EP4698525A1 - Dérivés de composés acétylène substitués et leur utilisation pharmaceutique - Google Patents

Dérivés de composés acétylène substitués et leur utilisation pharmaceutique

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Publication number
EP4698525A1
EP4698525A1 EP24792979.7A EP24792979A EP4698525A1 EP 4698525 A1 EP4698525 A1 EP 4698525A1 EP 24792979 A EP24792979 A EP 24792979A EP 4698525 A1 EP4698525 A1 EP 4698525A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
group
halogen
optionally substituted
carbamoyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP24792979.7A
Other languages
German (de)
English (en)
Inventor
Jung Hun Lee
Ja Heouk Khoo
Jung Hwan Kim
Soongyu Choi
Young Whan Park
Minyoung Im
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Avelos Therapeutics Inc
Original Assignee
Avelos Therapeutics Inc
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Filing date
Publication date
Application filed by Avelos Therapeutics Inc filed Critical Avelos Therapeutics Inc
Publication of EP4698525A1 publication Critical patent/EP4698525A1/fr
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems

Definitions

  • the present disclosure belongs to a technical field of medicine, and particularly relates to acetylene derivates with inhibitory effects on polymerase theta, pharmaceutical compositions containing the same, and preparation methods and uses thereof.
  • DNA double strand breaks are detrimental to cells as they contribute to genome instability, which can induce cell death.
  • DSBs DNA double strand breaks
  • three pathways are performed in cells: non-homologous end joining (NHEJ), homologous recombination (HR), and theta-mediated end-joining (TMEJ).
  • NHEJ non-homologous end joining
  • HR homologous recombination
  • TMEJ theta-mediated end-joining
  • the NHEJ pathway joins the broken ends of DNA strands together without using a homologous template.
  • the HR and TMEJ pathways have commonality in that they both use a homologous sequence.
  • HR is a high-fidelity DNA repair pathway
  • TMEJ is an error-prone DNA repair pathway that uses microhomologies.
  • the TMEJ pathway involves poly-(ADP-ribose) polymerase PARP1, DNA ligase III, and Polymerase theta.
  • Polymerase theta (Pol ⁇ , encoded by POLQ ) is a 290kDa polymerase A family enzyme, and is known to mediate the TMEJ pathway (Feng et al., 2019, Nature Communication, 10:4286).
  • Pol ⁇ possesses a N-terminal helicase-like domain and a C-terminal DNA polymerase domain separated by a non-structured central amino acid sequence.
  • the helicase domain of Pol ⁇ acts to displace Replication Protein A (RPA) bound to a single strand DNA overhang and facilitate annealing of micro-homologous sequences that flank a DSB. Then, the polymerase domain of Pol ⁇ acts to initiate DNA synthesis to fill in gaps (Zatreanu et al., 2021, Nature Communication, 12:3636).
  • RPA Replication Protein A
  • the TMEJ pathway is also known as alternative NHEJ (alt-NHEJ) pathway or microhomology-mediated end joining (MMEJ) pathway (Zatreanu et al., 2021, Nature Communication, 12:3636).
  • the TMEJ pathway serves as an essential backup pathway in the event that the NHEJ or HR pathway is compromised (Higgins, G. S. et al., 2018. Science, 359(6381), 1217-1218). Accordingly, DNA-repair deficient cancers are dependent on other compensatory repair pathway, and HR- or NHEJ-deficient cancers are dependent on the TMEJ backup pathway.
  • PARP inhibitors PARPi
  • HR-deficient tumors have been successfully treated by way of applying PARPi.
  • PARPi often face the issue of developing resistance (Drzewiecka et al., 2022, Genes, 13:1101; and Higgins, G. S. et al., 2018. Science, 359(6381), 1217-1218).
  • pol ⁇ has been identified as another promising therapeutic target for cancers. While pol ⁇ is overexpressed in various cancers, it is little expressed (largely absent) in normal cells (Higgins, G. S. et al., 2018. Science, 359(6381), 1217-1218; and Ceccaldi et al., 2015, Nature, 518:258). Indeed, human neoplasms including those of the lung, stomach, small intestine, rectum, and colon overexpress pol ⁇ , and the expression level of pol ⁇ is particularly high in lung cancer, breast cancer, ovarian cancer, colorectal cancer and gastric cancer, etc.
  • Pol ⁇ depletion causes both HR-proficient and HR-deficient tumor cells to become more sensitive to other treatments such as radiation or chemotherapy (Drzewiecka et al., 2022, Genes, 13:1101, and Goullet de Rugy T et al., 2016, Biology open, 5(10), 1485-1492).
  • the present disclosure provides novel acetylene derivatives, compositions comprising the same, and preparation methods and uses thereof.
  • the acetylene derivatives have an inhibitory activity for polymerase theta, and can be effectively used for treating various types of cancers.
  • the present disclosure relates to a compound of the following Formula (I):
  • each of R 1 , R 2 , R 3 , R 4 and R 5 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, hydroxy, and -NR x R y , wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • X is selected from the group consisting of methylene, ethylene, n-propylene, -NH-, -NR z1 -, and -CR z2 R z3 -, wherein each of said methylene, ethylene, and n-propylene is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • each of Y and Z is independently selected from the group consisting of -N- and -CR w -;
  • W is selected from the group consisting of carbon and sulfur
  • n 1 or 2, provided that when W is carbon, n is 1; and when W is sulfur, n is 2;
  • A is selected from the group consisting of 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, halogen, 3-10 membered cycloalkyl, -NR x R y , amino, mercapto, and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • L 1 is selected from the group consisting of absent, -(C 1 -C 6 )alkylene-, and -(C 1 -C 6 )alkylene-NH-;
  • L 2 is selected from the group consisting of absent, and -(C 1 -C 6 )alkylene-, wherein said alkylene is optionally substituted with one or more selected from C 1 -C 6 alkyl, and halogen;
  • R 6 is selected from the group consisting of phenyl and a 3-10 membered heterocyclyl group, wherein each of said phenyl and heterocyclyl group is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C 1 -C 6 alkoxy, mercapto, amino, -COOH, -S(O) 2 NH 2 , -NR 61 R 62 , -NHC(O)R 63 , -C(O)NR 64 R 65 , 5-6 membered heterocyclyl, and -CH 2 -R 66 , wherein each of said alkyl, alkoxy, and heterocyclyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, and deuterium;
  • each of R 61 and R 62 is selected from the group consisting of hydrogen, and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl, or
  • R 61 and R 62 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 5-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R 63 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, NH 2 , and C 2 -C 6 alkenyl, wherein each of said alkyl and alkenyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • each of R 64 and R 65 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl, or
  • R 64 and R 65 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 5-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R 66 is a 5-10 membered heterocyclyl group, wherein said heterocyclyl group is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, oxo, carbamoyl, and amino;
  • each of R x and R y is independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • R z1 is C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • R z2 and R z3 taken together with the carbon atom to which they are attached, form a 3-6 membered cycloalkane ring, wherein said cycloalkane ring is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R w is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halogen, cyano, deuterium, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, 3-10 membered cycloalkyl, -NR x R y , hydroxy, amino, mercapto, and carbamoyl,
  • the present disclosure provides a pharmaceutical composition for treating or preventing diseases or disorders, such as diseases or disorders mediated by polymerase theta, which comprises one or more of the compounds disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable carrier(s) or excipient(s).
