 Cycloalkyl is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is a C3-6 monocyclic cycloalkyl group. The ring-forming carbon atoms of a cycloalkyl group may optionally be oxidized to form an oxo or sulfide group. Cycloalkyl groups also include cycloalkylidenes. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, bicyclo[1,1,1]pentanyl, bicyclo[2,1,1]hexanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.In some embodiments, the cycloalkyl group includes a single saturated carbocyclic ring of three to eight ring carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl group may optionally be substituted with one or more substituents, such as one, two, or three 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.

[040] A 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 substituted by a chemical moiety as follows: Petition 870230091982, dated 10 / 17 / 2023, p. 32 / 422 25 / 378 described below in “Optional Substitution.” In some respects, a substituted cycloalkyl group may incorporate an exo- or endocyclic alkene (e.g., cyclohex-2-en1-yl). In some respects, a cycloalkyl group is unsubstituted or not optionally substituted.

[041] Cycloalkyloxycarbonyl means a -C(O)-OR' group where R' is (C3-C6)cycloalkyl as defined in this document.

[042] “Phenyloxycarbonyl refers to a C(O)-O-phenyl group.

[043] Heteroaryl means a monocyclic monovalent, bicyclic fused or tricyclic fused radical of 5 to 14 atoms per ring containing one or more, preferably one, two, three or four ring heteroatoms independently selected from -O-, -S(O)n- (n is 0, 1, or 2), -N-, and -N(R')-, and the remaining atoms per ring being carbon, wherein the ring comprising a monocyclic radical is aromatic and wherein at least one of the fused rings comprising a bicyclic or tricyclic radical is aromatic. One or two ring carbon atoms of any non-aromatic rings comprising a bicyclic or tricyclic radical may be substituted by a -C(O)-, -C(S)- or -C(=NH)- group. R' is hydrogen, alkyl, hydroxyl, alkoxy, acyl, or alkylsulfonyl. Unless otherwise stated, the valence may be located on any atom of any ring of the heteroaryl group, where the valence rule permits.In particular, when the valence point is located on the nitrogen, an additional nitrogen substituent is not present. More specifically, the term heteroaryl includes, but does not include. Petition 870230091982, dated 10 / 17 / 2023, page 33 / 422 26 / 378 limitation, 1,2,4-triazolyl, 1,3,5-triazolyl, phthalimidyl, pyridinyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, 2,3-di-hydro-1H-indolyl (including, e.g. 2,3-di-hydro-1H-indol-2-yl or 2,3-di-hydro-1H-indol-5-yl and the like), isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, benzodioxol-4-yl, benzofuranyl, cinolinyl, indolizinyl, naphthyridin-3-yl, phthalazin-3-yl, phthalazin-4-yl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, iso-oxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, tetra-hydroisoquinolinyl (including, for example, tetrahydroisoquinolin-4-yl or tetra-hydroisoquinolin-6-yl and the like), pyrrolo[3,2-c]pyridinyl (including, for example, pyrrolo[3,2-c]pyridin-2-yl or pyrrolo[3,2c]pyridin-7-yl e benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl, benzothienyl and derivatives thereof,and N-oxide or a protected derivative thereof.

[044] A 5-membered heteroaryl ring is a heteroaryl group having five ring atoms, wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are independently selected from N, O, and S. Exemplary five-membered ring heteroaryls include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. Petition 870230091982, dated 10 / 17 / 2023, p. 34 / 422 27 / 378

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

[046] Heteroarylene means a monocyclic, bicyclic or tricyclic divalent radical of 5 to 14 atoms per ring containing one or more, preferably one, two, three or four ring heteroatoms independently selected from -O-, -S(O)n- (n is 0, 1 or 2), -N- and -N(R19)-, the remaining atoms per ring being carbon, wherein the ring comprising a monocyclic radical is aromatic and wherein at least one of the fused rings comprising a bicyclic or tricyclic radical is aromatic. One or two ring carbon atoms of any non-aromatic rings comprising a bicyclic or tricyclic radical may be substituted by a -C(O)-, -C(S)- or -C(=NH)- group. R19 is hydrogen, alkyl or alkenyl. Unless otherwise stated, valences may be located on any atom of any ring in the heteroarylene group, where the valence rule permits.In particular, when the valence point is located on the nitrogen, an additional nitrogen substituent is not present. More specifically, the term heteroaryl includes, but is not limited to, thien-di-yl, benzo[d]isoxazole-di-yl, benzo[d]isothiazole-di-yl, 1hindazole-di-yl (optionally substituted at position N1 by R19), benzo[d]oxazole-di-yl, benzo[d]thiazole-di-yl. Petition 870230091982, dated 10 / 17 / 2023, page 35 / 422 28 / 378 1H-benzo[d]imidazol-di-yl (optionally substituted at position N1 by R19), 1H-benzo[d][1,2,3]triazol-di-yl (optionally substituted at position N1 by R19), imidazo[1,2-α]pyridin-di-yl, cinolin-di-yl, quinolin-di-yl, pyridin-di-yl, 1-oxide-pyridin-di-yl, [1,2,4]triazol[4,3-a]pyridin-diyl, and 2,3-dihydroimidazo[1,2-a]pyridin-diyl and the like.

[047] As used in this document, heterocycloalkyl or heterocycle refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, having at least one heteroatom ring member independently selected from boron, nitrogen, sulfur, oxygen, and phosphorus, and having 4 to 14 members per ring, 4 to 10 members per ring, 4 to 7 members per ring, or 4 to 6 members per ring. Included in the term heterocycloalkyl are monocyclic heterocycloalkyl groups of 4, 5, 6, and 7 members. Heterocycloalkyl groups may include mono- or bicyclic or polycyclic ring or spirocycle systems (e.g., having two or three fused or bridging rings). In some embodiments, the heterocycloalkyl group is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen.Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group may optionally be oxidized to form an oxo or sulfide group or other oxidized bond (e.g., C(O), S(O), C(S), S(O)2, N-oxide and the like) or a nitrogen atom may be quaternized. The heterocycloalkyl group may be linked through an atom of... Petition 870230091982, dated 10 / 17 / 2023, p. 36 / 422 29 / 378 ring-forming carbon or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains from 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains from 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are chemical moieties that have one or more aromatic rings fused (i.e., having a common bond with) to the heterocycloalkyl ring, for example, benzo- or thienyl derivatives of cyclopentane, cyclohexane, and the like. A heterocycloalkyl group containing a fused aromatic ring may be linked through any ring-forming atom, including a ring-forming atom of the fused aromatic ring. Examples of heterocycloalkyl groups include azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, morpholino, 3-oxa-9-azaspiro[5.5]undecanyl, 1-oxa-8-azaspiro[4.5]decanyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl, 4,5,6,7-tetrahydrothiazol[5,4-c]pyridinyl and thiomorpholino.

[048] “Heterocycloalkyl” or “heterocycle” 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 substituted by an independently selected chemical moiety of fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio. In some respects, a substituted heterocyclyl group may incorporate an exo- or endocyclic alkene (e.g., cyclohex-2-en-1-yl). In some respects, the group is unsubstituted or not Petition 870230091982, dated 10 / 17 / 2023, p. 37 / 422 30 / 378 optionally replaced. OPTIONAL REPLACEMENT

[049] A group is optionally substituted in this document unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or not substituted. In certain embodiments, alkyl, alkenyl, alkynyl, carbocycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted. “Optionally substituted” refers to a group that may be substituted or not substituted (e.g., alkyl group “substituted” or “not substituted”, alkenyl “substituted” or “not substituted”, alkynyl “substituted” or “not substituted”, cycloalkyl “substituted” or “not substituted”, heterocycloalkyl “substituted” or “not substituted”, aryl “substituted” or “not substituted” or heteroaryl “substituted” or “not substituted”).In general, the term “substituted” means that at least one hydrogen atom in a group is replaced by a permissible substituent, for example, a substituent that, upon substitution, results in a stable compound, for example, a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent in one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is the same or different in each position. The term “substituted” is considered to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein. Petition 870230091982, dated 10 / 17 / 2023, p. 38 / 422 31 / 378 document resulting in the formation of a stable compound. The present invention contemplates any and all such combinations in order to achieve a stable compound. For the purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein that satisfies the valences of the heteroatoms and results in the formation of a stable chemical fraction. The invention is not intended to be limited in any way by the exemplary substituents described herein.

[050] Exemplary carbon atom substituents include, but are not limited to, halogen (halo), -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORaa, -ON(Rbb)2, -N(Rbb)2, -N(Rbb)3+X-, -N(ORcc)Rbb, -SH, -SRaa, -SSRcc, -C(=O)Raa, -CO2H, -CHO, -C(ORcc)2, -CO2Raa, -OC(=O)Raa, -OCO2Raa, -C(=O)N(Rbb)2, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=O)NRbbSO2Raa, -NRbbSO2Raa, -SO2N(Rbb)2, -SO2Ra, -SO2ORRa, -OS2Ra, -S(=O)Ra, -OS(=O)Ra, -Si(Ra)3, -OSi(Raa)3 -C(=S)N(Rbb)2, -C(=O)SRaa, -C(=S)SRaa, -SC(=S)SRaa, -SC(=O)SRa, -OC(=O)SRa, -SC(=O)ORa, -SC(=O)Roa, -P(=O)2Roa, -OP(=O)2Raa, -P(=O)(Raa)2, -OP(=O)(Raa)2, -OP(=O)(ORcc) 2, -P(=O)2N(Rbb)2, -OP(=O)2N(Rbb)2, -P(=O)(NRbb)2, -OP(=O)(NRbb)2, -NRbbP(=O)(ORcc)2, -NRbbP(=O)(NRbb)2, -OP(Rcc)2, -OP(Rcc)3, -B(ORcc)2, -BRaa(ORcc), C1-10 alkyl, C1-10 per-haloalkyl, C210 alkenyl, C2-10 alkynyl, (C3-C10) carbocycloalkyl, 3- to 14-membered heterocycloalkyl com1 heterocyl, (C1 aryl,)(C6-aryl members, em that each rents, Petition 870230091982, dated 10 / 17 / 2023, p. 39 / 422 32 / 378 alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 Rdd groups; or two geminal hydrogens on a carbon atom are replaced by the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb or =NORcc; Each case of Raaé is independently selected from (C1-C10) alkyl, (C1-C10) per-haloalkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, (C3-C10) cycloalkyl, 3- to 14-membered heterocycloalkyl, (C6-C14) aryl and 5- to 14-membered heteroaryl, or two Raa groups are joined to form a 3- to 14-membered heterocycloalkyl or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 Rdd groups; Each case of Rbb is independently selected from hydrogen, (C1-C10) per-haloalkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, (C3-C10) cycloalkyl, C6-14 aryl, and heteroaryl with 5 to 14 members, or two Rbb groups are joined to form a heterocycloalkyl ring of 3 to 14 members or heteroaryl ring of 5 to 14 members, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 Rdd groups; each case of Rcc, independently, selected from hydrogen, (C1-C10) alkyl, (C1-C10) perhaloalkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, (C3-C10) cycloalkyl, 3- to 14-membered heterocycloalkyl, (C6-C14) aryl and 5- to 14-membered heteroaryl, or two Rcc groups Petition 870230091982, dated 10 / 17 / 2023, page 40 / 422 33 / 378 are joined to form a 3- to 14-membered heterocycloalkyl or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted by 20, 1, 3, 4, Rdd groups; each case of Rddé, independently, selected from halide, -CN, -NO2, -SO2H, -SO3H, -OH, -ORee, -ON(Rff)2, -N(Rff)2, -N(Rff)3+X-' -N(ORee)Rff, -SH, -SRee, -SSRee, -C(=O)Ree, -CO2H, -CO2Ree, -OC(=O)Ree, -OCO2Ree, -C(=O)N(Rff)2, -OC(=O)N(Rff)2, -NRffC(=O)Ree, -NRffCO2Ree, -NRffC(=O)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2, -NRffC(=NRff)N(Rff)2, -NRffSO2Ree, -SO2N(Rff)2, -SO2Ree, -SO2ORee, -OSO2Ree, -S(=O)Ree, -Si(Ree)3, -OSi(Ree)3, -C(=S)N(Rff)2, -C(=O)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=O)2Ree, -P(=O)(Ree)2, -OP(=O)(Ree)2, -OP(=O)(ORee)2, (C1-C10) alkyl, (C1-C10) per-haloalkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, (C3-C10) cycloalkyl, 3- to 10-membered heterocycloalkyl, (C6-C10) aryl, heteroaryl with 5 to 10 members, in which each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 Rgg groups, or two Rddgeminais substituents can be joined to form =O or =S; each case of Reeé, independently, selected from (C1-C6) alkyl, (C1-C6) per-haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C10) cycloalkyl, (C6-C10) aryl, 3- to 10-membered heterocycloalkyl, and 3- to 10-membered heteroaryl, in which each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is Petition 870230091982, dated 10 / 17 / 2023, page. 41 / 422 34 / 378 independently replaced by 0, 1, 2, 3, 4 or 5 groups Rgg; Each Rff group is independently selected from hydrogen, (C1-C6) alkyl, (C1-C6) perhaloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C10) cycloalkyl, (C6-C10) aryl, and heteroaryl groups with 5 to 10 members, or two Rff groups are joined to form a 3- to 10-membered heterocycloalkyl ring or a 5- to 10-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl aryl, and heteroaryl group is independently substituted by 0, 1, 2, 3, 4, or 5 groups. Rgg; and each case of Rgg is, independently, halogen, -CN, -NO2, -SO2H, -SO3H, —OH, -OC1-6 alkyl, -ON(Ci-6 alkyl)2, -N(Ci-6 alkyl)2, -N(Ci-6 alkyl)3+X-' -NH(Ci-6 alkyl)2+X-' -NH2(Ci-6 alkyl) +X-' -NH3+X-, -N(OCi-6 alkyl)(C1-6 alkyl), -N(OH)(Ci-6 alkyl), -NH(OH), -SH, -SC1-6 alkyl, -SS(Ci-6 alkyl), -C(=O)(Ci-6 alkyl), -CO2H, -CO2(Ci-6 alkyl), -OC(=O)(Ci-6 alkyl), -OCO -C(=O)N(Ci-6 alkyl)2, -OC(=O)NH(Ci-6 alkyl), -NHC(=O)( Ci-6 alkyl), -N(Ci-6 alkyl)C(=O)( C1-6 alkyl), -NHCO2(Ci-6 alkyl), -NHC(=O)NH(Ci-6 alkyl,2) -NHC(=O)NH(Ci-6 alkyl), -NHC(=O)NH2, -C(=NH)O(Ci-6 alkyl), -OC(=NH)(Ci-6 alkyl), -OC(=NH)OCi-6 alkyl, -C(=NH)N(Ci-6 alkyl)2, -C(=NH)N(Ci-6 alkyl), -C(=NH)NH2, -OC(=NH)N(Ci-6 alkyl)2, -OC(NH)NH(Ci-6 alkyl), -OC(NH)NH2, -NHC(NH)N(Ci-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(Ci-6 alkyl), -SO2N(Ci-6 alkyl)2, -SO2NH(Ci-6 alkyl), -SO2NH2, -SO2C1-6 alkyl, -SO2OC1-6 alkyl, -OSO2C1-6 alkyl, -SOCi-6 alkyl, -Si(Ci-6 alkyl)3, -OSI(Ci-6 alkyl)3 -C(=S)N(Ci-6 alkyl)2, C(S)N(Ci-6 alkyl)2, C(S)N(Ci-6), C(=S)NH2, Petition 870230091982, of 17 / 10 / 2023, p. 42 / 422 35 / 378 -C(=O)S(Ci-6 alkyl), -C(=S)SCi-6 alkyl, -SC(=S)SCi-6 alkyl, -P(=O)2(Ci-6 alkyl), -P(=O)(Ci-6 alkyl)2, -OP(=O)(C1-6 alkyl)2, -OP(=O)(OC1-6 alkyl)2, (C1-C1) alkyl, (C1-C1) per-haloalkyl, (C2-C1) alkenyl, (C2-C1) alkynyl, (C3-C10) cycloalkyl, (C1-C10) aryl, 3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl; or two Rgggeminal substituents may be joined to form =O or =S; where X- is a counterion. [05i] As noted earlier, nitrogen atoms can be substituted or unsubstituted as the valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -ORaa, -N(Rcc)2, -CN, -C(=O)Raa, -C(=O)N(Rcc)2, -CO2Raa, -SO2Raa, -C(=NRbb)Raa, -C(=NRcc)ORaa, -C(=NRcc)N(Rcc)2, -SO2N(Rcc)2, -SO2Rcc, -SO2ORcc, -SORaa, -C(=S)N(Rcc)2, -C(=O)SRcc, -C(=S)SRcc, -P(=O) 2Raa, -P(=O)(Raa)2, -P(=O) 2N(Rcc)2, -P(=O)(NRcc)2, (C1-C10) alkyl, (C1-C10) perhaloalkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, (C3-C10) cycloalkyl, 3- to 4-membered heterocycloalkyl, (C1-C1u) aryl and 5- to 4-membered heteroaryl, or two Rcc groups attached to an N atom are joined to form a 3- to 4-membered heterocycloalkyl ring or a 5- to 4-membered heteroaryl ring, wherein each alkyl, Alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently substituted by 0, 1, 2, 3, 4, or 5 Rdd groups, wherein Raa, Rbb, Rcce, and Rdd are as defined above.

[052] In certain embodiments, the substituent present on the nitrogen atom is a protecting group of Petition 870230091982, dated 10 / 17 / 2023, pp. 43 / 422 36 / 378 nitrogen (also referred to in this document as an “amino protecting group”). Nitrogen protecting groups include, but are not limited to, -OH, -ORaa, -N(Rcc)2, -C(=O)Raa, -C(=O)N(Rcc)2, -CO2Raa, -SO2Raa, -C(=NRcc)Raa, -C(=NRcc)ORaa, -C(=NRcc)N(Rcc)2, -SO2N(Rcc)2, -SO2Rcc, -SO2ORcc, -SORaa, -C(=S)N(Rcc)2, -C(=O)SRcc, -C(=S)SRcc, (C1-C10) alkyl (e.g., aralkyl, heteroaralkyl), (C2-C10) . 4 or 5 groups Rdd, and where Raa, Rbb, Rcce Rddsion as defined in this document. Nitrogen protection groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[053] For example, nitrogen protecting groups such as amide groups (e.g., -C(=O)Raa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanine derivative, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o Petition 870230091982, dated 10 / 17 / 2023, pp. 44 / 422 37 / 378 phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinamide, N-acetylmethionine derivative, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide.

[054] Nitrogen protecting groups such as carbamate groups (e.g., -C(=O)ORaa) include, but are not limited to, 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 (DBDTmoc), 4-methoxyphenacyl carbamate (fenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), carbamate 1-(1-adamantyl)-1-methylethyl (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2trichloroethyl carbamate (TCBOC), 1-methyl-1-(4biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-tbutylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc),1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), aliphatic carbamate (Alloc), 1-isopropylaliphatic carbamate (Ipaoc), cinamila carbamate (Coc), 4-nitrocinamila carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinil carbamate, alquilditio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-carbamate, Petition 870230091982, 17 / 10 / 2023, pág. 45 / 422 38 / 378 dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-antrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(ptoluenesulfonyl)ethyl carbamate, [2-(1,3dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, carbamate 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chloromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, onitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, tamyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate,cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxycylvinyl 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, isoborinyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, carbamate de 1-methyl-1-(3,5-dimethoxyphenyl)ethyla, carbamato de 1-methylPetição 870230091982, de 17 / 10 / 2023, pág. 46 / 422, 39 / 378 1-(p-phenylazophenyl)ethyl, 1-methyl-1phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyla carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyla carbamate, 4(trimethylamônio)benzyl carbamate and 2,4,6trimethylbenzyl carbamate.

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

[056] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)acyl derivative, N'-p-toluenesulfonylaminoacyl derivative, N'-phenylaminothioacyl derivative, N-benzoylphenylalanine derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one derivative, N-phthalimide, N-dithiasuccinimide (Dts), N2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-adduct. [Note: The last line appears to be a fragment of a larger document and doesn't translate directly. It's omitted from the translation as it's not part of the main text.] 40 / 378 1,1,4,4-tetramethyldisilylazacyclopentane (STABASE), 1,3dimethyl-1,3,5-triazacyclohexan-2-one 5-substituted, 1,3dibenzyl-1,3,5-triazacyclohexan-2-one 5-substituted, 3,5dinitro-4-pyridone 1-substituted, N-methylamine, Nalylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3pyrolin-3-yl)amine, quaternary ammonium salts,Nbenzylamine, N-di(4-methoxyphenyl)methylamine,N-5dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4methoxyphenyl)diphenylmethyl]amine (MMTr),N-9phenylfluorenylamine (PhF), N-2,7-dichloro-9fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N'N-2-picolylamino oxide, N-1,1-dimethylthiomethyleneamine,Nbenzylideneamine, Np-methoxybenzylideneamine,Ndiphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine,N,N'isopropylidenediamine, Np-nitrobenzylideneamine,Nsalicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, N-amine oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide and 3 Petition 870230091982, dated 10 / 17 / 2023, pp. 48 / 422 41 / 378 nitropyridinesulfenamide (Npys).

[057] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as a “hydroxyl protecting group”). Oxygen protecting groups include, but are not limited to, -Raa, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, -Si(Raa)3, -P(Rcc)2, -P(Rcc)3, -P(=O)2Raa, -P(=O)(Raa)2, -P(=O)(ORcc) 2, -P(=O)2N(Rbb)2, and -P(=O)(NRbb)2, where Raa, Rbb, and Rcc are as defined herein. Oxygen shielding groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[058] Exemplary oxygen protecting groups include, but are not limited to, 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), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4 Petition 870230091982, dated 10 / 17 / 2023, pp. 49 / 422 42 / 378 methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7aocta-hydro-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-2fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, pmethoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn),p methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, pcyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N oxide, diphenylmethyl, p, p' dinitrobenzidryl, 5-dibenzosuberyl, triphenylmethyl, αnaphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(pmethoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'bromophenacyloxyphenyl)diphenylmethyl, 4,4',4-tris(4,5dichlorophthalimidophenyl)methyl, 4,4',4tris(levulinoyloxyphenyl)methyl, 4,4',4tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'pyrenylmethyl, 9-antryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl10-oxo)anthryl, 1,3-benzodithiolan-2-yl, S,S-benzisothiazolyl dioxide, trimethylsilyl (TMS), triethylsilyl (TES) (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, Petition 870230091982, dated 10 / 17 / 2023, page 50 / 422 43 / 378 methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinate), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonium)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, aliphatic 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-(1,1,3,3tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, 2,4-dinitrophenylsulfenate alkyl, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). Petition 870230091982, 17 / 10 / 2023, pág. 51 / 422 44 / 378

[059] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also called a “thiol protecting group”). Sulfur protecting groups include, but are not limited to, -Raa, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, —C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, -Si(Raa)3, -P(Rcc)2, -P(Rcc)3, -P(=O)2Raa, -P(=O)(Raa)2, -P(=O)(ORcc)2, -P(=O)2N(Rbb)2, and -P(=O)(NRbb)2, where Raa, Rbb, and Rcc are as defined herein. The sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[060] As used in this document, a “leaving group (LG)” is a term known in the art that denotes a molecular fragment that departs with an electron pair in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule. As used in this document, a leaving group may be an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501 to 502). Exemplary leaving groups include, but are not limited to, halo (e.g., chlorine, bromine, iodine), -ORaa (where the O atom is attached to a carbonyl group, wherein Raa is as defined in this document), -O(C=O)RLG, or -O(SO)2RLG (e.g., tosyl, mesyl, besyl), wherein RLG is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl. In certain Petition 870230091982, dated 10 / 17 / 2023, page 52 / 422 45 / 378 modes, the leaving group is a halogen.

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

[062] “Yield” for each of the reactions described in this document is expressed as a percentage of the theoretical yield.

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

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

[065] “Therapeutically effective quantity” is a Petition 870230091982, dated 10 / 17 / 2023, p. 53 / 422 46 / 378 The amount of a compound of the invention that, when administered to a patient, improves a symptom of the disease. The amount of a compound of the invention that constitutes a “therapeutically effective amount” will vary depending on the compound, the state of the disease and its severity, the age of the patient to be treated, and the like. The therapeutically effective amount can be routinely determined by an element of common knowledge in the art due to their own knowledge and this disclosure.

[066] “Cancer” refers to states of proliferative cellular disease, including, but not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Head and neck: squamous cell carcinomas of the head and neck, larynx and hypopharynx cancer, nasal cavity and paranasal sinus cancer, nasopharynx cancer, salivary gland cancer, oral and oropharyngeal cancer; Lung: bronchogenic carcinoma (squamous cell lung cancer, small undifferentiated cell, large undifferentiated cell, adenocarcinoma, non-small cell), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Colon: colorectal cancer, adenocarcinoma, gastrointestinal stromal tumors, lymphoma, carcinoids, Turcot syndrome;Gastrointestinal: gastric cancer, adenocarcinoma of the gastroesophageal junction, esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma); Petition 870230091982, dated 10 / 17 / 2023, page 54 / 422 47 / 378 carcinoid tumors, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's 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;Genitourinary tract: kidneys (adenocarcinoma, Wilms' tumor [nephroblastoma], lymphoma, leukemia, renal cell carcinoma), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, urothelial carcinoma), prostate (adenocarcinoma, sarcoma, castration-resistant prostate cancer), testicle (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma), clear cell carcinoma, papillary carcinoma; Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors; Thyroid: medullary thyroid cancer, differentiated thyroid cancer, papillary thyroid cancer, follicular thyroid cancer, Hurthle cell cancer, and cancer of; Petition 870230091982, dated 10 / 17 / 2023, page 55 / 422 48 / 378 anaplastic thyroid; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, Paget's disease), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial cancer), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosatecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematological: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, dysplastic nevus moles, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. Thus, the term "cancer cell" as used in this document includes a cell affected by any of the conditions identified above.

[067] “Pharmaceutically acceptable salts” includes “pharmaceutically acceptable acid addition salts” and Petition 870230091982, dated 10 / 17 / 2023, page 56 / 422 49 / 378 “pharmaceutically acceptable base addition salts”. “Pharmaceutically acceptable acid addition salts” refers to those salts that retain the biological efficacy of the free bases and that are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

[068] “Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Exemplary salts are ammonium, potassium, sodium, calcium and magnesium salts. Pharmaceutically acceptable salts derived from non-toxic organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, Petition 870230091982, dated 10 / 17 / 2023, page 57 / 422 50 / 378 purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. (See, for example, SM Berge, et al., “Pharmaceutical Salts”, J. Pharm. Sci., 1977;66:1 to 19 which is incorporated herein by reference.)

[069] The term “compound”, as used in this document, is intended to include all stereoisomers, geometric isomers, tautomers and isotopes of the structures depicted. The term is also intended to refer to compounds of the inventions, regardless of how they are prepared, for example, synthetically, through a biological process (e.g., metabolism or enzymatic conversion) or a combination thereof.

[070] The compounds of the invention may also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

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

[072] In addition, many of the steps and process sequences described in this document may be alternated. Petition 870230091982, dated 10 / 17 / 2023, page 58 / 422 51 / 378

[073] In general, the nomenclature in this Application is based on nomenclature conventions adopted by the International Union of Pure and Applied Chemistry (IUPAC). The chemical structures shown herein were prepared using CHEMDRAW®. Any open valence appearing on a carbon, oxygen, or nitrogen atom in the structures herein indicates the presence of a hydrogen atom. MODALITIES OF THE INVENTION

[074] One aspect provides a compound of formula A: Rn A or a pharmaceutically acceptable salt thereof, wherein the variables and substituents in formula A are as defined in the Summary of the Invention.

[075] In one embodiment of this aspect, the compound of formula A is a compound of formula A-1. A-1

[076] In another embodiment of this aspect, the compound of formula A is a compound of formula A-2. Petition 870230091982, dated 10 / 17 / 2023, p. 59 / 422 52 / 378 A-2

[077] composed of In a further embodiment of this aspect, formula A is a compound of formula A-3: A-3 where

[078] formula A-3

[079] compound of Ra1é -H or (C1-C6) alkyl. In an additional embodiment, R1 in the compound is -H. In a further embodiment of this aspect, formula A is a compound of formula A-4: where subscribed r

[080] In A-4, ring A is heteroaryl and is 1, 2, 3, or 4. In this modality, R2 has 5 to 14 members; and the -H is used. Petition 870230091982, dated 10 / 17 / 2023, p. 60 / 422 53 / 378

[081] In an additional embodiment, r in formula A-4 is either 2.

[082] In an additional embodiment of the formula A: Ri is -H, (C1-C6) alquila opcionalmente substitutída, halo, -ORa, NO2, -NH2, -NHRa, -NRaRa, -SRa, -SORa, or -S(O)2Ra, and R2 is selected from the group that consists of (C2-C6) alkenila, (C2-C6) alquinila, (C6-C10) arila, (C3-C10) cycloalquila, -CN, -NHORa, -C(O)Ra, -C(O)NRaRa, -C(O)NHORa,C(O)ORa, -C(O)NRaS(O)2Ra, -OC(O)NRaRa, NRaC(O)Ra,NRaC(=NRa)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -C(=NRa)Ra,C(=NOH)Ra, -C(=NORa)Ra, -C(=NOH)NRa, -C(=NCN)NRaRa,NRaC(=NCN)NRaRa, -C(=NRa)NRaRa, -NRaC(=NRa)NRaRa, -NRaS(O)Ra, NRaS(O)2Ra, -NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra,S(O)2NRaC(O)Ra, -P(O)RaRa, -P(O)(ORa)(ORa), -B(OH)2, -B(ORa)2 and -S(O)2NRaRa.

[083] Numa modality desta modality, R1 é -H.

[084] In a further embodiment: R1 is selected from the group consisting of (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C10) aryl, (C3-C10) cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, -CN, -NHORa, -C(O)Ra, -C(O)NRaRa, -C(O)NHORa, -C(O)ORa,C(O)NRaS(O)2Ra, -OC(O)NRaRa, -NRaC(O)Ra, -NRaC(=NRa)Ra,NRaC(O)ORa, -NRaC(O)NRaRa, -C(=NRa)Ra, -C(=NOH)Ra, -C(=NOH)NRa, -C(=NORa)Ra, -C(=NCN)NRaRa, -NRaC(=NCN)NRaRa, -C(=NRa)NRaRa, NRaC(=NRa)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa,S(O)Ra, -S(O)NRaRa, -S(O)2Ra, -S(O)2NRaC(O)Ra, -P(O)RaRa,P(O)(ORa)(ORa), -B(OH)2, -B(ORa)2, and -S(O)2NRaRa; and R2 is -H, (C1-C6) optionally substituted alkyl, halo, -ORa, -NO2, -NH2, -NHRa, -NRaRa, -SRa, -SORa or -S(O)2Ra.

[085] In a form of this form, R2 is —H. Petition 870230091982, dated 10 / 17 / 2023, page 61 / 422 54 / 378

[086] In another form: Ri is (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C10) aryl, (C3-C10) cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, -CN, -NHORa, -C(O)Ra, -C(O)NRaRa, -C(O)NHORa, -C(O)ORa, -C(O)NRaS(O)2Ra, -OC(O)NRaRa, -NRaC(O)Ra, -NRaC(=NRa)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa,C(=NRa)Ra, -C(=NOH)Ra, -C(=NORa)Ra, -C(=NOH)NRa,C(=NCN)NRaRa, -NRaC(=NCN)NRaRa, -C(=NRa)NRaRa,NRaC(=NRa)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa,S(O)Ra, -S(O)NRaRa, -S(O)2Ra, -S(O)2NRaC(O)Ra, -P(O)RaRa,P(O)(ORa)(ORa), -B(OH)2, -B(ORa)2, or -S(O)2NRaRa; and R2 is selected from the group consisting of -H, halo, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C6-C10) aryl-(C1-C4) alkylene-, (C3-C10) cycloalkyl-(C1-C4) alkylene-, (5- to 14-membered heteroaryl)-(C1-C4) alkylene-, (4- to 14-membered heterocycloalkyl)-(C1-C4) alkylene-, CN, -NO2, -ORa, -SRa, -NHORa, -C(O)Ra, -C(O)NRaRa, -C(O)NHORa, -C(O)ORa, -C(O)NRaS(O)2Ra, -OC(O)Ra, -OC(O)NRaRa, -NHRa, NRaRa, -NRaC(O)Ra, -NRaC(=NRa)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa,C(=NRa)Ra, -C(=NOH)Ra, -C(=NOH)NRa, -C(=NORa)Ra,C(=NCN)NRaRa, -NRaC(=NCN)NRaRa, -C(=NRa)NRaRa,NRaC(=NRa)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa,S(O)Ra, -S(O)NRaRa, -S(O)2Ra, -S(O)2NRaC(O)Ra, -P(O)RaRa,P(O)(ORa)(ORa), -B(OH)2, -B(ORa)2; and -S(O)2NRaRa.

