Tricyclic Derivatives Useful as PARP7 Inhibitors

Abstract

Provided are compounds of formula (I), their stereoisomers, their deuterated derivatives, or pharma- ceutically acceptable salts, intermediates for preparing the compounds, processes for preparing the compounds, compositions comprising same, and methods of using same, that inhibit the activity of PARP7. [Formula 1] TIFF2024506612000898.tif34170

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to PCT / CN2021 / 076144, filed February 9, 2021; PCT / CN2021 / 091050, filed April 29, 2021; PCT / CN2021 / 117189, filed September 8, 2021; PCT / CN2021 / 119368, filed September 18, 2021; PCT / CN2021 / 124714, filed October 19, 2021; PCT / CN2021 / 128807, filed November 4, 2021; and PCT / CN2021 / 129056, filed November 5, 2021, all of which are incorporated herein by reference in their entireties.

[0002] The present invention relates to compounds that inhibit the activity of PARP7, their stereoisomers, their deuterated derivatives, or pharmaceutically acceptable salts thereof, intermediates for preparing the compounds, processes for preparing the compounds, compositions comprising same, and methods of using same. [Background technology]

[0003] Members of the poly(ADP-ribose) polymerase (PARP) family of enzymes use β-NAD as a substrate for the chain addition of ADP-ribose moieties onto target proteins. +PARPs catalyze the post-translational modification of proteins using a process called PARsylation. In the 1960s, this post-translational modification was first characterized with the identification of PARP1 and its role in DNA repair. Subsequently, 16 additional members of the PARP family have been identified, each of which possesses a structurally similar PARP catalytic domain. Furthermore, in addition to its well-studied role in DNA repair, PARylation has now been shown to regulate various processes, such as cell proliferation, apoptosis, DNA methylation, transcriptional regulation, and WNT signaling. Depending on their various catalytic activities, the PARP family can be divided into three categories: mono-PARPS (which catalyze the transfer of mono-ADP-ribose units to their substrates), including the majority of PARP family members; poly-PARPS (which catalyze the transfer of poly-ADP-ribose units to their substrates), including PARP1, PARP2, PARP5A, and PARP5b; and PARP13, the only PARP family member whose catalytic activity could not be demonstrated in vitro or in vivo.

[0004] The mono-PARP protein family plays an important role in multiple stress responses related to the development of cancer, inflammatory diseases, and neurodegenerative diseases. PARP7, a mono-PARP family member, has been demonstrated to be overly active within tumors and play a key role in cancer cell survival. Research has shown that many cancer cells depend on PARP7 for internal cell survival and that PARP7 allows cancer cells to "hide" from the immune system. Inhibition of PARP7 can effectively inhibit cancer cell proliferation, restore interferon signaling, effectively prevent cancer cells from evading the immune system, and inhibit the "brakes" of innate and adaptive immune mechanisms. In several cancer models, PARP7 inhibitors have shown sustained tumor growth inhibition, potent antiproliferative effects, and restoration of interferon signaling. Currently, few studies have been reported on PARP7 inhibitors. Therefore, there is still a need for therapeutic compounds and methods for treating PARP7-related cancers. Summary of the Invention [Means for solving the problem]

[0005] The present invention provides compounds of formula (I): [ka] A stereoisomer thereof, a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof is provided, wherein each of the variables is defined as follows:

[0006] Intermediates for preparing the compounds of the invention are also provided herein.

[0007] Methods for preparing the compounds of the invention are also provided herein.

[0008] Also provided herein is the use of the compounds of the present invention as targeted PARP7 protein ligands in PROTAC compounds that act as degradation regulators of PARP7 protein.

[0009] Also provided herein are pharmaceutical compositions comprising an effective therapeutic amount of a compound of the present invention, a stereoisomer thereof, a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0010] Also provided herein is a method for inhibiting the activity of PARP7, comprising contacting an effective amount of a compound of the present invention, a stereoisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention with PARP7 or a cell in which inhibition of PARP7 is desired.

[0011] Also provided herein is the use of a compound of the present invention, a stereoisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention for the manufacture of a medicament for the treatment of cancer.

[0012] Also provided herein is a method of treating a subject having cancer, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, a stereoisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

[0013] Also provided herein is a compound of the present invention, a stereoisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention for use in the treatment of cancer. DETAILED DESCRIPTION OF THE INVENTION

[0014] The following aspects are provided herein:

[0015] [1]. A compound of formula (I), its stereoisomer, its deuterated derivative, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, Ring A is selected from a 4- to 20-membered carbocyclic ring, a 4- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; said ring A is optionally substituted with t1Z1; Each occurrence of Z1 is independently selected from halogen, -C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10 Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~10 Alkoxy, -CN, -NO2, -N3, oxo, -OR a1 , -SR a1 , -NR c1 R d1 , -C(=O)R b1 , -C(=O)OR a1 , -OC(=O)R b1 , -OC(=O)OR a1 , -C(=O)NR c1 R d1 , -OC(=O)NR c1R d1 , -C(=NR e1 )R b1 , -C(=NR e1 )NR c1 R d1 , -NR c1 C(=NR e1 )NR c1 R d1 , -NR c1 C(=O)R b1 , -NR c1 C(=O)OR a1 , -NR c1 C(=O)NR c1 R d1 , -S(=O)R b1 , -S(=O)OR a1 , -OS(=O)R b1 , -OS(=O)OR a1 , -S(=O)NR c1 R d1 , -NR c1 S(=O)R b1 , -NR c1 S(=O)OR a1 , -OS(=O)NR c1 R d1 , -NR c1 S(=O)NR c1 R d1 , -S(=O)2R b1 , -S(=O)2OR a1 , -OS(=O)2R b1 , -OS(=O)2OR a1 , -S(=O)2NR c1 R d1 , -NR c1 S(=O)2R b1 , -NR c1 S(=O)2OR a1 , -OS(=O)2NR c1 R d1 , -NR c1 S(=O)NR c1 R d1 , -P(R a1 )2, -P(=O)(R b1 )2, -P(=O)2, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 20-membered heteroaryl, wherein -C 1~10Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10 Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~10 alkoxy, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 20-membered heteroaryl are independently selected from halogen, —C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10 Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~10 Alkoxy, -CN, -NO2, -N3, oxo, -OR a1 , -SR a1 , -NR c1 R d1 , -C(=O)R b1 , -C(=O)OR a1 , -OC(=O)R b1 , -OC(=O)OR a1 , -C(=O)NR c1 R d1 , -OC(=O)NR c1 R d1 , -C(=NR e1 )R b1 , -C(=NR e1 )NR c1 R d1 , -NR c1 C(=NR e1 )NR c1 R d1 , -NR c1 C(=O)R b1 , -NR c1 C(=O)OR a1 , -NR c1 C(=O)NR c1 R d1 , -S(=O)R b1 , -S(=O)OR a1 , -OS(=O)R b1 , -OS(=O)OR a1 , -S(=O)NRc1 R d1 , -NR c1 S(=O)R b1 , -NR c1 S(=O)OR a1 , -OS(=O)NR c1 R d1 , -NR c1 S(=O)NR c1 R d1 , -S(=O)2R b1 , -S(=O)2OR a1 , -OS(=O)2R b1 , -OS(=O)2OR a1 , -S(=O)2NR c1 R d1 , -NR c1 S(=O)2R b1 , -NR c1 S(=O)2OR a1 , -OS(=O)2NR c1 R d1 , -NR c1 S(=O)NR c1 R d1 , -P(R a1 )2, -P(=O)(R b1 )2, -P(=O)2, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 20-membered heteroaryl; Optionally, two Z1 together with the atom to which they are both attached form a 3- to 20-membered carbocyclic ring or a 3- to 20-membered heterocyclic ring, wherein the 3- to 20-membered carbocyclic ring or the 3- to 20-membered heterocyclic ring is selected from the group consisting of one or more R X1 optionally replaced by; Optionally, two adjacent Z1, together with the atoms to which they are each attached, form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring, wherein each of the rings independently contains one or more R X2 optionally replaced by; Optionally, two non-adjacent Z1 are joined together to form C 0~6 forms an alkylene bridge, where each of the carbon atoms in the bridge is —CH(R X3 )-, -C(R X3 )2-, -HC=CH-, -RX3 C=CH-, -HC=CR X3 -, -R X3 C=CR X3 -, -C≡C-, -C(=O)-, -O-, -NH-, -NR X3 -, -S-, -S(=O)-, -S(=O)2-, -PH-, -PR X3 -, -P(=O)H-, -P(=O)R X3 -, -C(=O)O-, -OC(=O)-, -C(=O)NH-, -C(=O)NR X3 -, -NR X3 C(=O)-, -NHC(=O)-, -S(=O)O-, -OS(=O)-, -S(=O)2O-, -OS(=O)2-, -S(=O)NH-, -S(=O)NR X3 -, -NHS(=O)-, -NR X3 S(=O)-, -S(=O)2NH-, -S(=O)2NR X3 -, -NHS(=O)2-, -NR X3 S(=O)2-, -OC(=O)O-, -NHC(=O)O-, -NR X3 C(=O)O-, -OC(=O)NH-, -OC(=O)NR X3 -, -NHC(=O)NH-, -NHC(=O)NR X3 -, -NR X3 C(=O)NH- or -NR X3 C(=O)NR X3 - optionally substituted with one or two members selected from; R X1 , R X2 or R X3 Each occurrence of represents independently a halogen, -C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10 Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~10 Alkoxy, -CN, -NO2, -N3, oxo, -OR a1 , -SR a1 , -NR c1 R d1 , -C(=O)R b1、-C(=O)OR a1 、-OC(=O)R b1 、-OC(=O)OR a1 、-C(=O)NR c1 R d1 、-OC(=O)NR c1 R d1 、-C(=NR e1 )R b1 、-C(=NR e1 )NR c1 R d1 、-NR c1 C(=NR e1 )NR c1 R d1 、-NR c1 C(=O)R b1 、-NR c1 C(=O)OR a1 、-NR c1 C(=O)NR c1 R d1 、-S(=O)R b1 、-S(=O)OR a1 、-OS(=O)R b1 、-OS(=O)OR a1 、-S(=O)NR c1 R d1 、-NR c1 S(=O)R b1 、-NR c1 S(=O)OR a1 、-OS(=O)NR c1 R d1 、-NR c1 S(=O)NR c1 R d1 、-S(=O)2R b1 、-S(=O)2OR a1 、-OS(=O)2R b1 、-OS(=O)2OR a1 、-S(=O)2NR c1 R d1 、-NR c1 S(=O)2R b1 、-NR c1 S(=O)2OR a1 、-OS(=O)2NR c1 R d1 、-NR c1 S(=O)2NR c1 R d1 、-P(Ra1 )2, -P(=O)(R b1 )2, -P(=O)2, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 20-membered heteroaryl, wherein said -C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10 Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~10 Alkoxy, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl or 5- to 20-membered heteroaryl is selected from the group consisting of halogen, -C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10 Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~10 Alkoxy, -CN, -NO2, -N3, oxo, -OR a1 , -SR a1 , -NR c1 R d1 , -C(=O)R b1 , -C(=O)OR a1 , -OC(=O)R b1 , -OC(=O)OR a1 , -C(=O)NR c1 R d1 , -OC(=O)NR c1 R d1 , -C(=NR e1 )R b1 , -C(=NR e1 )NR c1 R d1 , -NR c1 C(=NR e1 )NR c1 R d1 , -NR c1 C(=O)R b1 , -NR c1 C(=O)OR a1 , -NR c1 C(=O)NRc1 R d1 , -S(=O)R b1 , -S(=O)OR a1 , -OS(=O)R b1 , -OS(=O)OR a1 , -S(=O)NR c1 R d1 , -NR c1 S(=O)R b1 , -NR c1 S(=O)OR a1 , -OS(=O)NR c1 R d1 , -NR c1 S(=O)NR c1 R d1 , -S(=O)2R b1 , -S(=O)2OR a1 , -OS(=O)2R b1 , -OS(=O)2OR a1 , -S(=O)2NR c1 R d1 , -NR c1 S(=O)2R b1 , -NR c1 S(=O)2OR a1 , -OS(=O)2NR c1 R d1 , -NR c1 S(=O)NR c1 R d1 , -P(R a1 )2, -P(=O)(R b1 )2, -P(=O)2, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 20-membered heteroaryl; t1 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Ring B is selected from a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; said ring B is optionally substituted with t2Z2; Each occurrence of Z2 is independently selected from halogen, -C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~10 Alkoxy, -CN, -NO2, -N3, oxo, -OR a2 , -SR a2 , -NR c2 R d2 , -C(=O)R b2 , -C(=O)OR a2 , -OC(=O)R b2 , -OC(=O)OR a2 , -C(=O)NR c2 R d2 , -OC(=O)NR c2 R d2 , -C(=NR e2 )R b2 , -C(=NR e2 )NR c2 R d2 , -NR c2 C(=NR e2 )NR c2 R d2 , -NR c2 C(=O)R b2 , -NR c2 C(=O)OR a2 , -NR c2 C(=O)NR c2 R d2 , -S(=O)R b2 , -S(=O)OR a2 , -OS(=O)R b2 , -OS(=O)OR a2 , -S(=O)NR c2 R d2 , -NR c2 S(=O)R b2 , -NR c2 S(=O)OR a2 , -OS(=O)NR c2 R d2 , -NR c2 S(=O)NR c2 R d2 , -S(=O)2R b2 , -S(=O)2OR a2 , -OS(=O)2R b2 , -OS(=O)2OR a2 , -S(=O)2NR c2 R d2, -NR c2 S(=O)2R b2 , -NR c2 S(=O)2OR a2 , -OS(=O)2NR c2 R d2 , -NR c2 S(=O)NR c2 R d2 , -P(R a2 )2, -P(=O)(R b2 )2, -P(=O)2, a 3- to 20-membered carbocyclyl, a 3- to 20-membered heterocyclyl, a 6- to 12-membered aryl or a 5- to 20-membered heteroaryl ring, wherein -C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10 Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~10 alkoxy, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 20-membered heteroaryl are independently selected from halogen, —C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10 Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~10 Alkoxy, -CN, -NO2, -N3, oxo, -OR a2 , -SR a2 , -NR c2 R d2 , -C(=O)R b2 , -C(=O)OR a2 , -OC(=O)R b2 , -OC(=O)OR a2 , -C(=O)NR c2 R d2 , -OC(=O)NR c2 R d2 , -C(=NR e2 )R b2 , -C(=NR e2 )NR c2 Rd2 , -NR c2 C(=NR e2 )NR c2 R d2 , -NR c2 C(=O)R b2 , -NR c2 C(=O)OR a2 , -NR c2 C(=O)NR c2 R d2 , -S(=O)R b2 , -S(=O)OR a2 , -OS(=O)R b2 , -OS(=O)OR a2 , -S(=O)NR c2 R d2 , -NR c2 S(=O)R b2 , -NR c2 S(=O)OR a2 , -OS(=O)NR c2 R d2 , -NR c2 S(=O)NR c2 R d2 , -S(=O)2R b2 , -S(=O)2OR a2 , -OS(=O)2R b2 , -OS(=O)2OR a2 , -S(=O)2NR c2 R d2 , -NR c2 S(=O)2R b2 , -NR c2 S(=O)2OR a2 , -OS(=O)2NR c2 R d2 , -NR c2 S(=O)NR c2 R d2 , -P(R a2 )2, -P(=O)(R b2 )2, -P(=O)2, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 20-membered heteroaryl; Optionally, two Z2 together with the atom to which they are both attached form a 3- to 20-membered carbocyclic ring or a 3- to 20-membered heterocyclic ring, wherein the 3- to 20-membered carbocyclic ring or the 3- to 20-membered heterocyclic ring is selected from the group consisting of one or more R X4 optionally replaced by; Optionally, two adjacent Z2, together with the atoms to which they are each attached, form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring, wherein each of the rings independently contains one or more R X5 optionally replaced by; Optionally, two non-adjacent Z2 are joined together to form C 0~6 forms an alkylene bridge, where each of the carbon atoms in the bridge is —CH(R X6 )-, -C(R X6 )2-, -HC=CH-, -R X6 C=CH-, -HC=CR X6 -, -R X6 C=CR X6 -, -C≡C-, -C(=O)-, -O-, -NH-, -NR X6 -, -S-, -S(=O)-, -S(=O)2-, -PH-, -PR X6 -, -P(=O)H-, -P(=O)R X6 -, -C(=O)O-, -OC(=O)-, -C(=O)NH-, -C(=O)NR X6 -, -NR X6 C(=O)-, -NHC(=O)-, -S(=O)O-, -OS(=O)-, -S(=O)2O-, -OS(=O)2-, -S(=O)NH-, -S(=O)NR X6 -, -NHS(=O)-, -NR X6 S(=O)-, -S(=O)2NH-, -S(=O)2NR X6 -, -NHS(=O)2-, -NR X6 S(=O)2-, -OC(=O)O-, -NHC(=O)O-, -NR X6 C(=O)O-, -OC(=O)NH-, -OC(=O)NR X6 -, -NHC(=O)NH-, -NHC(=O)NR X6 -, -NR X6 C(=O)NH- or -NR X6 C(=O)NRX6 - optionally substituted with one or two members selected from; R X4 , R X5 or R X6 Each occurrence of represents independently a halogen, -C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10 Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~10 Alkoxy, -CN, -NO2, -N3, oxo, -OR a2 , -SR a2 , -NR c2 R d2 , -C(=O)R b2 , -C(=O)OR a2 , -OC(=O)R b2 , -OC(=O)OR a2 , -C(=O)NR c2 R d2 , -OC(=O)NR c2 R d2 , -C(=NR e2 )R b2 , -C(=NR e2 )NR c2 R d2 , -NR c2 C(=NR e2 )NR c2 R d2 , -NR c2 C(=O)R b2 , -NR c2 C(=O)OR a2 , -NR c2 C(=O)NR c2 R d2 , -S(=O)R b2 , -S(=O)OR a2 , -OS(=O)R b2 , -OS(=O)OR a2 , -S(=O)NR c2 R d2 , -NR c2 S(=O)R b2 , -NR c2 S(=O)OR a2, -OS(=O)NR c2 R d2 , -NR c2 S(=O)NR c2 R d2 , -S(=O)2R b2 , -S(=O)2OR a2 , -OS(=O)2R b2 , -OS(=O)2OR a2 , -S(=O)2NR c2 R d2 , -NR c2 S(=O)2R b2 , -NR c2 S(=O)2OR a2 , -OS(=O)2NR c2 R d2 , -NR c2 S(=O)NR c2 R d2 , -P(R a2 )2, -P(=O)(R b2 )2, -P(=O)2, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 20-membered heteroaryl, wherein -C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10 Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~10 alkoxy, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 20-membered heteroaryl are independently selected from halogen, —C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10 Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~10 Alkoxy, -CN, -NO2, -N3, oxo, -OR a2 , -SR a2 , -NR c2 R d2 , -C(=O)R b2、-C(=O)OR a2 、-OC(=O)R b2 、-OC(=O)OR a2 、-C(=O)NR c2 R d2 、-OC(=O)NR c2 R d2 、-C(=NR e2 )R b2 、-C(=NR e2 )NR c2 R d2 、-NR c2 C(=NR e2 )NR c2 R d2 、-NR c2 C(=O)R b2 、-NR c2 C(=O)OR a2 、-NR c2 C(=O)NR c2 R d2 、-S(=O)R b2 、-S(=O)OR a2 、-OS(=O)R b2 、-OS(=O)OR a2 、-S(=O)NR c2 R d2 、-NR c2 S(=O)R b2 、-NR c2 S(=O)OR a2 、-OS(=O)NR c2 R d2 、-NR c2 S(=O)NR c2 R d2 、-S(=O)2R b2 、-S(=O)2OR a2 、-OS(=O)2R b2 、-OS(=O)2OR a2 、-S(=O)2NR c2 R d2 、-NR c2 S(=O)2R b2 、-NR c2 S(=O)2OR a2 、-OS(=O)2NR c2 R d2 、-NR c2 S(=O)2NR c2 R d2 、-P(Ra2 )2, -P(=O)(R b2 )2, -P(=O)2, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 20-membered heteroaryl; t2 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Ring C is selected from a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; said ring C is optionally substituted with t3Z3; Each occurrence of Z3 is independently selected from halogen, -C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10 Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~10 Alkoxy, -CN, -NO2, -N3, oxo, -OR a3 , -SR a3 , -NR c3 R d3 , -C(=O)R b3 , -C(=O)OR a3 , -OC(=O)R b3 , -OC(=O)OR a3 , -C(=O)NR c3 R d3 , -OC(=O)NR c3 R d3 , -C(=NR e3 )R b3 , -C(=NR e3 )NR c3 R d3 , -NR c3 C(=NR e3 )NR c3 R d3 , -NR c3 C(=O)R b3 , -NR c3 C(=O)OR a3 , -NR c3 C(=O)NR c3 R d3 , -S(=O)R b3, -S(=O)OR a3 , -OS(=O)R b3 , -OS(=O)OR a3 , -S(=O)NR c3 R d3 , -NR c3 S(=O)R b3 , -NR c3 S(=O)OR a3 , -OS(=O)NR c3 R d3 , -NR c3 S(=O)NR c3 R d3 , -S(=O)2R b3 , -S(=O)2OR a3 , -OS(=O)2R b3 , -OS(=O)2OR a3 , -S(=O)2NR c3 R d3 , -NR c3 S(=O)2R b3 , -NR c3 S(=O)2OR a3 , -OS(=O)2NR c3 R d3 , -NR c3 S(=O)NR c3 R d3 , -P(R a3 )2, -P(=O)(R b3 )2, -P(=O)2, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 20-membered heteroaryl, wherein -C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10 Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~10 alkoxy, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 20-membered heteroaryl are independently selected from halogen, —C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~10 Alkoxy, -CN, -NO2, -N3, oxo, -OR a3 , -SR a3 , -NR c3 R d3 , -C(=O)R b3 , -C(=O)OR a3 , -OC(=O)R b3 , -OC(=O)OR a3 , -C(=O)NR c3 R d3 , -OC(=O)NR c3 R d3 , -C(=NR e3 )R b3 , -C(=NR e3 )NR c3 R d3 , -NR c3 C(=NR e3 )NR c3 R d3 , -NR c3 C(=O)R b3 , -NR c3 C(=O)OR a3 , -NR c3 C(=O)NR c3 R d3 , -S(=O)R b3 , -S(=O)OR a3 , -OS(=O)R b3 , -OS(=O)OR a3 , -S(=O)NR c3 R d3 , -NR c3 S(=O)R b3 , -NR c3 S(=O)OR a3 , -OS(=O)NR c3 R d3 , -NR c3 S(=O)NR c3 R d3 , -S(=O)2R b3 , -S(=O)2OR a3 , -OS(=O)2R b3 , -OS(=O)2OR a3 , -S(=O)2NR c3 R d3, -NR c3 S(=O)2R b3 , -NR c3 S(=O)2OR a3 , -OS(=O)2NR c3 R d3 , -NR c3 S(=O)NR c3 R d3 , -P(R a3 )2, -P(=O)(R b3 )2, -P(=O)2, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 20-membered heteroaryl; Optionally, two Z3 together with the atom to which they are both attached form a 3- to 20-membered carbocyclic ring or a 3- to 20-membered heterocyclic ring, wherein the 3- to 20-membered carbocyclic ring or the 3- to 20-membered heterocyclic ring is selected from the group consisting of one or more R X7 optionally replaced by; Optionally, two adjacent Z3, together with the atoms to which they are each attached, form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring, wherein each of the rings independently contains one or more R X8 optionally replaced by; Optionally, two non-adjacent Z3 are joined together to form C 0~6 forms an alkylene bridge, where each of the carbon atoms in the bridge is —CH(R X9 )-, -C(R X9 )2-, -HC=CH-, -R X9 C=CH-, -HC=CR X9 -, -R X9 C=CR X9 -, -C≡C-, -C(=O)-, -O-, -NH-, -NR X9 -, -S-, -S(=O)-, -S(=O)2-, -PH-, -PR X9 -, -P(=O)H-, -P(=O)R X9 -, -C(=O)O-, -OC(=O)-, -C(=O)NH-, -C(=O)NR X9 -, -NR X9C(=O)-, -NHC(=O)-, -S(=O)O-, -OS(=O)-, -S(=O)2O-, -OS(=O)2-, -S(=O)NH-, -S(=O)NR X9 -, -NHS(=O)-, -NR X9 S(=O)-, -S(=O)2NH-, -S(=O)2NR X9 -, -NHS(=O)2-, -NR X9 S(=O)2-, -OC(=O)O-, -NHC(=O)O-, -NR X9 C(=O)O-, -OC(=O)NH-, -OC(=O)NR X9 -, -NHC(=O)NH-, -NHC(=O)NR X9 -, -NR X9 C(=O)NH- or -NR X9 C(=O)NR X9 - optionally substituted with one or two members selected from; R X7 , R X8 or R X9 Each occurrence of represents independently a halogen, -C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10 Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~10 Alkoxy, -CN, -NO2, -N3, oxo, -OR a3 , -SR a3 , -NR c3 R d3 , -C(=O)R b3 , -C(=O)OR a3 , -OC(=O)R b3 , -OC(=O)OR a3 , -C(=O)NR c3 R d3 , -OC(=O)NR c3 R d3 , -C(=NR e3 )R b3 , -C(=NR e3 )NR c3 R d3 , -NR c3 C(=NRe3 )NR c3 R d3 , -NR c3 C(=O)R b3 , -NR c3 C(=O)OR a3 , -NR c3 C(=O)NR c3 R d3 , -S(=O)R b3 , -S(=O)OR a3 , -OS(=O)R b3 , -OS(=O)OR a3 , -S(=O)NR c3 R d3 , -NR c3 S(=O)R b3 , -NR c3 S(=O)OR a3 , -OS(=O)NR c3 R d3 , -NR c3 S(=O)NR c3 R d3 , -S(=O)2R b3 , -S(=O)2OR a3 , -OS(=O)2R b3 , -OS(=O)2OR a3 , -S(=O)2NR c3 R d3 , -NR c3 S(=O)2R b3 , -NR c3 S(=O)2OR a3 , -OS(=O)2NR c3 R d3 , -NR c3 S(=O)NR c3 R d3 , -P(R a3 )2, -P(=O)(R b3 )2, -P(=O)2, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 20-membered heteroaryl, wherein -C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10 Alkyl, HaloC 2~10 Alkenyl, HaloC 2~10Alkynyl, HaloC 1~10 The alkoxy, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 20-membered heteroaryl rings are independently selected from the group consisting of halogen, -C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10 Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~10 Alkoxy, -CN, -NO2, -N3, oxo, -OR a3 , -SR a3 , -NR c3 R d3 , -C(=O)R b3 , -C(=O)OR a3 , -OC(=O)R b3 , -OC(=O)OR a3 , -C(=O)NR c3 R d3 , -OC(=O)NR c3 R d3 , -C(=NR e3 )R b3 , -C(=NR e3 )NR c3 R d3 , -NR c3 C(=NR e3 )NR c3 R d3 , -NR c3 C(=O)R b3 , -NR c3 C(=O)OR a3 , -NR c3 C(=O)NR c3 R d3 , -S(=O)R b3 , -S(=O)OR a3 , -OS(=O)R b3 , -OS(=O)OR a3 , -S(=O)NR c3 R d3 , -NR c3 S(O)R b3 , -NR c3 S(=O)OR a3 , -OS(=O)NR c3 Rd3 , -NR c3 S(=O)NR c3 R d3 , -S(=O)2R b3 , -S(=O)2OR a3 , -OS(=O)2R b3 , -OS(=O)2OR a3 , -S(=O)2NR c3 R d3 , -NR c3 S(=O)2R b3 , -NR c3 S(=O)2OR a3 , -OS(=O)2NR c3 R d3 , -NR c3 S(=O)NR c3 R d3 , -P(R a3 )2, -P(=O)(R b3 )2, -P(=O)2, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 20-membered heteroaryl; t3 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; [ka] is X1-X2, then X1 and X2 are independently selected from C, N, or CH; [ka] But if X1=X2, then X1 is C and X2 is C; [ka] is X3-X4, then X3 and X4 are independently selected from C, N or CH; [ka] But if X3=X4, then X3 is C and X4 is C; X5 is selected from C, N, or CH; Y1 is -C(RY1 )2-、-R Y1 C=CR Y1 -、-C≡C-、-C(=O)-、-O-、-NR Y1 -、-S-、-S(=O)-、-S(=O)2-、-PR Y1 -、-P(=O)R Y1 -、-C(=O)O-、-OC(=O)-、-C(=O)NR Y1 -、-NR Y1 C(=O)-、-S(=O)O-、-OS(=O)-、-S(=O)2O-、-OS(=O)2-、-S(=O)NR Y1 -、-NR Y1 S(=O)-、-S(=O)2NR Y1 -、-NR Y1 S(=O)2-、-OC(=O)O-、-NR Y1 C(=O)O-、-OC(=O)NR Y1 - or - NR Y1 C(=O)NR Y1 -からまする Y2が、-C(R Y2 )2-、-R Y2 C=CR Y2 -、-C≡C-、-C(=O)-、-O-、-NR Y2 -、-S-、-S(=O)-、-S(=O)2-、-PR Y2 -、-P(=O)R Y2 -、-C(=O)O-、-OC(=O)-、-C(=O)NR Y2 -、-NR Y2 C(=O)-、-S(=O)O-、-OS(=O)-、-S(=O)2O-、-OS(=O)2-、-S(=O)NR Y2 -、-NR Y2 S(=O)-、-S(=O)2NR Y2 -、-NR Y2 S(=O)2-、-OC(=O)O-、-NR Y2 C(=O)O-、-OC(=O)NR Y2 - or - NR Y2 C(=O)NR Y2 -からまする Y3が、-C(R Y3 )2-、-R Y3 C=CR Y3-, -C≡C-, -C(=O)-, -O-, -NR Y3 -, -S-, -S(=O)-, -S(=O)2-, -PR Y3 -, -P(=O)R Y3 -, -C(=O)O-, -OC(=O)-, -C(=O)NR Y3 -, -NR Y3 C(=O)-, -S(=O)O-, -OS(=O)-, -S(=O)2O-, -OS(=O)2-, -S(=O)NR Y3 -, -NR Y3 S(=O)-, -S(=O)2NR Y3 -, -NR Y3 S(=O)2-, -OC(=O)O-, -NR Y3 C(=O)O-, -OC(=O)NR Y3 -or-NR Y3 C(=O)NR Y3 -Selected from; R Y1 , R Y2 or R Y3 Each occurrence of represents independently hydrogen, halogen, -C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10 Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~10 Alkoxy, -CN, -NO2, -N3, oxo, -OR a4 , -SR a4 , -NR c4 R d4 , -C(=O)R b4 , -C(=O)OR a4 , -OC(=O)R b4 , -OC(=O)OR a4 , -C(=O)NR c4 R d4 , -OC(=O)NR c4 R d4 , -C(=NR e4 )R b4 , -C(=NR e4 )NR c4 R d4 , -NR c4 C(=NRe4 )NR c4 R d4 , -NR c4 C(=O)R b4 , -NR c4 C(=O)OR a4 , -NR c4 C(=O)NR c4 R d4 , -S(=O)R b4 , -S(=O)OR a4 , -OS(=O)R b4 , -OS(=O)OR a4 , -S(=O)NR c4 R d4 , -NR c4 S(=O)R b4 , -NR c4 S(=O)OR a4 , -OS(=O)NR c4 R d4 , -NR c4 S(=O)NR c4 R d4 , -S(=O)2R b4 , -S(=O)2OR a4 , -OS(=O)2R b4 , -OS(=O)2OR a4 , -S(=O)2NR c4 R d4 , -NR c4 S(=O)2R b4 , -NR c4 S(=O)2OR a4 , -OS(=O)2NR c4 R d4 , -NR c4 S(=O)NR c4 R d4 , -P(R a4 )2, -P(=O)(R b4 )2, -P(=O)2, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 20-membered heteroaryl, wherein -C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10 Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6Alkynyl, HaloC 1~10 alkoxy, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 20-membered heteroaryl are