  • the composition comprises one or more of the compounds in a therapeutically effective amount.
  • the composition comprises one or more of the compounds in a prophylactically effective amount.
  • the present disclosure provides the use of the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition disclosed herein in the manufacture of a medicament for the treatment or prevention of diseases or disorders mediated by polymerase theta.
  • the present disclosure provides a method of treating or preventing diseases or disorders, such as diseases or disorders mediated by polymerase theta, in a subject, comprising administering to the subject at least one compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition disclosed herein.
  • the present disclosure provides the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition disclosed herein, for use in treating or preventing diseases or disorders, such as diseases or disorders mediated by polymerase theta.
  • C 1-6 alkyl is intended to encompass C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 alkyl.
  • C 6-14 aryl refers to a radical of a carbocyclic aromatic group, whether or not fused to one or more groups, having 6 to 14 ring carbon atoms and zero heteroatoms.
  • the aryl may have 6-10 membered ring carbon atoms.
  • the aryl group may be monocylic or polycylic (e.g., bicyclic or tricyclic). Examples of the aryl group include, but are not limited to, phenyl, naphtyl, anthracyl, and the like.
  • the aryl group also includes ring systems wherein the aryl ring, as defined herein, is fused with one or more cycloalkyl or heterocyclyl groups wherein the point of attachment is on the aryl ring.
  • the number of substituents may be any number as long as valence of ths substitued atom and the substituent permit, for example 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 5, 2 to 4, 2 to 3, 3 to 5, 3 to 4, and the like.
  • numeric value when used with a corresponding numeric value, is meant to encompass variations within ⁇ 20% of the numeric value, typically ⁇ 10% of the numeric value, often ⁇ 5% of the numeric value, and most often ⁇ 2% of the numeric value. In some embodiments, the term “about” can mean the numeric value itself.
  • a compound of Formula (I) (including subsets of each formula), or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
  • compound of the present disclosure refers to the following compound of Formula (I) (including subsets of each formula), or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
  • the present disclosure relates to a compound of Formula (I):
  • each of R 1 , R 2 , R 3 , R 4 and R 5 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, hydroxy, and -NR x R y , wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • X is selected from the group consisting of methylene, ethylene, n-propylene, -NH-, -NR z1 -, and -CR z2 R z3 -, wherein each of said methylene, ethylene, and n-propylene is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • each of Y and Z is independently selected from the group consisting of -N- and -CR w -;
  • W is selected from the group consisting of carbon and sulfur
  • n 1 or 2, provided that when W is carbon, n is 1; and when W is sulfur, n is 2;
  • A is selected from the group consisting of 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, halogen, 3-10 membered cycloalkyl, -NR x R y , amino, mercapto, and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • L 1 is selected from the group consisting of absent, -(C 1 -C 6 )alkylene-, and -(C 1 -C 6 )alkylene-NH-;
  • L 2 is selected from the group consisting of absent, and -(C 1 -C 6 )alkylene-, wherein said alkylene is optionally substituted with one or more selected from C 1 -C 6 alkyl, and halogen;
  • R 6 is selected from the group consisting of phenyl and a 3-10 membered heterocyclyl group, wherein each of said phenyl and heterocyclyl group is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C 1 -C 6 alkoxy, mercapto, amino, -COOH, -S(O) 2 NH 2 , -NR 61 R 62 , -NHC(O)R 63 , -C(O)NR 64 R 65 , 5-6 membered heterocyclyl, and -CH 2 -R 66 , wherein each of said alkyl, alkoxy, and heterocyclyl is optionally substituted one or more selected from with C 1 -C 6 alkyl, halogen, and deuterium;
  • each of R 61 and R 62 is selected from the group consisting of hydrogen, and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl, or
  • R 61 and R 62 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 5-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R 63 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, NH 2 , and C 2 -C 6 alkenyl, wherein each of said alkyl and alkenyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • each of R 64 and R 65 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl, or
  • R 64 and R 65 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 5-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R 66 is a 5-10 membered heterocyclyl group, wherein said heterocyclyl group is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, oxo, carbamoyl, and amino;
  • each of R x and R y is independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • R z1 is C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • R z2 and R z3 taken together with the carbon atom to which they are attached, form a 3-6 membered cycloalkane ring, wherein said cycloalkane ring is optionally substituted with one or more selected selected from C 1 -C 6 alkyl and halogen; and
  • R w is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halogen, cyano, deuterium, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, 3-10 membered cycloalkyl, -NR x R y , hydroxy, amino, mercapto, and carbamoyl,
  • A is selected from the group consisting of 5-12 membered monocyclic or bicyclic aryl or heteroaryl, preferably, A is selected from the group consisting of 6-10 membered monocyclic or bicyclic aryl or heteroaryl, more preferably, A is selected from the group consisting of 6-membered monocyclic aryl or heteroaryl and 10-membered bicyclic aryl or heteroaryl, still more preferably, A is 6-membered monocyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, 3-10 membered cycloalkyl, -NR x R y , amino, mercapto, and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy, and
  • A is selected from phenyl, pyridinyl, pyrrolyl, pyrazoly, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinolizyinyl, quinoxalinyl, pthalazinyl, quinazolinyl, cinnolinyl, and naphthyl, wherein each of said phenyl, pyridinyl, pyrrolyl, pyrazoly, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinolizyinyl, quinoxalinyl, pthalazinyl, quinazolinyl, isoquinol
  • A is phenyl, wherein said phenyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, 3-10 membered cycloalkyl, and -NR x R y , wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and R 1 -R 6 , L 1 , L 2 , X, Y, Z, W and n are as defined above.
  • A is selected from the group consisting of 5-12 membered monocyclic or bicyclic aryl or heteroaryl, preferably, A is selected from the group consisting of 6-10 membered monocyclic or bicyclic aryl or heteroaryl, more preferably, A is selected from the group consisting of 6-membered monocyclic aryl or heteroaryl and 10-membered bicyclic aryl or heteroaryl, still more preferably, A is 6-membered monocyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from an unsubstituted C 1 -C 6 alkyl, a substituted C 1 -C 6 alkyl with halogen, and halogen; more preferably, each of said aryl and heteroaryl is independently optionally substituted with one or more selected from methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, triflu
  • A is selected from a group consisting of phenyl, pyridinyl, pyrrolyl, pyrazoly, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinolizyinyl, quinoxalinyl, pthalazinyl, quinazolinyl, cinnolinyl, and naphthyl, wherein each of said phenyl, pyridinyl, pyrrolyl, pyrazoly, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinolizyinyl, quinoxalinyl, pthalazinyl, quina
  • A is phenyl, wherein said phenyl is optionally substituted with one or more selected from an unsubstituted C 1 -C 6 alkyl, a substituted C 1 -C 6 alkyl with halogen, halogen, cyano, and deuterium; preferably, said phenyl is optionally substituted with one or more selected from an unsubstituted C 1 -C 6 alkyl, a substituted C 1 -C 6 alkyl with halogen, and halogen; more preferably, said phenyl is optionally substituted with one or more selected from methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, and iodo; more preferably, said phenyl is optionally substituted with one or more selected from methyl, fluoro, and chloro; and R 1 -R 6 , L 1
  • A is ,
  • R a1 is selected from the group consisting of hydrogen and fluoride
  • R a2 is selected from the group consisting of methyl and chloride
  • R a3 is selected from the group consisting of hydrogen, and fluoride
  • R a4 is selected from the group consisting of hydrogen, and methyl
  • R a5 is selected from the group consisting of hydrogen, and fluoride
  • R 1 -R 6 , L 1 , L 2 , X, Y, Z, W and n are as defined above.