[087] In a form of this form, R2 is -H.

[088] In another form: R1 is selected from the group consisting of -H, halo, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C6-C10) aryl, (C3 Petition 870230091982, dated 10 / 17 / 2023, page 62 / 422 55 / 378 Cio) cycloalkyl, 5- to 14-membered heteroaryl, 4 to 14-membered heterocycloalkyl, (Cg-Cio) aryl-(C1-C4) alkylene-, (C3-C10) cycloalkyl- (C1-C4) alkylene-, (5 to 14 membered heteroaryl)-(C1-C4) alkylene-, (4-membered heterocycloalkyl to 14 members)-(C1-C4) alkylene-, CN, -NO2, -ORa, -SRa, -NHORa, -C(O)Ra, -C(O)NRaRa, -C(O)NHORa, -C(O)ORa, -C(O)NRaS(O)2Ra, -OC(O)Ra, -OC(O)NRaRa, -NHRa,NRaRa, -NRaC(O)Ra, -NRaC(=NRa)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa,C(=NRa)Ra, -C(=NOH)Ra, -C(=NORa)Ra, -C(=NOH)NRa,C(=NCN)NRaRa, -NRaC(=NCN)NRaRa, -C(=NRa)NRaRa,NRaC(=NRa)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa,S(O)Ra, -S(O)NRaRa, -S(O)2Ra, -S(O)2NRaC(O)Ra, -P(O)RaRa,P(O)(ORa)(ORa), -B(OH)2, -B(ORa)2, and -S(O)2NRaRa; and In one version of this modality, R1 is -H.

[089] In another additional mode: R1 and R2, obtained from the atoms to which they are attached, form a fused (C3-C7) cycloalkyl ring or a fused heterocycloalkyl ring with 4 to 10 members; wherein the (C3-C7) cycloalkyl ring or a fused heterocycloalkyl ring with 4 to 10 members are optionally substituted, each, by 1, 2 or 3 independently selected Rb substituents, provided that the compound is not 1-[2-(4-Fluorophenyl)acetyl]cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododeca[b]naphthalen-4-yloxy)phenyl]amide.

[090] In a further embodiment: R1 and R2, obtained close to the atoms to which they are attached, form a fused (C3-C7) cycloalkyl ring or a fused 4- to 10-membered heterocycloalkyl ring, wherein the Petition 870230091982, dated 10 / 17 / 2023, p. 63 / 422 56 / 378 a fused (C3-C7) cycloalkyl ring or a fused 4- to 10-membered heterocycloalkyl ring is optionally substituted, each by 1, 2 or 3 independently selected Rb substituents, provided that the compound is not a compound having the formula: wherein ring E is a fused 4- to 10-membered heterocycloalkyl group.

[091] In another embodiment, R1 in the compound of formula A, A-1 or A-3,—or A-4 is selected from the group consisting of -H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2Ce) alkynyl, -C(=NO-(C1-Ce) alkyl)Ra, -CN, -C(O)ORa, C(O)NRaRa, -C(O)NHORa, -S(O)2NRaRa, phenyl, 5- to 6-membered heteroaryl, (C3-C6) cycloalkyl and 4- to 6-membered heterocycloalkyl.

[092] In another embodiment, R1 is selected from the group consisting of -H, (C1-Ce) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -C(=NO-(C1-C6) alkyl)Ra, -CN, C(O)ORa, -C(O)NRaRa, -C(O)NHORa, -S(O)2NRaRa, phenyl, 5- to 6-membered heteroaryl, (C3-C6) cycloalkyl, and 4- to 6-membered heterocycloalkyl; and R2 is H, (C1-C6) optionally substituted alkyl, halo, -ORa, -NO2, -NH2, -NHRa, -NRaRa, -SRa, -SORa, or -S(O)2Ra.

[093] In another embodiment, R1 is selected from the group consisting of -H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -C(=NO-(C1-C6) alkyl)Ra, -CN, Petition 870230091982, 10 / 17 / 2023, p. 64 / 422 57 / 378 C(O)ORa, -C(O)NRaRa, -C(O)NHORa, -S(O)2NRaRa, phenyl, 5- to 6-membered heteroaryl, (C3-C6) cycloalkyl and 4- to 6-membered heterocycloalkyl; and R2 is selected from the group consisting of -H, halo, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C6-C10) aryl, (C3C10) cycloalkyl, (C6-C10) aryl-(C1-C4) alkylene-, (C3-C10) cycloalkyl-(C1-C4) alkylene-, (5- to 14-membered heteroaryl)-(C1-C4) alkylene-, (4- to 14-membered heterocycloalkyl)-(C1-C4) alkylene-, -CN, -NO2, -ORa, -SRa, -NHORa, C(O)Ra, -C(O)NRaRa, -C(O)NHORa, -C(O)ORa, -C(O)NRaS(O)2Ra,OC(O)Ra, -OC(O)NRaRa, -NHRa, -NRaRa, -NRaC(O)Ra, -NRaC(=NRa)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -C(=NRa)Ra, -C(=NOH)Ra,C(=NOH)NRa, -C(=NORa)Ra, -C(=NCN)NRaRa, -NRaC(=NCN)NRaRa,C(=NRa)NRaRa, -NRaC(=NRa)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra,NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O)2Ra, -S(O)2NRaC(O)Ra, -P(O)RaRa, -P(O)(ORa)(ORa), -B(OH)2, -B(ORa)2; and -S(O)2NRaRa.

[094] In another embodiment, Ri is selected from the group consisting of -H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -C(=NO-(C1-C6) alkyl)Ra, -CN, C(O)ORa, -C(O)NRaRa, -C(O)NHORa, -S(O)2NRaRa, phenyl, 5- to 6-membered heteroaryl, -(C3-C6) cycloalkyl, and 4- to 6-membered heterocycloalkyl; and R2 is (C2-C6) alkenyl, (C2-C6) alkynyl, -CN, -NHORa, -C(O)Ra, -C(O)NRaRa, -C(O)NHORa, -C(O)ORa, -C(O)NRaS(O)2Ra, OC(O)NRaRa, -NRaC(O)Ra, -NRaC(=NRa)Ra, -NRaC(O)ORa,NRaC(O)NRaRa, -C(=NRa)Ra, -C(=NOH)Ra, -C(=NOH)NRa, -C(=NORa)Ra, -C(=NCN)NRaRa, -NRaC(=NCN)NRaRa, -C(=NRa)NRaRa,NRaC(=NRa)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa,S(O)Ra, -S(O)NRaRa, -S(O)2Ra, -S(O)2NRaC(O)Ra, -P(O)RaRa, Petition 870230091982, dated 10 / 17 / 2023, page 65 / 422 58 / 378 P(O)(ORa)(ORa), -B(OH)2, -B(ORa)2, or -S(O)2NRaRa.

[095] In an additional embodiment, Ri is -H, RaNHC(O), RaOC(O)-, (C1-C6) alkyl, (Ci-Ce) alkoxy, or -C(=NO-CH3)Ra, and R2 is selected from 2-methoxyethoxy, azetidin1-yl, methylamino, 3-morpholinopropoxy, 2-methoxyethoxy, 2hydroxyethoxy, propoxy, 2-hydroxypropoxy, methoxycarbonyl, carboxy, carbamoyl, methylcarbamoyl, (2hydroxyethoxy)carbamoyl, (2,2-dihydroxyethoxy)carbamoyl, (oxetan-3-yloxy)carbamoyl, methoxycarbamoyl, 2trimethylsilylethynyl, ethynyl, sulfamoyl, acetyl, and C(=NOCH3)CH3.

[096] In an additional embodiment of formula A, and A- 2, and R2 is selected from the group consisting of -H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -C(=NO(C1-C6) alkyl)Ra, -CN, -C(O)ORa, -C(O)NRaRa, -C(O)NHORa, and - S(O) 2NRaRa.

[097] In a further embodiment, R1 is -H, optionally substituted (C1-C6) alkyl, halo, -ORa, -NO2, -NH2, NHRa, -NRaRa, -SRa, -SORa, or S(O)2Ra, and R2 is selected from the group consisting of -H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -C(=NO(C1-C6) alkyl)Ra, -CN, -C(O)ORa, -C(O)NRaRa, -C(O)NHORa, S(O)2NRaRa, phenyl, and (C3-C6) cycloalkyl.

[098] In a further embodiment, R1 is selected from the group consisting of -H, optionally substituted (C1-C6) alkyl, halo, -ORa, -NO2, -NH2, -NHRa, NRaRa, -SRa, -SORa, and -S(O)2Ra, R2 is selected from the group consisting of -H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -C(=NO(C1-C6) alkyl)Ra, -CN, -C(O)ORa, -C(O)NRaRa, -C(O)NHORa, Petition 870230091982, dated 10 / 17 / 2023, p. 66 / 422 59 / 378 S(O)2NRaRa, .

[099] In a further embodiment, Ri is selected from the group consisting of (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C10) aryl, (C3-C10) cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, -CN, -NHORa, -C(O)Ra, -C(O)NRaRa, -C(O)NHORa, -C(O)ORa, C(O)NRaS(O)2Ra, -OC(O)NRaRa, -NRaC(O)Ra, -NRaC(=NRa)Ra,NRaC(O)ORa, -NRaC(O)NRaRa, -C(=NRa)Ra, -C(=NOH)Ra, -C(=NOH)NRa, -C(=NORa)Ra, -C(=NCN)NRaRa, -NRaC(=NCN)NRaRa, -C(=NRa)NRaRa, NRaC(=NRa)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, -NRaS(O)2NRaRa,S(O)Ra, -S(O)NRaRa, -S(O)2Ra, -S(O)2NRaC(O)Ra, -P(O)RaRa,P(O)(ORa)(ORa), -B(OH)2, -B(ORa)2, and -S(O)2NRaRa; and R2 is selected from the group consisting of -H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -C(=NO(C1-C6) alkyl)Ra, -CN, -C(O)ORa, -C(O)NRaRa, -C(O)NHORa,S(O)2NRaRa.

[0100] In a further embodiment, R1 is selected from the group consisting of -H, halo, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, (C1C6) haloalkoxy, (C6-C10) aryl, (C3-C10) cycloalkyl, 5- to 14-membered heteroaryl, 4- to 14-membered heterocycloalkyl, (C6-C10) aryl-(C1-C4) alkylene-, (C3-C10) cycloalkyl-(C1-C4) alkylene-, (5- to 14-membered heteroaryl)-(C1-C4) alkylene-, (4- to 14-membered heterocycloalkyl)-(C1-C4) alkylene-, -CN, -NO2, -ORa, -SRa, -NHORa,C(O)Ra, -C(O)NRaRa, -C(O)NHORa, -C(O)ORa, -C(O)NRaS(O)2Ra,OC(O)Ra, -OC(O)NRaRa, -NHRa, -NRaRa, -NRaC(O)Ra, -NRaC(=NRa)Ra, -NRaC(O)ORa, -NRaC(O)NRaRa, -C(=NRa)Ra, -C(=NOH)Ra,C(=NORa)Ra, -C(=NOH)NRa, -C(=NCN)NRaRa, -NRaC(=NCN)NRaRa,C(=NRa)NRaRa, -NRaC(=NRa)NRaRa, -NRaS(O)Ra, -NRaS(O)2Ra, Petition 870230091982, of 10 / 17 / 2023, p. 67 / 422 60 / 378 NRaS(O)2NRaRa, -S(O)Ra, -S(O)NRaRa, -S(O).7 , -S(O)2NRaC(O)Ra, -P(O)RaRa, -P(O)(ORa)(ORa), -B(OH)2, -B(ORa)2, and -S(O)2NRaRa; and R2 is selected from the group consisting of -H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -C(=NO(C1-C6) alkyl)Ra, -CN, -C(O)ORa, -C(O)NRaRa, -C(O)NHORa, S(O)2NRaRa.

[0101] In a further embodiment, Ri is selected from the group consisting of 2-methoxyethylamino, azetidin1-yl, methylamino, 3-morpholinopropoxy, 2-methoxyethoxy, 2hydroxyethoxy, propoxy, 2-hydroxypropoxy, methoxycarbonyl, carboxy, carbamoyl, methylcarbamoyl, 2-oxazolyl, pyrazol3-yl, pyrazol-4-yl, 4-isoxazolyl, 3,5-dimethylisoxazol-4yl, 1-methyl-pyrazol-4-yl, 2-methyl-pyrazol-3-yl, 2-ethylpyrazol-3-yl, 2-(2-hydroxyethyl)-pyrazol-3-yl, 2-(2,2,2trifluoroethyl)-pyrazol-3-yl, 2-(2-fluoroethyl)-pyrazol-3yl, 2-(2,2-difluoroethyl)-pyrazol-3-yl, 2-trifluoromethylpyrazol-3-yl, 2-difluoromethyl-pyrazol-3-yl, 1-methylimidazol-4-yl, 1-methyl-imidazol-2-yl, 1H-imidazol-2-yl, (2-hydroxyethoxy)carbamoyl, (2,2-dihydroxyethoxy)carbamoyl, (oxetan-3-yloxy)carbamoyl, methoxycarbamoyl, 2-trimethylsilylethynyl, ethynyl, 1,3,4oxadiazol-3-yl, 1H-1,2,3-triazol-5-yl, sulfamoyl, acetyl, and —C(=NOCH3)CH3; and R2 is -H, -RaNHC(O)-, -RaOC(O)-, (C1-C6) alkyl, (C1-C6) alkoxy, or -C(=NO-CH3)Ra.

[0102] In an additional embodiment of formula A-4, the subscript r is 1 or 2.

[0103] In an additional embodiment of the above aspect and embodiments, R10 and R11 are each -H.

[0104] In an additional embodiment of the above aspect and Petition 870230091982, dated 10 / 17 / 2023, p. 68 / 422 61 / 378 modalities, subscriber number 1.

[0105] In an additional embodiment of the above aspect and embodiments, the subscript m is 1.

[0106] In an additional embodiment of the above aspect and embodiments, the subscript p is 1.

[0107] In another embodiment, a compound of the formula A is a compound with the formula B: (Rl4)p B or a pharmaceutically acceptable salt thereof, where R1 and R2 are as defined in (i), (ii) or (iii) of formula A; and R3, R10, R11, R14, R4, n, p, m and Y are as defined as follows: Each R3 is selected independently from the group consisting of -H, halo, -OH, -CN, optionally substituted (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, -NH2, -NH(C1-C6)alkyl, -N(C1-C6 alkyl)2, and (C3C6) cycloalkyl, where (C1-C6) alkoxy, -NH(C1-C6)alkyl, N(C1-C6 alkyl)2, and (C3-C6) cycloalkyl are each optionally substituted; Each of R10 and R11 is selected independently from the group consisting of -H, (C1-C6) alkyl, (C1C6) alkoxy, and (C1-C6) haloalkoxy; Each R14 is selected independently from the group consisting of -halo, -OH, -NH2, -CN, (C1-C6) alkyl, Petition 870230091982, dated 10 / 17 / 2023, p. 69 / 422 62 / 378 (C1-C6) alkoxy, (C1-C6) haloalkyl, (Ci-Ce) haloalkoxy, COOH, -NH(Ci-Ce)alkyl, -N(Ci-C6 alkyl)2, phenyl, phenyl- (CiC2) alkylene, (C3-C6) cycloalkyl, (C3-C6) cycloalkyl- (CiC4) alkylene-, heterocycloalkyl with 4 to 6 members, (heterocycloalkyl with 4 to 6 members)-(Ci-C4) alkylene-, heteroaryl with 5 to 6 members, (heteroaryl with 5 to 6 members)-(Ci-C4) alkylene- and -ORe, in which a (Ci-C6) alkylates, phenyl, phenyl-(Ci-C2) alkylene, (C3-C6) cycloalkyl, (C3-C6) cycloalkyl-(Ci-C4) alkylene-, 4- to 6-membered heterocycloalkyl, (4- to 6-membered heterocycloalkyl)-(Ci-C4)alkylene-, 5- to 6-membered heteroaryl, and (5- to 6-membered heteroaryl)-(Ci-C4) alkylene- of Ri4 são, each um, optionally substituted; each R4 is selected independently from -H, halo, -OH, (Ci-C6) alkyl, (Ci-C6) alkoxy, (Ci-C6) haloalkyl and (Ci-C6) haloalkoxy, wherein the (Ci-C6) alkyl are each, (Ci-C6) alkoxy, (Ci-C6) haloalkyl and (Ci-C6) haloalkoxy are optionally substituted, each independently; each Ra is independently selected from -H, (Ci-C6) alkyl, (Ci-C6) haloalkyl, (C6-Cio) aryl, (C3-Cio) cycloalkyl, 5- to 14-membered heteroaryl, 4 to 14-membered heterocycloalkyl, (C6-Cio) aryl-(C1-C4) alkylene-, (C3-Cio) cycloalkyl-(C1-C4) alkylene-, (5- to -14-membered heteroaryl)-(C1-C4) alkylene- and (4- to 14-membered heterocycloalkyl)-(C1-C4) alkylene-, wherein (C1-C6) alkyl, (C1-C6) haloalkyl, (C6-Cio) aryl, (C3-Cio) cycloalkyl, 5 to 14 membered heteroaryl, 4 to 14 membered heterocycloalkyl, (C6-Cio) aryl-(C1-C4) alkylene-, (C3-Cio) cycloalkyl-(C1-C4) alkylene-, Petition 870230091982, dated 10 / 17 / 2023, page 70 / 422 63 / 378 (5- to 14-membered heteroaryl)-(C1-C4)alkylene- and (4- to 14-membered heterocycloalkyl)-(C1-C4)alkylene- are optionally substituted, each independently; n, p, and em are, each independently, integers from 0 to 3; and Y is selected from -O-, -S-, -SO-, -SO2-, -NHe, and -N((C1-C6) alkyl)-.

[0108] In one embodiment of formulas A and B: (i) R1 is selected from the group consisting of: (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C10) aryl, (C3- (C10) cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl, wherein (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C10) aryl, (C3-C10) cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are optionally substituted, each independently, -CN, -P(O)RaRa, P(O)(ORa)2, B(OH)2, B(ORa)2, X2Ra, where -N-(C1-C6) alkylS(O)2NH-, -S(O)2NHC(O)-, and RaXY2Ylem that vwar indicates the attachment point, where: Y1 is absent, or it is -NH-, -N-(C1-C6)alkyl-, or -O-, Y2 is absent, or is -O-, -NH-, -NHO-, -N-(C1-C6)alkyl-, -N2H2-, -NH-S(O)-, or -NH-S(O)2-; or A — Y 2 is or optionally replaced by 5 X. .7 , where “uwxr” indicates attachment points, where ring A is a ring with 3, 4, 5, 6 or 7 members; and Petition 870230091982, dated 10 / 17 / 2023, p. 71 / 422 64 / 378 Z1 is O, NH, N-(C1-C6) alkyl, NOH, NO-(C1-C6) alkyl, or NCN; and R2 is: — H or a selected group from the group consisting of: (C1-C6) alkyl, halo, -NO2, and X1Ra, where X1 is -O-, -S, -SO-, -SO2-, —SO2NH—, —SO2NRa—, -NH-, and -N-(C1—Ce) alkyl—, where (C1-Ce) alkyl is optionally substituted.

[0109] In another form of formulas A and B: (ii) Ri is selected from the group consisting of: (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C10) aryl, (C3-C10) cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl, wherein (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C10) aryl, (C3-C10) cycloalkyl, 5- to 14-membered heteroaryl and 4- to 14-membered heterocycloalkyl are optionally substituted, each independently; P(O)RaRa, P(O)(ORa)(ORa), B(OH)2, B(ORa)2, CN, X2Ra, where X2 is -NHO—, -NH-S(O)-, —N—(C1 — C6)alkyl — S(O)-, -NH-S(O)2-, -N-(Ci-C6) alkyl-S(O)2Ra-, -NH-S(O)-NH-, -N- (C1_Cg) alkyl-S(O)NH-, —NH—S(O) 2NH—, —N— (Ci-Cê) alkyl— S(O)2NH-, -S(O)-, —S(O)2 — , —S(O)2NHC(O), and z1 RaA v Y1, where: Y1 is absent, or is -NH—, —N—(C1 — C6) alkyl—, or -O—, Y2 is absent, or it is —O—, —NH—, —NHO—, —N— (C1-Cê) alkyl — , —N2H2 — , —NH—S(O)—, or —NH—S(O)2, or A N-^— Y 2 is 5 'XJ optionally replaced, where Petition 870230091982, dated 10 / 17 / 2023, p. 72 / 422 65 / 378 indicates attachment points, where ring A is a ring with 3, 4, 5, 6 or 7 members; Z1 is -O-, -NH-, -N-(C1-Cg) alkyl-, -NOH-, -NO-(C1-Cg) alkyl-, or -NCN-; and R2 is selected from the group consisting of H, halo, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-Cg) haloalkyl, (C1-Cg) haloalkoxy, (C6-C10) aryl- (C1-C4) alkylene-, (C3-C10) cycloalkyl- (C1-C4) alkylene-, (5- to 14-membered heteroaryl)-(C1-C4) alkylene-, and (4 to 14-membered heterocycloalkyl)-(C1C4) alkylene-, where (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, (C1-Cg) haloalkoxy, (C6-C10) aryl, (C3C10) cycloalkyl, (C6-C10) aryl-(C1-C4)alkylene-, (C3-C10)cycloalkyl-(C1-C4)alkylene-, (5- to 14-membered heteroaryl)-(C1-C4)alkylene-, and (4- to 14-membered heterocycloalkyl)-(C1-C4)alkylene- are optionally substituted, each independently, CN, NO2, P(O)RaRa, P(O)(ORa)(ORa), B(OH)2, B(ORa)2, X1Ra, where X1 is -O-, -S-, -NH-, or -N-(C1-Cg)-, -NHO-, -NH-S(O) -, -N- (C1-Cg)alkyl-S(O) -, -NH-S(O) 2-, -N- (C1 — Cg) alkyl-S(O)2-, -NH-S(O)-NH-, -N-(C1-Cg) alkyl-S(O)NH-, -NHS(O) 2NH—, -N- (C1-Cg) alkyl-S(O) 2NH-, — S(O) 2NHC(O) -, -NHS(O)Ra-, -N- (C1-Cg) alkyl-S(O)Ra-, -NH-S(O) 2Ra-, -N- (Ci—Cg) alkyl-S(O)2Ra-, and Z1'2 Yl, where: Y1 is absent or is -NH-, -N-(C1-Cg) alkyl- or -O-; Y2 is absent or is -O-, -NH-, -NHO-, -N-(C1-Cg)alkyl, —N2H2—, —NH—S(O)-, or —NH—S(O)2—, or Petition 870230091982, dated 10 / 17 / 2023, p. 73 / 422 66 / 378 SÃ AN~5— Y 2 is S / / ' optionally replaced, where ring A is a ring with 3, 4, 5, 6 or 7 members and where ''vw' ” indicates attachment points; and Z1 is O, NH, N-(C1-C6) alkyl, NOH, NO-(C1-C6) alkyl, or NCN,

[0110] In another embodiment of formulas A and B: (iii) R1 and R2, obtained close to the atoms to which they are attached, form a 4 to 10 membered heterocycloalkyl ring optionally substituted by 1, 2 or 3 groups selected independently of the group consisting of halo, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1C6) haloalkoxy, -CN, —OH, -NH2, provided that the compound is not 1-[2-(4-Fluorophenyl)-acetyl]-cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa1-aza-cyclododeca[b]naphthalen-4-yloxy)-phenyl]-amide.

[0111] In an additional embodiment of the compound of formulas A and B: R1 is —H, -CN, (C1-C6) alkyl, (C3-C10) cycloalkyl, (C6C10) aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -S(O)2NHRa, -P(O)RaRa, -ORaou Z1RaY^YX where ά / w' indicates the fixing point, where: Y1 is absent or is -NH—, -N-(C1-Ce) alkyl— or —O—; Y2 is absent or is —O—, -NH-, -NHO-, —N— (C1-C6) alkyl-, —NH—NH—, -NH-S(O)- or NH-S(O)2; and Z1 is —O, —NH, -N- (C1-Cg)alkyl, —N—OH or —N—O (C1 — Cg)alkyl. Petition 870230091982, dated 10 / 17 / 2023, p. 74 / 422 67 / 378

[0112] In another form of formulas A and B: R2 is -H, halo, -X1Ra, (C2-C6) alkenyl, (C2-C6) alkynyl or Z1 R° A ' 2 ' 1 where αλλ / ' indicates the point of attachment, where: Y1 is absent or is NH, N-(C1-Ce) alkyl or O; Y2 is absent or is O, NH, NHO, N-(Ci-Ce) alkyl, N2H2, NH-S(O) or NH-S(O)2; and Z1 is -O, -NH, -N-(Ci-Ce)alkyl, -NOH- or -NO(CiCe)alkyl.

[0113] In another embodiment of formulas A and B, R3 is -H or halo.

[0114] In another embodiment of formulas A and B, R4 is -H or halo.

[0115] In another embodiment of formulas A and B, where R14 is -H or halo.

[0116] In another embodiment of formulas A and B, Y is -THE-.

[0117] In another embodiment, the compound of B is a compound of the formula B-1 or B-2: B-1 Petition 870230091982, dated 10 / 17 / 2023, p. 75 / 422 68 / 378 or a pharmaceutically acceptable salt thereof.

[0118] In a Formula B-1 modality: Ra1 is optionally substituted (C1-C6) alkyl; R1 is -H, -CN, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted phenyl, optionally substituted 4- to 6-membered heterocycloalkyl, optionally substituted 5- to 6-membered heteroaryl, -SO2-(C1-C6)alkyl, -SO2NH2, -SO2-NH(C1-Ce)alkyl, P(O)((C1-C6)alkyl)2, or Z1 RaAY2Ylem that ' / vw' indicates the attachment point, where: Y1 is missing; Y2 is absent or is -O-, -NH-, -NHO-, -NH-NH- or -N (C1-C6) alkyl-; ςμ A Y2 is S \__ ring A is a ring optionally replaced, where the one with 3, 4, 5, 6 or 7 members where -'vw' indicates attachment points; Z1 is O, NH, N-(C1-C6) alkyl, NHO or NO-(C1-C6) alkyl; and Rae-H, -(C1-C6) alkyl, 4- to 6-membered heterocycloalkyl, 3- to 6-membered cycloalkyl, -(C2-C6) alkylene. Petition 870230091982, dated 10 / 17 / 2023, p. 76 / 422 69 / 378 OH, -CH2CHOH-(C2-C6) alkylene-OH, -(C2-C6) alkylene-NH2, (C2-C6) alkylene-NH(C1-Ce), -(C2-C6) alkylene-N(C1-Ce)2, or - (C2-C6) alkylene-N-(4 to 6 membered heterocycloalkyl);

[0119] In another form of the B-1 formula: Ra1é (C1-C6) alkyl; R1 is -H, -CN, optionally substituted cyclopropyl, optionally substituted phenyl, optionally substituted 4- to 6-membered azetidinyl, optionally substituted pyrolidinyl, 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 Z1 Ri is '2 '1, where: Y1 is missing; Y2 is O, NH, NHO, NH-NH or N-(C1-C6) alkyl; or Y2 is optionally substituted azetidinyl; Z1 is O, NH or N-(C1-C6) alkyl; and Raé 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- to 6-membered heterocycloalkyl, wherein heterocycloalkyl is optionally substituted.

[0120] In a form of the B-2 formula: Ra2 is (C1-C6) optionally substituted alkyl; Petition 870230091982, dated 10 / 17 / 2023, p. 77 / 422 70 / 378 z1RaY^YK R2 is 1 2 1 1 where ''vw' indicates the fixing point, where: Yi is absent; Y2 is absent or is -O- or -NH-; and Z1 is O; and Rae -H or -(C1-C6) alkyl.

[0121] In another form of the B-2 formula: Ra2e (C1-C6) alkyl; Z1 RaJL R2 is Y2Y2 where “υχτνχτ indicates the point of attachment, where: Y1 is missing; Y2 is absent or is -O- or -NH-; and Z1 is O or NO- (C1-C6) alkyl; and Rae -H or -(C1-C6) alkyl.

[0122] In another embodiment of formula B-1, Ra1 is methoxy.

[0123] In another embodiment of the B-2 formula, Ra2 is methoxy.

[0124] In another form, the compound of the formula B is a compound with the formula B-3 or B-4: Frog B-3 Petition 870230091982, dated 10 / 17 / 2023, p. 78 / 422 71 / 378 B-4 or a pharmaceutically acceptable salt thereof.

[0125] In an embodiment of formula B-3: R1 is -H or (C1-C6) alkyl; and Y1 is missing; Y 2 is absent or is -O-, -NHO-, or -NH-; and Z1 is O or NO-(C1-C6) alkyl; and Rae -H or -(C1-C6) alkyl.

[0126] In another form of the B-3 formula: R 1 is -H or methyl; Y1 is missing; Y 2 is absent or is -O-, -NHO-, or -NH-; and Z1é O ou NO-Me; e Raé -H or Me.

[0127] In another form of the B-3 formula: R1 and Ra, close to the atoms to which they are attached, form a 4- to 6-membered heterocycloalkyl ring optionally substituted with halo, (C1-C6) alkyl, or (C1-C6) haloalkyl.

[0128] In a form of formula B-4: Y1 is missing; Y 2 is O, NH, NHO, NH-NH or N-(C1-C6) alkyl; or Y2 is optionally substituted azetidinyl; Z1 is O, NH, NO-(C1-C6) alkyl or N-(C1-C6) alkyl; and Raé 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) Petition 870230091982, dated 10 / 17 / 2023, p. 79 / 422 72 / 378 alkyl)2, -(C2-C6) alkylene-(optionally substituted 4 to 6 membered heterocycloalkyl), or optionally substituted 4 to 6 membered heterocycloalkyl; R2 is -H, -F, -Cl, -Br, -(C1-C6)alkoxy, -O-(C2C6)alkylene-OH, -O-(C2-C6)alkylene-O-(C1-C6 alkyl), (C2C6)alkylene-O-(C1-C6)alkyl, -NH2, -NH-(C1-C6 alkyl), -NH(C1-C6)alkylene-(optionally substituted 4- to 6-membered heterocycloalkyl), or -NH-(C2-C6)alkylene-O-(C1-C6 alkyl).

[0129] In another form of the B-4 formula: Y1 is missing; Y 2 is O, NH, NHO, NH-NH or N-(C1-C6) alkyl; or Y2 is optionally substituted azetidinyl; Z1 is O, NH, NO-(C1-C6) alkyl, N-(C1-C6) alkyl; and Raé -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), (C1C6)alkylene-(optionally substituted pyrrolidinyl), optionally substituted azetidinyl or optionally substituted oxetanyl; R2 is -H, -F, -Cl, -Br, methoxy, -O-(C2-C6)alkylene-OH, -O-(C2-C6)alkylene-OMe, -NH2, -NH-(C1-C6 alkyl), -NH-(C2C6)alkylene-OMe, -NH-(C2-C6)alkylene-(optionally substituted morpholinyl), or -NH-(C2-C6)alkylene-O-(C1-C6 alkyl).

[0130] In another form of the B-4 formula: R2 and Ra, together with the atoms to which they are attached, form a 4- to 6-membered heterocycloalkyl ring optionally substituted with halo, (C1-C6) alkyl or (C1C6) haloalkyl.

[0131] In another form, the compound of the formula B is a compound with the formula B-5: Petition 870230091982, dated 10 / 17 / 2023, p. 80 / 422 73 / 378 or a pharmaceutically acceptable salt thereof, wherein ring A in formula B-5 is a heteroaryl or aryl with 5 to 6 optionally substituted members.

[0132] In a form of the B-5 formula: Ring A is an optionally substituted (C6-C10) aryl, optionally substituted (C3-C10) cycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 4- to 10-membered heterocycloalkyl; and R2 is H or (C1-C6)alkoxy.

[0133] In another form of the B-5 formula: ring A is an 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 R2 is H or methoxy.