independently selected from halogen, —C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10 Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~10 Alkoxy, -CN, -NO2, -N3, oxo, -OR a4 , -SR a4 , -NR c4 R d4 , -C(=O)R b4 , -C(=O)OR a4 , -OC(=O)R b4 , -OC(=O)OR a4 , -C(=O)NR c4 R d4 , -OC(=O)NR c4 R d4 , -C(=NR e4 )R b4 , -C(=NR e4 )NR c4 R d4 , -NR c4 C(=NR e4 )NR c4 R d4 , -NR c4 C(=O)R b4 , -NR c4 C(=O)OR a4 , -NR c4 C(=O)NR c4 R d4 , -S(=O)R b4 , -S(=O)OR a4 , -OS(=O)R b4 , -OS(=O)OR a4 , -S(=O)NR c4 R d4 , -NR c4 S(=O)R b4 , -NR c4 S(=O)OR a4 , -OS(=O)NR c4 Rd4 , -NR c4 S(=O)NR c4 R d4 , -S(=O)2R b4 , -S(=O)2OR a4 , -OS(=O)2R b4 , -OS(=O)2OR a4 , -S(=O)2NR c4 R d4 , -NR c4 S(=O)2R b4 , -NR c4 S(=O)2OR a4 , -OS(=O)2NR c4 R d4 , -NR c4 S(=O)NR c4 R d4 , -P(R a4 )2, -P(=O)(R b4 )2, -P(=O)2, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 20-membered heteroaryl; m1 is selected from 0, 1, 2, 3, 4, 5 or 6; m2 is selected from 0, 1, 2, 3, 4, 5 or 6; m3 is selected from 0, 1, 2, 3, 4, 5 or 6; m4 is selected from 0, 1, 2, 3, 4, 5 or 6; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 or R 15 are independently hydrogen, halogen, -C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10 Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~10 Alkoxy, -CN, -NO2, -N3, oxo, -OR a5 , -SR a5、-NR c5 R d5 、-C(=O)R b5 、-C(=O)OR a5 、-OC(=O)R b5 、-OC(=O)OR a5 、-C(=O)NR c5 R d5 、-OC(=O)NR c5 R d5 、-C(=NR e5 )R b5 、-C(=NR e5 )NR c5 R d5 、-NR c5 C(=NR e5 )NR c5 R d5 、-NR c5 C(=O)R b5 、-NR c5 C(=O)OR a5 、-NR c5 C(=O)NR c5 R d5 、-S(=O)R b5 、-S(=O)OR a5 、-OS(=O)R b5 、-OS(=O)OR a5 、-S(=O)NR c5 R d5 、-NR c5 S(=O)R b5 、-NR c5 S(=O)OR a5 、-OS(=O)NR c5 R d5 、-NR c5 S(=O)NR c5 R d5 、-S(=O)2R b5 、-S(=O)2OR a5 、-OS(=O)2R b5 、-OS(=O)2OR a5 、-S(=O)2NR c5 R d5 、-NR c5 S(=O)2R b5 、-NR c5 S(=O)2OR a5 、-OS(=O)2NR c5 R d5 、-NRc5 S(=O)NR c5 R d5 , -P(R a5 )2, -P(=O)(R b5 )2, -P(=O)2, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 20-membered heteroaryl, wherein -C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10 Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~10 The alkoxy, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 20-membered heteroaryl rings are independently selected from the group consisting of halogen, -C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10 Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~10 Alkoxy, -CN, -NO2, -N3, oxo, -OR a5 , -SR a5 , -NR c5 R d5 , -C(=O)R b5 , -C(=O)OR a5 , -OC(=O)R b5 , -OC(=O)OR a5 , -C(=O)NR c5 R d5 , -OC(=O)NR c5 R d5 , -C(=NR e5 )R b5 , -C(=NR e5 )NR c5 R d5 , -NR c5 C(=NR e5 )NR c5 R d5 , -NR c5 C(=O)R b5 , -NRc5 C(=O)OR a5 , -NR c5 C(=O)NR c5 R d5 , -S(=O)R b5 , -S(=O)OR a5 , -OS(=O)R b5 , -OS(=O)OR a5 , -S(=O)NR c5 R d5 , -NR c5 S(=O)R b5 , -NR c5 S(=O)OR a5 , -OS(=O)NR c5 R d5 , -NR c5 S(=O)NR c5 R d5 , -S(=O)2R b5 , -S(=O)2OR a5 , -OS(=O)2R b5 , -OS(=O)2OR a5 , -S(=O)2NR c5 R d5 , -NR c5 S(=O)2R b5 , -NR c5 S(=O)2OR a5 , -OS(=O)2NR c5 R d5 , -NR c5 S(=O)NR c5 R d5 , -P(R a5 )2, -P(=O)(R b5 )2, -P(=O)2, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 20-membered heteroaryl; Optionally, (R in Y Y1 ) and R 13 together with the atoms to which they are each attached form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; each said ring is independently optionally substituted with tZ; Optionally, (R in Y Y1 ) and R 15together with the atoms to which they are each attached form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; each said ring is independently optionally substituted with tZ; Optionally, (R in Y Y1 ) and R1, together with the atoms to which they are each attached, form a ring D, wherein ring D is selected from a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; said ring D is optionally substituted with t6Z6; Optionally, (R in Y Y1 ) and R3, together with the atoms to which they are each attached, form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; each said ring is independently optionally substituted with t7Z7; Optionally, (R in Y Y1 ) and R5, together with the atoms to which they are each attached, form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; each said ring is independently optionally substituted with t8Z8; optionally, R1 and R3, together with the atoms to which they are each attached, form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; each said ring is independently optionally substituted with t9Z9; Optionally, R1 and R5, together with the atoms to which they are each attached, form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; each of said rings independently comprises t 10 Z 10 optionally replaced by; Optionally, R and (R in Y Y2 ) together with the atoms to which they are each attached form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; each said ring independently comprises t 11 Z 11 optionally replaced by; Optionally, R3 and R5, together with the atoms to which they are each attached, form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; each said ring independently being selected from the group consisting of t 12 Z 12 optionally replaced by; Optionally, R3 and (R in Y2 Y2 ) together with the atoms to which they are each attached form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; each said ring independently comprises t 13 Z 13 optionally replaced by; Optionally, R3 and R7, together with the atoms to which they are each attached, form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; each said ring independently being selected from the group consisting of t 14 Z 14 optionally replaced by; Optionally, R5 and (R in Y2 Y2 ) together with the atoms to which they are each attached form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; each said ring independently comprises t 15 Z 15 optionally replaced by; Optionally, R5 and R7 together with the atoms to which they are each attached form a ring G, said ring G being selected from a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; said ring G being selected from t 16 Z 16 optionally replaced by; Optionally, R5 and R9, together with the atoms to which they are each attached, form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; each of said rings independently comprises t 17 Z 17 optionally replaced by; Optionally, (R in Y Y2) and R7, together with the atoms to which they are each attached, form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; each of said rings independently comprises t 18 Z 18 optionally replaced by; Optionally, (R in Y Y2 ) and R9, together with the atoms to which they are each attached, form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; each said ring independently comprises t 19 Z 19 optionally replaced by; Optionally, (R in Y Y2 ) and R 11 together with the atoms to which they are respectively attached, form a ring F, said ring F being selected from a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; said ring F being selected from t 20 Z 20 optionally replaced by; Optionally, R7 and R9, together with the atoms to which they are each attached, form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; each of said rings independently represents t 21 Z 21 optionally replaced by; Optionally, R7 and R 11 together with the atoms to which they are each attached, form a ring H, said ring H being selected from a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; said ring H being 22 Z 22 optionally replaced by; Optionally, R7 and (R in Y3 Y3 ) together with the atoms to which they are each attached form a ring E, said ring E being selected from a 3- to 20-membered carbocycle, a 3- to 20-membered heterocycle, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; each said ring is independently 23 Z 23 optionally replaced by; Optionally, R and R 11together with the atoms to which they are each attached form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; each said ring independently comprises t 24 Z 24 optionally replaced by; Optionally, R and (R in Y Y3 ) together with the atoms to which they are each attached form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; each said ring independently comprises t 25 Z 25 optionally replaced by; Optionally, R9 and Z3, together with the atoms to which they are each attached, form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; each of said rings independently comprises t 26 Z 26 optionally replaced by; Optionally, R 11 and (R in Y3 Y3 ) together with the atoms to which they are each attached form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; each said ring independently comprises t 27 Z 27 optionally replaced by; Optionally, R 11 and Z3 together with the atoms to which they are each attached form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; each said ring independently represents t 28 Z 28 optionally replaced by; Optionally, (R in Y Y3 ) and Z3 together with the atoms to which they are each attached form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; each said ring independently comprises t 29 Z 29 optionally replaced by; Optionally, R1 and R2, together with the atom to which they are both attached, form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; each said ring independently being selected from the group consisting of t 30 Z 30 optionally replaced by; Optionally, R3 and R4, together with the atom to which they are both attached, form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; each said ring independently being selected from the group consisting of t 31 Z 31 optionally replaced by; Optionally, R5 and R6, together with the atom to which they are both attached, form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; each said ring independently being selected from the group consisting of t 32 Z 32 optionally replaced by; Optionally, R7 and R8, together with the atom to which they are both attached, form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; each of said rings independently represents t 33 Z 33 optionally replaced by; Optionally, R and R 10 together with the atoms to which they are both attached form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; each said ring independently comprises t 34 Z 34 optionally replaced by; Optionally, R 11 and R 12 together with the atoms to which they are both attached form a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, a 6- to 12-membered aryl ring, or a 5- to 20-membered heteroaryl ring; each said ring independently comprises t 35 Z 35 optionally replaced by; t4, t5, t6, t7, t8, t9, t 10 , t 11 , t 12 , t 13 , t 14 , t 15 , t 16 , t17 , t 18 , t 19 , t 20 , t 21 , t 22 , t 23 , t 24 , t 25 , t 26 , t 27 , t 28 , t 29 , t 30 , t 31 , t 32 , t 33 , t 34 , or t 35 is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Z4, Z5, Z6, Z7, Z8, Z9, Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , Z 16 , Z 17 , Z 18 , Z 19 , Z 20 , Z 21 , Z 22 , Z 23 , Z 24 , Z 25 , Z 26 , Z 27 , Z 28 , Z 29 , Z 30 , Z 31 , Z 32 , Z 33 , Z 34 , or Z 35 are independently halogen, -C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10 Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~10 Alkoxy, -CN, -NO2, -N3, oxo, -OR a6 , -SR a6 , -NR c6 Rd6 、-C(=O)R b6 、-C(=O)OR a6 、-OC(=O)R b6 、-OC(=O)OR a6 、-C(=O)NR c6 R d6 、-OC(=O)NR c6 R d6 、-C(=NR e6 )R b6 、-C(=NR e6 )NR c6 R d6 、-NR c6 C(=NR e6 )NR c6 R d6 、-NR c6 C(=O)R b6 、-NR c6 C(=O)OR a6 、-NR c6 C(=O)NR c6 R d6 、-S(=O)R b6 、-S(=O)OR a6 、-OS(=O)R b6 、-OS(=O)OR a6 、-S(=O)NR c6 R d6 、-NR c6 S(=O)R b6 、-NR c6 S(=O)OR a6 、-OS(=O)NR c6 R d6 、-NR c6 S(=O)NR c6 R d6 、-S(=O)2R b6 、-S(=O)2OR a6 、-OS(=O)2R b6 、-OS(=O)2OR a6 、-S(=O)2NR c6 R d6 、-NR c6 S(=O)2R b6 、-NR c6 S(=O)2OR a6 、-OS(=O)2NR c6 R d6 、-NR c6 S(=O)2NRc6 R d6 , -P(R a6 )2, -P(=O)(R b6 )2, -P(=O)2, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 20-membered heteroaryl, wherein -C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10 Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~10 The alkoxy, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 20-membered heteroaryl may independently be one or more substituents halogen, —C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10 Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~10 Alkoxy, -CN, -NO2, -N3, oxo, -OR a6 , -SR a6 , -NR c6 R d6 , -C(=O)R b6 , -C(=O)OR a6 , -OC(=O)R b6 , -OC(=O)OR a6 , -C(=O)NR c6 R d6 , -OC(=O)NR c6 R d6 , -C(=NR e6 )R b6 , -C(=NR e6 )NR c6 R d6 , -NR c6 C(=NR e6 )NR c6 R d6 , -NR c6 C(=O)R b6 , -NR c6 C(=O)ORa6 , -NR c6 C(=O)NR c6 R d6 , -S(=O)R b6 , -S(=O)OR a6 , -OS(=O)R b6 , -OS(=O)OR a6 , -S(=O)NR c6 R d6 , -NR c6 S(=O)R b6 , -NR c6 S(=O)OR a6 , -OS(=O)NR c6 R d6 , -NR c6 S(=O)NR c6 R d6 , -S(=O)2R b6 , -S(=O)2OR a6 , -OS(=O)2R b6 , -OS(=O)2OR a6 , -S(=O)2NR c6 R d6 , -NR c6 S(=O)2R b6 , -NR c6 S(=O)2OR a6 , -OS(=O)2NR c6 R d6 , -NR c6 S(=O)NR c6 R d6 , -P(R a6 )2, -P(=O)(R b6 )2, -P(=O)2, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 20-membered heteroaryl; R a1 , R b1 , R c1 , R d1 , R e1 , R a2 , R b2 , R c2 , R d2 , R e2 , R a3 , R b3 , R c3 , R d3 , R e3 , Ra4 , R b4 , R c4 , R d4 , R e4 , R a5 , R b5 , R c5 , R d5 , R e5 , R a6 , R b6 , R c6 , R d6 or R e6 Each occurrence of represents independently hydrogen, halogen, -C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10 Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~10 Alkoxy, -CN, -NO2, -N3, oxo, -N(R 16 )2, -OR 16 , -SR 16 , -S(=O)R 17 , -S(=O)2R 17 , -C(=O)R 17 , -C(=O)OR 16 , -OC(=O)R 17 , -C(=O)N(R 16 )2, -NR 16 C(=O)R 17 , -OC(=O)OR 16 , -NR 16 C(=O)OR 16 , -OC(=O)N(R 16 )2, -NR 16 C(=O)N(R 16 )2, -S(=O)OR 16 , -OS(=O)R 17 , -S(=O)N(R 16 )2, -NR 16 S(=O)R 17 , -S(=O)2OR 16 , -OS(=O)2R 17 , -S(=O)2R 17 , -NR 16 S(=O)2R 17 , -OS(=O)2OR16 , -NR 16 S(=O)2OR 16 , -OS(=O)2N(R 16 )2, -NR 16 S(=O)2N(R 16 )2, -P(R 16 )2, -P(=O)(R 17 )2, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 20-membered heteroaryl, wherein -C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10 Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~10 The alkoxy, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 20-membered heteroaryl ring is / are not halogen, -C 1~10 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~10 Alkoxy, HaloC 1~10 Alkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~10 Alkoxy, -CN, -NO2, -N3, oxo, -N(R 16 )2, -OR 16 , -SR 16 , -S(=O)R 17 , -S(=O)2R 17 , -C(=O)R 17 , -C(=O)OR 16 , -OC(=O)R 17 , -C(=O)N(R 16 )2, -NR 16 C(=O)R 17 , -OC(=O)OR 16 , -NR 16 C(=O)OR 16 , -OC(=O)N(R 16 )2, -NR 16 C(=O)N(R 16 )2, -S(=O)OR16 , -OS(=O)R 17 , -S(=O)N(R 16 )2, -NR 16 S(=O)R 17 , -S(=O)2OR 16 , -OS(=O)2R 17 , -S(=O)2R 17 , -NR 16 S(=O)2R 17 , -OS(=O)2OR 16 , -NR 16 S(=O)2OR 16 , -OS(=O)2N(R 16 )2, -NR 16 S(=O)2N(R 16 )2, -P(R 16 )2, -P(=O)(R 17 ) optionally substituted independently with one or more substituents selected from 2, 3- to 20-membered carbocyclyl, 3- to 20-membered heterocyclyl, 6- to 12-membered aryl, or 5- to 20-membered heteroaryl; Each occurrence of heterocyclyl or heterocyclic is independently selected from -C(=O)-, -O-, -C(=O)O-, -OC(=O)-, -NR 16 -, -C(=O)NR 16 -, -NR 16 C(=O)-, -S-, -S(=O)-, -S(=O)O-, -OS(=O)-, -S(=O)NR 16 -, -NR 16 S(=O)-, -S(=O)2-, -S(=O)2O-, -OS(=O)2-, -S(=O)2NR 16 -, -NR 16 S(=O)2-, -PR 16 -, -P(=O)R 17 -, -P(=O)R 17 -NR 16 -, -NR 16 -P(=O)R 17 -, -P(=O)2-, -NR 16 -P(=O)2- or -P(=O)2-NR 16 -containing one or more ring members selected from; heteroaryl, at each occurrence, contains one or more heteroatoms independently selected from N, O, or S; Each R 16 or R 17 are independently hydrogen, halogen, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 1~6 Alkoxy, -C 1~6 Haloalkyl, HaloC 2~6 Alkenyl, HaloC 2~6 Alkynyl, HaloC 1~6 Alkoxy, -CN, -NO2, -N3, oxo, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 alkyl), -OH, -O(C 1~6 alkyl), -SH, -S(C 1~6 alkyl), -S(=O)(C 1~6 alkyl), -S(=O)2(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -C(=O)OH, -C(=O)(OC 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -C(=O)NH2, -C(=O)NH(C 1~6 alkyl), -C(=O)N(C 1~6 alkyl)2, -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -OC(=O)O(C 1~6 alkyl), -NHC(=O)(OC 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(OC 1~6 alkyl), -OC(=O)NH(C 1~6 alkyl), -OC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -N(C 1~6 alkyl)C(=O)NH2, -N(C 1~6 alkyl)C(=O)NH(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)N(C1~6 alkyl)2, -S(=O)(OC 1~6 alkyl), -OS(=O)(C 1~6 alkyl), -S(=O)NH2, -S(=O)NH(C 1~6 alkyl), -S(=O)N(C 1~6 alkyl)2, -NHS(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)(C 1~6 alkyl), -S(=O)2(OC 1~6 alkyl), -OS(=O)2(C 1~6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1~6 alkyl), -S(=O)2N(C 1~6 alkyl)2, -NHS(=O)2(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2(C 1~6 alkyl), -OS(=O)2O(C 1~6 alkyl), -NHS(=O)2O(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2O(C 1~6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1~6 alkyl), -OS(=O)2N(C 1~6 alkyl)2, -NHS(=O)2NH2, -NHS(=O)2NH(C 1~6 alkyl), -NHS(=O)2N(C 1~6 alkyl)2, -N(C 1~6 alkyl)S(=O)2NH2, -N(C 1~6 alkyl)S(=O)2NH(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2N(C 1~6 alkyl)2, -PH(C 1~6 alkyl), -P(C 1~6 alkyl)2, -P(=O)H(C 1~6 alkyl), -P(=O)(C 1~6alkyl)2, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein said —C 1~6 Alkyl, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, -C 2~6 Alkenyl, -C 2~6 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl is selected from the group consisting of halogen, —C 1~3 Alkyl, HaloC 1~3 Alkyl, HaloC 1~3 Alkoxy, -C 2~3 Alkenyl, -C 2~3 Alkynyl, -CN, -NO2, -N3, oxo, -NH2, -NH(C 1~3 alkyl), -N(C 1~3 alkyl), -OH, -O(C 1~3 alkyl), -SH, -S(C 1~3 alkyl), -S(=O)(C 1~3 alkyl), -S(=O)2(C 1~3 alkyl), -C(=O)(C 1~3 alkyl), -C(=O)OH, -C(=O)(OC 1~3 alkyl), -OC(=O)(C 1~3 alkyl), -C(=O)NH2, -C(=O)NH(C 1~3 alkyl), -C(=O)N(C 1~3 alkyl)2, -NHC(=O)(C 1~3 alkyl), -N(C 1~3 alkyl)C(=O)(C 1~3 alkyl), -OC(=O)O(C 1~3 alkyl), -NHC(=O)(OC 1~3 alkyl), -N(C 1~3 alkyl)C(=O)(OC 1~3 alkyl), -OC(=O)NH(C 1~3 alkyl), -OC(=O)N(C 1~3 alkyl)2, -NHC(=O)NH2, -NHC(=O)NH(C1~3 alkyl), -NHC(=O)N(C 1~3 alkyl)2, -N(C 1~3 alkyl)C(=O)NH2, -N(C 1~3 alkyl)C(=O)NH(C 1~3 alkyl), -N(C 1~3 alkyl)C(=O)N(C 1~3 alkyl)2, -S(=O)(OC 1~3 alkyl), -OS(=O)(C 1~3 alkyl), -S(=O)NH2, -S(=O)NH(C 1~3 alkyl), -S(=O)N(C 1~3 alkyl)2, -NHS(=O)(C 1~3 alkyl), -N(C 1~3 alkyl)S(=O)(C 1~3 alkyl), -S(=O)2(OC 1~3 alkyl), -OS(=O)2(C 1~3 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1~3 alkyl), -S(=O)2N(C 1~3 alkyl)2, -NHS(=O)2(C 1~3 alkyl), -N(C 1~3 alkyl)S(=O)2(C 1~3 alkyl), -OS(=O)2O(C 1~3 alkyl), -NHS(=O)2O(C 1~3 alkyl), -N(C 1~3 alkyl)S(=O)2O(C 1~3 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1~3 alkyl), -OS(=O)2N(C 1~3 alkyl)2, -NHS(=O)2NH2, -NHS(=O)2NH(C 1~3 alkyl), -NHS(=O)2N(C 1~3 alkyl)2, -N(C 1~3 alkyl)S(=O)2NH2, -N(C 1~3 alkyl)S(=O)2NH(C 1~3 alkyl), -N(C 1~3 alkyl)S(=O)2N(C 1~3 alkyl)2, -PH(C 1~3alkyl), -P(C 1~3 alkyl)2, -P(=O)H(C 1~3 alkyl), -P(=O)(C 1~3 alkyl) optionally substituted with one or more substituents selected from 2, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6-membered aryl, or 5- to 6-membered heteroaryl.