  • each of R 611 , R 612 , R 613 , R 614 , R 621 , R 631 , R 632 , R 633 , R 634 , R 641 , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , and R 6i is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halogen, cyano, oxo, carbamoyl, C 1 -C 6 alkoxy, amino, -COOH, -S(O) 2 NH 2 , -NR 61 R 62 , -NHC(O)R 63 , -C(O)NR 64 R 65 , 5-6 membered heterocyclyl, and -CH 2 -R 66 , wherein each of said alkyl, alkoxy, and heterocyclyl is optionally substituted with one or more selected from C 1 -
  • each of R 64 and R 65 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl, or
  • R 66 is a 6-10 membered heterocyclyl group, wherein said heterocyclyl group is optionally substituted with one or more selected from oxo, and carbamoyl;
  • R 1 -R 5 , ring A, L 1 , L 2 , X, Y, Z, W and n are as defined above.
  • R 6 is selected from the group consisting of:
  • each of R 61 and R 62 is selected from the group consisting of hydrogen, and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl, or
  • R 61 and R 62 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 6-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R 63 is selected from the group consisting of C 1 -C 6 alkyl, NH 2 , and C 2 -C 6 alkenyl, wherein each of said alkyl and alkenyl is optionally substituted with halogen;
  • each of R 64 and R 65 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl, or
  • R 64 and R 65 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 5-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with C 1 -C 6 alkyl;
  • R 66 is a 6-10 membered heterocyclyl group, wherein said heterocyclyl group is optionally substituted with one or more selected from oxo, and carbamoyl;
  • R 1 -R 5 , ring A, L 1 , L 2 , X, Y, Z, W and n are as defined above.
  • R 6 is selected from the group consisting of:
  • each of R 611 , R 612 , R 613 , R 614 , R 621 , R 631 , R 632 , R 633 , R 634 , R 641 , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , and R 6i is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, fluoro, chloro, bromo, iodo, cyano, oxo, carbamoyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, n-propoxy, isopropoxy, amino, -COOH, -S(O) 2 NH 2 , -NR 61 R 62 , -NHC(O)R 63 , -C(O)NR 64 R 65
  • each of R 61 and R 62 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, and isopropyl, or
  • R 61 and R 62 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 6-8 membered heterocyclic group, which is:
  • R 63 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, NH 2 , ethenyl, 1-fluoroethenyl, and 1,2-difluoroethenyl;
  • each of R 64 and R 65 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, and isopropyl, or
  • R 64 and R 65 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 6-8 membered heterocyclic group, which is:
  • R 66 is a 6-10 membered heterocyclyl group, which is:
  • R 1 -R 5 , ring A, L 1 , L 2 , X, Y, Z, W and n are as defined above.
  • R 6 is selected from the group consisting of:
  • each of R 611 , R 612 , R 613 , R 614 , R 621 , R 631 , R 632 , R 633 , R 634 , R 641 , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , and R 6i is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, fluoro, cyano, oxo, carbamoyl, methoxy, difluoromethoxy, isopropoxy, amino, -COOH, -S(O) 2 NH 2 , -NR 61 R 62 , -NHC(O)R 63 , -C(O)NR 64 R 65 , -CH 2 -R 66 ,
  • each of R 61 and R 62 is selected from the group consisting of hydrogen, ethyl, and isopropyl, or
  • R 61 and R 62 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 6-8 membered heterocyclic group, which is:
  • R 63 is selected from the group consisting of methyl, NH 2 , ethenyl, and 1-fluoroethenyl;
  • each of R 64 and R 65 is selected from the group consisting of hydrogen, and methyl, or
  • R 64 and R 65 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 6-8 membered heterocyclic group, which is:
  • R 66 is a 6-10 membered heterocyclyl group, which is:
  • R 1 -R 5 , ring A, L 1 , L 2 , X, Y, Z, W and n are as defined above.
  • R 6 is phenyl, wherein said phenyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C 1 -C 6 alkoxy, mercapto, amino, -COOH, -S(O) 2 NH 2 , -NR 61 R 62 , -NHC(O)R 63 , -C(O)NR 64 R 65 , 5-6 membered heterocyclyl, and -CH 2 -R 66 , wherein each of said alkyl, alkoxy, and heterocyclyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, and deuterium; and R 1 -R 5 , R 61 -R 66 , ring A, L 1 , L 2 , X, Y, Z, W and n are as defined above.
  • R 6 is phenyl, wherein said phenyl is optionally with one or more from C 1 -C 6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C 1 -C 6 alkoxy, mercapto, amino, -COOH, -S(O) 2 NH 2 , and -C(O)NR 64 R 65 , wherein each of said alkyl, and alkoxy is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, and deutrium;
  • each of R 64 and R 65 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl;
  • R 1 -R 5 , ring A, L 1 , L 2 , X, Y, Z, W and n are as defined above.
  • R 6 is phenyl, wherein said phenyl is optionally with one or more from C 1 -C 6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, and -C(O)NR 64 R 65 , wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, and deuterium;
  • each of R 64 and R 65 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl; and R 1 -R 5 , R 64 -R 65 , ring A, L 1 , L 2 , X, Y, Z, W and n are as defined above.
  • R 6 is phenyl, wherein said phenyl is optionally with carbamoyl; and R 1 -R 5 , R 64 -R 65 , ring A, L 1 , L 2 , X, Y, Z, W and n are as defined above.
  • R 6 is
  • each of R 651 , R 652 , R 653 , R 654 , and R 655 is hydrogen, or carbamoyl; and R 1 -R 5 , R 64 -R 65 , ring A, L 1 , L 2 , X, Y, Z, W and n are as defined above.