[0134] Another form of a compound with formulas A and B is a compound with formula C: Petition 870230091982, dated 10 / 17 / 2023, page 81 / 422 74 / 378 C or a pharmaceutically acceptable salt thereof, wherein: Y1 is missing; Y2 is O, NH, NHO, NH-NH or N-(Ci-Cg) alkyl; or Y2 is optionally substituted azetidinyl; Z is O, NH, NO- (C1-C1) alkyl or N- (C1-C1) alkyl; Raé -H, (Ci—Cg) alkyl, - (C2—C6) alkylene-OH, CH2CHOH-(C2-Cg) alkylene-OH, —(C2 — C6) alkylene—NH2, —(C2 — Cg) alkylene-NH(C1-C6) alkyl, -(C2-Cg) alkylene-N((Ci — Cg) alkyl)2, -(C2-Cg) alkylene—optionally substituted 4 to 6 membered heterocycloalkyl) or optionally substituted 4 to 6 membered heterocycloalkyl; R2 is -H, -F, -Cl, -Br, -(C1-C1)alkoxy, -O-(C2-C1)alkylene-OH, -O-(C2-C6)alkylene-O-(C1-C6 alkyl), (C2C6)alkylene—O—(C1-C1) alkyl, -NH2, -NH-(C1-C1 alkyl), -NH—(C1-C1)alkylene-(optionally substituted 4- to 6-membered heterocycloalkyl), -NH-(C2-C6)alkylene-O-(C1-C6 alkyl); and are each independently integers from 0 to 3. [0i35] In another form of formula C: Yi is absent; Y2 is O, NH, NHO, NH—NH or N-(Ci-Cg) alkyl; or Y2 is optionally substituted azetidinyl; Zié O, NH, NO— (Ci-Cg) alkyl or N— (Ci-Cg) alkyl; Petition 870230091982, dated 10 / 17 / 2023, page 82 / 422 75 / 378 Raé -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), (C1C6)alkylene-(optionally substituted pyrrolidinyl), optionally substituted azetidinyl or optionally substituted oxetanyl; R2 is -H, -F, -Cl, -Br, methoxy, -O-(C2-C6)alkylene-OH, -O- (C2-Ce)alkylene-OMe, -NH2, -NH- (C1-C6 alkyl), —NH- (C2Ce)alkylene-OMe, -NH- (C2-Ce)alkylene- (optionally substituted morpholinyl) or -NH-(C2-C6)alkylene-O-(C1-C6 alkyl); eenem or each 0 or 1.

[0136] In another form of formula C: R2 and Ra, close to the atoms to which they are attached, form a 4- to 6-membered heterocycloalkyl ring optionally substituted with halo, (C1-C6) alkyl and (C1-C6) haloalkyl; and are each independently integers from 0 to 3.

[0137] Another form of formula C is a compound of formula C-1. C-1 or a pharmaceutically acceptable salt thereof, where: Y2 is O, NH, NHO, NH-NH or N-(C1-C6) alkyl; or Petition 870230091982, dated 10 / 17 / 2023, p. 83 / 422 76 / 378 Y2 is optionally substituted azetidinyl; Z1 is O, NH, NO- (C1-C6) alkyl or N- (C1-C6) alkyl; Raé -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), (C1C6)alkylene-(optionally substituted azetidinyl pyrrolidinyl; R2 is -H, -F, -Cl, -Br, optionally substituted), substituted or oxetanyl methoxy, -O-(C2-C6)alkylene-OH, -O-(C2-C6)alkylene-OMe, -NH2, -NH-(C1-C6 alkyl), -NH-(C2C6)alkylene-OMe, -NH-(C2-Ce)alkylene-(optionally substituted morpholinnyl) or -NH-(C2-C6)alkylene-O-(C1-C6 alkyl); eenem are each independently 0 or 1.

[0138] Another embodiment of formulas A and B is a compound of formula D: Frog

[0139] In a form of formula D: R1 is -H or (C1-C6) alkyl; and Y1 is missing; Y2 is absent or is -O-, -NHO-, or -NH-; and Z1 is O or NO-(C1-C6) alkyl; Raé -H or - (C1-C6) alkyl; and Petition 870230091982, dated 10 / 17 / 2023, p. 84 / 422 77 / 378 are not each, independently, integers from 0 to 3.

[0140] In another form of formula D: R1 is -H or methyl; Y1 is missing; Y2 is absent or is -O-, -NHO-, or -NH-; and Z1é O ou NO-Me; e Raé -H ou -Me. Nor are they each, independently, whole numbers from 0 to 1.

[0141] In another form of formula D: R1 and Ra, close to the atoms to which they are attached, form a 4- to 6-membered heterocycloalkyl ring optionally substituted with halo, (C1-C6) alkyl or (C1-C6) haloalkyl; and are each independently integers from 0 to 1.

[0142] Another form of formula D is a compound of formula D-1. Z1 D-1

[0143] Another form of formulas A and B is a compound of formula E: Petition 870230091982, dated 10 / 17 / 2023, p. 85 / 422 78 / 378 or a pharmaceutically acceptable salt thereof, wherein: ring A is an optionally substituted (C6-C10) aryl, optionally substituted (C3-C10) cycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 4- to 10-membered heterocycloalkyl; and R2 is H or (C1-C6)alkoxy.

[0144] In another form of formula E: ring A is an 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 R2 is H or methoxy.

[0145] Another form of formulas A and B is a compound of formula F: Petition 870230091982, dated 10 / 17 / 2023, p. 86 / 422 79 / 378 or a pharmaceutically acceptable salt thereof, wherein Ra1 is optionally substituted (C1-C6) alkyl; R1 is -H, -CN, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted phenyl, optionally substituted 4- to 6-membered heterocycloalkyl, optionally substituted 5- to 6-membered heteroaryl, -SO2-(C1-C6)alkyl, -SO2NH2, -SO2-NH(C1-C6)alkyl, or P(O)((C1-C6)alkyl)2, or z1 / Άχ '2'1 where ά / w' indicates the attachment point, where: Y1 is missing; Y 2 is absent or is -O-, -NH-, -NHO-, -NH-NH- or -N-(C1-C6)alkyl-; A N-^— Y 2 is i2 \ 2 optionally replaced, where ring A is a ring with 3, 4, 5, 6 or 7 members where vx / wn ” indicates attachment points; Z1 is O, NH, N-(C1-C6) alkyl, NHO or NO-(C1-Cg) alkyl; and Raé -H, -(C1-C6) alkyl, 4- to 6-membered heterocycloalkyl, 3- to 6-membered cycloalkyl, -(C2-C6) alkyleneOH, -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 to 6 membered heterocycloalkyl);

[0146] In another form of the F formula: Ra1é metila; R1 is -H, -CN, optionally substituted cyclopropyl, optionally substituted phenyl, azetidinyl with 4 to 6 Petition 870230091982, dated 10 / 17 / 2023, page 87 / 422 80 / 378 members optionally substituted, optionally substituted pyrolidinyl, 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 z1RaY^YX R1 is '2 '1 , where: Y1 is missing; Y 2 is O, NH, NHO, NH-NH or N-(C1-Ce) alkyl; or Y2 is optionally substituted azetidinyl; Z1 is O, NH or N-(C1-C6) alkyl; and Raé 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- to 6-membered heterocycloalkyl, wherein heterocycloalkyl is optionally substituted.

[0147] Another form of formulas A and B is a compound of formula G: or a pharmaceutically acceptable salt thereof, wherein: Ra1 is optionally substituted (C1-C6) alkyl; Petition 870230091982, dated 10 / 17 / 2023, p. 88 / 422 81 / 378 z1 RaA. R2 is Y2Ylem where ' / wv' indicates the attachment point, where: Yi is absent; Y2 is absent or is -O-, or -NH-; and Z1 is O; and Rae -H or -(C1-C6) alkyl.

[0148] In another form of formula G: Ra2e methyl; Z1 RaΛ. R2 is Y2Ylem where “u-uw” indicates the attachment point, where: Y1 is missing; Y2 is absent or is -O-, or -NH-; and Z1 is O or NO-(C1-C6) alkyl; and Rae -H, or -(C1-C6) alkyl.

[0149] Another embodiment of formulas A and B is a compound to modulate kinase activity according to formula H: or a pharmaceutically acceptable salt thereof, where: 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; where when R1 is selected from the group that Petition 870230091982, dated 10 / 17 / 2023, p. 89 / 422 82 / 378 consists 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-Ce)alkoxy; where R1 is -H, optionally substituted (C1-Ce) alkyl or optionally substituted (C1-Ce) alkoxy, R2 is -CO-NR5R6 or -CO2R7; or R1 and R2 obtained together with the atoms to which they are attached form optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; R3 is selected from the group consisting of -H, optionally substituted (C1-C6) alkyl, -CN, and halo; R4 is -H or halo; 7t£>< is optionally replaced by one, two, three or four groups selected independently from the group consisting of halo and (C1-Ce) alkyl, where “ «a / w ” indicate attachment points; R5 and Re are each independently -H; optionally substituted (C1-Ce) alkyl; or optionally substituted C1-C6 alkoxy; R7 is -H or optionally substituted (C1-C6) alkyl; R8 and R9 are each independently -H or optionally substituted (C1-Ce) alkyl; or R8 and R9 can connect to form an optionally substituted heterocycle; and Y is selected from the group consisting of O, S, SO, SO2, NH and N-((C1-Ce) alkyl).

[0150] In an embodiment of a compound of formula I, Y is O.

[0151] In another form, R3 is -H. Petition 870230091982, dated 10 / 17 / 2023, p. 90 / 422 83 / 378

[0152] In another embodiment, XX is unsubstituted.

[0153] In another embodiment, R4 is halo.

[0154] In another embodiment, R4 is parafluorine.

[0155] In another embodiment, R2 is -H, halo, or optionally substituted (C1-C6)-alkoxy.

[0156] In another embodiment, R1 is -CN.

[0157] In another embodiment, R1 is -CO2H.

[0158] In another embodiment, R1 is -CO2-Me.

[0159] In another embodiment, R1 is -CO-NHR6.

[0160] In another embodiment, R1 is -CO-NH2.

[0161] In another embodiment, R1 is -CO-NMeR6.

[0162] In another embodiment, R3 is -H or halo.

[0163] In another embodiment, R1 is selected to of the group consisting of -CN, -(SO2)NH2, -OMe, \ A. LI LI LI / N. (SO2)CH3h, O / , HO / , H2N / , h Petition 870230091982, dated 10 / 17 / 2023, p. 91 / 422 84 / 378 in which v <vw' é o ponto de fixação.

[0164] In another mode, Ri is selected to starting from the group that consists of where 'jxrw' is the attachment point.

[0165] In another scenario, R1 is selected from the group that consists Me where >ΛΛΛ / ' ” is the attachment point.

[0166] In another embodiment, R2 is selected from the group consisting of -H, -CN, -Br, -F, -Cl, -OMe, -CH3, Petition 870230091982, dated 10 / 17 / 2023, p. 92 / 422 85 / 378 CH2NH2, NH2, NHMe, ο η o,efixação.

[0167] In a methoxy.

[0168] In a

[0169] In a

[0170] In a

[0171] In a

[0172] In a

[0173] In a H ' , in which other modality, another modality,R2 another modality,R1 another modality,R1 another modality,R1 another modality,R1 another modality, άλλ / ' ” is the point of R1 is -H, methyl, or -CO2H. It is -CO2-Me. It is -CO-NHR6. It is -CO-NH2. It is -CO-NMeR6. R1 is selected from the group consisting of

[0174] In another scenario, Ri and R2 are obtained together to form

[0175] In a further embodiment, the compound of formula I is a compound of formula I-1: I-1 where R6 is (C1-C6) alkyl, R2 is (C1-C6) alkoxy, R3 is -H or halo, and R4 is halo.

[0176] In another aspect, the invention provides a compound of formula A or AI which is given in Table 1 Petition 870230091982, dated 10 / 17 / 2023, p. 93 / 422 86 / 378 below.

[0177] TABLE 1: SPECIFIC COMPOUNDS OF THE INVENTION No. Structure Name 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylate methyl acid 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid 1-N-[4-(6-carbamoyl-7methoxyquinolin-4yl)oxyphenyl]-1-N'-(4fluorophenyl)cyclopropane-1,1-dicarboxamide 1-N'-(4-fluorophenyl) 1-N-[4-[7-methoxy-6(methylcarbamoyl)quinol-4yl]oxyphenyl]cyclopropane-1,1-dicarboxamide 1-N-[4-[6(ethylcarbamoyl)-7methoxyquinolin-4yl]oxyphenyl]-1-N'-(4fluorophenyl)cyclopropane-1,1-dicarboxamide 1-N-[4-[6-[2(dimethylamino)ethylcarbammoyl]-7methoxyquinolin-4yl]oxyphenyl]-1-N,-(4fluorophenyl)cyclopropane-1,1-dicarboxamide Petition 870230091982, dated 10 / 17 / 2023, page 94 / 422 87 / 378 No. Structure Name 1-N'-(4-fluorophenyl)1-N-[4-[7-methoxy-6-(2piperidin-1ylethylcarbamoyl)quinol in-4yl]oxyphenyl]cyclopropa no-1,1-dicarboxamida 1-N'-(4-fluorophenyl)1-N-[4-[7-methoxy-6-(2morpholine-4ylethylcarbamoyl)quinol in-4yl]oxyphenyl]cyclopropa no-1,1-dicarboxamida 1-N'-(4-fluorophenyl) 1-N-[4-[7-methoxy-6(oxethan-3ylcarbamoyl)quinolin4yl]oxyphenyl]cyclopropa no-1,1-dicarboxamida 1-N'-(4-fluorophenyl)1-N-[4-[7-methoxy-6[(1-methylazetidin-3yl)carbamoyl]quinolin4yl]oxyphenyl]cyclopropano-1,1-dicarboxamide 1-N-[4-[6-(azetidine1-carbonyl)-7methoxyquinolin-4yl]oxyphenyl]-1-N'-(4fluorophenyl)cyclopropa no-1,1-dicarboxamida 1-N'-(4-fluorophenyl)1-N-[4-[6-(3hidroxiazetidine-1carbonyl)-7methoxyquinolin-4yl]oxyphenyl]cyclopropa no-1,1-dicarboxamida Petition 870230091982, 17 / 10 / 2023, pág. 95 / 422 88 / 378 n° Structure Name 1-N’ -(4-fluorofenil)1-N-[4-[7-metoxi-6(metoxicarbamoil)quino lin-4il]oxifenil]ciclopropa no-1,1-dicarboxamida 1-N’-(4-fluorofenil) 1-N-[4-[6(hidroxicarbamoil)-7metoxiquinolin-4il]oxifenil]ciclopropa no-1,1-dicarboxamida 1-N’-(4-fluorofenil) 1-N-[4-[7-metoxi-6[[(2R)-pirrolidin-2il]metilcarbamoil]quin olin-4il]oxifenil]ciclopropa no-1,1-dicarboxamida 1-N’-(4-fluorofenil)1-N-[4-[7-metoxi-6[[(2S)-pirrolidin-2il]metilcarbamoil]quin olin-4il]oxifenil]ciclopropa no-1,1-dicarboxamida 1-N’-(4-fluorofenil)1-N-[4-[7-metoxi-6(oxetan-3iloxicarbamoil)quinoli n-4il]oxifenil]ciclopropa no-1,1-dicarboxamida 1-N’-(4-fluorofenil)1-N-[4-[6-(2hidroxietoxicarbamoil) -7-metoxiquinolin-4il]oxifenil]ciclopropa no-1,1-dicarboxamida 1-N-[4-[6-(2,3-dihidroxypropoxycarbamoi l)-7-methoxyquinolin-4yl]oxyphenyl]-1-N' -(4fluorophenyl)cyclopropa no-1,1-dicarboxamida Enantiômero 1 Petition 870230091982, 17 / 10 / 2023, pág. 96 / 422 89 / 378 n° Estrutura Name 1-N-[4-[6-(2,3-dihidroxypropoxycarbamoi l)-7-methoxyquinolin-4yl]oxyphenyl]-1-N'-(4fluorophenyl)cyclopropa no-1,1-dicarboxamida Enantiômero 2 1-N'-(4-fluorophenyl) 1-N-[4-[6(hidrazinecarbonyl)-7methoxyquinolin-4yl]oxyphenyl]cyclopropa no-1,1-dicarboxamida 1-N-[4-(6-acetyl-7methoxyquinolin-4yl)oxyphenyl]-1-N'-(4fluorophenyl)cyclopropane-1,1-dicarboxamida 1-N'-(4-fluorophenyl) 1-N-[4-[7-methoxy-6[(E)-N-methoxy-Cmethylcarbonimidoyl]quinone-4yl]oxyphenyl]cyclopropano-1,1-dicarboxamide 1-N'-(4-fluorophenyl)1-N-[4-[7-methoxy-6[(Z)-N-methoxy-Cmethylcarbonimidoyl]quinolin-4yl]oxyphenyl]cyclopropano-1,1-dicarboxamide Petition 870230091982, dated 10 / 17 / 2023, p. 97 / 422 90 / 378 No. Structure Name 1-N-[4-(6-cyano-7-methoxyquinolin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropano-1,1-dicarboxamide 1-N'-(4-fluorophenyl)1-N-[4-[7-methoxy-6(1,3-oxazol-2yl)quinolin-4yl]oxyphenyl]cyclopropane-1,1-dicarboxamide 1-N'-(4-fluorophenyl) 1-N-[4-[7-(2hydroxyethoxy)-6-(1,3oxazol-2-yl)quinolin4yl]oxyphenyl]cyclopropane-1,1-dicarboxamide 1-N-[4-(6dimethylphosphoryl-7methoxyquinolin-4yl)oxyphenyl]-1-N'-(4fluorophenyl)cyclopropane-1,1-dicarboxamide 1-N-[4-(6carbamoylquinolin-4yl)oxyphenyl]-1-N'-(4fluorophenyl)cyclopropane-1,1-dicarboxamide 1-N'-(4-fluorophenyl)1-N-[4-[6(methylcarbamoyl)quinol in-4yl]oxyphenyl]cyclopropane-1,1-dicarboxamide Petition 870230091982, dated 10 / 17 / 2023, p. 98 / 422 91 / 378 no. Structure Name 1-N'-(4-fluorophenyl)1-N-[4-[6-[(1methylazetidin-3yl)carbamoyl]quinolin4yl]oxyphenyl]cyclopropa no-1,1-dicarboxamida 1-N-[4-(6-carbamoyl-7fluoroquinolin-4yl)oxyphenyl]-1-N' -(4fluorophenyl)cyclopropane-1,1-dicarboxamida 1-N-[4-(6-carbamoyl-7chloroquinolin-4yl)oxyphenyl]-1-N' -(4fluorophenyl)cyclopropane-1,1-dicarboxamida 1-N-[4-(7-bromo-6carbamoylquinolin-4yl)oxyphenyl]-1-N' -(4fluorophenyl)cyclopropane-1,1-dicarboxamida 1-N-[4-[6-carbamoyl-7(2methoxyethylamino)quinol in-4-yl]oxyphenyl]-1N' -(4fluorophenyl)cyclopropano-1,1-dicarboxamide 1-N-[4-[6-carbamoyl-7(3-morpholin-4ylpropylamino)quinolin -4-yl]oxyphenyl]-1-N'(4fluorophenyl)cyclopropano-1,1-dicarboxamide Petition 870230091982, 17 / 10 / 2023, pág. 99 / 422 92 / 378 n° Structure Name 1-N-[4-[7-(azetidin-1yl)-6carbamoylquinolin-4yl]oxyphenyl]-1-N'-(4fluorophenyl)cyclopropane-1,1-dicarboxamide 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-7-(methylamino)quinoline-6-carboxylic acid 1-N-[4-[6-carbamoyl-7(methylamino)quinolin4-yl]oxyphenyl]-1-N'(4fluorophenyl)cyclopropane-1,1-dicarboxamide 1-N'-(4-fluorophenyl)1-N-[4-[7(methylamino)-6(methylcarbamoyl)quinol in-4yl]oxyphenyl]cyclopropane-1,1-dicarboxamide 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-7-(methylamino)quinoline-6-carboxylate methyl Petition 870230091982, dated 10 / 17 / 2023, page 100 / 422 93 / 378 no. Structure Name 1-N-[4-(7-amino-6carbamoylquinolin-4yl)oxyphenyl]-1-N'-(4fluorophenyl)cyclopropane-1,1-dicarboxamide 1-N-[4-[7-amino-6(methylcarbamoyl)quinol-4-yl]oxyphenyl]-1N'-(4fluorophenyl)cyclopropane-1,1-dicarboxamide 7-amino-4-[4[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]quinoline-6-carboxylic acid 7-amino-4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]quinoline-6-carboxylate methyl 1-N'-(4-fluorophenyl)1-N-[4-[(2-methyl-4oxo-2,3-dihydropyrido[3.2g][1.3]benzoxazin-6yl)oxy]phenyl]cyclopropane-1,1-dicarboxamide Petition 870230091982, dated 10 / 17 / 2023, p. 101 / 422 94 / 378 no. Structure Name 1-N-[4-[(2-ethyl-4-oxo2,3-dihydropyrido[3.2g][1,3]benzoxazin-6yl)oxy]phenyl]-1-N'-(4fluorophenyl)cyclopropane-1,1-dicarboxamide 106 110 115 1-N-[4-[6-carbamoyl-7(3-morpholin-4ylpropoxy)quinolin-4yl]oxyphenyl]-1-N' -(4fluorophenyl)cyclopropano-1,1-dicarboxamide 1-N-[4-[6-carbamoyl-7(2methoxyethoxy)quinolin4-yl]oxyphenyl]-1-N'(4fluorophenyl)cyclopropano-1,1-dicarboxamide 1-N-[4-[6-carbamoyl-7(2hydroxytoxi)quinolin4-yl]oxiphenyl]-1-N'(4fluorophenyl)cyclopropano-1,1-dicarboxamide 1-N'-(4-fluorophenyl) 1-N-[4-[7-(2hidroxietoxi)-6(methylcarbamoyl)quinol in-4yl]oxyphenyl]cyclopropa no-1,1-dicarboxamida 1-N-[4-[6-carbamoyl-7(2hydroxypropoxy)quinols n-4-yl]oxyphenyl]-1-N'(4fluorophenyl)cyclopropano-1,1-dicarboxamide Petition 870230091982, 17 / 10 / 2023, pág. 102 / 422 95 / 378 n° Structure Name 116 1-N' -(4-fluorophenyl)1-N-[4-[7-(2hidroxypropoxy)-6(methylcarbamoyl)quinol in-4yl]oxyphenyl]cyclopropa no-1,1-dicarboxamida 125 1-N'-(4-fluorophenyl) 1-N-[4-[7-(2hydroxypropoxy)-6(1,3-oxazol-2yl)quinolin-4yl]oxyphenyl]cyclopropane-1,1-dicarboxamide 128 4-[2-chloro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylate methyl 129 130 131 4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylate methyl acid 4-[2-chloro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid 4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid Petition 870230091982, dated 10 / 17 / 2023, page 103 / 422 96 / 378 n° Structure Name 132 vySVxx ο σ f / ei 1-N'-[4-(6-carbamoyl7-methoxyquinolin-4yl)oxy-3-chlorophenyl]1-N-(4fluorophenyl)cycloprop no-1,1-dicarboxamide 133 F xrmi 1 0 1-N′-[4-(6-carbamoyl7-methoxyquinoline-4yl)oxy-3-fluorophenyl]1-N-(4fluorophenyl)cyclopropa no-1,1-dicarboxamide 134 wWi house LÍ ο σ f γί7-chlo-xy-ό[6-N (methylcarbamoyl)quinol in-4-yl]oxyphenyl]-1-N(4- fluorophenyl)cyclopropa no-1,1-dicarboxamide 135 YpVn p cr ^Ocô 1 1-N'-[3-fluoro-N4-[7methoxy-6(methyl-phenyl]-xy-in-4) (4- fluorophenyl)cyclopropane no-1,1-dicarboxamide 140 . / nVa .....τϊΧ 0 4-[4-[[1-[(4fluorophenyl)carbamoyl] cyclopropanocarbonyl]a mino]phenoxy]-6methylquinoline de methylcarboxylate Petition 870230091982, dated 10 / 17 / 2023, p. 104 / 422 No. 97 / 378 Structure Name 141 acid 4-[4-[[1-[(4fluorophenyl)carbamoyl] cyclopropanocarbonyl]a mino]phenoxy]-6methylquinoline-7carboxylic acid 142 1-N-[4-(7-carbamoyl-6methylquinolin-4yl)oxyphenyl]-1-N'-(4fluorophenyl)cyclopropane-1,1-dicarboxamide 143 1-N'-(4-fluorophenyl)1-N-[4-[6-methyl-7(methylcarbamoyl)quinol in-4yl]oxyphenyl]cyclopropane-1,1-dicarboxamide 150 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxyquinoline-7-carboxylate methyl 151 4-[4-[[1-[(4fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6methoxyquinoline-7carboxylic acid Petition 870230091982, dated 10 / 17 / 2023, page 105 / 422 98 / 378 No. Structure Name 152 1-N-[4-(7-carbamoyl-6methoxyquinolin-4yl)oxyphenyl]-1-N'-(4fluorophenyl)cyclopropane-1,1-dicarboxamide 153 162 1-N'-(4-fluorophenyl)1-N-[4-[6-methoxy-7(methylcarbamoyl)quinol-4yl]oxyphenyl]cyclopropane-1,1-dicarboxamide 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]quinoline-7-carboxylate methyl 164 165 166 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]quinoline-7-carboxylic acid 1-N-[4-(7carbamoylquinolin-4yl)oxyphenyl]-1-N'-(4fluorophenyl)cyclopropane-1,1-dicarboxamide 1-N'-(4-fluorophenyl) 1-N-[4-[7(methylcarbamoyl)quinol in-4yl]oxyphenyl]cyclopropane-1,1-dicarboxamide 1-N'-(4-fluorophenyl) 1-N-[4-[7-(2hydroxyethoxycarbamoyl)quinolin-4yl]oxyphenyl]cyclopropane-1,1-dicarboxamide Petition 870230091982, dated 10 / 17 / 2023, page 106 / 422 99 / 378 No. Structure Name 167 1-N' -(4-fluorophenyl)1-N-[4- [7-(oxetan-3yloxycarbamoyl)quinols n-4yl]oxyphenyl]cyclopropa no-1,1-dicarboxamida 169 1-N-[4- [7-[[(2R) -2,3dihydroxypropoxy]carbamoyl]quinolin-4yl]oxyphenyl]-1-N' -(4fluorophenyl)cyclopropano-1,1-dicarboxamide 170 1-N-[4-[7-[[(2S) -2,3dihydroxypropoxy]carbamoyl]quinolin-4yl]oxiphenyl]-1-N' -(4fluorophenyl)cyclopropano-1,1-dicarboxamide 175 1-N-[4-[6-(3-cyano-2fluorophenyl)-7methoxyquinolin-4yl]oxyphenyl]-1-N' -(4fluorophenyl)cyclopropa no-1,1-dicarboxamida 176 1-N'-(4-fluorophenyl) 1-N-[4-(7-methoxy-6pyridin-2-ylquinolin4yl)oxyphenyl]cyclopropa no-1,1-dicarboxamida 1-N'-(4-fluorophenyl)1-N-[4-[7-methoxy-6-(1methylimidazol-4yl)quinolin-4yl]oxyphenyl]cyclopropa no-1,1-dicarboxamida 180 1-N'-(4-fluorophenyl)1-N-[4-[7-methoxy-6-(5methylfuran-2yl)quinolin-4yl]oxyphenyl]cyclopropano-1,1-dicarboxamide Petition 870230091982, 17 / 10 / 2023, pág. 107 / 422 100 / 378 n° Structure Name 181 2-[4-[4-[[1-[(4fluorophenyl)carbamoyl]cyclopropanocarbonyl]amino]fenoxy]-7methoxyquinolin-6yl]pyrrol-1carboxylate de tertbutyl 182 1-N'-(4-fluorophenyl) 1-N-[4-[7-methoxy-6-(1methylpyrazol-4yl)quinolin-4yl]oxyphenyl]cyclopropa no-1,1-dicarboxamida 183 1-N'-(4-fluorophenyl) 1-N-[4-[7-methoxy-6(1,2-oxazol-4yl)quinolin-4yl]oxyphenyl]cyclopropano-1,1-dicarboxamide 184 1-N-[4-[6-(3,5dimethyl-1,2-oxazol-4yl)-7-methoxyquinolin4-yl]oxyphenyl]-1-N'(4fluorophenyl)cyclopropa no-1,1-dicarboxamida 185 1-N'-(4-fluorophenyl)1-N-[4-[7-methoxy-6(1H-pyrazol-5yl)quinolin-4yl]oxyphenyl]cyclopropano-1,1-dicarboxamide 1-N'-(4-fluorophenyl) 1-N-[4-[7-methoxy-6(1H-pyrazol-4yl)quinolin-4yl]oxyphenyl]cyclopropa no-1,1-dicarboxamida 187 1-N-[4-(6-cyclopropyl7-methoxyquinolin-4yl)oxyphenyl]-1-N'-(4fluorophenyl)cyclopropa no-1,1-dicarboxamida Petition 870230091982, 17 / 10 / 2023, pág. 108 / 422 101 / 378 n° Structure Name 188 1-N' -(4-fluorophenyl)1-N-[4-[7-methoxy-6(1H-pyrrol-2yl)quinolin-4yl]oxyphenyl]cyclopropano-1,1-dicarboxamide 191 1-N'-(4-fluorophenyl) 1-N-[4-[6-(1Himidazol-2-yl) -7methoxyquinolin-4yl]oxyphenyl]cyclopropano-1,1-dicarboxamide 192 1-N'-(4-fluorophenyl) 1-N-[4-[7-methoxy-6(1,3-oxazol-5yl)quinolin-4yl]oxyphenyl]cyclopropano-1,1-dicarboxamide 193 1-N'-(4-fluorophenyl)1-N-[4-[7-methoxy-6[(E)-methoxyiminomethyl]quinolin-4yl]oxyphenyl]cyclopropano-1,1-dicarboxamide 3-[4-[4-[[1-[(4fluorophenyl)carbamoyl]cyclopropanocarbonyl]amino]fenoxy]-7methoxyquinolin-6-yl] 3-hidroxiazetidina-1carboxylato de tercbutila 1-N'-(4-fluorophenyl)1-N-[4-[6-(3hidroxioxetan-3-yl)-7methoxyquinolin-4yl]oxyphenyl]cyclopropa no-1,1-dicarboxamida 1-N'-(4-fluorophenyl) 1-N-[4-[6-(3hidroxiazetidin-3-yl)7-methoxyquinolin-4yl]oxyphenyl]cyclopropa no-1,1-dicarboxamida Petition 870230091982, 17 / 10 / 2023, pág. 109 / 422 102 / 378 n° Estrutura Name 198 1-N-[4-[6-(azetidin-1yl)-7-methoxyquinolin4-yl]oxyphenyl]-1-N'(4fluorophenyl)cyclopropa no-1,1-dicarboxamida 199 1-N'-(4-fluorophenyl) 1-N-[4-[6-(3hidroxiazetidin-1-yl) 7-methoxyquinolin-4yl]oxyphenyl]cyclopropa no-1,1-dicarboxamida 200 1-N-[4-[6-(3,3difluoroazetidin-1yl)-7-methoxyquinolin4-yl]oxyphenyl]-1-N'(4fluorophenyl)cyclopropa no-1,1-dicarboxamida 201 1-N'-(4-fluorophenyl) 1-N-[4-(7-methoxy-6pyridin-3-ylquinolin4yl)oxyphenyl]cyclopropa no-1,1-dicarboxamida 202 1-N'-(4-fluorophenyl)1-N-[4-(7-methoxy-6pyridin-4-ylquinolin4yl)oxyphenyl]cyclopropa no-1,1-dicarboxamida 1-N'-(4-fluorophenyl)1-N-[4-[6-(1H-pyrazol5-yl)quinolin-4yl]oxyphenyl]cyclopropano-1,1-dicarboxamide 206 1-N'-(4-fluorophenyl)1-N-[4-(7-methoxy-6sulfamoylquinolin-4yl)oxyphenyl]cyclopropa no-1,1-dicarboxamida Petition 870230091982, 17 / 10 / 2023, pág. 110 / 422 103 / 378 n° Structure Name 207 1-N' -(4-fluorophenyl)1-N-[4-[7-methoxy-6(methylsulfamoyl)quinol in-4yl]oxyphenyl]cyclopropa no-1,1-dicarboxamida 208 1-N-[4-[6(ethylsulfamoyl)-7methoxyquinolin-4yl]oxyphenyl]-1-N'-(4fluorophenyl)cyclopropane-1,1-dicarboxamide 210 213 214 1-N'-(4-fluorophenyl) 1-N-[4-(6sulfamoylquinolin-4yl)oxyphenyl]cyclopropane-1,1-dicarboxamide 1-N'-(4-fluorophenyl) 1-N-[4-(7-methoxy-6methylsulfonylquinolin4yl)oxyphenyl]cyclopropane-1,1-dicarboxamide 1-N'-(4-fluorophenyl)1-N-[4-[7(methoxycarbamoyl)quinolin-4yl]oxyphenyl]cyclopropane-1,1-dicarboxamide 1-N-[4-[7(ethylcarbamoyl)quinolin-4-yl]oxyphenyl]-1-N'(4fluorophenyl)cyclopropane-1,1-dicarboxamide 1-N'-(4-fluorophenyl)1-N-[4-[7-methoxy-6(1,3,4-oxadiazol-2yl)quinolin-4yl]oxyphenyl]cyclopropane-1,1-dicarboxamide Petition 870230091982, dated 10 / 17 / 2023, page 111 / 422 104 / 378 No. Structure Name 221 1-N’-(4-fluorofenil)1-N-[4-[6-(1,3,4oxadiazol-2il)quinolin-4il]oxifenil]ciclopropa no-1,1-dicarboxamida 254 1-N'-(4-fluorofenil) 1-N-[4-(7sulfamoilquinolin-4il)oxifenil]ciclopropa no-1,1-dicarboxamida 255 256 262 263 1-N-[4-(7acetilquinolin-4il)oxifenil]-1-N' -(4fluorofenil)ciclopropa no-1,1-dicarboxamida; ou 1-N'-(4-fluorofenil) 1-N-[4-[7-[(E)-Nmetoxi-Cmetilcarbonimidoil]qui nolin-4il]oxifenil]ciclopropa no-1,1-dicarboxamida 1-N-[3-fluoro-4-[7metoxi-6(metilcarbamoil)quinol in-4-il]oxifenil]-1N' - (4-fluorofenil)-1N' -metilciclopropano1,1-dicarboxamida 1-N'-(4-fluorofenil)1-N-[4-[7-metoxi-6(metilcarbamoil)quinol in-4-il]oxifenil]-1N'-metilciclopropano1,1-dicarboxamida 1-N'-(2-chloro-4fluorophenyl)-1-N-[3fluoro-4-[7-methoxy-6(methylcarbamoyl)quinol in-4yl]oxyphenyl]cyclopropa no-1,1-dicarboxamida Petition 870230091982, 17 / 10 / 2023, pág. 112 / 422 105 / 378 n° Structure Name 265 1-N-[3-fluoro-4-[7methoxy-6(methylcarbamoyl)quinol in-4-yl]oxyphenyl]-1N'-(4-fluoro-2methylphenyl)cyclopropane-1,1-dicarboxamide 267 1-N'-(4-fluoro-2,6dimethylphenyl)-1-N-[3fluoro-4-[7-methoxy-6(methylcarbamoyl)quinol in-4yl]oxyphenyl]cyclopropa no-1,1-dicarboxamida 268 1-N-[3-fluoro-4-[7methoxy-6(methylcarbamoyl)quinol in-4-yl]oxyphenyl]-1N' -(4-fluoro-2methoxyphenyl)cyclopropano-1,1-dicarboxamide 269 1-N-[3-fluoro-4-[7methoxy-6(methylcarbamoyl)quinol in-4-yl]oxyphenyl]-1N'-(4-fluoro-2-propane2yloxyphenyl)cyclopropane-1,1-dicarboxamida 270 1-N'-(2-cyclopropyl-4fluorophenyl)-1-N-[3fluoro-4-[7-methoxy-6(methylcarbamoyl)quinol in-4yl]oxyphenyl]cyclopropa no-1,1-dicarboxamida 273 1-N'-[3-fluoro-4-[7methoxy-6(methylcarbamoyl)quinol in-4-yl]oxyphenyl]-1-N[4(trifluoromethyl)phenyl]cyclopropane-1,1dicarboxamide Petition 870230091982, 17 / 10 / 2023, pág. 113 / 422 106 / 378 n° Structure Name 274 1-N-(4-chlorophenyl)-1N' -[3-fluoro-4-[7methoxy-6(methylcarbamoyl)quinol in-4yl]oxyphenyl]cyclopropano-1,1-dicarboxamide 278 1-N'-(4-fluorophenyl) 1-N-[4-[7-[(E)-methoxyiminomethyl]quinolin-4yl]oxyphenyl]cyclopropano-1,1-dicarboxamide 279 1-N'-(4-fluorophenyl)1-N-[4-[7-methoxy-6(methylcarbamoylamino)q uinolin-4yl]oxyphenyl]cyclopropane-1,1-dicarboxamida 280 281 282 N-[4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-7-methoxyquinolin-6-yl]methyl carbamate 1-N'-(4-fluorophenyl)1-N-[4-[7(methylcarbamoylamino)quinolin-4yl]oxyphenyl]cyclopropane-1,1-dicarboxamide Methyl N-[4-[4-[[1-[(4fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]quinolin7-yl]carbamate 283 1-N-[4-[6-(3-ethyl1,2,4-oxadiazol-5-yl)7-methoxyquinolin-4yl]oxyphenyl]-1-N'-(4fluorophenyl)cyclopropane-1,1-dicarboxamide Petition 870230091982, dated 10 / 17 / 2023, page 114 / 422 107 / 378 no. Structure Name 292 293 1-N'-[3-fluoro-4-[6methyl-7(methylcarbamoyl)quinol in-4-yl]oxyphenyl]-1-N(4fluorophenyl)cyclopropane-1,1-dicarboxamide 1-N'-[2,5-difluoro-4[6-methyl-7(methylcarbamoyl)quinol in-4-yl]oxyphenyl]-1-N(4fluorophenyl)cyclopropano-1,1-dicarboxamide 1-N'-[2-chloro-5fluoro-4-[6-methyl-7(methylcarbamoyl)quinol in-4-yl]oxyphenyl]-1-N(4fluorophenyl)cyclopropano-1,1-dicarboxamide 1-N-(4-fluorophenyl)-1N'-[2,3,5-trifluoro-4[6-methyl-7(methylcarbamoyl)quinol in-4yl]oxyphenyl]cyclopropa no-1,1-dicarboxamida 1-N'-[4-(7-carbamoyl6-methylquinolin-4yl)oxy-3-fluorophenyl]1-N-(4fluorophenyl)cyclopropa no-1,1-dicarboxamida 1-N'-[4-(7-carbamoyl6-methylquinolin-4yl)oxy-2,5difluorophenyl]-1-N-(4fluorophenyl)cyclopropane-1,1-dicarboxamida Petition 870230091982, 17 / 10 / 2023, pág. 115 / 422 108 / 378 n° Structure Name 301 302 1-N'-[3-fluoro-4-[7(2hidroxietoxiccarbamoyl) quinolin-4yl]oxyphenyl]-1-N-(4fluorophenyl)cyclopropa no-1,1-dicarboxamida 1-N'-[2,5-difluoro-4[7-(2-hydroxyethoxycarbamoyl)quinolin-4yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropano-1,1-dicarboxamide or a pharmaceutically acceptable salt thereof.