[0016] [2]. [ka] The part, [ka] Selected from; The compound according to [1], wherein each occurrence of X5 is independently selected from C, N, or CH.

[0017] [3]. [ka] The part, [ka] Selected from; The compound according to [1] or [2], wherein each occurrence of X5 is independently selected from N.

[0018] [4] The compound according to any one of [1] to [3], wherein ring A is selected from a 4- to 10-membered cycloalkyl ring, a 4- to 10-membered cycloalkenyl ring, a 4- to 10-membered heterocycloalkyl ring, a 4- to 10-membered heterocycloalkenyl ring, a 6- to 10-membered aryl ring, or a 5- to 12-membered heteroaryl ring.

[0019] [5]. Ring A is a 4-membered monocyclic cycloalkyl ring, a 4-membered monocyclic cycloalkenyl ring, a 4-membered monocyclic heterocycloalkyl ring, a 4-membered monocyclic heterocycloalkenyl ring, a 5-membered monocyclic cycloalkyl ring, a 5-membered monocyclic cycloalkenyl ring, a 5-membered bridged cycloalkyl ring, a 5-membered bridged cycloalkenyl ring, a 5-membered fused cycloalkyl ring, a 5-membered fused cycloalkenyl ring, a 5-membered monocyclic heterocycloalkyl ring, a 5-membered monocyclic heterocycloalkenyl ring, a 5-membered bridged heterocycloalkyl ring, a 5-membered bridged heterocycloalkenyl ring, a 5-membered fused heterocycloalkyl ring, a 5-membered fused heterocyclo Alkenyl ring, 6-membered monocyclic cycloalkyl ring, 6-membered monocyclic cycloalkenyl ring, 6-membered bridged cycloalkyl ring, 6-membered bridged cycloalkenyl ring, 6-membered fused cycloalkyl ring, 6-membered fused cycloalkenyl ring, 6-membered monocyclic heterocycloalkyl ring, 6-membered monocyclic heterocycloalkenyl ring, 6-membered bridged heterocycloalkyl ring, 6-membered bridged heterocycloalkenyl ring, 6-membered fused heterocycloalkyl ring, 6-membered fused heterocycloalkenyl ring, 7-membered monocyclic cycloalkyl ring, 7-membered monocyclic cycloalkenyl ring, 7-membered spirocyclic cycloalkyl ring, 7-membered spirocyclic cycloalkenyl ring nyl ring, 7-membered fused cycloalkyl ring, 7-membered fused cycloalkenyl ring, 7-membered bridged cycloalkyl ring, 7-membered bridged cycloalkenyl ring, 7-membered monocyclic heterocycloalkyl ring, 7-membered monocyclic heterocycloalkenyl ring, 7-membered spirocyclic heterocycloalkyl ring, 7-membered spirocyclic heterocycloalkenyl ring, 7-membered fused heterocycloalkyl ring, 7-membered fused heterocycloalkenyl ring, 7-membered bridged heterocycloalkyl ring, 7-membered bridged heterocycloalkenyl ring, 8-membered monocyclic cycloalkyl ring, 8-membered monocyclic cycloalkenyl ring, 8-membered spirocyclic cycloalkyl ring, 8-membered spiro ring cycloalkenyl ring, 8-membered fused cycloalkyl ring, 8-membered fused cycloalkenyl ring, 8-membered bridged cycloalkyl ring, 8-membered bridged cycloalkenyl ring, 8-membered monocyclic heterocycloalkyl ring, 8-membered monocyclic heterocycloalkenyl ring, 8-membered spirocyclic heterocycloalkyl ring, 8-membered spirocyclic heterocycloalkenyl ring, 8-membered fused heterocycloalkyl ring, 8-membered fused heterocycloalkenyl ring, 8-membered bridged heterocycloalkyl ring, 8-membered bridged heterocycloalkenyl ring, 9-membered monocyclic cycloalkyl ring, 9-membered monocyclic cycloalkenyl ring, 9-membered spirocyclic cycloalkyl ring,9-membered spirocyclic cycloalkenyl ring, 9-membered fused cycloalkyl ring, 9-membered fused cycloalkenyl ring, 9-membered bridged cycloalkyl ring, 9-membered bridged cycloalkenyl ring, 9-membered monocyclic heterocycloalkyl ring, 9-membered monocyclic heterocycloalkenyl ring, 9-membered spirocyclic heterocycloalkyl ring, 9-membered spirocyclic heterocycloalkenyl ring, 9-membered fused heterocycloalkyl ring, 9-membered fused heterocycloalkenyl ring, 9-membered bridged heterocycloalkyl ring, 9-membered bridged heterocycloalkenyl ring, 10 10-membered monocyclic cycloalkyl ring, 10-membered monocyclic cycloalkenyl ring, 10-membered spirocyclic cycloalkyl ring, 10-membered spirocyclic cycloalkenyl ring, 10-membered fused cycloalkyl ring, 10-membered fused cycloalkenyl ring, 10-membered bridged cycloalkyl ring, 10-membered bridged cycloalkenyl ring, 10-membered monocyclic heterocycloalkyl ring, 10-membered monocyclic heterocycloalkenyl ring, 10-membered spirocyclic heterocycloalkyl ring, 10-membered spirocyclic heterocycloalkenyl ring, 10-membered fused heterocycloalkynyl ring each occurrence of said heterocycloalkyl or heterocycloalkenyl is independently selected from N, O, S, —C(═O)—, —C(═O)O—, —OC(═O)—, —O—C ... The compound according to any one of [1] to [4], wherein the heteroaryl contains one or more ring members selected from -, -C(=O)NH-, -NHC(=O)-, -S(=O)-, -S(=O)O-, -OS(=O)-, -S(=O)NH-, -NHS(=O)-, -S(=O)2-, -S(=O)2O-, -OS(=O)2-, -S(=O)2NH-, or -NHS(=O)2-; and wherein each occurrence of the heteroaryl contains one or more heteroatoms independently selected from N, O, or S.

[0020] [6] Ring A is selected from a 5-membered monocyclic heterocycloalkyl ring, a 6-membered monocyclic heterocycloalkyl ring, a 7-membered monocyclic heterocycloalkyl ring, an 8-membered monocyclic heterocycloalkyl ring, a 5-membered monocyclic heterocycloalkenyl ring, a 6-membered monocyclic heterocycloalkenyl ring, a 7-membered monocyclic heterocycloalkenyl ring, an 8-membered monocyclic heterocycloalkenyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring, and the heterocycloalkyl or heterocycloalkenyl is

[0022] The compound according to any one of [1] to [5], wherein each occurrence of heteroaryl contains 1, 2, or 3 ring members independently selected from N, O, S, -C(=O)-, -C(=O)NH-, -NHC(=O)-, -S(=O)-, -S(=O)NH-, -NHS(=O)-, -S(=O)2-, -S(=O)2NH-, or -NHS(=O)2-; and each occurrence of heteroaryl contains 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S.

[0021] [7]. Ring A is a 5-membered monocyclic heterocycloalkyl ring containing one N, a 6-membered monocyclic heterocycloalkyl ring containing one N, a 7-membered monocyclic heterocycloalkyl ring containing one N, an 8-membered monocyclic heterocycloalkyl ring containing one N, a 5-membered monocyclic heterocycloalkenyl ring containing one N, a 6-membered monocyclic heterocycloalkenyl ring containing one N, a 7-membered monocyclic heterocycloalkenyl ring containing one N, an 8-membered monocyclic heterocycloalkenyl ring containing one N, a 5-membered heteroaryl ring containing one N, or a 6-membered heteroaryl ring containing one N. the heterocycloalkyl or heterocycloalkenyl, at each occurrence, optionally further contains one or two ring members independently selected from N, O, S, —C(═O)—, —C(═O)NH—, —NHC(═O)—, —S(═O)NH—, —NHS(═O)—, —S(═O)2—, —S(═O)2NH—, or —NHS(═O)2—; and the heteroaryl, at each occurrence, optionally further contains one, two, or three heteroatoms independently selected from N, O, or S.

[0022] [8]. Ring A is a 5-membered monocyclic heterocycloalkyl ring containing one N at position X2, a 6-membered monocyclic heterocycloalkyl ring containing one N at position X2, a 7-membered monocyclic heterocycloalkyl ring containing one N at position X2, an 8-membered monocyclic heterocycloalkyl ring containing one N at position X2, a 5-membered monocyclic heterocycloalkenyl ring containing one N at position X2, a 6-membered monocyclic heterocycloalkenyl ring containing one N at position X2, a 7-membered monocyclic heterocycloalkenyl ring containing one N at position X2, an 8-membered monocyclic heterocycloalkenyl ... a 8-membered monocyclic heterocycloalkenyl ring containing one N at position X2, a 5-membered monocyclic heterocycloalkenyl ring containing one N at position X2, a 5-membered monocyclic heterocycloalkenyl ring containing one N at position X2, a 6-membered monocyclic heterocycloalkenyl ring containing one N at position X2, a 7-membered monocyclic heterocycloalkenyl ring containing one N at position X2, a 7-membered monocyclic heterocycloalkenyl ring containing one N at position X2, a 7-membered monocyclic heterocycloalkenyl ring containing one N at position X2, a 7-membered monocyclic heterocycloalkenyl ring containing one N at position X2, a 7-membered

[0023] The compound according to any one of [1] to [7], wherein the heterocycloalkyl or heterocycloalkenyl is selected from an aryl ring or a 6-membered heteroaryl ring containing one N, wherein each occurrence of the heterocycloalkyl or heterocycloalkenyl optionally further contains one or two ring members independently selected from N, O, S, -C(=O)-, -C(=O)NH-, -NHC(=O)-, -S(=O)-, -S(=O)NH-, -NHS(=O)-, -S(=O)2-, -S(=O)2NH-, or -NHS(=O)2-; and each occurrence of the heteroaryl optionally further contains one, two, or three heteroatoms independently selected from N, O, or S.

[0023] [9] The compound according to any one of [1] to [8], wherein ring B is selected from a 6- to 10-membered aryl ring or a 5- to 10-membered heteroaryl ring.

[0024]

[10] . The compound according to any one of [1] to [9], wherein ring B is selected from a phenyl ring, a naphthalene ring, a 5-membered heteroaryl ring, a 6-membered heteroaryl ring, or a 10-membered heteroaryl ring, and the heteroaryl ring contains 1, 2, 3, 4, 5, or 6 heteroatoms selected from N, O, and S.

[0025]

[11] . The compound according to any one of [1] to

[10] , wherein ring B is selected from a phenyl ring, a naphthalene ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring, and the heteroaryl ring contains 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S.

[0026]

[12] . The compound according to any one of [1] to

[11] , wherein ring B is selected from a 5-membered heteroaryl ring containing one N or a 6-membered heteroaryl ring containing one N, and the heteroaryl ring optionally further contains 1, 2, or 3 heteroatoms selected from N, O, or S.

[0027]

[13] . The compound according to any one of [1] to

[12] , wherein ring B is selected from a 5-membered heteroaryl ring containing one N adjacent to X3 or a 6-membered heteroaryl ring containing one N adjacent to X3, and the heteroaryl ring optionally further contains 1, 2, or 3 heteroatoms selected from N, O, or S.

[0028]

[14] The compound according to any one of [1] to

[13] , wherein ring C is selected from a 3- to 10-membered carbocyclic ring and a 3- to 10-membered heterocyclic ring.