  • the present disclosure relates to a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih):
  • each of R 1 , R 2 , R 3 , R 4 and R 5 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, hydroxy, and -NR x R y , wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • X is selected from the group consisting of methylene, ethylene, n-propylene, -NH-, -NR z1 -, and -CR z2 R z3 -, wherein each of said methylene, ethylene, and n-propylene is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • W is selected from the group consisting of carbon and sulfur
  • n 1 or 2, provided that when W is carbon, n is 1; and when W is sulfur, n is 2;
  • A is selected from the group consisting of 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, halogen, 3-10 membered cycloalkyl, -NR x R y , amino, mercapto, and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • L 1 is selected from the group consisting of absent, -(C 1 -C 6 )alkylene-, and -(C 1 -C 6 )alkylene-NH-;
  • L 2 is selected from the group consisting of absent, and -(C 1 -C 6 )alkylene-, wherein said alkylene is optionally substituted with one or more selected from C 1 -C 6 alkyl, and halogen;
  • R 6 is selected from the group consisting of phenyl and a 3-10 membered heterocyclyl group, wherein each of said phenyl and heterocyclyl group is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C 1 -C 6 alkoxy, mercapto, amino, -COOH, -S(O) 2 NH 2 , -NR 61 R 62 , -NHC(O)R 63 , -C(O)NR 64 R 65 , 5-6 memebered heterocyclyl, and -CH 2 -R 66 , wherein each of said alkyl, alkoxy, and heterocyclyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, and deuterium;
  • each of R 61 and R 62 is selected from the group consisting of hydrogen, and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl, or
  • R 61 and R 62 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 5-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R 63 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, NH 2 , and C 2 -C 6 alkenyl, wherein each of said alkyl and alkenyl is optionally substituted with one or more from C 1 -C 6 alkyl and halogen;
  • each of R 64 and R 65 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl, or
  • R 64 and R 65 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 5-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R 66 is a 5-10 membered heterocyclyl group, wherein said heterocyclyl group is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, oxo, carbamoyl, and amino;
  • each of R x and R y is independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • R z1 is C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • R z2 and R z3 taken together with the carbon atom to which they are attached, form a 3-6 membered cycloalkane ring, wherein said cycloalkane ring is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R w is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halogen, cyano, deuterium, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, 3-10 membered cycloalkyl, -NR x R y , hydroxy, amino, mercapto, and carbamoyl,
  • the present disclosure relates to a compound of Formula (II):
  • each of R 1 , R 2 , R 3 , R 4 and R 5 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, hydroxy, and -NR x R y , wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • A is selected from the group consisting of 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, halogen, 3-10 membered cycloalkyl, -NR x R y , amino, mercapto, and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • each of Y and Z is independently selected from the group consisting of -N- and -CR w -;
  • L 2 is selected from the group consisting of absent, and -(C 1 -C 6 )alkylene-, wherein said alkylene is optionally substituted with one or more selected from C 1 -C 6 alkyl, and halogen;
  • each of R 61 and R 62 is selected from the group consisting of hydrogen, and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl, or
  • R 61 and R 62 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 5-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • each of R x and R y is independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and
  • R w is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halogen, cyano, deuterium, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, 3-10 membered cycloalkyl, -NR x R y , hydroxy, amino, mercapto, and carbamoyl.
  • the present disclosure relates to a compound of Formula (IIa-1):
  • each of R a1 , R a2 , R a3 , R a4 , and R a5 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halogen, cyano, deuterium, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, halogen, 3-10 membered cycloalkyl, -NR x R y , amino, mercapto, and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • L 2 is selected from the group consisting of absent, and -(C 1 -C 6 )alkylene-, wherein said alkylene is optionally substituted with one or more selected from C 1 -C 6 alkyl, and halogen;
  • each of R 61 and R 62 is selected from the group consisting of hydrogen, and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl, or
  • R 61 and R 62 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 5-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen; and
  • each of R x and R y is independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl,
  • each of R a1 , R a2 , R a3 , R a4 , and R a5 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, and iodo;
  • L 2 is selected from the group consisting of absent, methylene, 1,1-ethylene, 1,2-ethylene, 1,3-proplyene, 1,2-propylene, 1,1-propylene, 1,1-butylene, 1,2-butylene, 2,2-butylene, and ;
  • each of R 61 and R 62 is selected from the group consisting of hydrogen, and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl, or
  • R 61 and R 62 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 6-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen.
  • each of R a1 , R a2 , R a3 , R a4 , and R a5 is selected from the group consisting of hydrogen, methyl, fluoro, and chloro;
  • L 2 is selected from the group consisting of absent, methylene, and ;
  • each of R 61 and R 62 is selected from the group consisting of hydrogen, ethyl, and isopropyl, or
  • R 61 and R 62 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 6-8 membered heterocyclic group, which is:
  • the present disclosure relates to a compound of Formula (III):
  • each of R 1 , R 2 , R 3 , R 4 and R 5 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, hydroxy, and -NR x R y , wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • X is selected from the group consisting of methylene, ethylene, n-propylene, -NH-, -NR z1 -, and -CR z2 R z3 -, wherein each of said methylene, ethylene, and n-propylene is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • each of Y and Z is independently selected from the group consisting of -N- and -CR w -;
  • W is selected from the group consisting of carbon and sulfur
  • n 1 or 2, provided that when W is carbon, n is 1; and when W is sulfur, n is 2;
  • A is selected from the group consisting of 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, halogen, 3-10 membered cycloalkyl, -NR x R y , amino, mercapto, and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • L 2 is selected from the group consisting of absent, and -(C 1 -C 6 )alkylene-, wherein said alkylene is optionally substituted with one or more selected from C 1 -C 6 alkyl, and halogen;
  • R 6 is selected from the group consisting of phenyl and a 3-10 membered heterocyclyl group, wherein each of said phenyl and heterocyclyl group is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C 1 -C 6 alkoxy, mercapto, amino, -COOH, -S(O) 2 NH 2 , -NR 61 R 62 , -NHC(O)R 63 , -C(O)NR 64 R 65 , 5-6 memebered heterocyclyl, and -CH 2 -R 66 , wherein each of said alkyl, alkoxy, and heterocyclyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, and deuterium;
  • each of R 61 and R 62 is selected from the group consisting of hydrogen, and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl, or
  • R 61 and R 62 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 5-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R 63 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, NH 2 , and C 2 -C 6 alkenyl, wherein each of said alkyl and alkenyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • each of R 64 and R 65 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl, or
  • R 64 and R 65 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 5-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • each of R x and R y is independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • R z1 is C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • R w is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halogen, cyano, deuterium, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, 3-10 membered cycloalkyl, -NR x R y , hydroxy, amino, mercapto, and carbamoyl,
  • the present disclosure relates to a compound of Formula (IIIa):
  • each of Y and Z is independently selected from the group consisting of -N- and -CR w -;
  • L 2 is selected from the group consisting of absent, and -(C 1 -C 6 )alkylene-, wherein said alkylene is optionally substituted with one or more selected from C 1 -C 6 alkyl, and halogen;
  • R 6 is selected from the group consisting of phenyl and a 3-10 membered heterocyclyl group, wherein each of said phenyl and heterocyclyl group is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C 1 -C 6 alkoxy, mercapto, amino, -COOH, -S(O) 2 NH 2 , -NR 61 R 62 , -NHC(O)R 63 , -C(O)NR 64 R 65 , 5-6 memebered heterocyclyl, and -CH 2 -R 66 , wherein each of said alkyl, alkoxy, and heterocyclyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, and deuterium;
  • R 61 and R 62 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 5-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R 63 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, NH 2 , and C 2 -C 6 alkenyl, wherein each of said alkyl and alkenyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • each of R 64 and R 65 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl, or
  • R 66 is a 5-10 membered heterocyclyl group, wherein said heterocyclyl group is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, oxo, carbamoyl, and amino;
  • R w is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halogen, cyano, deuterium, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, 3-10 membered cycloalkyl, -NR x R y , hydroxy, amino, mercapto, and carbamoyl,
  • L 2 is selected from the group consisting of absent, and -(C 1 -C 6 )alkylene-, wherein said alkylene is optionally substituted with one or more selected from C 1 -C 6 alkyl, and halogen;
  • R 63 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, NH 2 , and C 2 -C 6 alkenyl, wherein each of said alkyl and alkenyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R 64 and R 65 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 5-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • each of R x and R y is independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl,
  • L 2 is selected from the group consisting of absent, methylene, 1,1-ethylene, 1,2-ethylene, 1,3-proplyene, 1,2-propylene, 1,1-propylene, 1,1-butylene, 1,2-butylene, 2,2-butylene, and ;
  • R 6 is selected from the group consisting of:
  • each of R 611 , R 612 , R 613 , R 614 , R 621 , R 631 , R 632 , R 633 , R 634 , R 641 , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , and R 6i is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halogen, cyano, oxo, carbamoyl, C 1 -C 6 alkoxy, amino, -COOH, -S(O) 2 NH 2 , -NR 61 R 62 , -NHC(O)R 63 , -C(O)NR 64 R 65 , 5-6 membered heterocyclyl, and -CH 2 -R 66 , wherein each of said alkyl, alkoxy, and heterocyclyl is optionally substituted with one or more selected from C 1 -
  • each of R 651 , R 652 , R 653 , R 654 , and R 655 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, and -C(O)NR 64 R 65 , wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, and deuterium;
  • each of R 61 and R 62 is selected from the group consisting of hydrogen, and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl, or
  • R 61 and R 62 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 6-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R 66 is a 6-10 membered heterocyclyl group, wherein said heterocyclyl group is optionally substituted with one or more selected from oxo, and carbamoyl.