[0178] GENERAL ADMINISTRATION

[0179] The administration of the compounds of the invention or their pharmaceutically acceptable salts in pure form or in an appropriate pharmaceutical composition may be carried out via any of the acceptable modes or agents of administration for similar purposes. Thus, administration may be, for example, oral, nasal, parenteral (intravenous, intramuscular or subcutaneous), topical, transdermal, intravaginal, intravesical, intracystem or rectal, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets, suppositories, pills, soft and hard elastic gelatin capsules, powders, solutions, suspensions, aerosols and the like, preferably in unit dosage forms suitable for simple administration of precise dosages.

[0180] The compositions will include a conventional pharmaceutical carrier or excipient and a compound of the invention such as the active agent(s), and, in addition, may Petition 870230091982, dated 10 / 17 / 2023, page 116 / 422 109 / 378 include other medicinal agents, pharmaceutical agents, carriers, adjuvants and the like. The compositions of the invention can be used in combination with anticancer agents or other agents that are generally administered to a patient being treated for cancer. Adjuvants include preservatives, humectants, suspending agents, sweeteners, flavorings, perfumes, emulsifiers and dispersants. Prevention of microorganism action can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be achieved by using agents that delay absorption, for example, aluminum monostearate and gelatin.

[0181] If desired, a pharmaceutical composition of the invention may also contain smaller amounts of auxiliary substances, such as humectants or emulsifiers, pH buffering agents, antioxidants and the like, such as, for example, citric acid, sorbitan monolaurate, triethylamine oleate, butylated hydroxytoluene and the like.

[0182] Suitable compositions 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 and the like), mixtures of Petition 870230091982, dated 10 / 17 / 2023, page 117 / 422 110 / 378 suitable, 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 a coating, such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0183] A preferred route of administration is oral administration, using a convenient daily dosing regimen that can be adjusted according to the severity of the disease condition being treated.

[0184] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.In such solid dosage forms, the active compound is mixed by addition with at least one common inert excipient (or carrier), such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, such as, for example, starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, such as, for example, cellulose derivatives, starch, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia gum; (c) humectants, such as, for example, glycerol; (d) disintegrating agents, such as, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and calcium carbonate; (e) solution retardants, such as, for example, paraffin; (f) absorption accelerators, such as, for example, quaternary ammonium compounds; (g) wetting agents, such as, for example, cetyl alcohol, and glycerol monostearate, magnesium stearate and the like; (h) absorbents, such as, for example, kaolin. Petition 870230091982, dated 10 / 17 / 2023, page 118 / 422 111 / 378 and bentonite; and (i) lubricants, such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also include buffering agents.

[0185] Solid dosage forms as described above may be prepared with coatings and substrates, such as enteric coatings and others well known in the art. These may contain pacifying agents, and may also be of such a composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of incorporated compositions that may be used are polymeric substances and waxes. The active compounds may also be in microencapsulated form, if suitable, with one or more of the excipients mentioned above.

[0186] Liquid dosage forms for oral administration include pharmaceutically acceptable elixirs, syrups, suspensions, solutions, and emulsions. Such dosage forms are prepared, for example, by dissolving, dispersing, and the like, a compound (or compounds) of the invention or a pharmaceutically acceptable salt thereof, and optionally, pharmaceutical excipients in a carrier, such as, for example, water, saline solution, aqueous dextrose, glycerol, ethanol, and the like; solubilizing and emulsifying agents, such as, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, and dimethylformamide; oils, in particular, cottonseed oil, peanut oil, germ oil Petition 870230091982, dated 10 / 17 / 2023, page 119 / 422 112 / 378 wheat, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters; or mixtures of these and similar substances, thus formed into a solution or suspension.

[0187] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances and the like.

[0188] Compositions for rectal administration are, for example, suppositories that can be prepared by mixing the compounds of the present invention with, for example, suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore melt while in a suitable body cavity and release the active component therein.

[0189] Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is mixed by addition under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.

[0190] In general, depending on the administration mode Petition 870230091982, dated 10 / 17 / 2023, page 120 / 422 113 / 378 intended, the pharmaceutically acceptable compositions will contain from about 1% to about 99% by weight of a compound (or compounds) of the invention or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient. In one example, the composition will be between about 5% and about 75% by weight of a compound (or compounds) of the invention or a pharmaceutically acceptable salt thereof, with the remainder being suitable pharmaceutical excipients.

[0191] The actual methods of preparing such dosage forms are known or will be evident to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 18th Edition, (Mack Publishing Company, Easton, Pa., 1990). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof for the treatment of a disease state according to the teachings of this invention.

[0192] The compounds of the invention or their pharmaceutically acceptable salts are administered in a therapeutically effective amount that will vary depending on a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, age, body weight, general health status, sex, diet, mode and time of administration, excretion rate, drug combination, the severity of the particular disease states and the host undergoing therapy. The compounds of the present invention may be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For an adult Petition 870230091982, dated 10 / 17 / 2023, pp. 121 / 422 For example, a normal human weighing approximately 70 kilograms would take a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day. However, the specific dosage used may vary. For example, the dosage may depend on several factors including the patient's requirements, the severity of the condition being treated, and the pharmacological activity of the compound being used. Determining ideal dosages for a particular patient is well known to be an element of common skill in the art.

[0193] COMBINATION THERAPY

[0194] A compound as disclosed herein may be administered as monotherapy or in combination (co-administered) with one or more additional therapies for the treatment of a disease or disorder, for example, a disease or disorder associated with hyperproliferation, such as cancer. Therapies that may be used in combination with a compound disclosed herein include: (i) surgery; (ii) radiotherapy (e.g., gamma radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and radioactive isotopes); (iii) endocrine therapy; (iv) adjuvant therapy, immunotherapy, CAR T-cell therapy; and (v) other chemotherapeutic agents.

[0195] The term co-administered (co-administration) refers to the simultaneous administration or any separate sequential administration of a compound of formula I' or a salt thereof, and an additional pharmaceutical ingredient or ingredients including cytotoxic agents and radiation treatment. If the administration does not Petition 870230091982, dated 10 / 17 / 2023, p. 122 / 422 115 / 378 for simultaneous administration, the compounds are administered in close temporal proximity to each other. Additionally, it does not matter if the compounds are administered in the same dosage form; for example, one compound may be administered topically and another compound may be administered orally.

[0196] Typically, any agent that has activity against a disease or condition being treated can be co-administered. Examples of such agents for cancer treatment can be found, for example, at https: / / www.cancer.gov / about-cancer / treatment / drugs (last accessed January 22, 2019) and in publicly available sources such as Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 11th edition (2018), Lippincott Williams & Wilkins Publishers. An element of common skill in the technique would be the ability to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the disease involved.

[0197] In one embodiment, the treatment method includes the co-administration of a compound as disclosed herein or a pharmaceutically acceptable salt thereof and at least one immunotherapy. Immunotherapy (also referred to as biological response-modifying therapy, biological therapy, biotherapy, immune therapy, or biological therapy) is treatment that uses parts of the immune system to fight disease. Immunotherapy can help the immune system recognize cancer cells or enhance a response against cancer cells. Immunotherapies include active and passive immunotherapies. Petition 870230091982, dated 10 / 17 / 2023, page 123 / 422 116 / 378 Active immunotherapies stimulate the body's own immune system, while passive immunotherapies generally use immune system components created outside the body.

[0198] Examples of active immunotherapies include, but are not limited to, vaccines including cancer vaccines, tumor cell vaccines (autologous or allogeneic), dendritic cell vaccines, antigen vaccines, anti-idiopathic vaccines, DNA vaccines, viral vaccines or Tumor Infiltrating Lymphocyte (TIL) Vaccine with Interleukin 2 (IL-2) or Killer Cell Therapy Activated by Lymphokine (LAK).

[0199] Examples of passive immunotherapies include, but are not limited to, monoclonal antibodies and targeted therapies containing toxins. Monoclonal antibodies include naked antibodies and conjugated monoclonal antibodies (also called identified, tagged, or loaded antibodies). Monoclonal antibodies do not have a drug or radioactive material attached, while conjugated monoclonal antibodies are attached to, for example, a chemotherapeutic drug (chemically identified), a radioactive particle (radioactively identified), or a toxin (immunotoxin).Examples of these nude monoclonal antibody drugs include, but are not limited to, rituximab (Rituxan), an antibody against the CD20 antigen used to treat, for example, B-cell non-Hodgkin lymphoma; trastuzumab (Herceptin), an antibody against the HER2 protein used to treat, for example, advanced breast cancer; alemtuzumab (Campath), an antibody against the CD52 antigen used to treat, for example, B-cell chronic lymphocytic leukemia (B-CLL); and cetuximab (Erbitux), an antibody. Petition 870230091982, dated 10 / 17 / 2023, pp. 124 / 422 117 / 378 against the EGFR protein is used, for example, in combination with irinotecan to treat, for example, colorectal cancer and advanced head and neck cancers; and Bevacizumab (Avastin) is an anti-angiogenesis therapy that works against the VEGF protein and is used, for example, in combination with chemotherapy, for example, metastatic colorectal cancer. Examples of conjugated monoclonal antibodies include, but are not limited to, the radioactively identified antibody Ibritumomab tiuxetan (Zevalin), which directly or indirectly delivers radioactivity to cancerous B lymphocytes and is used to treat, for example, B-cell non-Hodgkin lymphoma; and the radioactively identified antibody Tositumomab (Bexxar), which is used to treat, for example, certain types of non-Hodgkin lymphoma. and the immunotoxin Gemtuzumab ozogamicin (Mylotarg), which contains calicheamicin and is used to treat, for example, acute myelogenous leukemia (AML).BL22 is a monoclonal antibody conjugate for treating, for example, hairy cell leukemia; immunotoxins for treating, for example, leukemias, lymphomas, and brain tumors; and radioactively identified antibodies, such as OncoScint, for example, for colorectal and ovarian cancers, and ProstaScint, for example, for prostate cancers.

[0200] Additional examples of therapeutic antibodies that may be used include, but are not limited to, HERCEPTIN™ (Trastuzumab) (Genentech, Calif.), which is a humanized anti-HER2 monoclonal antibody for the treatment of patients with metastatic breast cancer; REOPRO.RTM. (abciximab) (Centocor), which is an anti-glycoprotein IIb / IIIa receptor antibody on platelets for the prevention of Petition 870230091982, dated 10 / 17 / 2023, page 125 / 422 118 / 378 obstruction formation; ZENAPAX™ (daclizumab) (Roche Pharmaceuticals, Switzerland) which is a humanized anti-CD25 monoclonal immunosuppressive antibody for the prevention of acute renal allograft rejection; PANOREX™ which is an antibody of IgG2a anti-17-IA murine cell surface antigen antibody (Glaxo Wellcome / Centocor); BEC2, a murine anti-idiopathic IgG antibody (GD3 epitope) (ImClone System); IMCC225, a chimeric anti-EGFR IgG antibody (ImClone System); VITAXIN™, a humanized anti-alpha V beta 3 integrin antibody (Applied Molecular). Evolution / Medlmmune); Campath 1H / LDP-03, which is a humanized anti-CD52 IgG1 antibody (Leukosite); Smart M195, which is a humanized anti-CD33 IgG antibody (Protein Design Lab / Kanebo); RITUXAN™, which is a chimeric anti-CD20 IgG1 antibody (IDEC Pharm / Genentech, Roche / Zettyaku); LYMPHOCIDE™ is a humanized anti-CD22 IgG antibody (Immunomedics); LYMPHOCIDE™ Y-90 (Immunomedics); Lymphoscan (identified with Tc-99m; radioactive imaging; Immunomedics); Nuvion (against CD3; Protein Design Labs); CM3 is a humanized anti-ICAM3 antibody (ICOS Pharm); IDEC-114 is a humanized anti-CD80 antibody (IDEC Pharm / Mitsubishi); ZEVALIN™ is a radioactively identified murine anti-CD20 antibody (IDEC / Schering AG); IDEC-131 is a humanized anti-CD40L antibody (IDEC / Eisai); IDEC-151 is a primatized anti-CD4 antibody (IDEC); IDEC-152 is a primatized anti-CD23 antibody (IDEC / Seikagaku); anti-CD3 SMART is a humanized anti-CD3 IgG (Protein Design Lab); 5G1.1 is a humanized anticomplementary factor 5 (C5) antibody (Alexion Pharm); D2E7 is a humanized anti-TNF-alpha antibody (CAT / BASF); CDP870 is a Fab fragment of Petition 870230091982, dated 10 / 17 / 2023, page 126 / 422 119 / 378 humanized anti-TNF-alpha (Celltech); IDEC-151 is a primatized IgG1 anti-CD4 antibody (IDEC Pharm / SmithKline Beecham); MDX-CD4 is a human IgG anti-CD4 antibody (Medarex / Eisai / Genmab); CD20 streptdavidin (+biotin-90; NeoRx); CDP571 is a humanized IgG4 anti-TNF-alpha antibody (Celltech); LDP-02 is a humanized beta7 anti-alpha4 antibody (LeukoSite / Genentech); OrthoClone OKT4A is a humanized IgG anti-CD4 antibody (Ortho Biotech); ANTOVA™ is a humanized IgG anti-CD40L antibody (Biogen); ANTEGREN™ is a humanized IgG anti-VLA-4 antibody (Elan); CAT-152 is a human anti-TGF-beta2 antibody (Cambridge Ab Tech). Others are provided in later paragraphs.

[0201] Immunotherapies that may be used in combination with a compound as disclosed herein include adjuvant immunotherapies. Examples include cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), macrophage inflammatory protein (MIP)-1-alpha, interleukins (including IL-1, IL-2, IL-4, IL-6, IL-7, IL-12, IL-15, IL-18, IL-21 and IL-27), tumor necrosis factors (including TNF-alpha), and interferons (including IFN-alpha, IFN-beta and IFN-gamma); aluminum hydroxide (alum); Bacillus Calmette-Guérin (BCG); Keyhole limpet hemocyanin (KLH); Incomplete Freund's adjuvant (IFA); QS-21; DETOX; Levamisole; and Dinitrophenyl (DNP), and combinations thereof, such as, for example, combinations of interleukins, for example, IL-2 with other cytokines, such as IFN-alpha.

[0202] In various modalities, a therapy Petition 870230091982, dated 10 / 17 / 2023, page 127 / 422 120 / 378 immunological or an immunotherapeutic agent may include one or more of the following: adoptive cell transfer, an angiogenesis inhibitor, Bacillus Calmette-Guérin therapy, biochemotherapy, a cancer vaccine, chimeric antigen receptor T-cell therapy (CAR), cytokine therapy, gene therapy, an immune checkpoint modulator, an immunoconjugate, a radioconjugate, oncolytic virus therapy, or targeted drug therapy. The function, or at least one of the functions, of the immunological therapy or immunotherapeutic agent is collectively referred to as an “immunotherapeutic agent” in this document.

[0203] This disclosure provides a method for preventing, treating, reducing, inhibiting, or controlling a neoplasm, tumor, or cancer in an individual in need thereof, involving administering a therapeutically effective amount of a combination comprising a compound of formula I' and an immunotherapeutic agent. In a non-limiting embodiment, the method comprises a therapeutically effective amount of a combination comprising a compound of formula I' in combination with an immunotherapeutic agent. In several embodiments, the combination provides a cooperative effect, an additive effect, or a synergistic effect in reducing the number of cancer cells when treated with the combination when compared to each treatment alone.In some modalities, administration of a therapeutically effective amount of a combination comprising a compound of formula I' and an immunotherapeutic agent results in synergistic antitumor activity and / or antitumor activity that is more potent than. Petition 870230091982, dated 10 / 17 / 2023, pp. 128 / 422 121 / 378 the additive effect of administering a compound of formula I' or an immunotherapeutic agent alone.

[0204] Human cancers harbor numerous genetic and epigenetic alterations, generating neoantigens potentially recognizable by the immune system (Sjoblom et al. (2006) Science 314:268-74). The adaptive immune system, comprised of T and B lymphocytes, has powerful anticancer potential with a broad capacity and exquisite specificity to respond to diverse tumor antigens. Additionally, the immune system demonstrates considerable plasticity and a memory component. The successful exploitation of all these attributes of the adaptive immune system would make immunotherapy unique among cancer treatment modalities.

[0205] The present disclosure provides a combination of a compound of formula I' and an immunotherapeutic agent. These exemplary combinations can be used to treat an individual with cancer. In various embodiments, immunotherapeutic agents that find utility in the present compositions, formulations and methods may include one or more agents or therapies including: an adoptive cell transfer, an angiogenesis inhibitor, Bacillus Calmette-Guérin therapy, biochemotherapy, a cancer vaccine, a chimeric antigen receptor (CAR) T-cell therapy, a cytokine therapy, gene therapy, an immune checkpoint modulator, for example, an immune checkpoint inhibitor, an immunoconjugate, a radioconjugate, an oncolytic virus therapy or a targeted drug therapy. Petition 870230091982, dated 10 / 17 / 2023, page 129 / 422 122 / 378

[0206] In certain embodiments of this disclosure, a therapeutically effective combination comprises a compound of formula I' and an immunotherapeutic agent. In several related embodiments, the compound of formula I' enhances the activity of the immunotherapeutic agent.

[0207] In certain embodiments of each of the aforementioned aspects, as well as other aspects and embodiments described elsewhere in this document, the immunotherapeutic agent enhances the activity of the compound of formula I'.

[0208] In certain embodiments of each of the aforementioned aspects, as well as other aspects and embodiments elsewhere in this document, the compound of formula I' and the immunotherapeutic agent act synergistically. In several embodiments described in this document, an exemplary immunotherapeutic agent is an immune cell modulator (e.g., T cells, dendritic cells, natural killer cells, and the like) chosen from an agonist or activator of a costimulatory molecule, wherein the modulator is a monoclonal antibody, a bispecific antibody comprising one or more immune checkpoint antigen-binding fractions, a trispecific antibody, or a multivalent antibody / fusion protein / construct involving immune cells known in the art.In some modalities, the immunotherapeutic agent may be an antibody that modulates a costimulatory molecule that binds to an antigen on the surface of an immune cell or a cancer cell. In each of these different modalities, the antibody modulator may be a monoclonal antibody, a polyclonal antibody, or a... Petition 870230091982, dated 10 / 17 / 2023, page 130 / 422 123 / 378 bispecific antibody, a trispecific or multispecific shape antibody, a fusion protein or a fragment thereof, for example, a Diabody, a single-chain diabody (sc) (scFv)2, a Miniantibody, a Minibody, a Barnase-barstar, an scFv-Fc, an sc(Fab)2, a Trimeric antibody construct, a Triabody antibody construct, a Trimerbody antibody construct, a Tribody antibody construct, a Colabody antibody construct, a (scFvTNFa)3 or an F(ab)3 / DNL antibody construct.

[0209] In certain embodiments of each of the aforementioned aspects, as well as other aspects and embodiments described elsewhere in this document, the immunotherapeutic agent is an agent that modulates immune responses, for example, a checkpoint inhibitor or a checkpoint agonist. In some embodiments, the immunotherapeutic agent is an agent that enhances antitumor immune responses. In some embodiments, the immunotherapeutic agent is an agent that enhances cell-mediated immunity. In some embodiments, the immunotherapeutic agent is an agent that enhances T cell activity. In some embodiments, the immunotherapeutic agent is an agent that enhances cytolytic T cell (CTL) activity. In some modalities, the immunotherapeutic agent is an antibody modulator that targets PD-1, PD-L1, PD-L2, CEACAM (e.g., CEACAM-1, -3 and / or -5), CTLA-4, TIM-3, LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, TGF beta, OX40, 41BB, LIGHT, CD40, GITR, TGF-beta, TIM-3, SIRP-alpha, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS, B7H3, B7H4, FAS and / or BTNL2, among others known in the technique. In some modalities, the Petition 870230091982, dated 10 / 17 / 2023, p. 131 / 422 124 / 378 An immunotherapeutic agent is an agent that increases natural killer (NK) cell activity. In some embodiments, the immunotherapeutic agent is an agent that inhibits suppression of an immune response. In some embodiments, the immunotherapeutic agent is an agent that inhibits suppressor cells or suppressor cell activity. In some embodiments, the immunotherapeutic agent is an agent or therapy that inhibits Treg activity. In some embodiments, the immunotherapeutic agent is an agent that inhibits the activity of inhibitory 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 includes a T cell modulator selected from an agonist or activator of a costimulatory molecule.In one embodiment, the agonist of the costimulatory molecule is chosen from agonist (e.g., an agonistic antibody or antigen-binding fragment thereof, or a soluble fusion) of ligands such as 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. In other modalities, the effector cell combination includes a bispecific T cell activator (e.g., a bispecific antibody molecule that binds to CD3) and a tumor antigen (e.g., EGFR, PSCA, PSMA, EpCAM, HER2, among others).

[0210] In some modalities, the immunotherapeutic agent is a PD-1 activity modulator, a PD-L1 activity modulator, an activity modulator Petition 870230091982, dated 10 / 17 / 2023, p. 132 / 422 125 / 378 of PD-L2, an activity modulator of CTLA-4, an activity modulator of CD28, an activity modulator of CD80, an activity modulator of CD86, an activity modulator of 4-1BB, an activity modulator of OX40, an activity modulator of KIR, an activity modulator of Tim-3, an activity modulator of LAG3, an activity modulator of CD27, an activity modulator of CD40, an activity modulator of GITR, an activity modulator of TIGIT, an activity modulator of CD20, an activity modulator of CD96, an IDO1 activity modulator, a SIRP-alpha activity modulator, a TIGIT activity modulator, a VSIG8 activity modulator, a BTLA activity modulator, a SIGLEC7 activity modulator, a SIGLEC9 activity modulator, an ICOS activity modulator, a B7H3 activity modulator, a B7H4 activity modulator, a FAS activity modulator, a BTNL2 activity modulator, a cytokine, a chemokine, an interferon, an interleukine, a lymphokine, a member of the tumor necrosis factor (TNF) family, or an immunostimulatory oligonucleotide.In some embodiments, the immunotherapeutic agent is an immune checkpoint modulator (e.g., an immune checkpoint inhibitor, e.g., a PD-1 activity inhibitor, a PD-L1 activity modulator, a PD-L2 activity modulator, a CTLA-4 modulator, 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., an anti-CD40 antibody molecule). Petition 870230091982, dated 10 / 17 / 2023, p. 133 / 422 126 / 378 example, CEACAM-1, -3 and / or -5), VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and / or TGF beta. In one embodiment, the inhibitor of an immune checkpoint molecule PD-1, PD-L1, LAG-3, TIM-3, CEACAM (e.g., CEACAM-1, -3 and / or -5), CTLA-4 or any combination thereof.

[0211] Inhibition of an inhibitory molecule can be performed at the DNA, RNA, or protein level. In some modalities, an inhibitory nucleic acid (e.g., a dsRNA, siRNA, or shRNA) can be used to inhibit the expression of an inhibitory molecule.In other embodiments, the inhibitor of an inhibitory signal is a polypeptide, for example, a soluble ligand (e.g., PD-1-Ig or CTLA-4 Ig), or an antibody or antigen-binding fragment thereof, for example, a monoclonal antibody, a bispecific antibody comprising one or more immune checkpoint antigen-binding fragments, a trispecific antibody, or a multivalent antibody / fusion protein / construct involving immune cells known in the art that binds to the inhibitory molecule; for example, an antibody or fragment thereof (also referred to as "an antibody molecule" in this document) 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.

[0212] In some embodiments, when 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 specifically to a member of the c-Met pathway and / or to a modulator. Petition 870230091982, dated 10 / 17 / 2023, p. 134 / 422 127 / 378 immune checkpoint (e.g., the bispecific antibody binds to both a hepatocyte growth factor receptor (HGFR) and an immune checkpoint modulator described herein, such as an antibody that binds to PD-1, PD-L1, PD-L2, or CTLA-4, LAG-3, OX40, 41BB, LIGHT, CD40, GITR, TGF-beta, TIM3, SIRP-alpha, TIGIT, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS, B7H3, B7H4, FAS, BTNL2, or CD27). In particular embodiments, the bispecific antibody binds specifically to a human HGFR protein and to one of PD-1, PD-L1, and CTLA-4.

[0213] In some modalities, the immunotherapeutic agent is a cytokine, for example, a chemokine, an interferon, an interleukin, a lymphokine, or a member of the tumor necrosis factor family. In some modalities, the cytokine is IL-2, IL-15, or interferon gamma.

[0214] In some embodiments of any of the above aspects or aspects described elsewhere in this document, the cancer is selected from the group consisting of lung cancer, pancreatic cancer, breast cancer, colon cancer, colorectal cancer, melanoma, gastrointestinal cancer, gastric cancer, renal cancer, ovarian cancer, liver cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, neuroblastoma, glioma, glioblastoma, glioblastoma multiforme, cervical cancer, stomach cancer, bladder cancer, head and neck cancer, and hepatoma.

[0215] In some modalities of any of the above aspects or aspects described elsewhere in this document, the individual's cancer or tumor does not respond to immune checkpoint inhibition (by Petition 870230091982, dated 10 / 17 / 2023, page 135 / 422 128 / 378 for example, any immune checkpoint inhibitor described herein, such as an antagonist of PD-1 or PD-L1 antagonist) or the individual's cancer or tumor has progressed after an initial response to immune checkpoint inhibition (e.g., to any immune checkpoint inhibitor described herein, such as a PD-1 antagonist or PD-L1 antagonist).

[0216] In some forms of any of the above aspects or of the aspects described elsewhere in this document, the individual is a human being.

[0217] A checkpoint inhibitor can be any molecule, agent, treatment, and / or method of inhibiting an immune checkpoint and / or promoting an immune checkpoint inhibitor, for example, by promoting an immune checkpoint inhibitor; by inhibiting a transcription factor involved in the expression of an immune checkpoint; and / or by acting in conjunction with some additional extrinsic factor. For example, a checkpoint inhibitor could include a treatment that inhibits transcription factors involved in the expression of immune checkpoint genes or promotes the expression of transcription factors for tumor suppressor genes, for example, BACH2 (Luan et al., (2016). Transcription Factors and Checkpoint Inhibitor Expression with Age: Markers of Immunosenescence. Blood, 128(22), 5983).Furthermore, a checkpoint inhibitor can inhibit the transcription of immune checkpoint genes; the modification and / or processing of immune checkpoint mRNA; the translation of immune checkpoint proteins; and / or molecules involved in immunity or the checkpoint pathway. Petition 870230091982, dated 10 / 17 / 2023, page 136 / 422 129 / 378 immune verification, for example, PD-1 transcription factors, such as HIF-1, STAT3, NF-κB, and AP-1, or the activation of common oncogenic pathways, such as JAK / STAT, RAS / ERK, or PI3K / AKT / mTOR (Zerdes et al., Genetic, transcriptional and post-translational regulation of the programmed death protein ligand 1 in cancer: biology and clinical correlations, Oncogene volume 37, pages 4639 to 4661 (2018), the publication of which is incorporated in its entirety by way of reference in this document).