[0029]

[15] . Ring C is selected from a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 7-membered carbocyclic ring, an 8-membered carbocyclic ring, a 9-membered carbocyclic ring, a 10-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, a 6-membered heterocyclic ring, a 7-membered heterocyclic ring, an 8-membered heterocyclic ring, a 9-membered heterocyclic ring, or a 10-membered heterocyclic ring, and each occurrence of the heterocyclic ring is independently selected from N, O, S, -C(=O)-, -C(=O)O-, -OC(=O) The compound according to any one of [1] to

[14] , containing one or more ring members selected from -, -C(=O)NH-, -NHC(=O)-, -S(=O)-, -S(=O)O-, -OS(=O)-, -S(=O)NH-, -NHS(=O)-, -S(=O)2-, -S(=O)2O-, -OS(=O)2-, -S(=O)2NH-, or -NHS(=O)2-.

[0030]

[16] . The compound according to any one of [1] to

[15] , wherein Ring C is selected from a 5-membered heterocycle, a 6-membered heterocycle, or a 7-membered heterocycle, each occurrence of which independently contains one ring member selected from N, and optionally further contains 1, 2, or 3 ring members selected from N, O, or S.

[0031]

[17] . The compound according to any one of [1] to

[16] , wherein ring C is selected from a 5-membered heterocycle containing one N and further containing one or two ring members selected from N, O, or S; a 6-membered heterocycle containing one N and further containing one or two ring members selected from N, O, or S; or a 7-membered heterocycle containing one N and further containing one or two ring members selected from N, O, or S.

[0032]

[18] . The compound according to any one of [1] to

[16] , wherein ring C is selected from a 5-membered heterocycle containing one N at position X2 and further containing one or two ring members selected from N, O, or S; a 6-membered heterocycle containing one N at position X2 and further containing one or two ring members selected from N, O, or S; or a 7-membered heterocycle containing one N at position X2 and further containing one or two ring members selected from N, O, or S.

[0033]

[19] . Ring A is a 5-membered monocyclic heterocycloalkyl ring containing one N, a 6-membered monocyclic heterocycloalkyl ring containing one N, a 7-membered monocyclic heterocycloalkyl ring containing one N, an 8-membered monocyclic heterocycloalkyl ring containing one N, a 5-membered monocyclic heterocycloalkenyl ring containing one N, a 6-membered monocyclic heterocycloalkenyl ring containing one N, a 7-membered monocyclic heterocycloalkenyl ring containing one N, an 8-membered monocyclic heterocycloalkenyl ring containing one N, a 5-membered heteroaryl ring containing one N, or a 5-membered monocyclic heterocycloalkenyl ring containing one N. wherein said heterocycloalkyl or heterocycloalkenyl, at each occurrence, optionally further contains one or two ring members independently selected from N, O, S, —C(═O)—, —C(═O)NH—, —NHC(═O)—, —S(═O)—, —S(═O)NH—, —NHS(═O)—, —S(═O)2—, —S(═O)2NH—, —NHS(═O)2—; wherein said heteroaryl, at each occurrence, optionally further contains one, two, or three heteroatoms independently selected from N, O, or S; Ring B is selected from a 5-membered heteroaryl ring containing one N or a 6-membered heteroaryl ring containing one N, said heteroaryl ring optionally further containing one or two heteroatoms selected from N, O or S; The compound according to any one of [1] to

[18] , wherein ring C is selected from a 5-membered heterocycle containing one N and further containing one or two ring members selected from N, O, or S; a 6-membered heterocycle containing one N and further containing one or two ring members selected from N, O, or S; or a 7-membered heterocycle containing one N and further containing one or two ring members selected from N, O, or S.

[0034]

[20] . Ring A is selected from a 5-membered monocyclic heterocycloalkenyl ring containing one N at position X2, a 6-membered monocyclic heterocycloalkenyl ring containing one N at position X2, or a 7-membered monocyclic heterocycloalkenyl ring containing one N at position X2, an 8-membered monocyclic heterocycloalkenyl ring containing one N at position X2, a 5-membered heteroaryl ring containing one N at position X2, or a 6-membered heteroaryl ring containing one N, wherein each occurrence of heteroaryl optionally further contains one or two ring members independently selected from N, O, S, -C(=O)-, -C(=O)NH-, -NHC(=O)-, -S(=O)-, -S(=O)NH-, -NHS(=O)-, -S(=O)2-, -S(=O)2NH-, -NHS(=O)2-; and each occurrence of heteroaryl optionally further contains one, two, or three heteroatoms independently selected from N, O, or S; Ring B is selected from a 5-membered heteroaryl ring containing one N adjacent to X3 or a 6-membered heteroaryl ring containing one N adjacent to X3, said heteroaryl ring optionally further containing one or two heteroatoms selected from N, O or S; The compound according to any one of [1] to

[19] , wherein ring C is selected from a 5-membered heterocycle containing one N at position X2 and further containing one or two ring members selected from N, O, or S; a 6-membered heterocycle containing one N adjacent to X3 and further containing one or two ring members selected from N, O, or S; or a 7-membered heterocycle containing one N adjacent to X3 and further containing one or two ring members selected from N, O, or S.

[0035] [twenty one]. [ka] The part, [ka] Selected from; During the ceremony: [ka] indicates - or =; [ka] indicates that ring B is a 5- or 6-membered aromatic ring; X5 is selected from N or CH; in some embodiments, X5 is selected from N; X2 is selected from N or CH; in some embodiments, X2 is selected from N; m7 is selected from 0, 1, 2, 3, 4, 5, or 6; in some embodiments, m7 is selected from 1, 2, or 3; in some embodiments, m7 is selected from 1 or 2; in some embodiments, m7 is selected from 2; m8 is selected from 0, 1, 2, 3, 4, 5, or 6; in some embodiments, m8 is selected from 1, 2, or 3; in some embodiments, m8 is selected from 1 or 2; in some embodiments, m8 is selected from 1; X3 is selected from N or C, and X4 is selected from N or C, with the proviso that X3 and X4 are not simultaneously N; X7 is selected from a bond, N, or CH; X6, X8 and X9 are each independently selected from N, CH, NH, O or S; when X7 is selected from a bond, X6, X8 and X9 are independently selected from N, CH, NH, O or S to form a 5-membered aromatic heteroaryl ring B; When X7 is selected from N or CH, X6, X8 and X9 are independently selected from N and CH to form a 6-membered aromatic ring B; Y4 is absent, CH, CH2, HC=CH, C≡C, C(=O), N, NH, O, S, S(=O), S(=O)2, PH, P(=O)H, C(=O)O, OC(=O), C(=O)NH, N HC(=O), S(=O)O, OS(=O), S(=O)2O, OS(=O)2, S(=O)NH, NHS(=O), S(=O)2NH, NHS(=O)2, OC(=O)O, NH-C(=O) O, OC(=O)NH, or NH-C(=O)-NH; in some embodiments, Y4 is selected from absent, CH, CH2, O, N, NH, S, C(=O), S(=O), S(=O)2, C(=O)NH, NHC(=O), S(=O)NH, NHS(=O), S(=O)2NH, or NHS(=O)2; in some embodiments, Y4 is selected from absent or CH2; Each occurrence of Y5 independently represents absent, CH, CH2, HC=CH, C≡C, C(=O), N, NH, O, S, S(=O), S(=O), PH, P(=O)H, C(=O)O, OC(=O), C(=O)NH, NHC(=O), S(=O)O, OS(=O), S(=O)2O, OS(=O)2, S(=O)NH, NHS(=O), S(=O)2NH, NHS(=O)2, OC(=O)O, NH-C(=O)O, OC(=O)O, In some embodiments, Y5 at each occurrence is independently selected from absent, CH, CH2, O, N, NH, S, C(=O), S(=O), S(=O), C(=O)NH, NHC(=O), S(=O)NH, NHS(=O), S(=O)NH, or NHS(=O)2; In some embodiments, Y5 at each occurrence is independently selected from absent or CH2; m9 is selected from 0, 1, 2, 3, 4, 5, or 6; in some embodiments, m9 is selected from 0, 1, 2, or 3; in some embodiments, m9 is selected from 0, 1, or 2; Y6 is selected from CH, CH2, CF2, CH(OH), HC=CH, C≡C, C(=O), N, NH, O, S, S(=O), S(=O), PH, P(=O)H, C(=O)O, OC(=O), C(=O)NH, NHC(=O), S(=O)O, OS(=O), S(=O)2O, OS(=O)2, S(=O)NH, NHS(=O), S(=O)2NH, NHS(=O)2, OC(=O)O, NH-C(=O)O, OC(=O)NH, or NH-C(=O)-NH; in certain embodiments wherein Y6 is selected from CH, CH2, CF2, CH(OH), C(=O), O, N, NH, S, S(=O), S(=O)2, C(=O)NH, NHC(=O), S(=O)NH, NHS(=O), S(=O)2NH, or NHS(=O)2; in some embodiments, Y6 is selected from CH, CH2, CF2, CH(OH), C(=O), O, N, NH, S, S(=O), S(=O)2, C(=O)NH, or NHC(=O).

[0036] [twenty two]. [ka] The part, [ka] The compound according to any one of [1] to

[21] , selected from:

[0037] [twenty three]. [ka] The part, [ka] Selected from; During the ceremony: X3 is selected from C; X4 is selected from C; X5 is CH or N; in some embodiments, X5 is N; X6 is selected from N, CH, NH, O, or S; in some embodiments, X6 is selected from N; X7 is selected from a bond, N, or CH; X8 is selected from N, CH, NH, O or S; X9 is selected from N, CH, NH, O or S; when X7 is selected from a bond, X6, X8 and X9 are each independently selected from N, CH, NH, O or S to form a 5-membered aromatic heteroaryl ring B; When X7 is selected from N or CH, X6, X8 and X9 are each independently selected from N and CH to form a phenyl ring or a 6-membered aromatic heteroaryl ring B; Y4 is selected from absent or CH2; each Y5 is independently selected from CH2; m9 is selected from 0, 1, 2, 3 or 4; Y6 is CH, CH2, CF2, CH(OH), C(=O), O, N, NH, S, S(=O), S(=O)2, * NHC(=O) ** or ** NHC(=O) * Selected from; * indicates the point of attachment to aromatic ring B, ** indicates the point of attachment to Y5; however: [ka] When m represents =, Y is absent, m is 0, and Y is selected from CH, N (in other words, [ka] If indicates =, then [ka] directly bonds to Y6 to form =Y6); [ka] represents -, Y4 is absent or CH2, m9 is 0, 1, 2, 3 or 4, Y6 is CH2, CF2, CH(OH), C(=O), O, NH, S, S(=O), S(=O)2, * NHC(=O) ** or ** NHC(=O) * The compound according to any one of [1] to

[22] , selected from the following:

[0038] [twenty four]. [ka] The part, [ka] Selected from; Preferably: X5 at each occurrence is independently selected from CH or N; in some embodiments, X5 at each occurrence is independently N; each occurrence of Y4 is independently selected from absent or CH2; each occurrence of Y5 is independently selected from CH2; m9 is selected from 0, 1, 2, 3 or 4; Each occurrence of Y6 is independently CH, CH2, CF2, CH(OH), C(=O), O, N, NH, S, S(=O), S(=O)2, * NHC(=O) ** or ** NHC(=O) * Selected from; * indicates the point of attachment to aromatic ring B, ** indicates the point of attachment to Y5; however: [ka] When m represents =, Y is absent, m is 0, and Y is selected from CH, N (in other words, [ka] indicates =, this = is directly bonded to Y6 to form =Y6); [ka] represents -, Y4 is absent or CH2, m9 is 0, 1, 2, 3 or 4, Y6 is CH2, CF2, CH(OH), C(=O), O, NH, S, S(=O), S(=O)2, * NHC(=O) ** or ** NHC(=O) * The compound according to

[22] or

[23] , selected from:

[0039] [twenty five]. [ka] The part, [ka] The compound according to any one of

[22] to

[24] , selected from:

[0040]

[26] . [ka] The part, [ka] The compound according to any one of

[24] to

[25] , selected from:

[0041]

[27] . [ka] The part, [ka] Selected from; During the ceremony: Y4 is absent or selected from CH2, Y5 is selected from CH2, and m9 is selected from 0, 1 or 2; [ka] Y6 in the formula is CH2, CF2, CH(OH), C(=O), O, NH, S, S(=O), S(=O)2, * NHC(=O) ** or ** NHC(=O) * Selected from; * indicates the point of attachment to aromatic ring B, ** indicates the point of attachment to Y5; [ka] The compound according to any one of

[24] to

[26] , wherein Y6 is selected from CH2, CH, N, or NH.

[0042]

[28] . [ka] The part, [ka] Selected from; Y4 is selected from absent or CH2; each occurrence of Y5 is independently selected from CH2; m9 is selected from 0, 1 or 2; Y6 is CH2, CF2, CHF, CH(OH), C(=O), O, NH, S, S(=O), S(=O)2, * NHC(=O) ** or ** NHC(=O) * Selected from; * indicates the point of attachment to aromatic ring B, ** indicates the point of attachment to Y5.

[0043]

[29] . [ka] The part, [ka] The compound according to

[28] , selected from:

[0044]

[30] . [ka] The part, [ka] The compound according to any one of

[27] to

[29] , selected from:

[0045]

[31] . [ka] The part, [ka] The compound according to any one of

[27] to

[30] , selected from TIFF2024506612000045.tif117170.

[0046]

[32] . [ka] The part, [ka] Selected from; During the ceremony, [ka] The part, [ka] Selected from; [ka] The part, [ka] The compound according to

[27] , selected from:

[0047]

[33] . [ka] The part, [ka] Selected from; [ka] The part, [ka] The compound according to

[32] , selected from:

[0048]

[34] . [ka] The part, [ka] The compound according to any one of [1] to

[33] , selected from TIFF2024506612000058.tif239170TIFF2024506612000059.tif241170TIFF2024506612000060.tif47170.

[0049]