  • each of R a1 , R a2 , R a3 , R a4 , and R a5 is selected from the group consisting of hydrogen, methyl, fluoro, and chloro;
  • R 6 is selected from the group consisting of:
  • each of R 611 , R 612 , R 613 , R 614 , R 621 , R 631 , R 632 , R 633 , R 634 , R 641 , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , and R 6i is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, fluoro, cyano, oxo, carbamoyl, methoxy, difluoromethoxy, isopropoxy, amino, -COOH, -S(O) 2 NH 2 , -NR 61 R 62 , -NHC(O)R 63 , -C(O)NR 64 R 65 , -CH 2 -R 66 ,
  • each of R 651 , R 652 , R 653 , R 654 , and R 655 is independently selected from the group consisting of hydrogen, and carbamoyl;
  • each of R 61 and R 62 is selected from the group consisting of hydrogen, ethyl, and isopropyl, or
  • R 61 and R 62 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 6-8 membered heterocyclic group, which is:
  • R 63 is selected from the group consisting of methyl, NH 2 , ethenyl, and 1-fluoroethenyl;
  • each of R 64 and R 65 is selected from the group consisting of hydrogen, and methyl, or
  • R 64 and R 65 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 6-8 membered heterocyclic group, which is:
  • R 66 is a 6-10 membered heterocyclyl group, which is:
  • the present disclosure relates to a compound of Formula (IIIb):
  • each of R 1 , R 2 , R 3 , R 4 and R 5 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, hydroxy, and -NR x R y , wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • each of Y and Z is independently selected from the group consisting of -N- and -CR w -;
  • A is selected from the group consisting of 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, halogen, 3-10 membered cycloalkyl, -NR x R y , amino, mercapto, and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • L 2 is selected from the group consisting of absent, and -(C 1 -C 6 )alkylene-, wherein said alkylene is optionally substituted with one or more selected from C 1 -C 6 alkyl, and halogen;
  • R 6 is selected from the group consisting of phenyl and a 3-10 membered heterocyclyl group, wherein each of said phenyl and heterocyclyl group is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C 1 -C 6 alkoxy, mercapto, amino, -COOH, -S(O) 2 NH 2 , -NR 61 R 62 , -NHC(O)R 63 , -C(O)NR 64 R 65 , 5-6 memebered heterocyclyl, and -CH 2 -R 66 , wherein each of said alkyl, alkoxy, and heterocyclyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, and deuterium;
  • each of R 61 and R 62 is selected from the group consisting of hydrogen, and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl, or
  • R 61 and R 62 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 5-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R 63 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, NH 2 , and C 2 -C 6 alkenyl, wherein each of said alkyl and alkenyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • each of R 64 and R 65 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl, or
  • R 64 and R 65 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 5-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R 66 is a 5-10 membered heterocyclyl group, wherein said heterocyclyl group is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, oxo, carbamoyl, and amino;
  • each of R x and R y is independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and
  • R w is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halogen, cyano, deuterium, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, 3-10 membered cycloalkyl, -NR x R y , hydroxy, amino, mercapto, and carbamoyl,
  • the present disclosure relates to a compound of Formula (IIIb-1):
  • each of R a1 , R a2 , R a3 , R a4 , and R a5 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halogen, cyano, deuterium, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, halogen, 3-10 membered cycloalkyl, -NR x R y , amino, mercapto, and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • L 2 is selected from the group consisting of absent, and -(C 1 -C 6 )alkylene-, wherein said alkylene is optionally substituted with one or more selected from C 1 -C 6 alkyl, and halogen;
  • R 6 is selected from the group consisting of phenyl and a 3-10 membered heterocyclyl group, wherein each of said phenyl and heterocyclyl group is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C 1 -C 6 alkoxy, mercapto, amino, -COOH, -S(O) 2 NH 2 , -NR 61 R 62 , -NHC(O)R 63 , -C(O)NR 64 R 65 , 5-6 memebered heterocyclyl, and -CH 2 -R 66 , wherein each of said alkyl, alkoxy, and heterocyclyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, and deuterium;
  • R 61 and R 62 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 5-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R 63 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, NH 2 , and C 2 -C 6 alkenyl, wherein each of said alkyl and alkenyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R 64 and R 65 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 5-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • each of R a1 , R a2 , R a3 , R a4 , and R a5 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, and iodo;
  • L 2 is selected from the group consisting of absent, methylene, 1,1-ethylene, 1,2-ethylene, 1,3-proplyene, 1,2-propylene, 1,1-propylene, 1,1-butylene, 1,2-butylene, 2,2-butylene, and ;
  • each of R 651 , R 652 , R 653 , R 654 , and R 655 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, and -C(O)NR 64 R 65 , wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, and deuterium;
  • R 61 and R 62 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 6-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • L 2 is selected from the group consisting of absent, methylene, and ;
  • each of R 611 , R 612 , R 613 , R 614 , R 621 , R 631 , R 632 , R 633 , R 634 , R 641 , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , R 6i , R 651 , R 652 , R 653 , R 654 , and R 655 is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, fluoro, cyano, oxo, carbamoyl, methoxy, difluoromethoxy, isopropoxy, amino, -COOH, -S(O) 2 NH 2 , -NR 61 R 62 , -NHC(O)R 63 , -C(O)NR 64 R 65 , -CH 2 -R 66 ,
  • each of R 61 and R 62 is selected from the group consisting of hydrogen, ethyl, and isopropyl, or
  • R 61 and R 62 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 6-8 membered heterocyclic group, which is:
  • R 63 is selected from the group consisting of methyl, NH 2 , ethenyl, and 1-fluoroethenyl;
  • R 64 and R 65 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 6-8 membered heterocyclic group, which is:
  • R 66 is a 6-10 membered heterocyclyl group, which is:
  • the present disclosure relates to a compound of Formula (IIIc-1):
  • each of R 1 , R 2 , R 3 , R 4 and R 5 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, hydroxy, and -NR x R y , wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • R z1 is C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • each of Y and Z is independently selected from the group consisting of -N- and -CR w -;
  • A is selected from the group consisting of 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, halogen, 3-10 membered cycloalkyl, -NR x R y , amino, mercapto, and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • L 2 is selected from the group consisting of absent, and -(C 1 -C 6 )alkylene-, wherein said alkylene is optionally substituted with one or more selected from C 1 -C 6 alkyl, and halogen;