[0218] Checkpoint inhibitors may include treatments, molecules, agents, and / or methods that regulate immune checkpoints at the transcriptional level, for example, using co-suppression of RNA interference pathways and / or post-transcriptional silencing (PTGS) (e.g., microRNAs, miRNAs; RNA silencing, small interfering RNA, or short interfering RNA (siRNA)). Transcriptional regulation of checkpoint molecules has been shown to involve mir-16, which has been shown to target the 3'UTR of 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 to v448). Mir-33a has also been shown to be involved in the regulation of PD-1 expression in cases of lung adenocarcinoma (Boldini et al.). al., Role of microRNA-33a in regulating the expression of PD-1 in lung adenocarcinoma, Cancer Cell Int.2017; 17: 105, the publication of which is incorporated in its entirety by reference in this document).

[0219] T cell-specific aptamer-siRNA chimeras have been suggested as a method of inhibiting Petition 870230091982, dated 10 / 17 / 2023, p. 137 / 422 130 / 378 molecules in the immune checkpoint pathway (Hossain et al., The aptamer-siRNA conjugates: reprogramming T cells for cancer therapy, Ther. Deliv. January 2015; 6(1): 14, the disclosure of which is incorporated herein by reference in its entirety.

[0220] Alternatively, members of the immune checkpoint pathway can be inhibited using treatments that affect associated pathways, for example, metabolism. For example, excessive supply of glycolytic intermediate pyruvate in mitochondria of CAD macrophages promoted PD-L1 expression via induction of bone morphogenetic protein 4 / phosphorylated SMAD1 / 5 / IFN regulatory factor 1 signaling pathway (BMP4 / p-SMAD1 / 5 / IRF1). Consequently, implementation of treatments that modulate the metabolic pathway may result in subsequent modulation of the immunoinhibitory PD-1 / PD-L1 checkpoint pathway (Watanabe et al., Pyruvate controls the checkpoint inhibitor PD-L1 and suppresses T-cell immunity, J Clin Invest. June 30, 2017; 127(7): 2725-2738).

[0221] Checkpoint immunity can be regulated via oncolytic viruses that selectively replicate in tumor cells and induce acute immune responses in the tumor microenvironment, i.e., by acting as genetic vectors that carry specific agents (e.g., antibodies, miRNA, siRNA, and the like) to cancer cells and effect their oncolysis and secretion of cytokines and chemokines to synergize with checkpoint inhibition (Shi et al., Cancer Immunotherapy: A Focus on the Regulation of Immunological Checkpoints, Int J Mol Sci.). Currently, there are clinical trials under study. Petition 870230091982, dated 10 / 17 / 2023, p. 138 / 422 131 / 378 which utilize the following viruses as checkpoint inhibitors: poliovirus, measles virus, adenovirus, poxvirus, herpes simplex virus (HSV), coxsackievirus, reovirus, Newcastle disease virus (NDV), T-VEC (a herpesvirus encoded with GM-CSF (granulocyte-macrophage colony-stimulating factor)), and H101 (Shi et al., supra).

[0222] Checkpoint inhibitors can operate at a level of checkpoint translation in immunity. The translation of mRNA into proteins represents a key event in the regulation of gene expression, thus, immune checkpoint translation inhibition is a method by which the checkpoint pathway can be inhibited.

[0223] Checkpoint inhibition can occur at any stage of the immune translation process. For example, drugs, molecules, agents, treatments, and / or methods can inhibit the initiation process (by which the 40S ribosomal subunit is recruited at the 5' end of mRNA and sweeps the 5'UTR of mRNA to its 3' end). Inhibition can occur by targeting the anticodon of the initiator methionyl transfer RNA (tRNA) (Met-tRNAi), its base pairing with the start codon, or the recruitment of the 60S subunit to initiate elongation and sequential amino acid addition in the translation of specific immune checkpoint genes. Alternatively, a checkpoint inhibitor can inhibit checkpoints at the translational level by preventing the formation of the ternary complex (TC), i.e., eukaryotic inhibitory factor (eIF)2 (or one or more of its α, β, and γ subunits); GTP; and Met-tRNAi.

[0224] Checkpoint inhibition can Petition 870230091982, dated 10 / 17 / 2023, page 139 / 422 132 / 378 occur via destabilization of eIF2a by preventing its phosphorylation via protein kinase R (PKR), PERK, GCN2, or HRI, or by preventing TCs from associating with the 40S ribosome and / or other initial factors, thus preventing the pre-initiation complex (PIC) from forming; inhibiting the eIF4F complex and / or its eIF4E buffer-binding protein, the eIF4G scaffold protein, or eIF4A helicase. Methods discussing translational cancer control are discussed in Truitt et al., New frontiers in translational control of the cancer genome, Nat Rev Cancer. April 26, 2016; 16(5): 288-304, the publication of which is incorporated herein by reference in its entirety.

[0225] Checkpoint inhibitors may also include treatments, molecules, agents and / or methods that regulate immune checkpoints at the cellular and / or protein level, for example, by inhibiting an immune checkpoint receptor. Checkpoint inhibition may occur via the use of antibodies, antibody fragments, antigen-binding fragments, small molecules and / or other drugs, agents, treatments and / or methods.

[0226] Immune checkpoints refer to inhibitory pathways in the immune system that are responsible for maintaining self-tolerance and modulating the degree of immune system response to minimize damage to peripheral tissue. However, tumor cells can also activate immune system checkpoints to decrease the effectiveness of the immune response ('blocking' the immune response) against tumor tissues. In contrast to most anticancer agents, checkpoint inhibitors do not directly target tumor cells, but instead, Petition 870230091982, dated 10 / 17 / 2023, page 140 / 422 133 / 378 target lymphocyte receptors or their ligands in order to enhance the endogenous antitumor activity of the immune system. (Pardoll, 2012, Nature Reviews Cancer 12:252264).

[0227] Until recently, cancer immunotherapy has focused substantial effort on approaches that enhance antitumor immune responses by adoptive transfer of activated effector cells, relevant antigens against immunization, or by delivering nonspecific immune-stimulating agents, such as cytokines. In the past decade, however, intensive efforts to develop specific immune checkpoint pathway inhibitors have begun to provide new immunotherapeutic approaches to treat cancer, including the development of the antibody (Ab), ipilimumab (YERVOY.RTM.), which binds to and inhibits CTLA-4 for the treatment of patients with advanced melanoma (Hodi et al. (2010) N Engl J Med 363:711-23) and the development of antibodies such as nivolumab and pembrolizumab (formerly lambrolizumab; USAN Council Statement (2013) Pembrolizumab: A submission on a nonproprietary name adopted by the USAN Council (ZZ-165), November 27, 2013). 2013) that specifically binds to the Programmed Death 1 (PD-1) receptor and blocks the inhibitory PD-1 / PD1 ligand pathway (Topalian et al. (2012a) N Engl J Med 366:244354; 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).

[0228] PD-1 is a checkpoint receiver Petition 870230091982, dated 10 / 17 / 2023, pp. 141 / 422 134 / 378 key immune system expressed by activated T and B cells and mediates immunosuppression. Nivolumab (formerly designated 5C4, BMS-936558, MDX-1106, or ONO-4538) is a fully human IgG4 PD-1 immune checkpoint inhibitor antibody (S228P) that selectively prevents interaction with PD-1 ligands (PD-L1 and PD-L2), thereby blocking the downregulation of antitumor T cell functions (US Patent No. 8,008,449; Wang et al. (2014) In vitro characterization of the anti-PD-1 antibody nivolumab, BMS936558, 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, if the BRAF V600 mutation is positive, a BRAF inhibitor, and for the treatment of squamous non-small cell lung cancer.

[0229] 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 in tumors at higher levels in regulatory T cells (also referred to as "Treg cells" in this document) compared to antitumor effector T cells (also referred to as "Teff cells" in this document), leading to the hypothesis that anti-CTLA-4 preferentially impacts Treg cells. "Therapeutic use of anti-CTLA-4 antibodies," Christian U. Blank and Alexander Enk, International Immunology, Volume 27, No. 1, pages 3-10. A recent study of a combination of PD-1 and CTLA-4 shows that blocking the combined CTLA-4 and PD-1 pathways also contributes to increasing the ratio of Teff cells to both regulatory T cells and MDSCs, thereby reducing suppression and promotion of Petition 870230091982, dated 10 / 17 / 2023, pp. 142 / 422 135 / 378 Inflammation in the tumor microenvironment. “Combination of CTLA-4 and PD-1 blockade expands T-cell infiltration and reduces regulatory and myeloid T cells within B16 melanoma tumors,” Curran et al., PNAS|2 March 2010; volume 107 (no. ); pages 4275-4280, the disclosure of which is incorporated in its entirety by reference in this document. The combination of a checkpoint inhibitor and another therapeutic agent (or agents) may intensify or prolong the antitumor response of the checkpoint inhibitor and / or effects of the therapeutic agent. In this regard, document WO 2015 / 069770 discloses a combination treatment based on the activation of an adaptive immune response, in particular, the combination of CTLA-4 and PD-1 inhibitors for the treatment of cancer. The publication of document WO 2015 / 069770 is incorporated in its entirety as a reference in the publication of this request.

[0230] One mechanism by which anti-CTLA-4 checkpoint blocking antibodies mediate the antitumor effect occurs by decreasing regulatory T cells. Due to the distinct mechanism of action of anti-CTLA-4 antibodies, they can successfully combine with anti-PD1 checkpoint blocking antibodies that function to release the suppressive signaling conferred on effector T cells. The dual blocking with these antibodies combines to enhance the antitumor response both preclinically (Proc Natl Acad Sci USA 2010, 107, 4275-4280) and clinically (N Engl J Med 2013, 369, 122-133; N Engl J Med 2015, 372, 2006-2017).

[0231] CTLA-4 attenuates the early activation of naive and memory T cells through interactions with its ligands. Petition 870230091982, dated 10 / 17 / 2023, page 143 / 422 136 / 378 B7-1 (CD80) and B7-2 (CD86) (Figure 1A). PD-1 is a receptor expressed on the surface of activated mature T cells, activated NK cells, B cells, monocytes, and multiple normal tissues and plays a crucial role in maintaining peripheral tolerance [20–21] (Figure 1A). In contrast to CTLA-4, PD-1 acts via interactions with its ligands PD-L1 (also known as B7-H1 or CD274) and is primarily involved in modulating T cell activity in peripheral tissues as well as providing an important immune resistance mechanism in the tumor microenvironment.

[0232] In some embodiments, the immunotherapeutic agent is a PD-1 activity modulator, a PD-L1 activity modulator, a PD-L2 activity modulator, a CTLA-4 activity modulator, a CD28 activity modulator, a CD80 activity modulator, a CD86 activity modulator, an activity modulator of 4-1BB, an activity modulator of OX40, an activity modulator of KIR, an activity modulator of Tim-3, an activity modulator of LAG3, an activity modulator of CD27, an activity modulator of CD40, an activity modulator of GITR, an activity modulator of TIGIT, an activity modulator of CD20, an activity modulator of CD96, an IDO1 activity modulator, a cytokine, a chemokine, an interferon, an interleukin, a lymphokine, a member of the tumor necrosis factor (TNF) family, or an immunostimulatory oligonucleotide. In some modalities, the immune checkpoint modulator is either an inhibitor or antagonist, or an activator or agonist, for example, a CD28 modulator, a 4-1BB modulator, an OX40 modulator, a CD27 modulator, a modulator of Petition 870230091982, dated 10 / 17 / 2023, page 144 / 422 137 / 378 CD8 0, a CD8 6 modulator, a CD4 0 modulator or a GITR modulator, a Lag-3 modulator, a 41BB modulator, a LIGHT modulator, a CD40 modulator, a GITR modulator, a TGF-beta modulator, a TIM-3 modulator, a SIRP-alpha modulator, a TIGIT modulator, a VSIG8 modulator, a BTLA modulator, a SIGLEC7 modulator, a SIGLEC9 modulator, an ICOS modulator, a B7H3 modulator, a B7H4 modulator, a FAS modulator and / or a BTNL2 modulator. In some embodiments, the immunotherapeutic agent is an immune checkpoint modulator as described above (e.g., an immune checkpoint modulator antibody that may be in the form of a monoclonal antibody, a bispecific antibody comprising one or more immune checkpoint antigen-binding fractions, a trispecific antibody, or a multivalent antibody / fusion protein / construct that engulfs immune cells known in the art).

[0233] Combination treatments with immune checkpoint inhibitor immunotherapeutic agents may include antibodies that specifically target immune system checkpoints, such as CTLA4, PD1, and PD-L1, and are the most promising new immunotherapy pathways for cancer and other diseases. Additionally, checkpoint targets such as TIM-3, LAG-3, various B-7 ligands, CHK1 and CHK2 kinases, BTLA, A2aR, and others are also under investigation. Currently, three checkpoint inhibitors have received fast-track approval from the U.S. Food and Drug Administration for cancer treatment, including ipilimumab (Yervoy®), a CTLA-4 inhibitor, and pembrolizumab (Keytruda®) and nivolumab (Opdivo®). Petition 870230091982, dated 10 / 17 / 2023, page 145 / 422 138 / 378 are both PD-1 inhibitors. In addition, several checkpoint inhibitor agents are in clinical trials.

[0234] Programmed Cell Death Protein 1 (PD1 or CD279), a 55-kD type 1 transmembrane protein, is a member of the CD28 family of T cell costimulatory receptors, which includes the immunoglobulin CD28 superfamily member, CTLA-4, inducible costimulatory receptor (ICOS), and BTLA. PD-1 is highly expressed on activated T cells and B cells. PD-1 expression can also be detected in memory subsets of T cells with varying levels of expression. Two specific ligands for PD-1 have been identified: programmed death ligand 1 (PD-L1, also known as B7-H1 or CD274) and PD-L2 (also known as B7DC or CD273). PD-L1 and PD-L2 have been shown to negatively regulate T cell activation after binding to PD-1 in both murine and human systems (Okazaki et al., Int Immunol., 2007; 19: 813-824).The interaction of PD1 with its ligands, PD-L1 and PD-L2, which are expressed on antigen-presenting cells (APCs) and dendritic cells (DCs), transmits negative regulatory stimuli to negatively modulate the immune response of activated T cells. Blocking PD-1 suppresses this negative signal and amplifies T cell responses.

[0235] Numerous studies indicate that the cancer microenvironment manipulates the PD-L1- / PD-1 signaling pathway and that the induction of PD-L1 expression is associated with the inhibition of immune responses against cancer, thus allowing cancer progression and metastasis. The signaling pathway of PD-L1 / PD-1 is a primary immune evasion mechanism for cancer for several reasons. First and foremost, this Petition 870230091982, dated 10 / 17 / 2023, page 146 / 422 The 139 / 378 pathway is involved in the downregulation of immune responses from activated effector T cells found in the periphery. Secondly, PD-L1 is upregulated in cancer microenvironments, while PD-1 is also upregulated in tumor-infiltrating T cells, thus potentially potentiating a vicious cycle of inhibition. Thirdly, this pathway is intrinsically involved in both innate and adaptive immune regulation through bidirectional signaling. These factors make the PD-1 / PD-L1 complex a central point through which cancer can manipulate immune responses and promote its own progression.

[0236] CTLA-4 (also known as cytotoxic T lymphocyte-associated protein 4, CTLA4, CTLA-4, CD152, differentiation cluster 152; ALPS5, CD, CELIAC3, GRD4, GSE, and IDDM12). CTLA-4 is a ~24.6-kDa type I single-pass membrane protein that plays an inhibitory role in T cell function. CTLA-4 was originally identified by differential screening of a murine cytotoxic T cell cDNA library, See Brunet et al., A new member of the immunoglobulin superfamily--CTLA4, Nature. July 16, 1987-22;328(6127):267-70, CTLA was shown to interact with 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 B cell activation antigen B7, J Exp Med.September 1, 1991;174(3):561-9, Sequential comparison between the region encoding human CTLA-4 DNA and the CD28 region reveals homology. Petition 870230091982, dated 10 / 17 / 2023, page 147 / 422 140 / 378 significant difference between both sequences with the greatest similarity between membrane juxtaposition and cytoplasmic regions; consequently, CTLA-4 is implicated in the suppression / reduction of T cell activity, and opposes CD28 activity. CTLA-4 deficient mice have been shown to exhibit massive lymphoproliferation. Chambers et al., Lymphoproliferation in CTLA-4-deficient mice is mediated by co-synthesis-dependent activation of CD4+ T cells, Immunity. December 7, 1997;7(6):885-95. It has been reported that blocking CTLA-4 increases T cell responses both in vitro and in vivo, intensifies an induced autoimmune disease, and exacerbates antitumor immunity. (See Luhder, J. Exp. Med. 1998; 187:427-432; Walunas et al., Immunity. 1994; 1:405-413; Kearney, J. Immunol. 1995; 155:1032-1036); Leach, Science 1996; 271:1734-1736). CTLA-4 has been reported as having an alternative and / or additional impact on the initial character of the T-cell immune response (Chambers, Curr. Opin. Immunol. 1997; 9:396-404; Bluestone, J. Immunol. 1997; 158:1989-1993; Thompson, Immunity 1997; 7:445-450).

[0237] The first immune checkpoint inhibitor to be tested in a clinical trial was ipilimumab (Yervoy, Bristol-Myers Squibb), a CTLA-4 mAb. CTLA-4 belongs to the immunoglobulin receptor superfamily which also includes PD-1, BTLA, TIM-3, and the immunoglobulin V activating domain suppressor (VISTA). Anti-CTLA-4 mAb is a powerful checkpoint inhibitor that removes the “breakdown” from both naive and antigen-experienced cells. The therapy enhances the antitumor function of CD8+ T cells, increases the proportion of CD8+ Petition 870230091982, dated 10 / 17 / 2023, p. 148 / 422 141 / 378 T cells to Foxp3+ regulatory T cells, and inhibits the suppressive function of regulatory T cells. The main disadvantage of anti-CTLA-4 mAb therapy is the generation of autoimmune toxicities due to effects on the target of an exuberant immune system that has lost the ability to refuse. Up to 25% of patients treated with ipilimumab have been reported to have developed serious grade 34 adverse events / autoimmune-type side effects including dermatitis, enterocolitis, hepatitis, endocrinopathies (including hypopigmentation, thyroiditis, and adrenalitis), arthritis, uveitis, nephritis, and aseptic meningitis. In contrast to the experience with anti-CTLA-4, anti-PD-1 therapy appears to be better tolerated and induces a relatively lower rate of autoimmune-type side effects.

[0238] In some embodiments, the immunotherapeutic agent is an agent that inhibits PD-1 activity. In some embodiments, the immunotherapeutic agent is an agent that inhibits PD-L1 and / or PD-L2 activity. In some embodiments, the immunotherapeutic agent is an agent that inhibits CTLA-4 activity. In some embodiments, the immunotherapeutic agent is an agent that inhibits CD80 and / or CD86 activity. In some embodiments, the immunotherapeutic agent is an agent that inhibits TIGIT activity. In some embodiments, the immunotherapeutic agent is an agent that inhibits KIR activity. In some embodiments, the immunotherapeutic agent is an agent that enhances or stimulates the activation activity of immune checkpoint receptors.

[0239] In some of the modalities of the methods described in this document, the immunotherapeutic agent Petition 870230091982, dated 10 / 17 / 2023, p. 149 / 422 142 / 378 is an antagonist of PD-1, an antagonist of PD-L1, an antagonist of PD-L2, an antagonist of CTLA-4, an antagonist of CD80, an antagonist of CD86, an antagonist of KIR, an antagonist of Tim-3, an antagonist of LAG3, an antagonist of TIGIT, an antagonist of CD20, an antagonist of CD96, or an antagonist of IDO1.

[0240] In some embodiments, the PD- antagonist is an antibody that binds specifically to PD-1. In some embodiments, the antibody that binds to PD-1 is pembrolizumab (KEYTRUDA®, MK-3475; Merck), pidilizumab (CT011; Curetech Ltd.), nivolumab (OPDIVO®, BMS-936558, MDX1106; Bristol Myers 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 that binds to PD-1 is described in PCT Publication WO 2014 / 179664, for example, an antibody identified as APE2058, APE1922, APE1923, APE1924, APE 1950 or APE1963 (Anaptysbio), or an antibody containing the CDR regions of either of these antibodies. In other embodiments, the PD-1 antagonist is a fusion protein that includes the extracellular domain of PD-L1 or PD-L2, for example, AMP-224 (AstraZeneca / MedImmune). In other embodiments, the PD-1 antagonist is a peptide inhibitor, for example, AUNP-12 (Aurigene).

[0241] In some modalities, the PD antagonist- L1 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 Petition 870230091982, dated 10 / 17 / 2023, p. 150 / 422 143 / 378 Squibb), avelumab (MSB0010718C; Merck KGaA), KD033 (Kadmon), the KD033 antibody portion, or STI-A1014 (Sorrento Therapeutics). In some embodiments, the antibody that binds to PD-L1 is described in PCT Publication WO 2014 / 055897, for example, Ab-14, Ab-16, Ab-30, Ab-31, Ab-42, Ab-50, Ab52, or Ab-55, or an antibody containing the CDR regions of any of these antibodies, the disclosure of which is incorporated in its entirety by reference herein.

[0242] In some modalities, the antagonist of CTLA-4 is an antibody that binds specifically to CTLA-4. In some embodiments, the antibody that binds to CTLA-4 is ipilimumab (YERVOY®; Bristol Myers Squibb) or tremelimumab (CP-675,206; Pfizer). In some embodiments, the CTLA-4 antagonist is a CTLA-4 fusion protein or a soluble CTLA-4 receptor, for example, KARR-102 (Kahr Medical Ltd.).

[0243] In some embodiments, the LAG3 antagonist is an antibody that specifically binds to LAG3. In some embodiments, the antibody that binds to LAG3 is IMP701 (Prima BioMed), IMP731 (Prima BioMed / GlaxoSmithKline), BMS-986016 (Bristol Myer Squibb), LAG525 (Novartis), and GSK2831781 (GlaxoSmithKline). In some embodiments, the LAG3 antagonist includes a soluble LAG3 receptor, for example, IMP321 (Prima BioMed).

[0244] In some embodiments, the KIR antagonist is an antibody that binds specifically to KIR. In some embodiments, the antibody that binds to KIR is lirilumab (Bristol Myer Squibb / Innate Pharma).

[0245] In some modalities, the agent Petition 870230091982, dated 10 / 17 / 2023, p. 151 / 422 144 / 378 immunotherapeutic used in the combinations disclosed in this document (for example, in combination with a compound of formula I') is an activator or agonist of a costimulatory molecule. In one embodiment, the agonist of the costimulatory molecule is chosen from an agonist (for example, an agonistic antibody or antigen-binding fragment thereof or a soluble fusion) of OX40, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a / CD18) ligand. ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83.

[0246] In some embodiments, the OX40 agonist includes the OX40 ligand or an OX40-binding portion thereof. 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 a vector (e.g., an expression vector or virus, such as an adenovirus) that is capable of expressing OX40 ligand. In some forms, the vector expressing OX40 is Delta-24-RGDOX (DNAtrix) or DNX2401 (DNAtrix).

[0247] In some embodiments, the 4-1BB agonist (CD137) is a binding molecule, such as an anticalin. In some embodiments, the anticalin is PRS-343 (Pieris AG). In some embodiments, the 4-1BB agonist is an antibody that binds specifically 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). Petition 870230091982, dated 10 / 17 / 2023, p. 152 / 422 145 / 378

[0248] In some embodiments, the CD27 agonist is an antibody that binds specifically to CD27. In some embodiments, the antibody that binds to CD27 is varlilumab (CDX-1127; Celldex).

[0249] In some embodiments, the GITR agonist comprises a GITR ligand or a GITR-binding portion thereof. In some embodiments, the GITR agonist is an antibody that specifically binds to GITR. In some embodiments, the GITR-binding antibody is TRX518 (GITR, Inc.), MK-4166 (Merck), or INBRX-110 (Five Prime). Therapeutics / Inhibition).

[0250] TIM-3 has been identified as another important inhibitory receptor expressed by depleted CD8+ T cells. In murine cancer models, it has been shown that more dysfunctional tumor-infiltrating CD8+ T cells actually co-express PD-1 and TIM-3.

[0251] LAG-3 is another recently identified inhibitory receptor that acts by limiting the function of effector T cells and increasing the suppressive activity of regulatory T cells. It has recently been reported that PD-1 and LAG-3 are extensively co-expressed by tumor-infiltrating T cells in mice, and that combined blockade of PD-1 and LAG-3 elicits potent synergistic antitumor immune responses in murine cancer models.

[0252] PD-1 pathway blockade can be combined with vaccines or other antibodies of the formula I' compound for enhanced 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. setembro, 107(9):4275-4280 (2010)). Petition 870230091982, dated 10 / 17 / 2023, p. 153 / 422 146 / 378

[0253] In some embodiments, immunotherapeutic agents useful in the compositions and methods described herein may include a monoclonal antibody, a bispecific antibody comprising one or more immune checkpoint antigen-binding fractions, a trispecific antibody, or a multivalent antibody / fusion protein / construct that envelops immune cells known in the art that specifically targets both PD-1 and PD-L1 ligand.

[0254] PD-1 (also known as Programmed Death 1, CD279, PDCD1) is a cell surface receptor with a critical role in regulating the balance between stimulatory and inhibitory signals in the immune system and in 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 with homology to CD28. The PD-1 structure is a monomeric type 1 transmembrane protein consisting of an extracellular immunoglobulin-type variable domain and a cytoplasmic domain containing an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immunoreceptor tyrosine-based switching motif (ITSM).PD-1 expression is inducible in T cells, B cells, natural killer (NK) cells, and monocytes, for example, after lymphocyte activation via 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 the ligands CD80, CD86, PD-1. (Reference 870230091982, 10 / 17 / 2023, page 154 / 422.) 147 / 378 L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273) are cell surface-expressed members of the B7 family (Freeman, Gordon et al. 2000 J Exp Med 192 1027; Latchman, Y et al. (2001 Nat Immunol 2 261). After ligand engagement, PD1 recruits phosphatases, such as SHP-1 and SHP-2, to its intracellular tyrosine motifs that subsequently dephosphorylate effector molecules activated by TCR or BCR signaling (Chemnitz, J et al. 2004 J Immunol 173 945954; Riley, James L 2009 Immunological Reviews 229 114-125). In this way, PD-1 transduces inhibitory signals in T and B cells only when they are simultaneously engaged with the TCR or BCR.

[0255] PD-1 has been shown to negatively regulate effector T cell responses via both intrinsic and extrinsic cell functional mechanisms. Inhibitory signaling via PD-1 induces a non-responsive state in T cells, resulting in the loss of the cells' ability to expand or clonally produce optimal levels of effector cytokines. PD-1 can also induce apoptosis in T cells via its ability to inhibit co-stimulatory survival signals, leading to reduced expression of key anti-apoptotic molecules such as Bcl-XL (Kier, Mary E et al. 2008 Annu Rev Immunol 26 677-704). In addition to these effects, recent publications implicate PD-1 as being involved in the suppression of effector cells by promoting the induction and maintenance of regulatory T cells (TREGs). For example, PD-L1 expressed in dendritic cells has been shown to act synergistically with TGF-β to promote the induction of CD4+ FoxP3+TREGs with enhanced suppressive function (Francisco, Loise M et al. 2009 J Exp Med 206). Petition 870230091982, dated 10 / 17 / 2023, page 155 / 422 148 / 378 3015-3029).

[0256] TIM-3 (also known as T-cell immunoglobulin and mucin-containing 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 type I single-pass 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. 4:10931101(2003)).

[0257] TIM-3 is selectively expressed on Th1 cells and phagocytic cells (e.g., macrophages and dendritic cells). The use of siRNA or a blocking antibody to reduce human expression resulted in increased secretion of interferon γ (IFN-γ) from CD4-positive T cells, implying the inhibitory role of TIM-3 on human T cells. Analysis of clinical samples from autoimmune patients showed no TIM-3 expression on CD4-positive cells. In particular, the level of TIM-3 expression is lower and IFN-γ secretion is higher in T cell clones derived from cerebrospinal fluid of multiple sclerosis patients than the secretions in clones derived from normal healthy individuals (Koguchi K et al., J Exp Med. 203:1413-8. (2006)).

[0258] TIM-3 is the receptor for Galectin-9 ligands, which is a member of the galectin family, molecules ubiquitously expressed in a variety of cell types that bind to β-galactoside; phosphatidylserine (PtdSer) (DeKryff et al., T cells / transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine). Petition 870230091982, dated 10 / 17 / 2023, p. 156 / 422 149 / 378 and mediate the phagocytosis of apoptotic cells, J Immunol. February 15, 2010;184(4):1918-30); High Mobility Group Protein 1 (also known as HMGB1, HMG1, HMG3, SBP-1, HMG-1 and high mobility group box 1) Chiba et al., Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1, Nat Immunol. September 2012;13(9):832-42); and Carcinoembryonic Antigen-Related Adhesion Molecule 1 (also known as CEACAM1, BGP, BGP1, BGPI, carcinoembryonic antigen-related adhesion molecule 1) (Huang et al., CEACAM1 regulates TIM-3-mediated tolerance and exhaustion, Nature. January 15, 2015;517(7534):38690).

[0259] BTLA (also known as B and T lymphocyte attenuator, BTLA1, CD272, and B and T lymphocyte associated) is a ~27.3-kDa type I single-pass membrane protein involved in lymphocyte inhibition during the immune response. BTLA is constitutively expressed on both B cells and T cells. BTLA interacts with HVEM (herpes virus entry mediator), a member of the tumor necrosis factor receptor (TNFR) family (Gonzalez et al., Proc. Natl. Acad. Sci. USA, 2005, 102: 1116-21). The interaction of BTLA, which belongs to the CD28 family of the immunoglobulin superfamily, and HVEM, a co-stimulatory tumor necrosis factor (TNF) receptor (TNFR), is unique as it defines a relationship between these two receptor families. BTLA contains an inhibitory motif of proximal membrane immunoreceptor tyrosine Toll-like receptor (ITIM) agonists and a switching motif based on distal immunoreceptor tyrosine. Petition 870230091982, dated 10 / 17 / 2023, p. 157 / 422 150 / 378 membrane (ITSM). Interruption of ITIM or ITSM abolished the ability of BTLA to recruit SHP1 or SHP2, suggesting that BTLA recruits SHP1 and SHP2 in a manner distinct from PD-1 and that both tyrosine motifs are required to block T cell activation. The cytoplasmic tail of BTLA also contains a third conserved tyrosine-containing motif in the cytoplasmic domain sequence similar to a Grb-2 recruitment site (YXN). Furthermore, a phosphorylated peptide containing this N-terminal tyrosine motif of BTLA can interact with GRB2 and the p85 subunit of PI3K in vitro, although the functional effects of this interaction remain unexplored in vivo (Gavrieli et al., Bioochem. Biophysi Res Commun, 2003, 312, 1236-43). BTLA is the receptor for PTPN6 / SHP-1, PTPN11 / SHP-2, TNFRSF14 / HVEM, and B7H4 ligands.

[0260] VISTA (also known as V-domain suppressor of T cell activation V, VSIR, B7-H5, B7H5, GI24, PP2135, SISP1, DD1alpha, VISTA, C10orf54, chromosome 10 54 open reading frame, PD-1H and V-complex immunoregulatory receptor) is a ~33.9-kDa type I single-pass membrane protein involved in the inhibitory response of T cells, in embryonic stem cell differentiation via inhibition of BMP4 signaling and in MMP14-mediated MMP2 activation (Yoon et al., Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53, Science. July 31, 2015; 349(6247): 1261669). VISTA interacts with the ligand VSIG-3 (Wang et al., VSIG-3 as a ligand of VISTA inhibits the function of human T cells, Immunology. January 2019;156(1):74-85)

[0261] LAG-3 (also known as the gene of Petition 870230091982, dated 10 / 17 / 2023, p. 158 / 422 151 / 378 Lymphocyte activation 3, LAG3, CD223 and lymphocyte activation 3) is a type I single-pass membrane protein of ~57.4 kDa involved in lymphocyte activation that also binds to HLA class II antigens. LAG-3 is a member of the immunoglobulin supergene family and is expressed on activated T cells (Huard et al., 1994, Immunogenetics). 39:213), NK cells (Triebel et al., 1990, J. Exp. Med. 171:1393-1405), regulatory T cells (Huang et al., 2004, Immunity 21:503-513; Camisaschi et al., 2010, J Immunol. 184:6545-6551; Gagliani et al., 2013, Nat Med 19:739-746) and plasmacytoid dendritic cells (DCs) (Workman et al., 2009, J Immunol 182:1885-1891). LAG-3 is a membrane protein encoded by a gene located on chromosome 12, and is structurally and genetically related to CD4. Similar to CD4, LAG-3 can interact with MHC class II molecules on the cell surface (Baixeras et al., 1992, J. Exp. Med. 176:327-337; Huard et al., 1996, Eur. J. Immunol. 26:1180- 1186). It has been suggested that the direct binding of LAG-3 to an MHC class II element 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 invigorate CD8+ lymphocytes in both tumor and autoantigen (Gross et al., 2007, J Clin Invest. 117:3383-3392) and viral models (Blackburn et al., 2009, Nat. Immunol. 10:29- 37) Additionally, the intraplasmic region of LAG-3 can interact with LAP (LAG-3 associated protein), which is a signal transduction molecule involved in the downregulation of the CD3 / TCR activation pathway (Iouzalen et al., 2001, Eur. J. Immunol. 31:2885-2891). Furthermore, T cells Petition 870230091982, dated 10 / 17 / 2023, p. 159 / 422 152 / 378 regulatory (Treg) CD4+CD25+ cells have been shown to express LAG-3 after activation, which contributes to the suppressive activity of Treg cells (Huang, C. et al., 2004, Immunity 21:503-513). LAG-3 can 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).