[35] Each occurrence of Z1, Z2 or Z3 independently represents halogen, -C 1~6 Alkyl, -C 1~6 Haloalkyl, -C 1~6 Haloalkoxy, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -CN, -NH, -NH(C 1~6 alkyl), -N(C 1~6 alkyl), -NH(3- to 10-membered cycloalkyl), -N(C 1~6alkyl)(3-10 membered cycloalkyl), -OH, -O(C 1~6 alkyl), -O-(3- to 10-membered cycloalkyl), -SH, -S(C 1~6 alkyl), -S(3-10 membered cycloalkyl), -S(=O)(C 1~6 alkyl), -S(=O)(3-10 membered cycloalkyl), -S(=O)2(C 1~6 alkyl), -S(=O)2(3-10 membered cycloalkyl), -C(=O)(C 1~6 alkyl), -C(=O)-(3-10 membered cycloalkyl), -C(=O)OH, -C(=O)(OC 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -C(=O)NH2, -C(=O)NH(C 1~6 alkyl), -C(=O)N(C 1~6 alkyl)2, -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -OC(=O)O(C 1~6 alkyl), -NHC(=O)(OC 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(OC 1~6 alkyl), -OC(=O)NH(C 1~6 alkyl), -OC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -N(C 1~6 alkyl)C(=O)NH2, -N(C 1~6 alkyl)C(=O)NH(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)N(C 1~6 alkyl)2, -S(=O)(OC 1~6 alkyl), -OS(=O)(C 1~6 alkyl), -S(=O)NH2, -S(=O)NH(C 1~6 alkyl), -S(=O)N(C 1~6 alkyl)2, -NHS(=O)(C 1~6 alkyl), -N(C1~6 alkyl)S(=O)(C 1~6 alkyl), -OS(=O)O(C 1~6 alkyl), -NHS(=O)O(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)O(C 1~6 alkyl), -OS(=O)NH2, -OS(=O)NH(C 1~6 alkyl), -OS(=O)N(C 1~6 alkyl)2, -NHS(=O)NH2, -NHS(=O)NH(C 1~6 alkyl), -NHS(=O)N(C 1~6 alkyl)2, -N(C 1~6 alkyl)S(=O)NH2, -N(C 1~6 alkyl)S(=O)NH(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)N(C 1~6 alkyl)2, -S(=O)2(OC 1~6 alkyl), -OS(=O)2(C 1~6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1~6 alkyl), -S(=O)2N(C 1~6 alkyl)2, -NHS(=O)2(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2(C 1~6 alkyl), -OS(=O)2O(C 1~6 alkyl), -NHS(=O)2O(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2O(C 1~6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1~6 alkyl), -OS(=O)2N(C 1~6 alkyl)2, -NHS(=O)2NH2, -NHS(=O)2NH(C 1~6 alkyl), -NHS(=O)2N(C 1~6 alkyl)2, -N(C 1~6 alkyl)S(=O)2NH2, -N(C 1~6 alkyl)S(=O)2NH(C 1~6 alkyl), -N(C 1~6alkyl)S(=O)2N(C 1~6 alkyl)2, -PH(C 1~6 alkyl), -P(C 1~6 alkyl)2, -P(=O)H(C 1~6 alkyl), -P(=O)(C 1~6 alkyl)2, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein said —C 1~6 Alkyl, -C 1~6 Haloalkyl, -C 1~6 Haloalkoxy, -C 2~6 Alkenyl, -C 2~6 Alkynyl, 3- to 10-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl are independently selected from the group consisting of halogen, —C 1~6 Alkyl, -C 1~6 Haloalkyl, -C 1~6 Haloalkoxy, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -CN, oxo, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 alkyl), -NH(3- to 10-membered cycloalkyl), -N(C 1~6 alkyl)(3-10 membered cycloalkyl), -OH, -O(C 1~6 alkyl), -O(3- to 10-membered cycloalkyl), -SH, -S(C 1~6 alkyl), -S(3-10 membered cycloalkyl), -S(=O)(C 1~6 alkyl), -S(=O)(3-10 membered cycloalkyl), -S(=O)2(C 1~6 alkyl), -S(=O)2(3-10 membered cycloalkyl), -C(=O)(C 1~6 alkyl), -C(=O)-(3-10 membered cycloalkyl), -C(=O)OH, -C(=O)(OC 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -C(=O)NH2, -C(=O)NH(C 1~6 alkyl), -C(=O)N(C 1~6 alkyl)2, -NHC(=O)(C 1~6 alkyl), -N(C1~6 alkyl)C(=O)(C 1~6 alkyl), -OC(=O)O(C 1~6 alkyl), -NHC(=O)(OC 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(OC 1~6 alkyl), -OC(=O)NH(C 1~6 alkyl), -OC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -N(C 1~6 alkyl)C(=O)NH2, -N(C 1~6 alkyl)C(=O)NH(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)N(C 1~6 alkyl)2, -S(=O)(OC 1~6 alkyl), -OS(=O)(C 1~6 alkyl), -S(=O)NH2, -S(=O)NH(C 1~6 alkyl), -S(=O)N(C 1~6 alkyl)2, -NHS(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)(C 1~6 alkyl), -OS(=O)O(C 1~6 alkyl), -NHS(=O)O(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)O(C 1~6 alkyl), -OS(=O)NH2, -OS(=O)NH(C 1~6 alkyl), -OS(=O)N(C 1~6 alkyl)2, -NHS(=O)NH2, -NHS(=O)NH(C 1~6 alkyl), -NHS(=O)N(C 1~6 alkyl)2, -N(C 1~6 alkyl)S(=O)NH2, -N(C 1~6 alkyl)S(=O)NH(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)N(C 1~6alkyl)2, -S(=O)2(OC 1~6 alkyl), -OS(=O)2(C 1~6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1~6 alkyl), -S(=O)2N(C 1~6 alkyl)2, -NHS(=O)2(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2(C 1~6 alkyl), -OS(=O)2O(C 1~6 alkyl), -NHS(=O)2O(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2O(C 1~6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1~6 alkyl), -OS(=O)2N(C 1~6 alkyl)2, -NHS(=O)2NH2, -NHS(=O)2NH(C 1~6 alkyl), -NHS(=O)2N(C 1~6 alkyl)2, -N(C 1~6 alkyl)S(=O)2NH2, -N(C 1~6 alkyl)S(=O)2NH(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2N(C 1~6 alkyl)2, -PH(C 1~6 alkyl), -P(C 1~6 alkyl)2, -P(=O)H(C 1~6 alkyl), -P(=O)(C 1~6 alkyl) optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from 2, 3- to 10-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; The compound according to any one of [1] to

[34] , wherein each occurrence of t1, t2, or t3 is independently selected from 0, 1, 2, 3, 4, 5, or 6.

[0050]

[36] Each occurrence of Z1, Z2 or Z3 is independently -F, -Cl, -Br, -C 1~3 Alkyl, -C 1~3Haloalkyl, -C 1~3 Haloalkoxy, -C 2~3 Alkenyl, -C 2~3 Alkynyl, -CN, -NH2, -NH(C 1~3 alkyl), -N(C 1~3 alkyl), -NH(3- to 6-membered cycloalkyl), -N(C 1~3 alkyl)(3- to 6-membered cycloalkyl), -OH, -O(C 1~3 alkyl), -O-(3- to 6-membered cycloalkyl), -SH, -S(C 1~3 alkyl), -S-(3- to 6-membered cycloalkyl), -S(=O)(C 1~3 alkyl), -S(=O)(3-6 membered cycloalkyl), -S(=O)2(C 1~3 alkyl), -S(=O)2-(3- to 6-membered cycloalkyl), -C(=O)(C 1~3 alkyl), -C(=O)-(3- to 6-membered cycloalkyl), -C(=O)OH, -C(=O)(OC 1~3 alkyl), -OC(=O)(C 1~3 alkyl), -C(=O)NH2, -C(=O)NH(C 1~3 alkyl), -C(=O)N(C 1~3 alkyl)2, -NHC(=O)(C 1~3 alkyl), -N(C 1~3 alkyl)C(=O)(C 1~3 alkyl), -S(=O)(OC 1~3 alkyl), -OS(=O)(C 1~3 alkyl), -S(=O)NH2, -S(=O)NH(C 1~3 alkyl), -S(=O)N(C 1~3 alkyl)2, -NHS(=O)(C 1~3 alkyl), -N(C 1~3 alkyl)S(=O)(C 1~3 alkyl), -S(=O)2(OC 1~3 alkyl), -OS(=O)2(C 1~3 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1~3 alkyl), -S(=O)2N(C 1~3 alkyl)2, -NHS(=O)2(C 1~3 alkyl), -N(C 1~3alkyl)S(=O)2(C 1~3 alkyl), -P(=O)H(C 1~3 alkyl), -P(=O)(C 1~3 alkyl)2, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein said —C 1~3 Alkyl, -C 1~3 Haloalkyl, -C 1~3 Haloalkoxy, -C 2~6 Alkenyl, -C 2~6 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl are independently selected from the group consisting of -F, -Cl, -Br, -C 1~3 Alkyl, -C 1~3 Haloalkyl, -CN, -NH2, -NH(C 1~3 alkyl), -N(C 1~3 alkyl), -OH, -O(C 1~3 alkyl), -SH, -S(C 1~3 alkyl), -S(=O)(C 1~3 alkyl), -S(=O)2(C 1~3 alkyl), -C(=O)(C 1~3 alkyl), -C(=O)OH, -C(=O)(OC 1~3 alkyl), -OC(=O)(C 1~3 alkyl), -C(=O)NH2, -C(=O)NH(C 1~3 alkyl), -C(=O)N(C 1~3 alkyl)2, -NHC(=O)(C 1~3 alkyl), -N(C 1~3 alkyl)C(=O)(C 1~3 alkyl), -S(=O)(OC 1~3 alkyl), -OS(=O)(C 1~3 alkyl), -S(=O)NH2, -S(=O)NH(C 1~3 alkyl), -S(=O)N(C 1~3 alkyl)2, -NHS(=O)(C 1~3 alkyl), -N(C 1~3 alkyl)S(=O)(C 1~3 alkyl), -S(=O)2(OC 1~3alkyl), -OS(=O)2(C 1~3 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1~3 alkyl), -S(=O)2N(C 1~3 alkyl)2, -NHS(=O)2(C 1~3 alkyl), -N(C 1~3 alkyl)S(=O)2(C 1~3 alkyl), -P(=O)H(C 1~3 alkyl), -P(=O)(C 1~3 alkyl) optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from 2- or 3- to 6-membered cycloalkyl; The compound according to any one of [1] to

[35] , wherein each occurrence of t1, t2, or t3 is independently selected from 0, 1, 2, or 3.

[0051]

[37] . Z1, Z2 or Z3, each occurrence, independently, is -Cl, -F, -Br, -CH3, -CD3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, [ka] -CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CHFCH3、-CF2CH3、-CN 、-NH2、-NH(CH3)、-N(CH3)2、-NH(CH2CH3)、-OH、-O-CH3、-O-CH2CH3、-O-CH 2CH2CH3、-O-CH(CH3)2、-O-CF3、-SH、-S-CH3、-S-CH2CH3、-S-CH2CH2CH3、- S-CH(CH3)2、-S-CF3、-S(=O)CH3、-S(=O)(CH2CH3)、-S(=O)(CH2CH2CH3)、-S (=O)(CH(CH3)2)、-S(=O)2CH3、-S(=O)2(CH2CH3)、-S(=O)2(CH2CH2CH3)、-S(=O)2(CH(CH3)2)、-COOH、-C(=O)(CH3)、-C(=O)(CH2CH3)、-C(=O)(CH(CH3)2)、-C(=O)(CF3)、-C(=O)(OCH3)、-C(=O)(OCH2CH3)、-C(=O)(OCH2CH3)、-C(=O)(OCH2CH3)、-C(=O)(OCH2CH3)、-C(=O)(OCH(CH3)2)、-OC(=O)(CH3)、-OC(=O)(CH2CH3)、-OC(=O)(CH2CH2 CH3)、-OC(=O)(CH(CH3)2)、-C(=O)NH2、-C(=O)NH(CH3)、-C(=O)NH(CH2CH3)、-C(=O)NH(CH2CH2CH3)、-C(=O)NH(CH(CH3)2)、-C(=O)N(CH3)2、-C(=O)N(CH2CH3)2、-NHC(=O)(CH3)、-NHC(=O)(CH2CH3)、-NHC(=O)(CH2CH2CH3)、-NHC(=O)(CH(CH3)2)、-N(CH3)C(=O)(CH3)、-S(=O)(OCH3)、-S(=O)(OCH2CH3) 、-S(=O)(OCH2CH2CH3)、-S(=O)(OCH(CH3)2)、-OS(=O)(CH3)、-OS(=O)(CH2CH3)、-OS(=O)(CH2CH2CH3)、-OS(=O)(CH(CH3)2)、-S(=O)NH2、-S(=O)NH(CH3)、-S(=O)NH(CH2CH3)、-S(=O)NH(CH2CH2CH3)、-S(=O)NH(CH(CH3)2)、-S(=O)N(CH3)2、-S(=O)N(CH3)(CH2CH3)、-NHS(=O)(CH3)、-NHS(=O)(CH2CH3)、-NHS(=O)(CH2CH2CH3), -NHS(=O)(CH(CH3)2), -N(CH3)S(=O)(CH3), -S(=O)2(OCH3), -S(=O)2(OCH2CH3), -S(=O)2(OCH2CH2CH3), -S(=O)2(OCH(CH3)2), -OS(=O)2(CH3), -OS(=O)2(CH2CH3), -OS(=O)2(CH2CH2CH3), -OS(=O)2(CH(CH3)2), -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2NH(CH2CH3), -S(=O)2NH(CH2CH2CH3), -S(=O)2NH(CH(CH3)2), -S(=O)2N(CH3)2, -S(=O)2N(CH3)(CH2CH3), -NHS(=O)2(CH3), -NHS(=O)2(CH2CH3), -NHS(=O)2(CH2CH2CH3), -NHS(=O)2(CH(CH3)2), -N(CH3)S(=O)2(CH3), -P(=O)H(CH3), -P(=O)H(CH2CH3), -P(=O)H(CH2CH2CH3), -P(=O)H(CH(CH3)2), -P(=O)(CH3)2, -P(=O)(CH3)(CH2CH3), -CH2-OH, -CH2CH2-OH, -CH(CH3)-OH, -CH2-SH, -CH2CH2-SH, -CH(CH3)-SH, -CH2-NH2, -CH2CH2-NH2, -CH(CH3)-NH2, -CH2-CN, -CH2CH2-CN, -CH(CH3)-CN, -O-CH3-O-CH3, -O-CH2CH3-O-CH3, -O-CH(CH3)-O-CH3, -O-CH2CH2CH3-O-CH3, -O-CH2CH(CH3)-O-CH3, -O-CH(CH3)CH2-O-CH3, -NH-O-CH3, -N(CH3)-O-CH3, -N(CH2CH3)-O-CH3, [Chemistry] selected from; a compound according to any one of [1] to

[36] , wherein t1, t2 or t3 is independently selected from 0, 1 or 2 each time it appears.

[0052]

[38] . Each occurrence of Z1 is independently -CH3, -F, -CN, -CD3, -CH2CH3, -Cl, -CH(CH3)2, [ka] , -CHF2, -CH2CF3, [ka] , -CO-CH3 or [ka] Selected from; The compound according to any one of [1] to

[37] , wherein each occurrence of t1 is independently selected from 0 or 1.

[0053]

[39] . Each occurrence of Z2 is independently -CF3, -F, -Cl, -Br, -CH3, -OCH3, -CN, -NH2, [ka] or -CO-CH3; The compound according to any one of [1] to

[38] , wherein each occurrence of t2 is independently selected from 0, 1, 2, or 3.

[0054]

[40] . Z3 at each occurrence is independently selected from -F, -OH, -CN; The compound according to any one of [1] to

[39] , wherein each occurrence of t3 is independently selected from 0, 1, or 2.

[0055]

[41] . [ka] The part, [ka] TIFF2024506612000069.tif232170TIFF2024506612000070.tif237170TIFF2024506612000071.tif221170TIFF20245066120 00072.tif230170TIFF2024506612000073.tif238170TIFF2024506612000074.tif248170TIFF2024506612000075.tif240170 The compound according to any one of [1] to

[40] , selected from TIFF2024506612000076.tif245170TIFF2024506612000077.tif239170TIFF2024506612000078.tif245170TIFF2024506612000079.tif241170TIFF2024506612000080.tif236170TIFF2024506612000081.tif154170.

[0056]