  • R 6 is selected from the group consisting of phenyl and a 3-10 membered heterocyclyl group, wherein each of said phenyl and heterocyclyl group is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C 1 -C 6 alkoxy, mercapto, amino, -COOH, -S(O) 2 NH 2 , -NR 61 R 62 , -NHC(O)R 63 , -C(O)NR 64 R 65 , 5-6 memebered heterocyclyl, and -CH 2 -R 66 , wherein each of said alkyl, alkoxy, and heterocyclyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, and deuterium;
  • each of R 61 and R 62 is selected from the group consisting of hydrogen, and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl, or
  • R 61 and R 62 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 5-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R 63 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, NH 2 , and C 2 -C 6 alkenyl, wherein each of said alkyl and alkenyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • each of R 64 and R 65 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl, or
  • R 64 and R 65 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 5-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R 66 is a 5-10 membered heterocyclyl group, wherein said heterocyclyl group is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, oxo, carbamoyl, and amino;
  • each of R x and R y is independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and
  • R w is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halogen, cyano, deuterium, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, 3-10 membered cycloalkyl, -NR x R y , hydroxy, amino, mercapto, and carbamoyl,
  • the present disclosure relates to a compound of Formula (IIIc-1):
  • each of R a1 , R a2 , R a3 , R a4 , and R a5 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halogen, cyano, deuterium, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, halogen, 3-10 membered cycloalkyl, -NR x R y , amino, mercapto, and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • R z1 is C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • L 2 is selected from the group consisting of absent, and -(C 1 -C 6 )alkylene-, wherein said alkylene is optionally substituted with one or more selected from C 1 -C 6 alkyl, and halogen;
  • R 6 is selected from the group consisting of phenyl and a 3-10 membered heterocyclyl group, wherein each of said phenyl and heterocyclyl group is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C 1 -C 6 alkoxy, mercapto, amino, -COOH, -S(O) 2 NH 2 , -NR 61 R 62 , -NHC(O)R 63 , -C(O)NR 64 R 65 , 5-6 memebered heterocyclyl, and -CH 2 -R 66 , wherein each of said alkyl, alkoxy, and heterocyclyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, and deuterium;
  • each of R 61 and R 62 is selected from the group consisting of hydrogen, and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl, or
  • R 61 and R 62 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 5-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R 63 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, NH 2 , and C 2 -C 6 alkenyl, wherein each of said alkyl and alkenyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • each of R 64 and R 65 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl, or
  • R 64 and R 65 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 5-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R 66 is a 5-10 membered heterocyclyl group, wherein said heterocyclyl group is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, oxo, carbamoyl, and amino; and
  • each of R x and R y is independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl,
  • each of R a1 , R a2 , R a3 , R a4 , and R a5 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, and iodo;
  • R z1 is C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl;
  • L 2 is selected from the group consisting of absent, methylene, 1,1-ethylene, 1,2-ethylene, 1,3-proplyene, 1,2-propylene, 1,1-propylene, 1,1-butylene, 1,2-butylene, 2,2-butylene, and ;
  • R 6 is selected from the group consisting of:
  • each of R 611 , R 612 , R 613 , R 614 , R 621 , R 631 , R 632 , R 633 , R 634 , R 641 , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , and R 6i is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halogen, cyano, oxo, carbamoyl, C 1 -C 6 alkoxy, amino, -COOH, -S(O) 2 NH 2 , -NR 61 R 62 , -NHC(O)R 63 , -C(O)NR 64 R 65 , 5-6 membered heterocyclyl, and -CH 2 -R 66 , wherein each of said alkyl, alkoxy, and heterocyclyl is optionally substituted with one or more selected from C 1 -
  • each of R 651 , R 652 , R 653 , R 654 , and R 655 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, and -C(O)NR 64 R 65 , wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, and deuterium;
  • each of R 61 and R 62 is selected from the group consisting of hydrogen, and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl, or
  • R 61 and R 62 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 6-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R 63 is selected from the group consisting of C 1 -C 6 alkyl, NH 2 , and C 2 -C 6 alkenyl, wherein each of said alkyl and alkenyl is optionally substituted with halogen;
  • each of R 64 and R 65 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl, or
  • R 64 and R 65 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 5-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with C 1 -C 6 alkyl;
  • R 66 is a 6-10 membered heterocyclyl group, wherein said heterocyclyl group is optionally substituted with one or more selected from oxo, and carbamoyl.
  • each of R a1 , R a2 , R a3 , R a4 , and R a5 is selected from the group consisting of hydrogen, methyl, fluoro, and chloro;
  • R z1 is methyl or isopropyl
  • L 1 is selected from the group consisting of absent, and methylene
  • L 2 is selected from the group consisting of absent, methylene, and ;
  • R 6 is selected from the group consisting of:
  • each of R 611 , R 612 , R 613 , R 614 , R 621 , R 631 , R 632 , R 633 , R 634 , R 641 , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , and R 6i is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, fluoro, cyano, oxo, carbamoyl, methoxy, difluoromethoxy, isopropoxy, amino, -COOH, -S(O) 2 NH 2 , -NR 61 R 62 , -NHC(O)R 63 , -C(O)NR 64 R 65 , -CH 2 -R 66 ,
  • each of R 651 , R 652 , R 653 , R 654 , and R 655 is independently selected from the group consisting of hydrogen, and carbamoyl;
  • each of R 61 and R 62 is selected from the group consisting of hydrogen, ethyl, and isopropyl, or
  • R 61 and R 62 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 6-8 membered heterocyclic group, which is:
  • R 63 is selected from the group consisting of methyl, NH 2 , ethenyl, and 1-fluoroethenyl;
  • each of R 64 and R 65 is selected from the group consisting of hydrogen, and methyl, or
  • R 64 and R 65 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 6-8 membered heterocyclic group, which is:
  • R 66 is a 6-10 membered heterocyclyl group, which is:
  • the present disclosure relates to a compound of Formula (IIId):
  • each of R 1 , R 2 , R 3 , R 4 and R 5 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, hydroxy, and -NR x R y , wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • n is an integer from 1 to 4.