[0262] 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. September 1995;25(9):2718-21).

[0263] Additionally, several kinases are known to be checkpoint inhibitors. For example, CHEK-1, CHEK-2, and A2aR.

[0264] CHEK-1 (also known as CHK 1 kinase, CHK1 and checkpoint kinase 1) is a ~54.4-kDa serine / threonine protein kinase that is involved in checkpoint-mediated cycle arrest and in the activation of DNA repair in response to DNA damage and / or unreplicated DNA.

[0265] 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 cycle arrest, DNA repair activation and double-strand break-mediated apoptosis.

[0266] A2aR (also known as adenosine A2A receptor, ADORA2A, adenosine A2a receptor, A2aR, ADORA2 and Petition 870230091982, dated 10 / 17 / 2023, p. 160 / 422 153 / 378 RDC8 is a ~44.7-kDa multipass membrane receptor for adenosine and other ligands.

[0267] In several embodiments, the immunotherapeutic agent may comprise an antibody or an antigen-binding fragment thereof. In this definition, immune checkpoint inhibitors include bispecific antibodies and multivalent antibody / fusion protein / construct that envelops immune cells known in the art. In some embodiments, immunotherapeutic agents comprising bispecific antibodies may include bispecific antibodies that are bivalent and bind to the same epitope of the immune checkpoint molecule, to two different epitopes of the same immune checkpoint molecule, or to different epitopes of two different immune checkpoints.

[0268] Persons of ordinary skill in the art may implement various bispecific antibody formats known in the field to target one or more of CTLA4, PD1, PD-L1 TIM-3, LAG-3, various B-7 ligands, B7H3, B7H4, CHK1 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 combination described in this document.

[0269] In several modalities, the immunotherapeutic agent may include a multivalent antibody / fusion protein / construct involving immune cells.

[0270] In one embodiment of the disclosure, the checkpoint inhibitor in combination with a compound of formula I' is used to reduce or inhibit metastasis of a tumor or Petition 870230091982, dated 10 / 17 / 2023, p. 161 / 422 154 / 378 primary cancer to other sites, or the formation or establishment of metastatic tumors or cancers in other sites distal to the primary tumor or cancer, thereby inhibiting or reducing tumor or cancer relapse or tumor or cancer progression.

[0271] In a further embodiment of the disclosure, a combination therapy is provided to treat cancer comprising a compound of formula I' and checkpoint inhibitor blockers with the potential to elicit potent and durable immune responses with enhanced therapeutic benefit and more manageable toxicity.

[0272] In a further embodiment of the disclosure, a combination therapy is provided for treating cancer comprising a compound of formula I' and an immune checkpoint inhibitor. In another embodiment of the disclosure, a method is provided for treating cancer and / or preventing the establishment of metastases by employing a checkpoint inhibitor that acts synergistically with a compound of formula I'.

[0273] In additional embodiments, methods of disclosure include one or more of the following: 1) reducing or inhibiting the growth, proliferation, mobility, or invasiveness of tumor or cancer cells that potentially undergo or develop metastases; 2) reducing or inhibiting the formation or establishment of metastases originating from a primary tumor or cancer to one or more other sites, locations, or regions distinct from the primary tumor or cancer; 3) reducing or inhibiting the growth or proliferation of a metastasis to one or more other sites, locations, or regions from the primary tumor or cancer after a metastasis has formed or been established. Petition 870230091982, dated 10 / 17 / 2023, page 162 / 422 155 / 378 established, 4) reduce or inhibit the formation or establishment of additional metastasis after metastasis has formed or become established, 5) prolonged overall survival, 6) prolonged progression-free survival, or 7) disease stabilization.

[0274] In one embodiment of the disclosure, administration of the immunotherapeutic agent in combination therapy with a compound of formula I' provides a detectable or measurable improvement in a given individual's condition, such as relieving or enhancing one or more adverse (physical) symptoms or consequences associated with the presence of a cellular proliferative or hyperproliferative disorder, neoplasm, tumor or cancer or metastasis, that is, a therapeutic benefit or a beneficial effect.

[0275] A therapeutic benefit or beneficial effect consists of any objective or subjective improvement, transient, temporary or long-term, in the condition or pathology, or a reduction in the onset, severity, duration or frequency of an adverse symptom associated with or caused by cell proliferation or a hyperproliferative cellular disorder, such as neoplasia, tumor or cancer or metastasis. This may lead to improved survival. A satisfactory clinical outcome of a treatment method according to the disclosure is achieved, for example, when there is an incremental or partial reduction in the severity, duration or frequency of one or more associated pathologies, symptoms or adverse complications, or inhibition or reversal of one or more of the physiological, biochemical or cellular manifestations or characteristics of cell proliferation or a Petition 870230091982, dated 10 / 17 / 2023, page 163 / 422 156 / 378 hyperproliferative cellular disorder, such as neoplasm, tumor or cancer or metastasis. Therefore, a therapeutic benefit or enhancement may be, but is not limited to, the destruction of target proliferating cells (e.g., neoplasm, tumor or cancer or metastasis) or ablation of one or more, most or all of the pathologies, symptoms or adverse complications associated with or caused by cell proliferation or by the hyperproliferative cellular disorder, such as neoplasm, tumor or cancer or metastasis. However, a therapeutic benefit or enhancement need not be a cure or complete destruction of all target proliferating cells (e.g., neoplasm, tumor or cancer or metastasis) or ablation of all pathologies, symptoms or adverse complications associated with or caused by cell proliferation or by the hyperproliferative cellular disorder, such as neoplasm, tumor or cancer or metastasis.For example, the partial destruction of a tumor or cancerous cell mass, or a stabilization of the tumor or cancerous mass, size, or number of cells by inhibiting tumor or cancer progression or worsening, can reduce mortality and prolong lifespan, even if only by a few days, weeks, or months, despite a portion or volume of the tumor or cancerous mass, size, or cells remaining.

[0276] Specific non-limiting examples of therapeutic benefit include a reduction in neoplasia, tumor or cancer or metastasis volume (cell size or mass) or cell numbers, inhibiting or preventing an increase in neoplasia, tumor volume or cancer (e.g., stabilization), delaying or inhibiting neoplasia, tumor or cancer progression, worsening or metastasis, or Petition 870230091982, dated 10 / 17 / 2023, page 164 / 422 157 / 378 inhibition of neoplasia, tumor proliferation or cancer, growth or metastasis.

[0277] In one embodiment of the disclosure, administration of the immunotherapeutic agent in combination therapy with a compound of formula I' provides a detectable or measurable improvement or overall response according to irCR (as derived from time-point and tumor burden-based response assessments) including one or more of the following: (i) complete irCR disappearance of all lesions, whether measurable or not, and no new lesions (confirmed by a repeat, consecutive assessment no less than 4 weeks from the first documented date), (ii) irPR decrease in tumor burden by .50% relative to baseline (confirmed by a consecutive assessment at least 4 weeks after the first documentation).

[0278] Optionally, any method described in this document may not have an immediate effect. For example, treatment may be followed by an increase in neoplasia, mass, or number of tumor or cancerous cells, but, over time, stabilization or eventual reduction in the mass, size, or number of tumor cells may subsequently occur in a given individual.

[0279] Adverse symptoms and additional complications associated with neoplasia, tumor, cancer, and metastasis that can be inhibited, reduced, diminished, delayed, or prevented include, for example, nausea, loss of appetite, lethargy, pain, and discomfort. Thus, a decrease or partial or complete reduction in the severity, duration, or frequency of an adverse symptom or complication associated with or caused by a disorder. Petition 870230091982, dated 10 / 17 / 2023, page 165 / 422 158 / 378 hyperproliferative cells, an improvement in the quality of life and / or well-being of individuals, such as increased energy, appetite, psychological well-being, are all non-limiting examples of specific therapeutic benefits.

[0280] Therefore, a therapeutic benefit or enhancement may also include a subjective improvement in the quality of life of a treated individual. In the additional modality, a method prolongs or extends the useful life (survival) of the individual. In an additional modality, a method improves the quality of life of the individual.

[0281] In one embodiment, administration of the 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 others depending on the tumor, (vii) nutritional status (weight, appetite, serum albumin), (viii) pain control or analgesic use, (ix) CRP / albumin ratio.

[0282] Treatment with a compound of formula I' in combination therapy with an immunotherapeutic agent generates more complex immunity, including not only the development of innate immunity and type 1 immunity, but also immunoregulation that more efficiently restores appropriate immune functions. Petition 870230091982, dated 10 / 17 / 2023, page 166 / 422 159 / 378

[0283] In several exemplary methods, a checkpoint inhibitor antibody (monoclonal or polyclonal, bispecific, trispecific, or a multivalent antibody / fusion protein / construct involving immune cells) directed against a checkpoint molecule of interest (e.g., PD-1) can be sequenced, and then the polynucleotide sequence can be cloned into a vector for expression or propagation. The sequence encoding the antibody or antigen-binding fragment of interest can be retained in the vector in a host cell, and then the host cell can be expanded and frozen for future use. Production of recombinant monoclonal antibodies in cell culture can be performed 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; US Patent No. 7,314,622.

[0284] In some embodiments, the methods for producing recombinant antibodies may include the steps of culturing a host cell containing isolated nucleic acid (or acids) encoding the antibodies of the present disclosure. Methods for culturing a host cell containing isolated nucleic acid (or acids) encoding the antibodies of the present disclosure can be done in a variety of ways depending on the nature of the antibody. In some embodiments, in the case where the antibodies of the disclosure are traditional full-length antibodies, for example, a variable heavy chain region and a variable light chain region under conditions such that an antibody is produced and can be isolated. Petition 870230091982, dated 10 / 17 / 2023, page 167 / 422 160 / 378

[0285] In general, nucleic acids encoding antibodies or antigen-binding fragments are provided as described in this disclosure. Such polynucleotides encode both variable and constant strands of each of the heavy and light chains, although other combinations are also contemplated in this disclosure. This disclosure also includes oligonucleotide fragments derived from the polynucleotide sequences and nucleic acids complementary to these polynucleotides.

[0286] 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 the coding (sense) strand or the non-coding (antisense) strand. The coding sequence that codes for the polypeptide can be identical to the coding sequence or it can be a different coding sequence, which, as a result of redundancy or degeneracy of the genetic code, codes for the same polypeptides.

[0287] In some embodiments, nucleic acid (or acids) encoding the antibodies of the present disclosure is incorporated into expression vectors that may be extrachromosomal or designed to integrate into the genome of the host cell into which it is introduced. The expression vectors may contain any number of appropriate regulatory sequences (including, but not limited to, transcriptional and translational control sequences, promoters, ribosomal binding sites, enhancers, origins of replication and the like) or Petition 870230091982, dated 10 / 17 / 2023, page 168 / 422 161 / 378 other components (selection genes and the like), all of which are operatively linked as is known in the art. In some cases, two nucleic acids are used and each is placed in a different expression vector (e.g., heavy chain in a first expression vector, light chain in a second expression vector), or alternatively, they are placed in the same expression vector. It will be observed by those skilled in the art that the design of the expression vector (or vectors), including the selection of regulatory sequences, may depend on factors such as the choice of host cell, the desired level of protein expression, and the like.

[0288] In general, nucleic acids and / or expression can be introduced into a suitable host cell to create a recombinant host cell using any method appropriate for the selected host cell (e.g., transformation, transfection, electroporation, infection), such that the nucleic acid molecule (or molecules) is operatively linked to one or more expression control elements (e.g., in a vector, in a construct created by processes in the cell, integrated into the host cell genome). The recombinant host cell can be maintained under suitable conditions for expression (e.g., in the presence of an inducer, in a suitable non-human animal, in suitable culture media supplemented with appropriate salts, growth factors, antibiotics, nutritional supplements and the like), whereby the encoded polypeptide (or polypeptides) is produced.In some cases, heavy chains are produced in one cell and light chains in another cell. Petition 870230091982, dated 10 / 17 / 2023, page 169 / 422 162 / 378

[0289] Mammalian cell lines available as hosts for expression are known in the art and include many immortalized cell lines available to the American Type Culture Collection (ATCC), Manassas, VA, USA, including, but not limited to, Chinese hamster ovary (CHO) cells, HEK 293 cells, NSO cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney (COS) cells, human hepatocellular carcinoma cells (e.g., Hep G2), and a number of other cell lines. Non-mammalian cells, including but not limited to bacteria, yeast, insects, and plants, can also be used to express recombinant antibodies. In some embodiments, antibodies can be produced in transgenic animals, such as cows or chickens.

[0290] Exemplary and illustrative methods for molecular biology, expression, purification and screening of antibodies are described, for example, in Antibody Engineering, edited by Kontermann & Dubel, Springer, Heidelberg, 2001 and 2010; Hayhurst & Georgiou, 2001, Curr. Opin. Chem. Biol. 5:683-689; Maynard & Georgiou, 2000, Annu. Rev. Biomed. Eng. 2:339-76; and Morrison, S. (1985) Science 229:1202, whose publications are incorporated in their entirety by reference in this document.

[0291] In several embodiments, the polynucleotide sequence encoding the selected variable heavy chain and light chains can be used for genetic manipulation to humanize the antibody or enhance the antibody's affinity or other characteristics. Antibodies can also be customized for use in, for example, dogs, Petition 870230091982, dated 10 / 17 / 2023, p. 170 / 422 163 / 378 cats, primates, horses and cattle.

[0292] In some embodiments, fully human antibodies can be obtained by using commercially available mice that have been engineered to express specific human immunoglobulin proteins. Transgenic animals that are engineered to produce a more desirable (e.g., fully human antibodies) or more robust immune response can also be used for the generation of humanized or human antibodies. Examples of such technology are Xenomouse™ from Abgenix, Inc. (Fremont, Calif.) and HuMAb-Mouse® and TC Mouse™ from Medarex, Inc. (Princeton, NJ).

[0293] The immune checkpoint modulator antibodies of this disclosure can be recombinantly produced by first isolating the antibodies and antibody-producing cells from host animals, 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 employed is to express the antibody sequence in plants (e.g., tobacco) or in yeast cells (e.g., Pichia pastoris or Saccharomyces cerevisiae). Methods for recombinantly expressing antibodies in plants or yeast have been disclosed. See, for example, Peeters, et al. Vaccine 19:2756, 2001; Lonberg, N. and D. Huszar Int. Rev. Immunol 13:65, 1995; and Horwitz, AH et al., Proc. Natl. Acad. Sci. 85:8678-8682; whose publications are incorporated in their entirety by reference herein. Methods for manufacturing antibody derivatives, for example, domain, Petition 870230091982, dated 10 / 17 / 2023, page 171 / 422 164 / 378 single chain and similar are known in the art.

[0294] Immunoassays and flow cytometry sorting techniques, such as fluorescence-activated cell sorting (FACS), can be used to isolate antibodies that are specific for checkpoint molecules.

[0295] In some embodiments, a polynucleotide comprises a sequence encoding the heavy chain and / or light chain regions of the checkpoint inhibitor antibody or antigen-binding fragment thereof of the present disclosure. The sequence encoding the antibody or antigen-binding fragment thereof of interest may be maintained in the vector in a host cell, and then the host cell may be expanded and frozen for future use. Vectors (including expression vectors) and host cells are further described herein.

[0296] The disclosure includes affinity-matured checkpoint modulator antibodies. For example, affinity-matured antibodies can be produced by procedures known in the art (Marks et al., 1992, Bio / Technology, 10:779-783; Barbas et al., 1994, Proc Nat. Acad. Sci. USA 91:3809-3813, One way to characterize an antibody CDR and / or alter (such as enhance) the binding affinity of a polypeptide, such as an antibody, is termed “library scanning mutagenesis.” An exemplary method for providing affinity-maturing antibodies and antigen-binding fragments may include replacing one or more amino acid positions in the CDR with two or more (such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, Petition 870230091982, dated 10 / 17 / 2023, page 172 / 422 165 / 378 17, 18, 19, or 20) amino acids are selected using methods recognized in the art. A library of clones is generated, each with a complexity of two or more members (if two or more amino acids are substituted at each position). In general, the library also includes a clone comprising the native (unsubstituted) amino acid. A small number of clones, for example, about 20-80 clones (depending on the library complexity) from each library are screened for binding affinity with the target polypeptide (or with another binding target), and candidates with increased binding, the same binding, decreased binding, or no binding are identified. Methods for determining binding affinity are well known in the art.Binding affinity can be determined using, for example, Biacore™ surface plasmon resonance analysis which detects differences in binding affinity of approximately 2-fold or greater, Kinexa® Biosensor, scintillation proximity assays, ELISA, ORIGEN® immunoassay, fluorescence quenching, fluorescence transfer, and / or yeast display. Binding affinity can also be screened using a suitable bioassay. Biacore™ is particularly useful when the initial antibody already binds to a relatively high-affinity element, for example, a KD of approximately 10 nM or less. Then, the clone library can be recombinantly introduced into a selection construct using any method known in the art for selection, including phage display, yeast display, and ribosome display.

[0297] Antibodies can also be modified, for example, in the variable domains of the heavy and / or light chains, for example, to alter a binding property. Petition 870230091982, dated 10 / 17 / 2023, p. 173 / 422 166 / 378 of the antibody. Changes in the variable region can alter the binding affinity and / or specificity. In some embodiments, no more than one to five conservative amino acid substitutions are made in a CDR domain. In other embodiments, no more than one to three conservative amino acid substitutions are made in a CDR domain. For example, a mutation can be made in one or more of the CDR regions to increase or decrease the KD of the antibody directed to a checkpoint molecule, to increase or decrease kon, or to alter the binding specificity of the antibody. Techniques in site-directed mutagenesis are well known in the art. See, for example, Sambrook et al. and Ausubel et al.

[0298] Pharmaceutical compositions containing a compound of formula I' according to this disclosure shall comprise an effective amount of a compound of formula I', an immunotherapeutic agent and / or both, typically dispersed in a pharmaceutically acceptable carrier. The expressions “pharmaceutically acceptable” or “pharmaceutically acceptable” refer to entities and molecular compositions that do not produce an adverse, allergic or other undesirable reaction when administered to an animal, such as, for example, a human being, where appropriate. The preparation of a pharmaceutical composition containing a compound of formula I' shall be known to those skilled in the art in light of this disclosure, as exemplified by Remington's Pharmaceutical Sciences, 18th Edition, Mack Printing Company, 1990. Furthermore, for animal (e.g., human) administration, it shall be understood that the preparations must meet the standards of sterility, prionogenicity, and general safety. Petition 870230091982, dated 10 / 17 / 2023, page 174 / 422 167 / 378 and purity. A specific example of a pharmacologically acceptable carrier for combination compositions containing a compound of formula I' in the addition mixture with an immunotherapeutic agent as described herein is borate buffer or sterile saline solution (0.9% NaCl).

[0299] Formulations of an immunotherapeutic agent, for example, an immune checkpoint modulator antibody used in accordance with this disclosure, may be prepared for storage by mixing an antibody having the desired degree of purity with optionally pharmaceutically acceptable carriers, excipients or stabilizers as described and illustrated extensively in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Edition

[1980] , in the form of lyophilized formulations or aqueous solutions and / or suspensions.Acceptable carriers, excipients, buffers, or stabilizers are non-toxic to containers at the dosages and concentrations employed, and include suitable aqueous and / or non-aqueous excipients that can be used in the pharmaceutical compositions of the disclosure, for example, water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Appropriate flowability can be maintained, for example, by the use of coating materials, such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants, buffers, such as phosphate, citrate and other organic acids. Antioxidants. Petition 870230091982, dated 10 / 17 / 2023, page 175 / 422 168 / 378 may include, for example, (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol and the like; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than 10 residues).Other pharmaceutically acceptable excipients may include polypeptides; proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose or dextrins; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., protein and Zn complexes); and / or nonionic surfactants, such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG).

[0300] By way of illustration, pharmaceutical compositions may optionally contain pharmaceutically acceptable auxiliary substances as required. Petition 870230091982, dated 10 / 17 / 2023, page 176 / 422 169 / 378 to approximate physiological conditions, such as pH adjustment and buffering agents and toxicity adjustment agents, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride and sodium lactate. In some embodiments, the checkpoint inhibitor antibodies or antigen-binding fragments thereof of this disclosure are formulated and can be lyophilized for storage and reconstituted in a suitable excipient before use in accordance with lyophilization and reconstitution techniques known in the art. In an exemplary pharmaceutical composition containing one or more checkpoint inhibitor antibodies or antigen-binding fragments thereof, the composition is formulated as a preservative-free and sterile solution of one or more checkpoint inhibitor antibodies or antigen-binding fragments thereof for intravenous or subcutaneous administration.The formulation may be supplied as a pre-filled single-use pen, such as a single-use, for example, containing a pre-filled glass syringe of about 1 ml, or as a single-use institutional vial. Preferably, the pharmaceutical composition containing the checkpoint inhibitor antibody or antigen-binding fragment thereof is clear and colorless, with a pH of about 6.9-5.0, preferably a pH of 6.5-5.0, and even more preferably a pH ranging from about 6.0 to about 5.0. In various embodiments, the formulations comprising the pharmaceutical compositions may contain from about 500 mg to about 10 mg, or from about 400 mg to about 20 mg, or from about 300 mg to about 30 mg, or from about 200 mg to about 50 mg. Petition 870230091982, dated 10 / 17 / 2023, p. 177 / 422 170 / 378 of the checkpoint inhibitor antibody or antigen-binding fragment thereof per ml of solution when reconstituted and administered to the individual. Exemplary infusion or injection excipients may include mannitol, citric acid monohydrate, dibasic sodium phosphate dihydrate, monobasic sodium phosphate dihydrate, polysorbate 80, sodium chloride, sodium citrate, and water for parenteral administration, for example, intravenous, intramuscular, intraperitoneal, or subcutaneous administration.

[0301] In another exemplary embodiment, one or more immunotherapeutic agents or an antigen-binding fragment thereof are formulated for intravenous or subcutaneous administration as a sterile aqueous solution containing 1-75 mg / ml, or, more preferably, about 560 mg / ml, or, even more preferably, about 10-50 mg / ml, or, most preferably, about 10-40 mg / ml of antibody with sodium acetate, polysorbate 80 and sodium chloride at a pH ranging from about 5 to 6. Preferably, the intravenous or subcutaneous formulation is a sterile aqueous solution containing 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 mg / ml of the immunotherapeutic agent, for example, an immune checkpoint inhibitor antibody or an antigen-binding fragment thereof with sodium acetate at 20 mM, polysorbate 80 at 0.2 mg / ml and sodium chloride at 140 mM at pH 5.5.Additionally, a solution comprising a checkpoint inhibitor antibody or an antigen-binding fragment thereof may comprise, among many other compounds, histidine, mannitol, sucrose, trehalose, glycine, poly(ethylene) glycol, EDTA, methionine, and any combination thereof, and many other compounds. Petition 870230091982, dated 10 / 17 / 2023, page 178 / 422 171 / 378 known in the relevant art.

[0302] In one embodiment, a pharmaceutical composition of the present disclosure comprises the following components: 5-500 mg of an immunotherapeutic agent or antigen-binding fragment thereof of the present disclosure, 10 mM histidine, 5% sucrose and 0.01% polysorbate 80 at pH 5.8 with or without a compound of formula I'. This composition may be supplied as a lyophilized powder. When the powder is reconstituted to full volume, the composition retains the same formulation. Alternatively, the powder may be reconstituted to half volume, in which case the composition comprises 10-500 mg of an immunotherapeutic agent or antigen-binding fragment thereof of the present disclosure, 20 mM histidine, 10% sucrose and 0.02% polysorbate 80 at pH 5.8.

[0303] In one embodiment, part of the dose is administered by an intravenous bolus and the remainder by infusion of the immunotherapeutic agent formulation. For example, from about 0.001 to about 200 mg / kg, for example, from about 0.001 mg / kg to about 100 mg / kg, or from about 0.001 mg / kg to about 50 mg / kg, or from about 0.001 mg / kg to about 10 mg / kg of intravenous injection of the immunotherapeutic agent or antigen-binding fragment thereof may be given as a bolus, and the remainder of the antibody dose may be administered by intravenous injection. A predetermined dose of immunotherapeutic agent or antigen-binding fragment thereof may be administered, for example, over a period of one to two to five hours.

[0304] In an additional embodiment, part of the dose is administered by subcutaneous injection and / or infusion in the form Petition 870230091982, dated 10 / 17 / 2023, p. 179 / 422 172 / 378 of a bolus and the remainder by infusion of the immunotherapeutic agent formulation. In some exemplary doses, the immunotherapeutic agent formulation may be administered subcutaneously in a dose ranging from about 0.001 to about 200 mg / kg, for example, from about 0.001 mg / kg to about 100 mg / kg, or from about 0.001 mg / kg to about 50 mg / kg, or from about 0.001 mg / kg to about 10 mg / kg by intravenous injection of the immunotherapeutic agent or antigen-binding fragment thereof. In some embodiments, the dose may be given as a bolus, and the remainder of the immunotherapeutic agent dose may be administered by subcutaneous or intravenous injection. A predetermined dose of immunotherapeutic agent or antigen-binding fragment thereof may be administered, for example, over a period of one to two to five hours.

[0305] The formulation in this document may also contain more than one active compound as needed for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. For example, it may be desirable to provide one or more immunotherapeutic agents with other specificities. Alternatively or in addition, the composition may comprise an anti-inflammatory agent, a chemotherapeutic agent, a cytotoxic agent, a cytokine, a growth inhibitor and / or a small molecule antagonist. Such molecules are suitably present in combination in amounts that are effective for the intended purpose.

[0306] Formulations to be used for in vivo administration must be sterile or nearly sterile. That is Petition 870230091982, dated 10 / 17 / 2023, page 180 / 422 173 / 378 readily performed by filtration through sterile filtration membranes.

[0307] In various embodiments, the illustrative formulations of the pharmaceutical compositions described in this document can be prepared using methods widely known in the field of pharmaceutical formulations. In general, such preparatory methods may include the step of combining the active ingredient with a carrier or one or more other accessory ingredients, and then, if desired, packaging the product into a single-dose or multi-dose unit.

[0308] In some embodiments, the composition comprising a compound of formula I' may also be delivered in a vesicle, and the immunotherapeutic agent may be delivered in the same liposomal formulation, or in a separate formulation that is compatible with the liposomal formulation containing the compound of formula I'. In some illustrative examples, a liposome containing one or more liposomal surface fractions, for example, polyethylene glycol, antibodies and antibody fragments thereof targeting a desired tumor surface antigen, receptor, growth factor, glycoprotein, glycolipid or neoantigen that are selectively transported into specific cells or organs, thereby enhancing the delivery of the targeted drug.

[0309] In another embodiment, a compound of formula I' can be delivered into a vesicle, in particular, a liposome (see Langer, Science 249:1527-1533 (1990); Treat et al., in LIPOSOMES IN THERAPY OF INFECTIOUS DISEASE AND CANCER, Lopez-Berestein and Fidler (eds.), Liss, Petition 870230091982, dated 10 / 17 / 2023, p. 181 / 422 174 / 378 NY, pages 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid.).

[0310] In yet another embodiment, a compound of formula I' or the co-composition containing the combination or a composition containing the immunotherapeutic agent may be delivered in 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, controlled release of the compound of formula I' may comprise polymeric materials to provide sustained, intermediate, pulsatile or alternating release (see MEDICAL APPLICATIONS OF CONTROLLED RELEASE, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); CONTROLLED DRUG BIOAVAILABILITY, DRUG PRODUCT DESIGN AND PERFORMANCE, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); see Levy et al., Science 228:190 (1985); During et al., Ann. Neurol. 25:351(1989); Howard et al., J. Neurosurg. 71:105 (1989)). Other controlled-release systems discussed in the review by Langer (Science 249:1527-1533 (1990)) may be used.

[0311] The ideal concentration of the active ingredient (or ingredients) in the chosen medium can be determined empirically according to procedures well known to a person skilled in the art, and will depend on the desired final pharmaceutical formulation and the use to be employed.

[0312] This disclosure also provides a pharmaceutical package or kit comprising one or more Petition 870230091982, dated 10 / 17 / 2023, page 182 / 422 175 / 378 containers filled with one or more of the ingredients of the pharmaceutical compositions of the disclosure, which will at least include a compound of formula I' and one or more checkpoint inhibitor antibodies or antigen-binding fragments thereof as described in this document. In other embodiments, the kit may contain one or more additional containers providing a pharmaceutically acceptable excipient, for example, a diluent. In one embodiment, a kit may comprise at least one container, wherein the container may include a compound of formula I', a checkpoint inhibitor antibody or an antigen-binding fragment thereof of the present disclosure. The kit may include a set of instructions for preparing and administering the final pharmaceutical composition to the individual in need thereof, for the treatment of a checkpoint molecule-mediated disease or disorder.

[0313] In some embodiments of the present disclosure, the immunotherapeutic agent is a population of immune cells that can be administered in combination with a compound of formula I' to treat an individual with cancer. In some embodiments, the immunotherapeutic agent is a population of immune cells, such as leukocytes (nucleated white blood cells) comprising (for example, expressing) a receptor that binds to an antigen of interest. A leukocyte of the present disclosure may be, for example, a neutrophil, an eosinophil, a basophil, a lymphocyte, or a monocyte. In some embodiments, a leukocyte is a lymphocyte. Examples of lymphocytes include T cells, B cells, Natural Killer (NK) cells, or NK T cells. In some Petition 870230091982, dated 10 / 17 / 2023, page 183 / 422 In 176 / 378 modalities, a T cell is a CD4+ Th (helper T) cell, a CD8+ cytotoxic T cell, a γδT cell, or a regulatory (suppressor) T cell. In some modalities, an immune cell is a dendritic cell.

[0314] In some embodiments, the immune cells of the present disclosure are genetically engineered to express an antigen-binding receptor. A cell is considered engineered if it contains an engineered (exogenous) nucleic acid. The engineered nucleic acids of the present disclosure may be introduced into a cell by any known method (e.g., conventional). For example, an engineered nucleic acid may be introduced into a cell by electroporation (see, for example, Heiser WC Transcription Factor Protocols: Methods in Molecular Biology.TM. 2000; 130: 117-134), by chemical substance (e.g., calcium phosphate or lipid), by transfection (see, for example, Lewis WH, et al., Somatic Cell Genet. May 1980; 6(3): 333-47; Chen C., et al., Mol Cell Biol. August 1987; 7(8): 2745-2752), by fusion with bacterial protoplasts containing recombinant plasmids (see, for example, Schaffner W. Proc Natl Acad Sci USA. April 1980; 77(4): 2163-7), by direct microinjection of DNA purified in the cell nucleus (see, for example, Capecchi MR Cell. November 1980; 22(2 Pt 2): 479-88) or by transduction from retroviruses.

[0315] Some aspects of the present disclosure provide an adoptive cell approach that involves isolating immune cells (e.g., T cells) from an individual with cancer, genetically manipulating the immune cells (e.g., to express an antigen-binding receptor, Petition 870230091982, dated 10 / 17 / 2023, page 184 / 422 177 / 378 such as a chimeric antigen receptor), expanding the cells ex vivo, and then reintroducing the immune cells into the individual. This method results in a greater number of manipulated immune cells in the individual compared to what could be achieved by conventional delivery and vaccination methods. In some embodiments, immune cells are isolated from an individual, expanded ex vivo without genetic modification, and then reintroduced into the individual.