[42] . (R in Y1 Y1 ), (R in Y2 Y2 ) or (R in Y3 Y3 ) each occurrence independently represents hydrogen, halogen, -C 1~6 Alkyl, -C 1~6 Haloalkyl, -C 1~6 Haloalkoxy, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -CN, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 alkyl), -NH(3- to 10-membered cycloalkyl), -N(C 1~6 alkyl)(3-10 membered cycloalkyl), -OH, -O(C 1~6 alkyl), -O-(3- to 10-membered cycloalkyl), -SH, -S(C 1~6 alkyl), -S(3-10 membered cycloalkyl), -S(=O)(C 1~6 alkyl), -S(=O)(3-10 membered cycloalkyl), -S(=O)2(C 1~6 alkyl), -S(=O)2(3-10 membered cycloalkyl), -C(=O)(C 1~6alkyl), -C(=O)-(3-10 membered cycloalkyl), -C(=O)OH, -C(=O)(OC 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -C(=O)NH2, -C(=O)NH(C 1~6 alkyl), -C(=O)N(C 1~6 alkyl)2, -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -OC(=O)O(C 1~6 alkyl), -NHC(=O)(OC 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(OC 1~6 alkyl), -OC(=O)NH(C 1~6 alkyl), -OC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -N(C 1~6 alkyl)C(=O)NH2, -N(C 1~6 alkyl)C(=O)NH(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)N(C 1~6 alkyl)2, -S(=O)(OC 1~6 alkyl), -OS(=O)(C 1~6 alkyl), -S(=O)NH2, -S(=O)NH(C 1~6 alkyl), -S(=O)N(C 1~6 alkyl)2, -NHS(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)(C 1~6 alkyl), -OS(=O)O(C 1~6 alkyl), -NHS(=O)O(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)O(C 1~6 alkyl), -OS(=O)NH2, -OS(=O)NH(C 1~6 alkyl), -OS(=O)N(C 1~6alkyl)2, -NHS(=O)NH2, -NHS(=O)NH(C 1~6 alkyl), -NHS(=O)N(C 1~6 alkyl)2, -N(C 1~6 alkyl)S(=O)NH2, -N(C 1~6 alkyl)S(=O)NH(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)N(C 1~6 alkyl)2, -S(=O)2(OC 1~6 alkyl), -OS(=O)2(C 1~6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1~6 alkyl), -S(=O)2N(C 1~6 alkyl)2, -NHS(=O)2(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2(C 1~6 alkyl), -OS(=O)2O(C 1~6 alkyl), -NHS(=O)2O(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2O(C 1~6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1~6 alkyl), -OS(=O)2N(C 1~6 alkyl)2, -NHS(=O)2NH2, -NHS(=O)2NH(C 1~6 alkyl), -NHS(=O)2N(C 1~6 alkyl)2, -N(C 1~6 alkyl)S(=O)2NH2, -N(C 1~6 alkyl)S(=O)2NH(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2N(C 1~6 alkyl)2, -PH(C 1~6 alkyl), -P(C 1~6 alkyl)2, -P(=O)H(C 1~6 alkyl), -P(=O)(C 1~6 alkyl)2, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein said —C 1~6Alkyl, -C 1~6 Haloalkyl, -C 1~6 Haloalkoxy, -C 2~6 Alkenyl, -C 2~6 Alkynyl, 3- to 10-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl are independently selected from the group consisting of halogen, —C 1~6 Alkyl, -C 1~6 Haloalkyl, -C 1~6 Haloalkoxy, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -CN, oxo, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 alkyl), -NH(3- to 10-membered cycloalkyl), -N(C 1~6 alkyl)(3-10 membered cycloalkyl), -OH, -O(C 1~6 alkyl), -O(3- to 10-membered cycloalkyl), -SH, -S(C 1~6 alkyl), -S(3-10 membered cycloalkyl), -S(=O)(C 1~6 alkyl), -S(=O)(3-10 membered cycloalkyl), -S(=O)2(C 1~6 alkyl), -S(=O)2(3-10 membered cycloalkyl), -C(=O)(C 1~6 alkyl), -C(=O)-(3-10 membered cycloalkyl), -C(=O)OH, -C(=O)(OC 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -C(=O)NH2, -C(=O)NH(C 1~6 alkyl), -C(=O)N(C 1~6 alkyl)2, -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -OC(=O)O(C 1~6 alkyl), -NHC(=O)(OC 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(OC 1~6 alkyl), -OC(=O)NH(C 1~6 alkyl), -OC(=O)N(C 1~6alkyl)2, -NHC(=O)NH2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -N(C 1~6 alkyl)C(=O)NH2, -N(C 1~6 alkyl)C(=O)NH(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)N(C 1~6 alkyl)2, -S(=O)(OC 1~6 alkyl), -OS(=O)(C 1~6 alkyl), -S(=O)NH2, -S(=O)NH(C 1~6 alkyl), -S(=O)N(C 1~6 alkyl)2, -NHS(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)(C 1~6 alkyl), -OS(=O)O(C 1~6 alkyl), -NHS(=O)O(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)O(C 1~6 alkyl), -OS(=O)NH2, -OS(=O)NH(C 1~6 alkyl), -OS(=O)N(C 1~6 alkyl)2, -NHS(=O)NH2, -NHS(=O)NH(C 1~6 alkyl), -NHS(=O)N(C 1~6 alkyl)2, -N(C 1~6 alkyl)S(=O)NH2, -N(C 1~6 alkyl)S(=O)NH(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)N(C 1~6 alkyl)2, -S(=O)2(OC 1~6 alkyl), -OS(=O)2(C 1~6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1~6 alkyl), -S(=O)2N(C 1~6 alkyl)2, -NHS(=O)2(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2(C 1~6alkyl), -OS(=O)2O(C 1~6 alkyl), -NHS(=O)2O(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2O(C 1~6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1~6 alkyl), -OS(=O)2N(C 1~6 alkyl)2, -NHS(=O)2NH2, -NHS(=O)2NH(C 1~6 alkyl), -NHS(=O)2N(C 1~6 alkyl)2, -N(C 1~6 alkyl)S(=O)2NH2, -N(C 1~6 alkyl)S(=O)2NH(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2N(C 1~6 alkyl)2, -PH(C 1~6 alkyl), -P(C 1~6 alkyl)2, -P(=O)H(C 1~6 alkyl), -P(=O)(C 1~6 The compound according to any one of [1] to

[41] , optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from alkyl), 2, 3 to 10-membered cycloalkyl, 3 to 6-membered heterocyclyl, 6 to 10-membered aryl, or 5 to 10-membered heteroaryl.

[0057]

[43] . (R in Y1 Y1 ), (R in Y2 Y2 ) or (R in Y3 Y3 ) each occurrence independently represents -H, -D, -F, -Cl, -Br, -C 1~3 Alkyl, -C 1~3 Haloalkyl, -C 1~3 Haloalkoxy, -C 2~3 Alkenyl, -C 2~3 Alkynyl, -CN, -NH, -NH(C 1~3 alkyl), -N(C 1~3 alkyl), -NH(3- to 6-membered cycloalkyl), -N(C 1~3 alkyl)(3- to 6-membered cycloalkyl), -OH, -O(C 1~3alkyl), -O-(3- to 6-membered cycloalkyl), -SH, -S(C 1~3 alkyl), -S-(3- to 6-membered cycloalkyl), -S(=O)(C 1~3 alkyl), -S(=O)(3-6 membered cycloalkyl), -S(=O)2(C 1~3 alkyl), -S(=O)2-(3- to 6-membered cycloalkyl), -C(=O)(C 1~3 alkyl), -C(=O)-(3- to 6-membered cycloalkyl), -C(=O)OH, -C(=O)(OC 1~3 alkyl), -OC(=O)(C 1~3 alkyl), -C(=O)NH2, -C(=O)NH(C 1~3 alkyl), -C(=O)N(C 1~3 alkyl)2, -NHC(=O)(C 1~3 alkyl), -N(C 1~3 alkyl)C(=O)(C 1~3 alkyl), -S(=O)(OC 1~3 alkyl), -OS(=O)(C 1~3 alkyl), -S(=O)NH2, -S(=O)NH(C 1~3 alkyl), -S(=O)N(C 1~3 alkyl)2, -NHS(=O)(C 1~3 alkyl), -N(C 1~3 alkyl)S(=O)(C 1~3 alkyl), -S(=O)2(OC 1~3 alkyl), -OS(=O)2(C 1~3 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1~3 alkyl), -S(=O)2N(C 1~3 alkyl)2, -NHS(=O)2(C 1~3 alkyl), -N(C 1~3 alkyl)S(=O)2(C 1~3 alkyl), -P(=O)H(C 1~3 alkyl), -P(=O)(C 1~3 alkyl)2, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein said —C 1~3 Alkyl, -C 1~3 Haloalkyl, -C1~3 Haloalkoxy, -C 2~6 Alkenyl, -C 2~6 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl are independently selected from the group consisting of -F, -Cl, -Br, -C 1~3 Alkyl, -C 1~3 Haloalkyl, -CN, -NH2, -NH(C 1~3 alkyl), -N(C 1~3 alkyl), -OH, -O(C 1~3 alkyl), -SH, -S(C 1~3 alkyl), -S(=O)(C 1~3 alkyl), -S(=O)2(C 1~3 alkyl), -C(=O)(C 1~3 alkyl), -C(=O)OH, -C(=O)(OC 1~3 alkyl), -OC(=O)(C 1~3 alkyl), -C(=O)NH2, -C(=O)NH(C 1~3 alkyl), -C(=O)N(C 1~3 alkyl)2, -NHC(=O)(C 1~3 alkyl), -N(C 1~3 alkyl)C(=O)(C 1~3 alkyl), -S(=O)(OC 1~3 alkyl), -OS(=O)(C 1~3 alkyl), -S(=O)NH2, -S(=O)NH(C 1~3 alkyl), -S(=O)N(C 1~3 alkyl)2, -NHS(=O)(C 1~3 alkyl), -N(C 1~3 alkyl)S(=O)(C 1~3 alkyl), -S(=O)2(OC 1~3 alkyl), -OS(=O)2(C 1~3 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1~3 alkyl), -S(=O)2N(C 1~3 alkyl)2, -NHS(=O)2(C 1~3 alkyl), -N(C 1~3 alkyl)S(=O)2(C 1~3 alkyl), -P(=O)H(C 1~3alkyl), -P(=O)(C 1~3 The compound according to any one of [1] to

[42] , optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from alkyl) 2- or 3- to 6-membered cycloalkyl.

[0058]

[44] . (R in Y1 Y1 ), (R in Y2 Y2 ) or (R in Y3 Y3 ) each occurrence independently represents -H, -D, -Cl, -F, -Br, -CH3, -CD3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, [ka] -CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CHFCH3、-CF2CH3、-CN 、-NH2、-NH(CH3)、-N(CH3)2、-NH(CH2CH3)、-OH、-O-CH3、-O-CH2CH3、-O-CH 2CH2CH3、-O-CH(CH3)2、-O-CF3、-SH、-S-CH3、-S-CH2CH3、-S-CH2CH2CH3、- S-CH(CH3)2、-S-CF3、-S(=O)CH3、-S(=O)(CH2CH3)、-S(=O)(CH2CH2CH3)、-S (=O)(CH(CH3)2)、-S(=O)2CH3、-S(=O)2(CH2CH3)、-S(=O)2(CH2CH2CH3)、-S(=O)2(CH(CH3)2)、-COOH、-C(=O)(CH3)、-C(=O)(CH2CH3)、-C(=O)(CH(CH3)2)、-C(=O)(CF3)、-C(=O)(OCH3)、-C(=O)(OCH2CH3)、-C(=O)(OCH2CH3)、-C(=O)(OCH2CH3)、-C(=O)(OCH2CH3)、-C(=O)(OCH(CH3)2)、-OC(=O)(CH3)、-OC(=O)(CH2CH3)、-OC(=O)(CH2CH2 CH3)、-OC(=O)(CH(CH3)2)、-C(=O)NH2、-C(=O)NH(CH3)、-C(=O)NH(CH2CH3)、-C(=O)NH(CH2CH2CH3)、-C(=O)NH(CH(CH3)2)、-C(=O)N(CH3)2、-C(=O)N(CH2CH3)2、-NHC(=O)(CH3)、-NHC(=O)(CH2CH3)、-NHC(=O)(CH2CH2CH3)、-NHC(=O)(CH(CH3)2)、-N(CH3)C(=O)(CH3)、-S(=O)(OCH3)、-S(=O)(OCH2CH3) 、-S(=O)(OCH2CH2CH3)、-S(=O)(OCH(CH3)2)、-OS(=O)(CH3)、-OS(=O)(CH2CH3)、-OS(=O)(CH2CH2CH3)、-OS(=O)(CH(CH3)2)、-S(=O)NH2、-S(=O)NH(CH3)、-S(=O)NH(CH2CH3)、-S(=O)NH(CH2CH2CH3)、-S(=O)NH(CH(CH3)2)、-S(=O)N(CH3)2、-S(=O)N(CH3)(CH2CH3)、-NHS(=O)(CH3)、-NHS(=O)(CH2CH3)、-NHS(=O)(CH2CH2CH3), -NHS(=O)(CH(CH3)2), -N(CH3)S(=O)(CH3), -S(=O)2(OCH3), -S(=O)2(OCH2CH3), -S(=O)2(OCH2CH2CH3), -S(=O)2(OCH(CH3)2), -OS(=O)2(CH3), -OS(=O)2(CH2CH3), -OS(=O)2(CH2CH2CH3), -OS(=O)2(CH(CH3)2), -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2NH(CH2CH3), -S(=O)2NH(CH2CH2CH3), -S(=O)2NH(CH(CH3)2), -S(=O)2N(CH3)2, -S(=O)2N(CH3)(CH2CH3), -NHS(=O)2(CH3), -NHS(=O)2(CH2CH3), -NHS(=O)2(CH2CH2CH3), -NHS(=O)2(CH(CH3)2), -N(CH3)S(=O)2(CH3), -P(=O)H(CH3), -P(=O)H(CH2CH3), -P(=O)H(CH2CH2CH3), -P(=O)H(CH(CH3)2), -P(=O)(CH3)2, -P(=O)(CH3)(CH2CH3), -CH2-OH, -CH2CH2-OH, -CH(CH3)-OH, -CH2-SH, -CH2CH2-SH, -CH(CH3)-SH, -CH2-NH2, -CH2CH2-NH2, -CH(CH3)-NH2, -CH2-CN, -CH2CH2-CN, -CH(CH3)-CN, -O-CH3-O-CH3, -O-CH2CH3-O-CH3, -O-CH(CH3)-O-CH3, -O-CH2CH2CH3-O-CH3, -O-CH2CH(CH3)-O-CH3, -O-CH(CH3)CH2-O-CH3, -NH-O-CH3, -N(CH3)-O-CH3, -N(CH2CH3)-O-CH3, [Chemistry] A compound according to any one of [1] to

[43] , selected from

[0059]

[45] . (R in Y1 Y1 ), (R in Y2 Y2 ), or (R in Y3 Y3) independently, -H, -D, -Cl, -F, -Br, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH3, -CF2C H3, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -O-CH3, -O-CH(CH3)2, -O-CF3, -SH, -S-CH3, -S-CH(CH3)2, -S-CF3, -S(=O)CH3, -S(=O)2CH3, -C(=O)(CH3), -C(= O)(CH2CH3), -C(=O)(CH(CH3)2), -C(=O)(CF3), -C(=O)NH2, -C(=O)NH(CH3), -NHC(=O)(CH3), -S(=O)NH2, -S(=O)NH(CH3), -NHS(=O)(CH3), -S(=O)2NH2 , -S(=O)2NH(CH3), -NHS(=O)2(CH3), -CH2-OH, -CH2CH2-OH, -CH(CH3)-OH, -CH2-NH2, -CH2CH2-NH2, -CH(CH3)-NH2, -CH2-CN, -CH2CH2-CN, -CH(CH3)-CN, [ka] The compound according to any one of [1] to

[44] , selected from:

[0060]

[46] . (R in Y1 Y1 ), (R in Y2 Y2 ) or (R in Y3 Y3 ) is independently selected from -H, -D, -CH3, or -CD3 at each occurrence.

[0061]