  • each of Y and Z is independently selected from the group consisting of -N- and -CR w -;
  • A is selected from the group consisting of 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, halogen, 3-10 membered cycloalkyl, -NR x R y , amino, mercapto, and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • L 2 is selected from the group consisting of absent, and -(C 1 -C 6 )alkylene-, wherein said alkylene is optionally substituted with one or more selected from C 1 -C 6 alkyl, and halogen;
  • R 6 is selected from the group consisting of phenyl and a 3-10 membered heterocyclyl group, wherein each of said phenyl and heterocyclyl group is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C 1 -C 6 alkoxy, mercapto, amino, -COOH, -S(O) 2 NH 2 , -NR 61 R 62 , -NHC(O)R 63 , -C(O)NR 64 R 65 , 5-6 memebered heterocyclyl, and -CH 2 -R 66 , wherein each of said alkyl, alkoxy, and heterocyclyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, and deuterium;
  • each of R 61 and R 62 is selected from the group consisting of hydrogen, and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl, or
  • R 61 and R 62 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 5-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R 63 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, NH 2 , and C 2 -C 6 alkenyl, wherein each of said alkyl and alkenyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • each of R 64 and R 65 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl, or
  • R 64 and R 65 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 5-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R 66 is a 5-10 membered heterocyclyl group, wherein said heterocyclyl group is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, oxo, carbamoyl, and amino;
  • each of R x and R y is independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and
  • R w is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halogen, cyano, deuterium, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, 3-10 membered cycloalkyl, -NR x R y , hydroxy, amino, mercapto, and carbamoyl,
  • the present disclosure relates to a compound of Formula (IIId-1):
  • each of R a1 , R a2 , R a3 , R a4 , and R a5 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halogen, cyano, deuterium, C 2 -C 6 alkenyl, hydroxy, C 1 -C 6 alkoxy, halogen, 3-10 membered cycloalkyl, -NR x R y , amino, mercapto, and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;
  • n is an integer from 1 to 4.
  • L 2 is selected from the group consisting of absent, and -(C 1 -C 6 )alkylene-, wherein said alkylene is optionally substituted with one or more selected from C 1 -C 6 alkyl, and halogen;
  • R 6 is selected from the group consisting of phenyl and a 3-10 membered heterocyclyl group, wherein each of said phenyl and heterocyclyl group is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C 1 -C 6 alkoxy, mercapto, amino, -COOH, -S(O) 2 NH 2 , -NR 61 R 62 , -NHC(O)R 63 , -C(O)NR 64 R 65 , 5-6 memebered heterocyclyl, and -CH 2 -R 66 , wherein each of said alkyl, alkoxy, and heterocyclyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, and deuterium;
  • each of R 61 and R 62 is selected from the group consisting of hydrogen, and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl, or
  • R 61 and R 62 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 5-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R 63 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, NH 2 , and C 2 -C 6 alkenyl, wherein each of said alkyl and alkenyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • each of R 64 and R 65 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl, or
  • R 64 and R 65 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 5-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R 66 is a 5-10 membered heterocyclyl group, wherein said heterocyclyl group is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, oxo, carbamoyl, and amino; and
  • each of R x and R y is independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl,
  • each of R a1 , R a2 , R a3 , R a4 , and R a5 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, and iodo;
  • n is an integer from 1 to 2;
  • L 2 is selected from the group consisting of absent, methylene, 1,1-ethylene, 1,2-ethylene, 1,3-proplyene, 1,2-propylene, 1,1-propylene, 1,1-butylene, 1,2-butylene, 2,2-butylene, and ;
  • R 6 is selected from the group consisting of:
  • each of R 611 , R 612 , R 613 , R 614 , R 621 , R 631 , R 632 , R 633 , R 634 , R 641 , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , and R 6i is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halogen, cyano, oxo, carbamoyl, C 1 -C 6 alkoxy, amino, -COOH, -S(O) 2 NH 2 , -NR 61 R 62 , -NHC(O)R 63 , -C(O)NR 64 R 65 , 5-6 membered heterocyclyl, and -CH 2 -R 66 , wherein each of said alkyl, alkoxy, and heterocyclyl is optionally substituted with one or more selected from C 1 -
  • each of R 651 , R 652 , R 653 , R 654 , and R 655 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, and -C(O)NR 64 R 65 , wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl, halogen, and deuterium;
  • each of R 61 and R 62 is selected from the group consisting of hydrogen, and C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl, or
  • R 61 and R 62 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 6-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one or more selected from C 1 -C 6 alkyl and halogen;
  • R 63 is selected from the group consisting of C 1 -C 6 alkyl, NH 2 , and C 2 -C 6 alkenyl, wherein each of said alkyl and alkenyl is optionally substituted with halogen;
  • each of R 64 and R 65 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl, or
  • R 64 and R 65 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 5-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with C 1 -C 6 alkyl;
  • R 66 is a 6-10 membered heterocyclyl group, wherein said heterocyclyl group is optionally substituted with one or more selected from oxo, and carbamoyl.
  • each of R a1 , R a2 , R a3 , R a4 , and R a5 is selected from the group consisting of hydrogen, methyl, fluoro, and chloro;
  • n 1;
  • L 2 is selected from the group consisting of absent, methylene, and ;
  • R 6 is selected from the group consisting of:
  • each of R 611 , R 612 , R 613 , R 614 , R 621 , R 631 , R 632 , R 633 , R 634 , R 641 , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , and R 6i is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, fluoro, cyano, oxo, carbamoyl, methoxy, difluoromethoxy, isopropoxy, amino, -COOH, -S(O) 2 NH 2 , -NR 61 R 62 , -NHC(O)R 63 , -C(O)NR 64 R 65 , -CH 2 -R 66 ,
  • each of R 651 , R 652 , R 653 , R 654 , and R 655 is independently selected from the group consisting of hydrogen, and carbamoyl;
  • each of R 61 and R 62 is selected from the group consisting of hydrogen, ethyl, and isopropyl, or
  • R 61 and R 62 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 6-8 membered heterocyclic group, which is:
  • R 63 is selected from the group consisting of methyl, NH 2 , ethenyl, and 1-fluoroethenyl;
  • R 64 and R 65 taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 6-8 membered heterocyclic group, which is:
  • R 66 is a 6-10 membered heterocyclyl group, which is:
  • R 1 -R 5 , Y, Z, L 2 , ring A, R 61 , and R 62 are as defined above.
  • Process B prepares the compound of Formula (III) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:
  • R 1 -R 5 , X, Y, Z, L 2 , ring A, R 6 , W, and n are as defined above, and
  • Hal 1 is a halide, preferably iodide.
  • step (i) comprises:
  • R 1 -R 5 , Y, Z, L 2 , and ring A are as defined above, and
  • each of Hal 2 and Hal 3 is a halide, preferably chloride, or bromide.
  • step (i) comprises:
  • R 1 -R 5 , Y, Z, L 2 , and ring A are as defined above, and
  • each of Hal 4 and Hal 5 is a halide, preferably bromide.
  • step (i) comprises:
  • R 1 -R 5 , Y, Z, L 2 , R z1 , and ring A are as defined above, and
  • each of Hal 6 , Hal 7 , and Hal 8 is a halide, preferably iodide, or bromide.
  • step (i) comprises:
  • R 1 -R 5 , Y, Z, L 2 , m, and ring A are as defined above, and
  • each of Hal 4 , Hal 9 , and Hal 10 is a halide, preferably bromide.
  • treat refers to a course of action (such as administering an inhibitor ofPol ⁇ or a pharmaceutical composition comprising same) initiated after a disease, disorder or condition, or a symptom thereof, has been diagnosed, observed, and the like so as to eliminate, reduce, suppress, mitigate, or ameliorate, either temporarily or permanently, at least one of the underlying causes of a disease, disorder, or condition afflicting a subject, or at least one of the symptoms associated with a disease, disorder, condition afflicting a subject.
  • treatment may also refer to inhibiting (e.g., arresting the development or further development of the disease, disorder or condition or clinical symptoms association therewith) an active disease.