[0316] The immune cells of this disclosure comprise receptors that bind to antigens, such as an antigen encoded by an exogenously delivered nucleic acid as provided herein. In some embodiments, a leukocyte is modified (e.g., genetically modified) to express a receptor that binds to an antigen. In some embodiments, the receptor may be a naturally occurring antigen receptor (normally expressed on the immune cell), a recombinant antigen receptor (normally not expressed on the immune cell), or a chimeric antigen receptor (CAR). The naturally occurring and recombinant antigen receptors covered by this disclosure include T cell receptors, B cell receptors, NK cell receptors, NKT cell receptors, and dendritic cell receptors.A “chimeric antigen receptor” refers to an artificial immune cell receptor that is engineered to recognize and bind to an antigen expressed by tumor cells. Generally, a CAR is designed for a T cell and is a chimera of a T cell receptor complex (TcR) signaling domain and an antigen recognition domain (e.g., a single-chain fragment (scFv) of a T cell). Petition 870230091982, dated 10 / 17 / 2023, p. 185 / 422 178 / 378 antibody) (Enblad et al., Human Gene Therapy. 2015; 26(8):498-505), the disclosure of which is incorporated in its entirety by way of reference in this document.

[0317] In some embodiments, an antigen-binding receptor is a chimeric antigen receptor (CAR). A T cell that has expressed a CAR is termed a CAR T cell. In some embodiments, a CAR T cell receptor comprises a T cell receptor complex (TcR) signaling domain and an antigen recognition domain (e.g., a single-chain fragment (scFv) of an antibody) (Enblad et al., Human Gene Therapy. 2015; 26(8):498-505) whose disclosure is incorporated herein by reference in its entirety.

[0318] There are four generations of CARs, each containing different components. First-generation CARs link an antibody-derived scFv to the intracellular signaling domain of CD3zeta (zeta. or z) of the T-cell receptor via hinge and transmembrane domains. Second-generation CARs incorporate an additional domain, for example, CD28, 4-1BB (41BB), or ICOS, to supply a co-stimulatory signal. Third-generation CARs contain two co-stimulatory domains fused to the CD3zeta chain of TcR. Third-generation co-stimulatory domains may include, for example, a combination of CD3z, CD27, CD28, 4-1BB, ICOS, or OX40. In some forms, CARs contain an ectodomain (e.g., CD3), commonly derived from a single-stranded variable fragment (scFv), a hinge, a transmembrane domain, and an ectodomain with a signaling domain (first generation), two domains Petition 870230091982, dated 10 / 17 / 2023, page 186 / 422 179 / 378 signaling (second generation) or three signaling domains (third generation) derived from CD3Z and / or co-stimulatory molecules (Maude et al., Blood. 2015; 125(26):4017-4023; Kakarla and Gottschalk, Cancer J. 2014; 20(2):151-155), the disclosure of which is incorporated in its entirety by reference herein.

[0319] In some embodiments, the chimeric antigen receptor (CAR) is a universal cytokine scavenging T cell (TRUCK), also known as a fourth-generation CAR. TRUCKs are CAR-directed T cells used as vehicles to produce and release a transgenic cytokine that accumulates in the targeted tissue, for example, a targeted tumor tissue. The transgenic cytokine is released after CAR engagement of the target. TRUCK cells can deposit a variety of therapeutic cytokines in the target. This can result in therapeutic concentrations at the targeted site and avoids systemic toxicity.

[0320] CARs typically differ in their functional properties. The CD3zeta signaling domain of the T-cell receptor, when involved, will activate and induce T-cell proliferation, but may lead to anergy (a lack of reaction by the body's defense mechanisms, resulting in the direct induction of peripheral lymphocyte tolerance). Lymphocytes are considered anergic when they do not respond to a specific antigen. The addition of a co-stimulatory domain in second-generation CARs has enhanced the replicative capacity and persistence of modified T cells. Similar antitumor effects are observed in vitro with CD28 or 4-1BB CARs, but pre-in vivo studies Petition 870230091982, dated 10 / 17 / 2023, page 187 / 422 180 / 378 clinical studies suggest that 4-1BB CARs may produce superior proliferation and / or persistence. Clinical trials suggest that both of these second-generation CARs are capable of inducing substantial T cell proliferation in vivo, but CARs containing the 4-1BB co-stimulatory domain appear to persist longer. Third-generation CARs combine multiple signaling (co-stimulatory) domains to increase potency. Fourth-generation CARs are further modified with a constitutive or inducible expression cassette for a transgenic cytokine that is released by CAR T cells to modulate the T cell response. See, for example, Enblad et al., Human Gene Therapy. 2015; 26(8):498-505; Chmielewski and Hinrich, Expert Opinion on Biological Therapy. 2015; 15(8): 1145-1154, whose disclosures are incorporated in their entirety by reference herein.

[0321] In some embodiments, an illustrative immunotherapeutic agent is a first-generation chimeric antigen receptor (CAR). In some embodiments, a chimeric antigen receptor is a third-generation CAR. In some embodiments, a chimeric antigen receptor is a second-generation CAR. In some embodiments, a chimeric antigen receptor is a third-generation CAR. In some embodiments, the chimeric antigen receptor is a fourth-generation CAR or a universal cytokine scavenging redirected T cell (TRUCK).

[0322] In some embodiments, a chimeric antigen receptor (CAR) comprises an extracellular domain comprising an antigen-binding domain, a transmembrane domain, and a cytoplasmic domain. In some Petition 870230091982, dated 10 / 17 / 2023, page 188 / 422 In 181 / 378 embodiments, a CAR is completely human. In some embodiments, the antigen-binding domain of a CAR is specific for one or more antigens. In some embodiments, a spacer domain or hinge domain is located between an extracellular domain (comprising the antigen-binding domain) and a transmembrane domain of a CAR, or between a cytoplasmic domain and a transmembrane domain of the CAR. A spacer domain refers to any glycopeptide or polypeptide that functions to link the transmembrane domain to the extracellular domain and / or the cytoplasmic domain in the polypeptide chain. A hinge domain refers to any glycopeptide or polypeptide that functions to provide flexibility to the CAR or domains thereof, or to prevent hysterical hindrance of the CAR or domains thereof.In some embodiments, a spacer domain or hinge domain may comprise up to 300 amino acids (e.g., 10 to 100 amino acids or 5 to 20 amino acids). In some embodiments, one or more spacer domains may be included in other regions of a CAR.

[0323] In some embodiments, a disclosure CAR comprises an antigen-binding domain, such as a single-chain Fv (scFv) specific for a tumor antigen. The choice of binding domain depends on the type and number of ligands that define the surface of a target cell. For example, the antigen-binding domain may be chosen to recognize a ligand that acts as a cell surface marker on target cells associated with a particular disease state, such as cancer or an autoimmune disease. Thus, examples of cell surface markers that may Petition 870230091982, dated 10 / 17 / 2023, p. 189 / 422 182 / 378 act as ligands for the antigen-binding domain in the CAR of this disclosure include markers associated with cancer cells and / or other forms of diseased cells. In some embodiments, a CAR is manipulated to target a tumor antigen of interest by manipulating a desired antigen-binding domain that specifically binds to an antigen on a tumor cell encoded by a manipulated nucleic acid as provided herein.

[0324] An antigen-binding domain (e.g., an scFv) that binds specifically 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 or associates more frequently, more rapidly, with longer duration, and / or with greater affinity to a particular target antigen than to alternative targets. An antigen-binding domain (e.g., an scFv) that binds specifically to a first target antigen may or may not bind specifically to a second target antigen. As such, specific binding does not necessarily require (although it may include) exclusive binding.

[0325] In some modalities, immune cells expressing a CAR are genetically modified to recognize multiple targets or antigens, allowing for the recognition of unique target or antigen expression patterns in tumor cells. Examples of CARs that can bind to multiple targets include: split-signal CARs that limit complete immune cell activation to tumors expressing multiple antigens; tandem CARs Petition 870230091982, dated 10 / 17 / 2023, pp. 190 / 422 183 / 378 (TanCARs) containing ectodomains that have two scFvs; and “universal ectodomain CARs” that incorporate avidin or a specific fluorescein isothiocyanate (FITC) scFv to recognize tumor cells that have been incubated with identified monoclonal antibodies (Mabs).

[0326] A CAR is considered “bispecific” if it recognizes two distinct antigens (it has two distinct antigen recognition domains). In some embodiments, a bispecific CAR comprises two distinct antigen recognition domains present in tandem in a single transgenic receptor (referred to as TanCAR; see, for example, Grada Z et al. Molecular Therapy Nucleic Acids 2013; 2:e105, incorporated in its entirety by reference herein). Thus, in some embodiments, the methods comprise delivering to a tumor a combination comprising a compound of formula I' and an immunotherapeutic agent, wherein the immunotherapeutic agent is a engineered nucleic acid encoding an antigen, or delivering to a tumor an engineered nucleic acid that induces expression of a self-antigen, and delivering to the tumor an immune cell expressing a bispecific CAR that binds to two antigens, one of which is encoded by the engineered nucleic acid.

[0327] In some modalities, a CAR is an antigen-specific inhibitory CAR (iCAR) that can be used, for example, to avoid toxicity outside the tumor (Fedorov, VD et al. Sci. Transl. Med. Published online December 11, 2013, incorporated in its entirety by reference herein). iCARs contain an antigen-specific inhibitory receptor, for example, for Petition 870230091982, dated 10 / 17 / 2023, pp. 191 / 422 184 / 378 block nonspecific immunosuppression, which can result from the expression of extra tumor targets. iCARs can be based, for example, on the inhibitory molecules CTLA-4 or PD1. In some modalities, these iCARs block T cell responses of T cells activated by their endogenous T cell receptor or by an activating CAR. In some modalities, this inhibitory effect is temporary.

[0328] In some modalities, CARs can be used in adoptive cell transfer, in which immune cells are removed from an individual and modified so that they express specific receptors for an antigen, for example, a tumor-specific antigen. The modified immune cells that can then recognize and destroy cancer cells are reintroduced into the individual (Pule, et al., Cytotherapy. 2003; 5(3): 211-226; Maude et al., Blood. 2015; 125(26): 4017-4023, each of which is incorporated in its entirety by reference herein).

[0329] According to other aspects of the disclosure, the tumor antigenic component in the vaccine of the invention is any natural or synthetic tumor-associated protein or peptide, or combination of tumor-associated proteins and / or peptides, or glycoproteins or glycopeptides. In still other aspects, the antigenic component may be patient-specific or common to many or most patients with a particular type of cancer. According to one aspect, the antigenic component consists of a cell lysate derived from tumor tissue removed from the patient being treated. In another aspect, the lysate may be manipulated or synthesized from exosomes derived from Petition 870230091982, dated 10 / 17 / 2023, page 192 / 422 185 / 378 tumor tissue. In yet another aspect, the antigenic component consists of a cellular lysate derived from tumor tissue extracted from one or more unrelated individuals or from tumor cell lines.

[0330] In various embodiments, an illustrative immunotherapeutic agent comprises one or more cancer vaccines for use in combination with a compound of formula I'. The tumor-associated antigen component of the vaccine may be manufactured by any of a variety of well-known techniques. For individual protein components, the antigenic protein is isolated from tumor tissue or a tumor cell line by standard chromatography, such as high-performance liquid chromatography or affinity chromatography, or alternatively, it is synthesized by standard recombinant DNA technology in a suitable expression system, such as E. coli, yeast, or plants. Then, the tumor-associated antigenic protein is purified from the expression system by standard chromatography. In the case of peptide antigenic components, these are generally prepared by standard automated synthesis.Proteins and peptides can be modified by adding amino acids, lipids, and other agents to enhance their incorporation into the vaccine delivery system (such as a multilamellar liposome). For a tumor-associated antigenic component derived from the patient's own tumor, or from tumors of other individuals or cell lines, the tumor tissue or a single-cell suspension derived from the tumor tissue is typically homogenized in a suitable buffer. The homogenate can also be fractionated, such as by... Petition 870230091982, dated 10 / 17 / 2023, page 193 / 422 186 / 378 centrifugation, to isolate particular cellular components, such as cell membranes or soluble material. Tumor material can be used directly, or tumor-associated antigens can be extracted for incorporation into the vaccine using a buffer containing a low concentration of a suitable agent, such as a detergent. An example of a detergent suitable for extracting antigenic proteins from tumor tissue, tumor cells, and tumor cell membranes is diheptanoyl phosphatidylcholine. Exosomes derived from tumor tissue or tumor cells, whether autologous or heterologous to the patient, can be used for the antigenic component for incorporation into the vaccine or as a starting material for extraction of tumor-associated antigens.

[0331] In some embodiments of the present disclosure, a cancer vaccine, wherein the cancer vaccine includes at least one tumor-associated antigen, at least one immunostimulant, and optionally, at least one cell-based immunotherapeutic agent. In some embodiments, the immunostimulant component in the cancer vaccine of the disclosure is any Biological Response Modifier (BRM) with the ability to enhance the efficacy of the therapeutic cancer vaccine to induce humoral and cellular immune responses against cancer cells in a patient. According to one aspect, the immunostimulant is a cytokine or combination of cytokines. Examples of such cytokines include interferons, such as IFN-gamma, interleukins, such as IL-2, IL-15, and IL-23, colony-stimulating factors, such as M-CSF and GM-CSF, and tumor necrosis factor. According to another aspect, the component Petition 870230091982, dated 10 / 17 / 2023, page 194 / 422 187 / 378 The disclosed cancer vaccine immunostimulant includes one or more adjuvant-type immunostimulatory agents, such as Toll-like APC receptor agonists or co-stimulatory / cellular adhesion membrane proteins with or without immunostimulatory cytokines. Examples of Toll-like receptor agonists include lipid A and CpG and co-stimulatory / adhesion proteins such as CD80, CD86, and ICAM-1.

[0332] In some embodiments, the immunostimulant is selected from the group consisting of IFN gamma (IFN-γ), IL2, IL-15, IL-23, M-CSF, GM-CSF, tumor necrosis factor, lipid A, CpG, CD80, CD86, and ICAM-1 or combinations thereof. In other embodiments, the cell-based immunotherapeutic agent is selected from the group consisting of dendritic cells, tumor-infiltrating T lymphocytes, chimeric antigen receptor-modified effector T cells directed to the patient's B-type tumor, B lymphocytes, natural killer cells, bone marrow cells, and any other cells of a patient's immune system or combinations thereof.In one aspect, the cancer vaccine immunostimulant includes one or more cytokines, such as interleukin 2 (IL-2), GMCSF, 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 lipid conjugate (MDP) and double-stranded RNA, or one or more co-stimulatory membrane proteins and / or cell adhesion proteins, such as CD80, CD86 and ICAM-1 or any combination thereof. In one aspect, the cancer vaccine includes an immunostimulant that is a cytokine selected from the group consisting of interleukin 2 (IL-2). Petition 870230091982, dated 10 / 17 / 2023, pp. 195 / 422 188 / 378 GM-CSF, M-CSF, and interferon gamma (IFN-γ). In another aspect, the cancer vaccine includes an immunostimulant that is a Toll-like receptor agonist and / or adjuvant selected from the group consisting of monophosphoryl lipid A, lipid A, and muramyl dipeptide (MDP) lipid conjugate and double-stranded RNA. In yet another aspect, the cancer vaccine includes an immunostimulant that is a co-stimulatory membrane protein and / or cell adhesion protein selected from the group consisting of CD80, CD86, and ICAM-1.

[0333] In various embodiments, an immunotherapeutic agent may include a cancer vaccine, wherein the cancer vaccine incorporates elements that can potentially be used to construct a fusion protein according to the invention and, in particular, with the following:

[0334] (a) cancer / testicular antigens including NYESO-1, SSX2, SCP1 as well as polypeptides of the RAGE, BAGE, GAGE ​​and MAGE families, for example, GAGE-1, GAGE-2, MAGE1, MAGE-2, MAGE-3, MAGE-4, MAGE-5, MAGE-6 and MAGE-12 which can be used, for example, to cover melanoma, lung, head and neck, NSCLC, breast, gastrointestinal and bladder tumors; (b) mutated antigens including p53 associated with various solid tumors, for example, colorectal, lung, head and neck cancer; p21 / Ras associated with, for example, melanoma, pancreatic cancer and colorectal cancer; CDK4 associated with, for example, melanoma; MUM1 associated with, for example, melanoma; caspase-8 associated with, for example, head and neck cancer; CIA 0205 is associated with, for example, bladder cancer; HLA-A2-R1701, beta-catenin, is associated with, for example, melanoma; TCR is associated with, for example, lymphoma. Petition 870230091982, dated 10 / 17 / 2023, page 196 / 422 189 / 378 non-Hodgkin T cells; BCR-abl associated with, for example, chronic myelogenous leukemia; triosephosphate isomerase; KIA 0205; CDC-27 and LDLR-FUT; (c) overexpressed antigens including Galectin 4 associated with, for example, colorectal cancer; Galectin 9 associated with, for example, Hodgkin's disease; proteinase 3 associated with, for example, chronic myelogenous leukemia; WT 1 associated with, for example, various leukemias; carbonic anhydrase associated with, for example, renal cancer; aldolase A associated with, for example, lung cancer; PRAME associated with, for example, melanoma; HER2 / neu associated with, for example, breast, colon, lung and ovarian cancer; mamaglobin, alpha-fetoprotein associated with, for example, hepatoma; KSA associated with, for example, colorectal cancer; Gastrin is associated with, for example, pancreatic and gastric cancer; telomerase catalytic protein, MUC-1, is associated with, for example, breast and ovarian cancer; G-250 is associated with, for example...renal cell carcinoma; p53 associated with, for example, breast cancer, colon cancer; and carcinoembryonic antigen associated with, for example, breast cancer, lung cancer and cancers of the gastrointestinal tract, such as colorectal cancer; (d) shared antigens including melanoma and melanocyte differentiation antigens, such as MART-1 / Melan A; gpl00; MC1R; melanocyte-stimulating hormone receptor; tyrosinase; tyrosinase-related protein 1 / TRP1 and tyrosinase-related protein 2 / TRP2 associated with, for example, melanoma; (e) prostate-associated antigens including PAP, PSA, PSMA, PSH-P1, PSM-P1, PSM-P2 associated with, for example, prostate cancer; (f) immunoglobulin idiotypes associated with myeloma and lymphoma cells. Petition 870230091982, dated 10 / 17 / 2023, page 197 / 422 190 / 378 B. In certain embodiments, one or more TAAs may be selected from pi 5, Hom / Mel-40, H-Ras, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Epstein-Barr virus antigens, EBNA, human papillomavirus (HPV) antigens including E6 and E7, hepatitis B and C virus antigens, human T-cell lymphotropic virus antigens, TSP-180, pl85erbB2, 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 27.29\BCAA), CA 195, CA 242, CA-50, CAM43, CD68\KP1, CO-029, FGF-5, Ga733 (EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB / 70K, NY-CO-1, RCAS1, SDCCAG16, TA-90 (Mac-2 binding protein / cyclophilin C-associated protein), TAAL6, TAG72, TLP, TPS, or any combination thereof.

[0335] In some embodiments, the cancer vaccines of the present disclosure for use in combination with a compound of formula I' may include a tumor antigen. comprising the entire amino acid sequence, a portion thereof, or specific immunogenic epitopes of one of the following human proteins: TCTN1 (SEQ ID NO. 1; Gene ID: ENSG00000204852), TCTN2 (SEQ ID NO. 2; Gene ID: ENSG00000168778), TCTN3 (SEQ ID NO. 3; Gene ID: ENSG00000119977), HIGD2A (SEQ ID NO. 4; Gene ID: ENSG00000146066), HIGD2B (SEQ ID NO. 5; Gene ID: ENSG00000175202), C4ORF32 (SEQ ID NO. 6; Gene ID: ENSG00000174749), FAM62A (E-SYT1, SEQ ID NO. 7; Gene ID: gene: ENSG00000139641), COLEC11 (SEQ ID NO. 8; Gene ID: ENSG00000118004), FSTL5 (SEQ ID NO. 9; Gene ID: ENSG00000168843), FAM82A2 (SEQ ID NO. 10; Gene ID: ENSG00000137824), SCARA5 (SEQ ID NO. 11; Gene ID: Petition 870230091982, dated 10 / 17 / 2023, pp. 198 / 422 191 / 378 ENSG00000168079) , VSTM1 (SEQ ID NO. 12; ID de Gene: ENSG00000189068) , RNF5 (SEQ ID NO. 13; ID de Gene: ENSG00000183574) , UNQ6126 (SEQ ID NO. 14; ID de Gene: gi|169216088), DPY19L3 (SEQ ID NO. 15; ID de Gene: ENSG00000178904) , SLC39A10 (SEQ ID NO. 16; ID de Gene: ENSG00000196950) , GPR107 (SEQ ID NO. 17; ID de Gene: ENSG00000148358) , COL20A1 (SEQ ID NO. 18; ID de Gene: ENSG00000101203) , GLT25D2 (SEQ ID NO. 19; ID de Gene: ENSG00000198756) , SYTL3 (SEQ ID NO. 20; ID de Gene: ENSG00000164674) , DENND1B (SEQ ID NO. 21; ID de Gene: ENSG00000162701) , C6orf98 (SEQ ID NO. 22; ID de Gene : EG: 387079), FAM69B (SEQ ID NO. 23; I D de Gene : ENSG00000165716), EMID1 (SEQ ID NO. 24; ID de Gene: OTTHUMG00000030824), KLRG2 (SEQ ID NO. 25; ID de gENE: ENSG00000188883), ERMP1 (SEQ ID NO. 26; ID de Gene: ENSG00000099219), VMO1 (SEQ ID NO. 27; Gene ID: ENSG00000182853), C9orf46 (SEQ ID NO. 28; Gene ID: ENSG00000107020), F1137107 (SEQ ID NO. 29; Gene ID: ENSG00000177990), YIPF2 (SEQ ID NO.: 30; Gene ID NO. ENSG00000130733), TRYX3 (SEQ ID NO. 31; PRSS58, ENSG00000258223, 2) , C14orf135 (SEQ ID NO . 32 ; Gene ID: ENSG00000126773) , ANGPTL7 (SEQ ID NO. 33; Gene ID: ENSG00000171819) , SEQ ID NO. 33; Gene ID NO. ENSG00000162341) , C18orf19 (SEQ ID NO. 35; Gene ID: ENSG00000177150) , OLFML1 (SEQ ID NO. 36; Gene ID: ENSG00000183801) , LYPD4 (SEQ ID NO. 37; Gene ID: ENSG00000183801) ENSG00000101203) , MEGF8 (SEQ ID NO. 38; Gene ID: ENSG00000105429) , F1142986 (SEQ ID NO. 39; Gene ID: ENSG00000196460) , SLC46A1 (SEQ ID NO. 40; Gene ID: 40 ENSG00000076351) , FAM180A (SEQ ID NO. 41; Gene ID: ENSG00000189320) , CRISP-3 (SEQ ID NO. 42; Gene ID: Petition 870230091982, of 17 / 10 / 2023, p. 199 / 422 192 / 378 ENSG00000096006) or combinations thereof. These tumor antigens are disclosed in documents WO2010 / 086162, WO2010 / 086163, WO2011 / 051278, WO2011 / 051276, WO2011 / 051277, WO2011 / 051280, WO2011 / 051271, WO2011 / 135068, WO2014 / 198919, the contents of which are incorporated in their entirety by reference in this document.

[0336] In several embodiments, an illustrative immunotherapeutic agent may include operable mRNA to encode any one or more of the aforementioned cancer antigens useful for synthesizing a cancer vaccine. In some illustrative embodiments, the mRNA-based cancer vaccine may have one or more of the following properties: a) the mRNA encoding each cancer antigen is interspersed with 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 with a single nucleotide linker; d) each cancer antigen comprises 20-40 amino acids and includes a centrally located SNP mutation; e) at least 40% of the cancer antigens have a higher affinity for the individual's MHC class I molecules; f) at least 40% of the cancer antigens have a higher affinity for the individual's MHC class II molecules;g) at least 40% of the cancer antigens have a predicted binding affinity of IC50 > 500 nM for HLA-A, HLA-B and / or DRB1; h) the mRNA encodes 1 to 15 cancer antigens; i) 10-60% of the cancer antigens have a binding affinity to MHC class I and 10-60% of the cancer antigens have a binding affinity to MHC class II; and / or j) the mRNA encoding the antigens of; Petition 870230091982, dated 10 / 17 / 2023, pp. 200 / 422 193 / 378 Cancer is organized in such a way that cancer antigens are ordered to minimize pseudoepitopes.

[0337] In several embodiments, the combination comprising a compound of formula I' and a cancer vaccine immunotherapeutic agent as disclosed herein may be used to elicit an immune response in an individual against a carcinogenic antigen.The method involves administering to the individual an RNA vaccine comprising at least one RNA polynucleotide having an open reading frame encoding at least one antigenic polypeptide or an immunogenic fragment thereof, thereby inducing in the individual a specific immune response to the antigenic polypeptide or an immunogenic fragment thereof in combination with the administration of a compound of formula I' in the same composition or in a separate composition administered at the same time or sequentially dosed, wherein the anti-antigenic polypeptide antibody titer is increased after vaccination relative to the anti-antigenic polypeptide antibody titer in an individual vaccinated with a prophylactically effective dose of a traditional cancer vaccine. An “anti-antigenic polypeptide antibody” is a serum antibody that binds specifically to the antigenic polypeptide.

[0338] A prophylactically effective dose is a therapeutically effective dose that prevents cancer progression to a clinically acceptable level. In some embodiments, the therapeutically effective dose is a dose listed in a vaccine information leaflet. A traditional vaccine as used herein refers to a vaccine other than the mRNA vaccines of the invention. For example, a vaccine Petition 870230091982, dated 10 / 17 / 2023, pp. 201 / 422 Traditional vaccines (194 / 378) include, but are not limited to, live microorganism vaccines, exterminated microorganism vaccines, subunit vaccines, protein antigen vaccines, DNA vaccines, and the like. By way of example, a traditional vaccine is a vaccine that has obtained regulatory approval and / or is registered by a national drug regulatory agency, for example, the Food and Drug Administration (FDA) in the United States or the European Medicines Agency (EMA).

[0339] In some embodiments, the anti-antigenic polypeptide antibody titer in the individual is increased by 1 log to 10 log after vaccination compared to the anti-antigenic polypeptide antibody titer in an individual vaccinated with a prophylactically effective dose of a traditional cancer vaccine. In some embodiments, the anti-antigenic polypeptide antibody titer in the individual is increased by 1 log after vaccination compared to the anti-antigenic polypeptide antibody titer in an individual vaccinated with a prophylactically effective dose of a traditional cancer vaccine. In some embodiments, the anti-antigenic polypeptide antibody titer in the individual is increased by 2 log after vaccination compared to the anti-antigenic polypeptide antibody titer in an individual vaccinated with a prophylactically effective dose of a traditional cancer vaccine.

[0340] Aspects of the invention provide nucleic acid vaccines comprising one or more RNA polynucleotides having a reading frame encoding a first antigenic polypeptide, wherein the RNA polynucleotide Petition 870230091982, dated 10 / 17 / 2023, page 202 / 422 195 / 378 is present in the formulation for in vivo administration to a host that confers an antibody titer superior to the criterion for seroprotection for the first antigen for an acceptable percentage of human individuals. In some embodiments, the antibody titer produced by the mRNA vaccines of the invention is a neutralizing antibody titer. In some embodiments, the neutralizing antibody titer is greater than that of a protein vaccine. In other embodiments, the neutralizing antibody titer produced by the mRNA vaccines of the invention is greater than that of a protein vaccine with adjuvant. In other embodiments, the neutralizing antibody titer produced by the mRNA vaccines of the 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, 2,000-10,000, 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.A neutralization titer is typically expressed as the highest serum dilution required to achieve a 50% reduction in the number of plaques.

[0341] In preferred aspects, RNA vaccine immunotherapeutic agents of the present disclosure (e.g., mRNA vaccines) produce prophylactic and / or therapeutically effective levels, concentrations, and / or titrators of antigen-specific antibodies in the blood or serum of a vaccinated individual. As defined herein, the term antibody titer refers to the amount of antigen-specific antibody produced in an individual, e.g., a human individual. In exemplary embodiments, the antibody titer is expressed as the inverse of the highest dilution. Petition 870230091982, dated 10 / 17 / 2023, p. 203 / 422 196 / 378 (in a series of dilutions) that still yields a positive result. In exemplary embodiments, the antibody titer is determined or measured by enzyme-linked immunosorbent assay (ELISA). In exemplary embodiments, the antibody titer is determined or measured by neutralization assay, for example, by microneutralization assay. In certain respects, the antibody titer measurement is expressed as a ratio, such as 1:40, 1:100 and the like.

[0342] In exemplary embodiments of the invention, an effective vaccine produces an antibody titer 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, greater than 1:10000. In exemplary embodiments, the antibody titer is produced or reached 10 days after vaccination, 20 days after vaccination, 30 days after vaccination, 40 days after vaccination, or 50 or more days after vaccination. In exemplary embodiments, the titer is produced or reached after a single dose of vaccine is administered to the individual. In other embodiments, the titer is produced or reached after multiple doses, for example, after a first and a second dose (e.g., a booster dose). In exemplary aspects of the invention, antigen-specific antibodies are measured in units of g / ml or are measured in units of IU / L (International Units per liter) or mIU / ml (milli-international units per ml).In exemplary embodiments of the invention, an effective vaccine produces >0.5 pg / ml, >0.1 pg / ml, >0.2 pg / ml, >0.35 pg / ml, >0.5 pg / ml, >1. Petition 870230091982, dated 10 / 17 / 2023, pp. 204 / 422 197 / 378 pg / ml, >2 pg / ml, >5 pg / ml or >10 pg / ml. In exemplary embodiments of the 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 exemplary embodiments, the antibody level or concentration is produced or reached 10 days after vaccination, 20 days after vaccination, 30 days after vaccination, 40 days after vaccination or 50 or more days after vaccination. In exemplary embodiments, the level or concentration is produced or reached after a single dose of vaccine is administered to the individual. In other embodiments, the level or concentration is produced or achieved after multiple doses, for example, after a first and a second dose (e.g., a booster dose). In exemplary embodiments, the level or concentration is determined or measured by enzyme-linked immunosorbent assay (ELISA).In exemplary embodiments, the antibody level or concentration is determined or measured by a neutralization assay, for example, by a microneutralization assay. Furthermore, nucleic acid vaccines are provided comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide or a concatemeric polypeptide, wherein the RNA polynucleotide is present in a formulation for in vivo administration to a host to elicit a high and longer-lasting antibody titer than an antibody titer elicited by an mRNA vaccine that has a stabilizing element or is formulated with an adjuvant and encodes the first antigenic polypeptide. In some embodiments, the RNA polynucleotide is formulated to... Petition 870230091982, dated 10 / 17 / 2023, pp. 205 / 422 198 / 378 produce neutralizing antibodies within one week of single administration. In some embodiments, the adjuvant is selected from a cationic peptide and an immunostimulatory nucleic acid. In some embodiments, the cationic peptide is protamine.

[0343] Immunotherapeutic agents comprising a nucleic acid vaccine comprising one or more RNA polynucleotides having an open reading frame comprising at least one chemical modification or, optionally, no nucleotide modification, the open reading frame encoding a first antigenic polypeptide or a concatemeric polypeptide, wherein the RNA polynucleotide is present in the formulation for administration in vivo to a host such that the level of antigen expression in the host significantly exceeds a level of antigen expression produced by an mRNA vaccine having a stabilizing element or formulated with an adjuvant and encoding the first antigenic polypeptide.

[0344] Other aspects provide nucleic acid vaccines comprising one or more RNA polynucleotides having an open reading frame comprising at least one chemical modification or, optionally, no chemical modification, the open reading frame encoding a first antigenic polypeptide or a concatemeric polypeptide, wherein the vaccine has at least 10 times less RNA polynucleotide than is required for an unmodified mRNA vaccine to produce an equivalent antibody titer. In some embodiments, the RNA polynucleotide is present at a dosage of 25-100 micrograms. Petition 870230091982, dated 10 / 17 / 2023, page 206 / 422 199 / 378

[0345] Aspects of the invention also provide a vaccine unit for use comprising between 10 μg and 400 μg of one or more RNA polynucleotides having an open reading frame comprising at least one chemical modification or, optionally, no nucleotide modification, the open reading frame encoding a first antigenic polypeptide or a concatemeric polypeptide, and a pharmaceutically acceptable carrier or excipient formulated for delivery to a human individual. In some embodiments, the vaccine further comprises a cationic lipid nanoparticle.

[0346] Aspects of the invention provide methods for creating, maintaining, or restoring antigenic memory for a tumor in an individual or population of individuals comprising administering to said individual or population an antigenic memory booster nucleic acid vaccine comprising (a) at least one RNA polynucleotide, said polynucleotide comprising at least one chemical modification or, optionally, no nucleotide modification and two or more codon-optimized open reading frames, said open reading frames encoding a set of reference antigenic 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 modalities, the administration step involves placing a suitable device for injecting the compound into the individual's muscle tissue. In some... Petition 870230091982, dated 10 / 17 / 2023, page 207 / 422 200 / 378 modalities, the administration step involves placing the individual's muscle tissue in contact with a suitable device for injecting the composition in combination with electroporation.