  • prevent refers to a course of action (such as administering a Pol ⁇ inhibitor or a pharmaceutical composition comprising same) initiated in a manner (e.g., prior to the onset of a disease, disorder, condition or symptom thereof) so as to prevent, suppress, inhibit or reduce, either temporarily or permanently, a subject's risk of developing a disease, disorder, condition or the like (as determined by, for example, the absence of clinical symptoms) or delaying the onset thereof, generally in the context of a subject predisposed to having a particular disease, disorder or condition.
  • the terms also refer to slowing the progression of the disease, disorder or condition or inhibiting the progression of the disease, disorder or condition such that it does not reach a harmful or otherwise undesired state.
  • inhibiting and “reducing,” or any variation of these terms in relation of Pol ⁇ , may refer to any measurable decrease or complete inhibition to achieve a desired result.
  • a decrease in Pol ⁇ activity of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, compared to a control group.
  • the term "about” as used herein means variations within ⁇ 20%, preferably, within ⁇ 10%, more preferably within ⁇ 5% of a given value.
  • the present disclosure provides a compound that prevents or treats a disease or disorder mediated by Pol ⁇ or a disease or disorder in which Pol ⁇ activity is implicated.
  • the disease or disorder mediated by Pol ⁇ is any of proliferative disorders.
  • proliferative disorders is used interchangeably herein and pertains to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo.
  • proliferative conditions include, but are not limited to, pre-malignant and malignant cellular proliferation, including but not limited to, malignant neoplasms and tumors, cancers, leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), and atherosclerosis.
  • the disease or disorder mediated by Pol ⁇ is any of HR-deficient cancers, including BRCA1- and BRCA2-deficient cancer, such as breast cancer, ovarian cancer ( J. Med. Chem. 2022, 65, 19, 13198-13215), prostate cancer (Biochim Biophys Acta Mol Basis Dis. 2020 Dec 1;1866(12):165954.), pancreas cancer (Cancers (Basel) 2022 Aug 23;14(17):4077), and lung cancer ( Cancers 2019 , 11 (5), 722).
  • BRCA1- and BRCA2-deficient cancer such as breast cancer, ovarian cancer ( J. Med. Chem. 2022, 65, 19, 13198-13215), prostate cancer (Biochim Biophys Acta Mol Basis Dis. 2020 Dec 1;1866(12):165954.), pancreas cancer (Cancers (Basel) 2022 Aug 23;14(17):4077), and lung cancer ( Cancers 2019 , 11 (5), 722).
  • the present compound, composition and method may further enhance the efficacy of cancer therapies with at least one of the following modes of action (MOAs): (1) therapeutic mode that induces DNA damage, (2) therapeutic mode that modulates cell cycles, and (3) therapeutic mode that inhibits components involved in DNA damage responses (DDRs).
  • MOAs modes of action
  • the therapeutically effective amount of the compound of Formula (I) provided herein is an amount sufficient to provide therapeutic benefits during the course of the treatment, or to delay or minimize one or more symptoms associated with cancer.
  • the therapeutically effective amount of a compound is the amount of the therapeutic agent that, when used alone or in combination with other therapies, provides such therapeutic benefits during the course of the treatment.
  • Effective amounts of the compound of the present disclosure vary depending upon many different factors, including means of administration, target site, physiological state of the patient, whether the patient is human or an animal, other medications administered, whether treatment is prophylactic or therapeutic, as well as the specific activity of the composition itself and its ability to elicit the desired response in the individual.
  • the patient can be a human or non-human mammal.
  • dosage regimens are adjusted to provide an optimum therapeutic response, i.e., to optimize safety and efficacy. Accordingly, a therapeutically effective amount is also one of which any undesired collateral effects are outweighed by the beneficial effects of administering the compound as described herein.
  • the terms “combination”, “combined”, and related terms refer to the simultaneous, separate or sequential administration of two or more therapeutic agents or therapies.
  • the compound disclosed herein may be administered with another therapeutic agent or therapy simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form.
  • the another therapy may be radiotherapy.
  • the another therapeutic agent may be an anti-cancer agent.
  • the anti-cancer agent may include DNA damage response (DDR) targeting anti-cancer agents.
  • DDR DNA damage response
  • the DNA damage response (DDR) is a collective term for the plethora of different intra- and inter-cellular signaling events and enzyme activities that result from the induction and detection of DNA damage.
  • a number of anti-cancer agents targeting DDR have been known and developed, e.g., PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK Inhibitors (e.g., CC-115, M3814 (nedisertib or peposertib), AZD7648), CHK1/2 Inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575,
  • a pharmaceutical composition including the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutical acceptable carrier, wherein the composition may be administered simultaneously, separately or sequentially with additional DDR targeting anti-cancer agent described above.
  • a method of treating or preventing diseases or disorders mediated by polymerase theta, in a subject comprising administering to the subject the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the method further comprises administering additional DDR targeting anti-cancer agent described above to the subject.
  • kits comprising:
  • composition or dosage form comprising the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof and, optionally, one or more pharmaceutically acceptable carriers;
  • composition or dosage form comprising additional DDR targeting anti-cancer agent described above, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof and, optionally, one or more pharmaceutically acceptable carriers.
  • the kit is for use in a method of treating and/or preventing diseases or disorders mediated by polymerase theta.
  • the first pharmaceutical composition or dosage form may be administered simultaneously, separately or sequentially with second pharmaceutical composition or dosage form.
  • the kit may further comprise a package insert comprising an instruction for simultaneous, sequential or separate use in the treatment and/or prevention of diseases or disorders mediated by polymerase theta.
  • the present disclosure further relates to a pharmaceutical composition, comprising a pharmaceutically effective amount of one or more of the compounds disclosed herein, and a pharmaceutically acceptable carrier(s) and/or excipient(s).
  • the composition may further comprise at least one of additional therapeutic agents in amounts effective for achieving the treatment or prevention of diseases or disorders disclosed herein.
  • Pharmaceutically acceptable carriers and excipients are well known in the art, and the choice of carriers and excipients will to a large extent depend on factors such as mode of administration, their effects on solubility and stability, and the nature of dosage form.
  • the present disclosure provides a method of treating or preventing diseases or disorders, such as diseases or disorders mediated by polymerase theta, in a subject in need of treatment or prevention, comprising administering to the subject at least one compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition disclosed herein.
  • a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.

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Abstract

L'invention concerne de nouveaux dérivés de composés acétylène, des compositions contenant les composés, et des procédés de préparation et des utilisations de ceux-ci. Les dérivés de composés acétylène sont des composés représentés par la formule (I), ou des tautomères, des stéréoisomères, des promédicaments, des formes cristallines, des formes marquées isotopiquement, des sels pharmaceutiquement acceptables, des hydrates ou des solvates de ceux-ci. Les composés et les compositions selon la présente invention peuvent être utilisés pour traiter des maladies ou des troubles médiés par polθ, en particulier, le cancer.
EP24792979.7A 2023-04-17 2024-04-16 Dérivés de composés acétylène substitués et leur utilisation pharmaceutique Pending EP4698525A1 (fr)

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PCT/KR2024/005100 WO2024219794A1 (fr) 2023-04-17 2024-04-16 Dérivés de composés acétylène substitués et leur utilisation pharmaceutique

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