[0347] Aspects of the invention provides methods of vaccinating an individual comprising administering to the individual a single dose of between 25 pg / kg and 400 pg / kg of a nucleic acid vaccine comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide or a concatemeric polypeptide in an amount effective to vaccinate the individual.

[0348] Other aspects provide nucleic acid vaccines comprising one or more RNA polynucleotides having an open reading frame comprising at least one chemical modification, the open reading frame encoding either a first antigenic polypeptide or a concatemeric polypeptide, wherein the vaccine has at least 10 times less RNA polynucleotide than is required for an unmodified mRNA vaccine to produce an equivalent antibody titer. In some embodiments, the RNA polynucleotide is present at a dosage of 25–100 micrograms.

[0349] In some embodiments, an illustrative immunotherapeutic agent may include one or more interfering RNAs that may be administered in combination with a compound of formula I'. An “RNA interfering agent” as used herein is defined as any agent that interferes with or inhibits the expression of a target biomarker gene by RNA interference (RNAi). Petition 870230091982, dated 10 / 17 / 2023, pp. 208 / 422 201 / 378 Such RNA interference agents include, but are not limited to, nucleic acid molecules including RNA molecules that are homologous to the target biomarker gene of the present invention or a fragment thereof, short interfering RNA (siRNA), and small molecules that interfere with or inhibit the expression of a target biomarker nucleic acid by RNA interference (RNAi). “Short interfering RNA” (siRNA), also referred to as “RNA interference” in this document, is defined as an agent that functions to display the expression of a target biomarker nucleic acid, for example, by RNAi. An siRNA may be chemically synthesized, may be produced by in vitro transcription, or may be produced in a host cell.In one embodiment, siRNA is a double-stranded RNA (dsRNA) molecule of about 15 to about 40 nucleotides in length, preferably about 15 to about 28 nucleotides, more preferably about 19 to about 25 nucleotides in length, and most preferably about 19, 20, 21 or 22 nucleotides in length, and may contain a 3' and / or 5' overhang on each strand that has 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 length of the overhang on one strand is not dependent on the length of the overhang on the second strand. Preferably, siRNA is capable of promoting RNA interference through post-transcriptional gene degradation or silencing (PTGS) of the target messenger RNA (mRNA).

[0350] An antisense oligonucleotide can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 or more nucleotides in length. A nucleic acid Petition 870230091982, dated 10 / 17 / 2023, p. 209 / 422 202 / 378 Antisense can be constructed using chemical synthesis and enzymatic linkage reactions with procedures known in the art. For example, an antisense nucleic acid (e.g., an antisense oligonucleotide) can be chemically synthesized using naturally occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or increase the physical stability of the duplex formed between the antisense and sense nucleic acids, for example, phosphorothioate derivatives and acridine-substituted nucleotides can be used.Examples of modified nucleotides that can be used to generate antisense nucleic acid include 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxymethyl)uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylkeosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylkeosine. 5'-methoxycarboxymethyluracil, 5methoxyuracil, 2-methylthio-N6-isopentenyladenine,uracil-5-oxyacetic acid (v), wibutoxosin, pseudouracil, queosin, 2-thiocytosine, 5-methyl-2-thiouracil,2thiouracil, 4-thiouracil, 5-methyluracil, acid methyl ester uracil-5-oxyacetic acid, uracil-5-oxyacetic acid (v),5methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w and 2,6-diaminopurine.Alternatively, the. Petition 870230091982, dated 10 / 17 / 2023, pp. 210 / 422 203 / 378 Antisense nucleic acid can be produced biologically using an expression vector in which a nucleic acid has been subcloned in an antisense orientation (that is, RNA transcribed from the inserted nucleic acid will have an antisense orientation for a target nucleic acid of interest described further in the following subsection).

[0351] The antisense nucleic acid molecules of the present invention are typically administered to an individual 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 to thereby inhibit the expression of the marker, for example, by inhibiting transcription and / or translation. Hybridization may occur by conventional nucleotide complementarity to form a stable duplex or, for example, in the case of an antisense nucleic acid molecule that binds to DNA duplexes through specific interactions in the major groove of the double helix. Examples of a route of administration of antisense nucleic acid molecules of the present invention include direct injection into a tissue site or infusion of the antisense nucleic acid into a body fluid associated with blood or bone marrow.Alternatively, antisense nucleic acid molecules can be modified to target selected cells and then administered systemically. For example, for systemic administration, antisense molecules can be modified so that they bind specifically to receptors or antigens expressed on a selected cell surface, for example, by linking antisense nucleic acid molecules to peptides or... Petition 870230091982, dated 10 / 17 / 2023, pp. 211 / 422 204 / 378 antibodies that bind to cell surface receptors or antigens. Antisense nucleic acid molecules can also be delivered to cells using vectors described in this document. To achieve sufficient intracellular concentrations of antisense molecules, vector constructs in which the antisense nucleic acid molecule is placed under the control of a strong pol II or pol III promoter are preferred.

[0352] Antigens that can be targeted to synthesize a corresponding antisense RNA molecule may include any antigen that is specific to one or more tumors, for example, antigens exemplified above with reference to cancer vaccines.

[0353] In some embodiments, a combination of an immunotherapeutic agent and a compound of formula I' may include a bispecific antibody immunotherapeutic agent. The bispecific antibody may include a protein construct that has a first antigen-binding moiety and a second antigen-binding site that binds to a cytotoxic immune cell. The first antigen-binding site may bind to a tumor antigen that is being specifically treated with the combination of the present invention. For example, the first antigen-binding moiety may bind to a non-limiting example of tumor antigens selected from: 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, among others. In some modalities, Petition 870230091982, dated 10 / 17 / 2023, pp. 212 / 422 205 / 378 The first antigen-binding fraction has specificity for a protein or peptide that is overexpressed in a tumor cell compared to a corresponding non-tumor cell. In some embodiments, the first antigen-binding fraction has specificity for a protein that is overexpressed in a tumor cell compared to a corresponding non-tumor cell. A corresponding non-tumor cell as used herein refers to a non-tumor cell that is of the same type as the original tumor cell type. Note that such proteins are not necessarily different from tumor antigens. Non-limiting examples include carcinoembryonic antigen (CEA), which is overexpressed in most carcinomas of the colon, rectum, breast, lung, pancreas, and gastrointestinal tract;Heregulin receptors (HER-2, neu, or cerbB-2), which are frequently overexpressed in breast, ovarian, colon, lung, prostate, and cervical cancers; epidermal growth factor receptor (EGFR), which is highly expressed in a range of solid tumors including breast, head and neck, non-small cell lung, and prostate cancers; asialoglycoprotein receptor; transferrin receptor; serpin enzyme complex receptor, which is expressed in hepatocytes; fibroblast growth factor receptor (FGFR), which is overexpressed in pancreatic ductal adenocarcinoma cells; vascular endothelial growth factor receptor (VEGFR) for anti-angiogenesis gene therapy; folate receptor, which is selectively overexpressed in 90% of non-mucinous ovarian carcinomas; cell surface glycocalyx; carbohydrate receptors; and receptor; Petition 870230091982, dated 10 / 17 / 2023, pp. 213 / 422 206 / 378 of polymeric immunoglobulin.

[0354] The second antigen-binding fraction is any molecule that binds specifically to an antigen or protein or polypeptide expressed on the surface of a cytotoxic immune cell (a CIK cell). Non-limiting explanatory antigens expressed on the surface of cytotoxic immune cells suitable for use with this disclosure may include CD2, CD3, CD4, CD5, CD8, CD11a, CD11b, CD14, CD16a, CD27, CD28, CD45, CD45RA, CD56, CD62L ligands, Fc receptor, LFA, LFA-1, TCRap, 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. In some modalities, the second antigen-binding fragment binds to CD3 of the cytotoxic immune cell, for example, a CIK cell. In some modalities, the second antigen-binding fragment binds to CD56 of the cytotoxic immune cell.In some embodiments, the second antigen-binding fragment binds to the Fc receptor of the cytotoxic immune cell. In some embodiments, the Fc region of the bispecific antibody binds to the Fc receptor of the cytotoxic immune cell. In some embodiments, a second antigen-binding fragment is any molecule that binds specifically to an antigen expressed on the surface of a cytotoxic immune cell (e.g., a CIK cell). The second antigen-binding fragment is specific for an antigen on a cytotoxic immune cell. Exemplary cytotoxic immune cells include, but are not limited to, CIK cells, T cells, CD8+ T cells, activated T cells, monocytes, etc. Petition 870230091982, dated 10 / 17 / 2023, pp. 214 / 422 207 / 378 natural killer (NK) cells, NK T cells, lymphokine-activated killer (LAK) cells, macrophages, and dendritic cells. The second antigen-binding fraction binds specifically to an antigen expressed on the surface of a cytotoxic immune cell. Exemplary non-limiting antigens expressed on the surface of cytotoxic immune cells suitable for modulation with the present disclosure may include CD2, CD3, CD4, CD5, CD8, CD11a, CD11b, CD14, CD16a, CD27, CD28, CD45, CD45RA, CD56 ligands. CD62L, Fc receptor, LFA, LFA-1, TCRap, 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. In other embodiments, the bispecific antibody modulator is an activator of a costimulatory molecule (e.g., an OX40 agonist). In one embodiment, the OX40 agonist is a bispecific antibody molecule for OX40 and for another tumor antigen or for a costimulatory antigen. The OX40 agonist may be administered alone or in combination with other immunomodulators, for example, in combination with an inhibitor (e.g., an antibody construct) of PD-1, PD-L1, CTLA-4, CEACAM (e.g., CEACAM-1, -3, and / or -5), TIM-3, or LAG-3. 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., a conforming anti-PD-1 molecule). Petition 870230091982, dated 10 / 17 / 2023, pp. 215 / 422 208 / 378 described in this document). The OX40 antibody molecule and the anti-PD-1 antibody molecule may be in the form of a separate antibody composition or as a bispecific antibody molecule. In other embodiments, the OX40 agonist may be administered in combination with another costimulatory molecule, for example, a GITR ligand agonist, 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. In some forms, the second antigen-binding fragment binds to the receptor on the cytotoxic immune cell, for example, a CIK cell.

[0355] In some embodiments, the bispecific antibody immunotherapeutic agent has specificities for a tumor antigen and for a CIK cell that places the tumor antigen expressed by the tumor cell in close proximity to the CIK cell, leading to the elimination of the tumor cell through antitumor cytotoxicity of the CIK cell. In some embodiments, the bispecific antibody has specificity for a tumor antigen but not specificity for a CIK cell; however, the Fc region of the bispecific antibody can bind to the Fc receptor of the CIK cell, which, in turn, places the tumor cell in close proximity to the CIK cell, leading to the elimination of the tumor cell through antitumor cytotoxicity of the CIK cell.In some modalities, the bispecific antibody has specificity for a CIK cell but not for a tumor cell; however, the Fc region of the bispecific antibody can bind to the Fc receptor of the tumor cell, which, in turn, exposes the cell to risk. Petition 870230091982, dated 10 / 17 / 2023, pp. 216 / 422 209 / 378 tumor in the vicinity of the CIK cell, leading to the elimination of the tumor cell through antitumor cytotoxicity of the CIK cell.

[0356] In some embodiments, a combination of an immunotherapeutic agent and a compound of formula I' may include a multivalent antibody / fusion protein / construct immunotherapeutic agent that engages immune cells. In several embodiments, an exemplar...

Claims

1. Compound of formula B-1: B-1 or a pharmaceutically acceptable salt thereof, characterized in that: Ra1 is optionally substituted (C1-C6) alkyl; R1 is -CN, optionally substituted phenyl, optionally substituted 4- to 6-membered heterocycloalkyl, optionally substituted 5- to 6-membered heteroaryl, -SO2-(C1-Ce) alkyl, -SO2NH2, -SO2-NH(C1-Ce) alkyl, P(O)((C1-C6) alkyl)2; or Z1 in II R1 is ' γ£ γγΥ where ά / w' indicates the fixation point, where: Y 1 is absent; Y 2 is absent or is -O-, -NH-, -NHO-, -NH-NH- or -N-(C1-C6) alkyl-; or Y2 is optionally replaced wherein ring A is a ring with 3, 4, 5, 6 or 7 members, where ' / vw' indicates attachment points; Z1 is O;and Petition 870260036975, of 20 / 04 / 2026, page 15 / 90 2 / 20 Ra is -H, -(C1-C6)alkyl, 4- to 6-membered heterocycloalkyl, 3- to 6-membered cycloalkyl, -(C2-C6)alkyleneOH, -CH2CHOH-(C2-C6)alkylene-OH, -(C2-C6)alkylene-NH2, (C2-C6)alkylene-NH(C1-C6)alkyl, -(C2-C6)alkylene-N((C1C6))alkyl)2, or -(C2-C6)alkylene-(4- to 6-membered heterocycloalkyl), wherein the heterocycloalkyl is optionally substituted; each R3 is independently -H or halo; each R4 is independently -H, halo, (C1-C6) alkyl, (C1-C6) alkoxy or (C1-C6) haloalkyl; R14 is -H or halo; Y is -O-; the subscript n is an integer of 1, 2, 3 or 4; the subscript m is an integer of 1, 2, 3, 4 or 5;and the subscript p is an integer of 0, 1, 2, 3 or 4, wherein, in each occurrence, optionally substituted means unsubstituted or substituted with substituents selected from halogen, -CN, -OH, -ORaa, -COORaa, alkyl (C1-C10), carbocycloalkyl (C3-C10), 3- to 14-membered heterocycloalkyl, aryl (C6-C14) and 5- to 14-membered heteroaryl, wherein Raa is alkyl (C1-C10); provided that the compound is not 1-N'-(4-fluorophenyl)-1N-[4-[7-methoxy-6-(methylcarbamoyl)quinolin-4yl]oxyphenyl]cyclopropane-1,1-dicarboxamide or a pharmaceutically acceptable salt thereof.

2. Compound according to claim 1, characterized in that: Ra1 is (C1-C6) alkyl; R1 is -CN, optionally substituted phenyl, azetidinyl. Petition 870260036975, dated 20 / 04 / 2026, p.16 / 90 3 / 20 optionally substituted, 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 z1 o ' R1 is Y2 Y 1 Y wherein: Y2 is O, NH, NHO, NH-NH or N-(C1-C6) alkyl-; or Y2 is optionally substituted azetidinyl; and Ra 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-(4 to 6 membered heterocycloalkyl), or 4 to 6 membered heterocycloalkyl, wherein heterocycloalkyl is optionally substituted.

3. Compound according to claim 2, characterized in that Ra1 is methyl.

4. Compound according to claim 1, characterized in that it is a compound of formula C: Petition 870260036975, dated 20 / 04 / 2026, p. 17 / 90 4 / 20 or a pharmaceutically acceptable salt thereof, wherein: Y2 is O, NH, NHO, NH-NH or N-(C1-C6) alkyl; or Y2 is optionally substituted azetidinyl; Ra 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-(4 to 6 membered heterocycloalkyl) or optionally substituted 4 to 6 membered heterocycloalkyl; and R2 is (C1-C6)alkoxy.

5. Compound according to claim 4, characterized in that Ra is H, methyl, ethyl, -(C2C6)alkylene-OH, -CH2CHOH-(C2-Cg)alkylene-OH, -(C2-C6)alkylene-NH2, -(C2-C6)alkylene-NHMe, -(C2-C6)alkyleneN(Me)2, optionally substituted azetidinyl or optionally substituted oxetanyl.

6. Compound according to claim 4 or 5, characterized in that it is a compound of formula C1: or a pharmaceutically graded salt.

7. Compound, characterized in that it is acceptable thereof. with claim 1 a compound of formula E: Petition 870260036975, dated 20 / 04 / 2026, page 18 / 90 5 / 20 or a pharmaceutically acceptable salt thereof, wherein: ring A is an 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.

8. Compound according to claim 1, characterized in that it is a compound of formula F: or a pharmaceutically acceptable salt thereof.

9. Compound according to claim 8, characterized in that: Ra1 is methyl; R1 is -CN, optionally substituted phenyl, optionally substituted azetidinyl, optionally substituted pyrrolidinyl. Petition 870260036975, dated 20 / 04 / 2026, page 1.19 / 90 6 / 20 substituted, 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 Z1 R1 is Y2 Y 1 y wherein: Y2 is O, NH, NHO, NH-NH or N-(C1-Ce)alkyl-; or Y2 is optionally substituted azetidinyl; and Ra 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-(4 to 6 membered heterocycloalkyl), and 4 to 6 membered heterocycloalkyl, wherein heterocycloalkyl is optionally substituted.

10. Compound according to claim 1, characterized in that it is a compound of formula H: or a pharmaceutically acceptable salt thereof, wherein: Y is -O-; R1 is selected from the group consisting of -CN, Petition 870260036975, dated 20 / 04 / 2026, p. 20 / 90 7 / 20 -CO-NR5R6, -CO2R7, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, SO2NR8R9 and (SO2)-(C1C6)alkyl; R2 is (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; R8 and R9 are each independently either -H or C1-C6 alkyl; provided that the compound is not 1-N'-(4-fluorophenyl)-1N-[4-[7-methoxy-6-(methylcarbamoyl)quinolin-4yl]oxyphenyl]cyclopropane-1,1-dicarboxamide or a pharmaceutically acceptable salt thereof.

11. Compound according to claim 10, characterized in that: R3 is H.

12. Compound according to claim 10, characterized in that R4 is a halo.

13. Compound according to claim 10, characterized in that Ri is -CN, -CO2H, -CO2-Me, -CONHR6, -CO-NH2- and -CO-NMeR6.

14. Compound according to claim 1, characterized in that Ri is selected from the group consisting of -CN, -(SO2)NH2, -(SO2)CH3, Petition 870260036975, dated 20 / 04 / 2026, page 21 / 90 8 / 20 15. Compound according to claim 10, characterized in that Ri is selected from the group consisting of O 16. Compound according to claim 1, characterized in that it is a compound of formula IA: r4 IA or a pharmaceutically acceptable salt thereof, wherein Rg is (C1-C6) alkyl, R2 is (C1-C6) alkoxy, R3 is -H or halo and R4 is halo, provided that the compound is free of 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylcarbamoyl)quinolin-4]oxyphenyl]cyclopropane-1,1-dicarboxamide or a pharmaceutically acceptable salt thereof.

17. Compound according to claim 1, characterized in that it is selected from the group consisting of: No. Structure Name 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylate methyl 1-N-[4-(6-carbamoyl-7-methoxyquinolin-4yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropano-1,1-dicarboxamide I 1-N-[4-[6-[(ethylcarbamoyl)-7-methoxyquinolin-4yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropano-1,1-dicarboxamide 1-N-[4-[6-[2-dimethylamino)ethylcarbamoyl]-7-methoxyquinolin-4yl]oxyphenyl]-1-N' -(4-fluorophenyl)cyclopropano-1,1-dicarboxamide 1-N'-(4-fluorophenyl)1-N-[4-[7-methoxy-6-(2-piperidin-1-ylethylcarbamoyl)quinol-4-yl]oxyphenyl]cyclopropano-1,1-dicarboxamide Petition 870260036975, dated 20 / 04 / 2026, p.23 / 90 10 / 20 n° Structure Name 1-N'-(4-fluorophenyl)1-N-[4-[7-methoxy-6-(2morfolin-4ylethylcarbamoyl)quinol in-4yl]oxiphenyl]cyclopropa no-1,1-dicarboxamide 1-N'-(4-fluorophenyl) 1-N-[4-[7-methoxy-6(oxetan-3ylcarbamoyl)quinolin4yl]oxiphenyl]cyclopropa no-1,1-dicarboxamide 1-N'-(4-fluorophenyl)1-N-[4-[7-methoxy-6[(1-metilazetidin-3yl)carbamoyl]quinolin4yl]oxiphenyl]cyclopropa no-1,1-dicarboxamide 1-N-[4-[6-(azetidine1-carbonyl)-7methoxyquinolin-4yl]oxyphenyl]-1-N' -(4fluorophenyl)cyclopropa no-1,1-dicarboxamida 1-N'-(4-fluorophenyl) 1-N-[4-[6-(3hidroxiazetidine-1carbonyl)-7methoxiquinolin-4yl]oxyphenyl]cyclopropa no-1,1-dicarboxamida 1-N'-(4-fluorophenyl) 1-N-[4-[7-methoxi-6(metoxicarbamoyl)quinolin-4yl]oxyphenyl]cyclopropa no-1,1-dicarboxamida Petição 870260036975, dated 20 / 04 / 2026, pág.24 / 90 11 / 20 no. Structure Name 1-N'-(4-fluorophenyl)1-N-[4-[6(hydroxycarbamoyl)-7methoxyquinolin-4yl]oxyphenyl]cyclopropane-1,1-dicarboxamide 1-N'-(4-fluorophenyl) 1-N-[4-[7-methoxy-6[[(2R)-pyrrolidin-2yl]methylcarbamoyl]quinolin-4yl]oxyphenyl]cyclopropane-1,1-dicarboxamide 1-N'-(4-fluorophenyl) 1-N-[4-[7-methoxy-6[[(2S)-pyrrolidin-2yl]methylcarbamoyl]quin olin-4yl]oxyphenyl]cyclopropane-1,1-dicarboxamide 1-N'-(4-fluorophenyl)1-N-[4-[7-methoxy-6(oxetan-3-yloxycarbamoyl)quinolin-4yl]oxyphenyl]cyclopropano-1,1-dicarboxamide 1-N'-(4-fluorophenyl)1-N-[4-[6-(2-hydroxyethoxycarbamoyl)-7-methoxyquinolin-4yl]oxyphenyl]cyclopropano-1,1-dicarboxamide 1-N-[4-[6-(2,3-dihydroxypropoxycarbamoyl)-7-methoxyquinolin-4yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropano-1,1-dicarboxamide Enantiomer 2 Petition 870260036975, dated 20 / 04 / 2026, page.25 / 90 12 / 20 no. Structure Name 1-N'-(4-fluorophenyl)1-N-[4-[6(hydrazinecarbonyl)-7methoxyquinolin-4yl]oxyphenyl]cyclopropane-1,1-dicarboxamide 1-N-[4-(6-acetyl-7methoxyquinolin-4yl)oxyphenyl]-1-N'-(4fluorophenyl)cycloprop no-1,1-dicarboxamide 1-N-[4-(6-cyano-7methoxyquinolin-4yl)oxyphenyl]-1-N'-(4fluorophenyl)cyclopropane no-1,1-dicarboxamide 1-N'-(4-fluorophenyl)1-N-[4-[7-(2-hydroxyethoxy)-6-(1,3-oxazol-2-yl)quinolin-4-yl]oxyphenyl]cyclopropano-1,1-dicarboxamide Petition 870260036975, dated 20 / 04 / 2026, p.26 / 90 13 / 20 n° Structure Name 1-N-[4-(6dimethylphosphoryl-7methoxyquinolin-4yl)oxiphenyl]-1-N' -(4fluorophenyl)cyclopropa no-1,1-dicarboxamide 1-N-[4-[6-carbamoyl-7(3-morpholin-4ylpropoxy)quinolin-4yl]oxiphenyl]-1-N'-(4fluorophenyl)cyclopropa no-1,1-dicarboxamide 103 1-N-[4-[6-carbamoyl-7(2methoxyethoxy)quinolin4-yl]oxiphenyl]-1-N'(4fluorophenyl)cyclopropa no-1,1-dicarboxamide 106 1-N-[4-[6-carbamoyl-7(2hidroxietoxi)quinolin4-yl]oxyphenyl]-1-N'(4fluorophenyl)cyclopropa no-1,1-dicarboxamida 110 1-N'-(4-fluorophenyl)1-N-[4-[7-(2hidroxietoxi)-6(methylcarbamoyl)quinol in-4yl]oxyphenyl]cyclopropa no-1,1-dicarboxamida 115 1-N-[4-[6-carbamoyl-7(2hidroxypropoxy)quinoli n-4-yl]oxyphenyl]-1-N'(4fluorophenyl)cyclopropa no-1,1-dicarboxamida Petição 870260036975, de 04 / 20 / 2026, pág.27 / 90 14 / 20 No. Structure Name 116 1-N'-(4-fluorophenyl)1-N-[4-[7-(2-hydroxypropoxy)-6(methylcarbamoyl)quinol-4yl]oxyphenyl]cyclopropano-1,1-dicarboxamide 125 1-N'-(4-fluorophenyl)1-N-[4-[7-(2-hydroxypropoxy)-6(1,3-oxazol-2yl)quinolin-4yl]oxyphenyl]cyclopropano-1,1-dicarboxamide 128 129 4-[2-chloro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylate methyl 4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]a mino]phenoxy]-7-methoxyquinoline-6-carboxylate methyl 132 1-N'-[4-(6-carbamoyl7-methoxyquinolin-4yl)oxy-3-chlorophenyl]1-N-(4-fluorophenyl)cyclopropano-1,1-dicarboxamide Petition 870260036975, dated 20 / 04 / 2026, page.28 / 90 15 / 20 n° Structure Name 133 1-N'-[4-(6-carbamoyl7-methoxyquinolin-4yl)oxi-3-fluorophenyl]1-N-(4fluorophenyl)cyclopropane-1,1-dicarboxamide 135 175 176 1-N'-[3-chloro-4-[7methoxy-6(methylcarbamoyl)quinol in-4-yl]oxiphenyl]-1-N(4fluorophenyl)cyclopropane-1,1-dicarboxamide 1-N'-[3-fluoro-4-[7methoxy-6(methylcarbamoyl)quinol in-4-yl]oxiphenyl]-1-N(4fluorophenyl)cyclopropane-1,1-dicarboxamide 1-N-[4-[6-(3-cyano-2fluorophenyl)-7methoxyquinolin-4yl]oxyphenyl]-1-N'-(4fluorophenyl)cyclopropa no-1,1-dicarboxamida 1-N'-(4-fluorophenyl) 1-N-[4-(7-methoxy-6pyridin-2-ylquinolin4yl)oxyphenyl]cyclopropa no-1,1-dicarboxamida 1-N'-(4-fluorophenyl) 1-N-[4-[7-methoxy-6-(1methylimidazol-4yl)quinolin-4yl]oxyphenyl]ciclopropa no-1,1-dicarboxamida Petição 870260036975, de 20 / 04 / 2026, pág.29 / 90 16 / 20 n° Structure Name 1-N'-(4-fluorophenyl)1-N-[4-[7-methoxy-6-(5methylfuran-2yl)quinolin-4yl]oxiphenyl]cyclopropane-1,1-dicarboxamide 182 1-N'-(4-fluorophenyl)1-N-[4-[7-methoxy-6-(1methylpyrazol-4yl)quinolin-4yl]oxiphenyl]cyclopropane-1,1-dicarboxamide 183 1-N'-(4-fluorophenyl)1-N-[4-[7-methoxy-6(1,2-oxazol-4yl)quinolin-4yl]oxiphenyl]cyclopropane-1,1-dicarboxamide 184 1-N-[4-[6-(3,5dimethyl-1,2-oxazol-4yl)-7-methoxyquinolin-4-yl]oxyphenyl]-1-N'(4fluorophenyl)cyclopropane-1,1-dicarboxamide 1-N'-(4-fluorophenyl)1-N-[4-[7-methoxy-6(1H-pyrazol-5yl)quinolin-4yl]oxyphenyl]cyclopropane-1,1-dicarboxamide 1-N'-(4-fluorophenyl) 1-N-[4-[7-methoxy-6(1H-pyrazol-4yl)quinolin-4yl]oxyphenyl]cyclopropane-1,1-dicarboxamide 188 1-N'-(4-fluorophenyl) 1-N-[4-[7-methoxy-6(1H-pyrrol-2yl)quinolin-4yl]oxyphenyl]cyclopropa no-1,1-dicarboxamida Petição 870260036975, de 20 / 04 / 2026, pág.30 / 90 17 / 20 n° Estrutura Nome 191 1-N'-(4-fluorofenil)1-N-[4-[6-(1Himidazol-2-yl)-7metoxiquinolin-4yl]oxifenil]ciclopropa no-1,1-dicarboxamida 192 195 196 1-N'-(4-fluorofenil)1-N-[4-[7-metoxi-6(1,3-oxazol-5yl)quinolin-4yl]oxifenil]ciclopropa no-1,1-dicarboxamida 3-[4-[4-[[1-[(4fluorofenil)carbamoil]ciclopropanocarbonyl]amino]fenoxy]-7metoxiquinolin-6-yl]3-hidroxiazetidina-1carboxylato de tercbutyl 1-N'-(4-fluorophenyl)1-N-[4-[6-(3hidroxioxetan-3-yl)-7methoxyquinolin-4yl]oxyphenyl]cyclopropa no-1,1-dicarboxamida 198 199 1-N'-(4-fluorophenyl) 1-N-[4-[6-(3hidroxiazetidin-3-yl)7-methoxiquinolin-4yl]oxyphenyl]cyclopropa no-1,1-dicarboxamida 1-N-[4-[6-(azetidin-1yl)-7-methoxiquinolin4-yl]oxyphenyl]-1-N'(4fluorophenyl)cyclopropa no-1,1-dicarboxamida 1-N'-(4-fluorophenyl)1-N-[4-[6-(3hidroxiazetidin-1-yl) 7-methoxiquinolin-4yl]oxyphenyl]cyclopropa no-1,1-dicarboxamida Petição 870260036975, dated 20 / 04 / 2026, pág.31 / 90 18 / 20 no. Structure 200 201 202 Name 1-N-[4-[6-(3,3difluoroazetidin-1yl)-7-methoxyquinolin4-yl]oxyphenyl]-1-N'(4fluorophenyl)cyclopropane-1,1-dicarboxamide 1-N'-(4-fluorophenyl)1-N-[4-(7-methoxy-6pyridin-3-ylquinolin4yl)oxyphenyl]cyclopropane-1,1-dicarboxamide 1-N'-(4-fluorophenyl)1-N-[4-(7-methoxy-6-sulfamoylquinolin-4yl)oxyphenyl]cyclopropano-1,1-dicarboxamide 207 1-N'-(4-fluorophenyl)1-N-[4-[7-methoxy-6(methylsulfamoyl)quinol-4yl]oxyphenyl]cyclopropano-1,1-dicarboxamide 208 1-N-[4-[6(ethylsulfamoyl)-7-methoxyquinolin-4yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropano-1,1-dicarboxamide 210 1-N'-(4-fluorophenyl)1-N-[4-(7-methoxy-6-methylsulfonylquinolin-4yl)oxyphenyl]cyclopropano-1,1-dicarboxamide Petition 870260036975, dated 20 / 04 / 2026, page.32 / 90 19 / 20 n° Estrutura Name 264 220 265 267 268 1-N'-(4-fluorophenyl)1-N-[4-[7-methoxy-6(1,3,4-oxadiazol-2yl)quinolin-4yl]oxiphenyl]cyclopropano-1,1-dicarboxamide 1-N'-(2-chloro-4fluorophenyl)-1-N-[3fluoro-4-[7-methoxy-6(methylcarbamoyl)quinol in-4yl]oxiphenyl]cyclopropano-1,1-dicarboxamide 1-N-[3-fluoro-4-[7methoxy-6(methylcarbamoyl)quinol in-4-yl]oxiphenyl]-1N' - (4-fluoro-2methylphenyl)cyclopropano-1,1-dicarboxamide 1-N'-(4-fluoro-2,6dimethylphenyl)-1-N-[3fluoro-4-[7-methoxy-6(methylcarbamoyl)quinol in-4yl]oxiphenyl]cyclopropan o-1,1-dicarboxamida 1-N-[3-fluoro-4-[7methoxy-6(methylcarbamoyl)quinol in-4-yl]oxiphenyl]-1N'- (4-fluoro-2methoxyphenyl)cyclopropan o-1,1-dicarboxamida 1-N-[3-fluoro-4-[7methoxy-6(methylcarbamoyl)quinol in-4-yl]oxiphenyl]-1N'- (4-fluoro-2-propan2yloxiphenyl)cyclopropan o-1,1-dicarboxamida Petição 870260036975, de 20 / 04 / 2026, pág.33 / 90 20 / 20 No. Structure Name 273 274 283 1-N'-[3-fluoro-4-[7methoxy-6(methylcarbamoyl)quinol in-4-yl]oxyphenyl]-1-N[4(trifluoromethyl)phenyl]cyclopropane-1,1-dicarboxamide 1-N-(4-chlorophenyl)-1N'-[3-fluoro-4-[7methoxy-6(methylcarbamoyl)quinol in-4yl]oxyphenyl]cyclopropane-1,1-dicarboxamide 1-N-[4-[6-(3-ethyl1,2,4-oxadiazol-5-yl)7-methoxyquinolin-4yl]oxyphenyl]-1-N'-(4fluorophenyl)cyclopropane-1,1-dicarboxamide or a pharmaceutically acceptable salt thereof.

18. Pharmaceutical composition characterized in that it comprises a compound, as defined in any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.