[47] . Each occurrence of Y1 independently represents -C(R Y1 )2-, -C(=O)-, -O-, -NR Y1 -, -S-, -S(=O)-, -S(=O)2-, -PR Y1 -, -P(=O)R Y1 -, -C(=O)NR Y1 -, -NRY1 C(=O)-, -S(=O)NR Y1 -, -NR Y1 S(=O)-, -S(=O)2NR Y1 - or -NR Y1 In certain embodiments, each occurrence of Y is independently selected from -C(R Y1 )2-, -C(=O)-, -O-, -NR Y1 -, -S-, -S(=O)-, -S(=O)2-, -C(=O)NR Y1 -, -NR Y1 C(=O)-, -S(=O)NR Y1 -, -NR Y1 S(=O)-, -S(=O)2NR Y1 - or -NR Y1 in certain embodiments, Y is selected from -CH-, -CH(CH)-, -CH(CHCH)-, -C(CH)-, -O-, -NH-, -N(CH)-, -N(CHCH)-, -N(CH(CH))-, -C(=O)-, -C(=O)NH-, -C(=O)N(CH)-, -NH-C(=O)-, -N(CH)-C(=O)-, -S-, -S(=O)-, -NH-S(=O)-, -N(CH)-S(=O)-, -S(=O)-, -NH-S(=O)-, or -N(CH)-S(=O)-; in certain embodiments, Y is selected from -O- or -NH-; Optionally, R in Y on adjacent carbon atoms Y1) and R1, together with the atoms to which they are each attached, form ring D, wherein ring D is selected from a 3- to 10-membered cycloalkyl ring, a 3- to 10-membered cycloalkenyl ring, a 3- to 10-membered heterocycloalkyl ring, a 3- to 10-membered heterocycloalkenyl ring, a 6- to 10-membered aryl ring, or a 5- to 12-membered heteroaryl ring; in some embodiments, ring D is a 3-membered monocyclic cycloalkyl ring, a 3-membered monocyclic cycloalkenyl ring, a 3-membered monocyclic heterocycloalkyl ring, a 3-membered monocyclic heterocycloalkenyl ring, a 4-membered monocyclic cycloalkyl ring, a 4-membered monocyclic cycloalkenyl ring, a 4-membered monocyclic hetero Cycloalkyl ring, 4-membered monocyclic heterocycloalkenyl ring, 4-membered fused cycloalkyl ring, 4-membered fused cycloalkenyl ring, 4-membered fused heterocycloalkyl ring, 4-membered fused heterocycloalkenyl ring, 5-membered monocyclic cycloalkyl ring, 5-membered monocyclic cycloalkenyl ring, 5-membered bridged cycloalkyl ring, 5-membered bridged cycloalkenyl ring, 5-membered fused cycloalkyl ring, 5-membered fused cycloalkenyl ring, 5-membered spirocyclic cycloalkyl ring, 5-membered spirocyclic cycloalkenyl ring, 5-membered monocyclic heterocycloalkyl ring, 5-membered monocyclic heterocycloalkenyl ring, 5-membered bridged heterocycloalkenyl ring alkyl ring, 5-membered bridged heterocycloalkenyl ring, 5-membered fused heterocycloalkyl ring, 5-membered fused heterocycloalkenyl ring, 5-membered spirocyclic heterocycloalkyl ring, 5-membered spirocyclic heterocycloalkenyl ring, 6-membered monocyclic cycloalkyl ring, 6-membered monocyclic cycloalkenyl ring, 6-membered bridged cycloalkyl ring, 6-membered bridged cycloalkenyl ring, 6-membered fused cycloalkyl ring, 6-membered fused cycloalkenyl ring, 6-membered spirocyclic cycloalkyl ring, 6-membered spirocyclic cycloalkenyl ring, 6-membered monocyclic heterocycloalkyl ring, 6-membered monocyclic heterocycloalkenyl ring, 6-membered bridged heterocycloalkenyl ring heterocycloalkyl ring, a 6-membered bridged heterocycloalkenyl ring, a 6-membered fused heterocycloalkyl ring, a 6-membered fused heterocycloalkenyl ring, a 6-membered spirocyclic heterocycloalkyl ring, a 6-membered spirocyclic heterocycloalkenyl ring, a 7-membered monocyclic cycloalkyl ring, a 7-membered monocyclic cycloalkenyl ring, a 7-membered spirocyclic cycloalkyl ring, a 7-membered spirocyclic cycloalkenyl ring, a 7-membered fused cycloalkyl ring, a 7-membered fused cycloalkenyl ring, a 7-membered bridged cycloalkyl ring, a 7-membered bridged cycloalkenyl ring, a 7-membered monocyclic heterocycloalkyl ring, a 7-membered monocyclic heterocycloalkenyl ring,7-membered spirocyclic heterocycloalkyl ring, 7-membered spirocyclic heterocycloalkenyl ring, 7-membered fused heterocycloalkyl ring, 7-membered fused heterocycloalkenyl ring, 7-membered bridged heterocycloalkyl ring, 7-membered bridged heterocycloalkenyl ring, 8-membered monocyclic cycloalkyl ring, 8-membered monocyclic cycloalkenyl ring, 8-membered spirocyclic cycloalkyl ring, 8-membered spirocyclic cycloalkenyl ring, 8-membered fused cycloalkyl ring, 8-membered fused cycloalkenyl ring, 8-membered bridged cycloalkyl ring, 8-membered bridged cycloalkenyl ring, 8-membered monocyclic heterocycloalkyl ring, 8-membered monocyclic heterocycloalkenyl ring, 8-membered spirocyclic heterocycloalkyl ring, 8-membered spirocyclic heterocycloalkenyl ring, 8-membered fused heterocycloalkyl ring, 8-membered fused heterocycloalkenyl ring, 8-membered bridged heterocycloalkyl ring, 8-membered bridged heterocycloalkenyl ring, 9-membered monocyclic cycloalkyl ring, 9-membered monocyclic cycloalkenyl ring, 9-membered spirocyclic cycloalkyl ring, 9-membered spirocyclic cycloalkenyl ring, 9-membered fused cycloalkyl ring, 9-membered fused cycloalkenyl ring, 9-membered bridged cycloalkyl ring, 9-membered bridged cycloalkenyl ring nyl ring, 9-membered monocyclic heterocycloalkyl ring, 9-membered monocyclic heterocycloalkenyl ring, 9-membered spirocyclic heterocycloalkyl ring, 9-membered spirocyclic heterocycloalkenyl ring, 9-membered fused heterocycloalkyl ring, 9-membered fused heterocycloalkenyl ring, 9-membered bridged heterocycloalkyl ring, 9-membered bridged heterocycloalkenyl ring, 10-membered monocyclic cycloalkyl ring, 10-membered monocyclic cycloalkenyl ring, 10-membered spirocyclic cycloalkyl ring, 10-membered spirocyclic cycloalkenyl ring, 10-membered fused cycloalkyl ring, 10-membered fused cycloalkenyl a 10-membered bridged cycloalkyl ring, a 10-membered bridged cycloalkenyl ring, a 10-membered monocyclic heterocycloalkyl ring, a 10-membered monocyclic heterocycloalkenyl ring, a 10-membered spirocyclic heterocycloalkyl ring, a 10-membered spirocyclic heterocycloalkenyl ring, a 10-membered fused heterocycloalkyl ring, a 10-membered fused heterocycloalkenyl ring, a 10-membered bridged heterocycloalkyl ring, a 10-membered bridged heterocycloalkenyl ring, a phenyl ring, a naphthalene ring, a 5-membered heteroaryl ring, a 6-membered heteroaryl ring, a 7-membered heteroaryl ring, an 8-membered heteroaryl ring,and wherein said heterocycloalkyl or heterocycloalkenyl, at each occurrence, contains one or more ring members selected from N, O, S, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)NH—, —NHC(═O)—, —S(═O)—, —S(═O)O—, —OS(═O)—, —S(═O)NH—, —NHS(═O)—, —S(═O)2—, —S(═O)2O—, —OS(═O)2—, —S(═O)2NH—, or —NHS(═O)2—; and wherein said heteroaryl, at each occurrence, contains one or more heteroatoms independently selected from N, O, or S; and wherein Ring D is a 4-membered monocyclic heterocycloalkyl ring, a 5-membered monocyclic heterocycloalkyl ring, a 6-membered monocyclic heterocycloalkyl ring, a 8-membered monocyclic heterocycloalkyl ring, a 9-membered monocyclic heterocycloalkyl ring, a 10-membered monocyclic heterocycloalkyl ring, a 5-membered monocyclic heterocycloalkyl ring, a 6-membered monocyclic heterocycloalkyl ring, a 9-membered monocyclic heterocycloalkyl ring, a 10 ... The compound according to any one of [1] to

[46] , wherein the heterocycloalkyl is selected from a cyclic heterocycloalkyl ring, a 6-membered monocyclic heterocycloalkyl ring, a 7-membered monocyclic heterocycloalkyl ring, a 9-membered spirocyclic heterocycloalkyl ring, a 9-membered fused heterocycloalkyl ring, and a 9-membered bridged heterocycloalkyl ring, wherein each occurrence of the heterocycloalkyl optionally further contains one or more ring members selected from N, O, and S; and in one embodiment, the compound according to any one of [1] to

[46] , wherein the ring D is selected from a 4-membered monocyclic heterocycloalkyl ring containing one N, a 5-membered monocyclic heterocycloalkyl ring containing one N, a 6-membered monocyclic heterocycloalkyl ring containing one N and optionally further containing one O, and a 9-membered fused heterocycloalkyl ring containing one N.

[0062]

[48] . Y1 is -C(R Y1 )2-, -O-, -NR Y1 selected from -, -S-, -S(=O)-, -S(=O)2-; where: R Y1 is hydrogen or -C 1~3 alkyl; or Y1 is -NR Y1 -, R on adjacent carbon atoms when selected from Y1 and R1 together with the atoms to which they are each attached, [ka] Forming; The compound according to any one of [1] to

[47] , wherein & indicates that when the carbon atom is a chiral carbon atom, the carbon atom in ring D has an R configuration or an S configuration; in one embodiment, & indicates that when the carbon atom is a chiral carbon atom, the carbon atom in ring D has an R configuration; in one embodiment, & indicates that when the carbon atom is a chiral carbon atom, the carbon atom in ring D has an S configuration.

[0063]

[49] . Y1 is -O- or -NR Y1 -Selected from; where: R Y1 is hydrogen or -C 1~3 alkyl; or R on adjacent carbon atoms Y1 and R1 together with the atoms to which they are each attached, [ka] Forming; & indicates that when the carbon atom is a chiral carbon atom, the carbon atom in ring D has the R or S configuration; in some embodiments, & indicates that when the carbon atom is a chiral carbon atom, the carbon atom in ring D has the R configuration; in some embodiments, & indicates that when the carbon atom is a chiral carbon atom, the carbon atom in ring D has the S configuration; In one embodiment, [ka] The part, [ka] Selected from; In one embodiment, [ka] The part, [ka] The compound according to any one of [1] to

[48] , selected from:

[0064]

[50] . The compound is represented by the following formula (II), formula (III) or formula (IV): [ka] Selected from; During the ceremony, In any one of the formulas, & indicates that when the carbon atom is a chiral carbon atom, the carbon atom is in the R or S configuration; in some embodiments, & in any one of the formulas indicates that when the carbon atom is a chiral carbon atom, the carbon atom is in the R configuration; in some embodiments, & in any one of the formulas indicates that when the carbon atom is a chiral carbon atom, the carbon atom is in the S configuration; The compound according to any one of [1] to

[49] , wherein m5 is selected from 0, 1, 2, 3, 4, 5, or 6; in certain embodiments, m5 is selected from 0, 1, or 2, and in certain embodiments, m5 is selected from 0; in certain embodiments, m5 is selected from 1; and in certain embodiments, m5 is selected from 2.

[0065]

[51] . The compound is represented by the following formula (V), formula (VI) or formula (VII): [ka] Selected from; The compound according to

[50] , wherein & in any one of the formulas indicates that when a carbon atom is a chiral carbon atom, the carbon atom is in the R configuration or the S configuration; in one embodiment, & in any one of the formulas indicates that when a carbon atom is a chiral carbon atom, the carbon atom is in the R configuration; in one embodiment, & in any one of the formulas indicates that when a carbon atom is a chiral carbon atom, the carbon atom is in the S configuration.

[0066]

[52] . The compound has the following formula: [ka] Select one of the following: TIFF2024506612000094.tif255169TIFF2024506612000095.tif255169TIFF2024506612000096.tif255170TIFF2024506612000097.tif255168TIFF2024506612000098.tif185170; The compound according to

[50] or

[51] , wherein & in any one of the formulas indicates that when a carbon atom is a chiral carbon atom, the carbon atom is in the R configuration or the S configuration; in one embodiment, & in any one of the formulas indicates that when a carbon atom is a chiral carbon atom, the carbon atom is in the R configuration; in one embodiment, & in any one of the formulas indicates that when a carbon atom is a chiral carbon atom, the carbon atom is in the S configuration.

[0067]

[53] . The compound has the following formula: [ka] TIFF2024506612000100.tif245170TIFF2024506612000101.tif255167TIFF20245066120001 02.tif255170TIFF2024506612000103.tif255165TIFF2024506612000104.tif254170TIFF202 Select one of the following: 4506612000105.tif255169TIFF2024506612000106.tif255166TIFF2024506612000107.tif255167TIFF2024506612000108.tif236170TIFF2024506612000109.tif255170; The compound according to any one of

[50] to

[52] , wherein & in any one of the formulae indicates that, when the carbon atom is a chiral carbon atom, the carbon atom has an R configuration or an S configuration; in one embodiment, & in any one of the formulae indicates that, when the carbon atom is a chiral carbon atom, the carbon atom has an R configuration; in one embodiment, & in any one of the formulae indicates that, when the carbon atom is a chiral carbon atom, the carbon atom has an S configuration.

[0068]

[54] . The compound has the following formula: [ka] TIFF2024506612000111.tif255161TIFF2024506612000112.tif255167TIFF20245066120001 13.tif251170TIFF2024506612000114.tif255169TIFF2024506612000115.tif255164TIFF20 Select one of the following: 24506612000116.tif242170TIFF2024506612000117.tif224170TIFF2024506612000118.tif234170TIFF2024506612000119.tif242170TIFF2024506612000120.tif37170; The compound according to any one of

[50] to

[53] , wherein & in any one of the formulae indicates that, when the carbon atom is a chiral carbon atom, the carbon atom has an R configuration or an S configuration; in one embodiment, & in any one of the formulae indicates that, when the carbon atom is a chiral carbon atom, the carbon atom has an R configuration; in one embodiment, & in any one of the formulae indicates that, when the carbon atom is a chiral carbon atom, the carbon atom has an S configuration.

[0069]

[55] . The compound has the following formula (VIII): [ka] Selected from; In the formula, R1, R2, R3, R4, R5, R6, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , Y1, Y2, X1, X2, X3, X4, Z1, Z2, Z3, Z 23 , ring A, ring B, ring C, m1, m2, m3, m4, t1, t2, t3 or t 23 The definition of is the same as any one of [1] to

[50] ; Ring E is a 3- to 15-membered carbocyclic ring, a 3- to 15-membered heterocyclic ring, -C 6~10 In some embodiments, ring E is selected from a 4- to 10-membered cycloalkyl ring, a 4- to 10-membered cycloalkenyl ring, a 4- to 10-membered cycloalkynyl ring, a 4- to 10-membered heterocycloalkyl ring, a 4- to 10-membered heterocycloalkenyl ring, -C 6~10 aryl ring or a 5- to 10-membered heteroaryl ring; wherein each occurrence of said heterocycloalkyl or heterocycloalkenyl ring contains 1, 2, 3, or 4 ring members independently selected from N, O, S, C(=O), C(=O)NH, NHC(=O), S(=O), S(=O)NH, NH-S(=O), S(=O)2, S(=O)2NH, NHS(=O)2; and wherein said heteroaryl ring contains 1, 2, 3, or 4 ring members selected from N, O, and S; In certain embodiments, Ring E is a 4-membered cycloalkyl ring; a 5-membered cycloalkyl ring; a 6-membered cycloalkyl ring; a 7-membered cycloalkyl ring; a 4-membered cycloalkenyl ring; a 5-membered cycloalkenyl ring; a 6-membered cycloalkenyl ring; a 7-membered cycloalkenyl ring; a 4-membered cycloalkynyl ring; a 5-membered cycloalkynyl ring; a 6-membered cycloalkynyl ring; a 7-membered cycloalkynyl ring; a 4-membered heterocycloalkyl ring; a 5-membered heterocycloalkyl ring; a 6-membered heterocycloalkyl ring; a 7-membered heterocycloalkyl ring; a 4-membered heterocycloalkenyl ring; a 5-membered heterocycloalkenyl ring; a 6-membered heterocycloalkenyl ring a 5-membered heteroaryl ring; a 6-membered heteroaryl ring; a 7-membered heteroaryl ring; an 8-membered heteroaryl ring; a 9-membered heteroaryl ring; or a 10-membered heteroaryl ring; wherein each occurrence of said heterocycloalkyl or heterocycloalkenyl ring independently contains one N and further contains 1, 2, 3, or 4 ring members selected from N, O, S, C(=O), S(=O), and S(=O)2; and said heteroaryl ring contains 1, 2, 3, or 4 ring members selected from N, O, and S; In one embodiment, the compound according to any one of [1] to

[50] , wherein ring E is selected from a 5-membered heterocycloalkyl ring containing one N and further containing 1, 2, or 3 ring members selected from C(=O), S(=O), or S(=O)2; or a 6-membered heterocycloalkyl ring containing one N and further containing 1, 2, or 3 ring members selected from C(=O), S(=O), and S(=O)2.

[0070]

[56] . The compound has the following formula: [ka] Select one of the following: In certain embodiments, the compound has the following formula: [ka] Select one of the following: In certain embodiments, the compound has the following formula: [ka] The compound according to

[55] , selected from:

[0071]

[57] .The compound has the following formula (IX): [ka] Selected from; In the formula, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 12 , R 13 , R 14 , R 15 , Y1, Y3, X1, X2, X3, X4, X5, Z1, Z2, Z3, Z 20 , ring A, ring B, ring C, m1, m2, m3, t1, t2, t3 or t 20 The definition of is the same as any one of [1] to

[50] ; X 10 is selected from C, N, or CH; Ring F is a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, -C 6~10 selected from an aryl ring or a 5- to 20-membered heteroaryl ring; In one embodiment, ring F is a 3- to 10-membered cycloalkyl ring, a 3- to 10-membered cycloalkenyl ring, a 3- to 10-membered heterocycloalkyl ring, a 3- to 10-membered heterocycloalkenyl ring, -C 6~10 selected from an aryl ring or a 5- to 10-membered heteroaryl ring; In certain embodiments, ring F is selected from a 3- to 10-membered heterocycloalkyl ring, a 3- to 10-membered heterocycloalkenyl ring, or a 5- to 10-membered heteroaryl ring; each occurrence of the heterocycloalkyl or heterocycloalkenyl ring contains one N and optionally further contains 1, 2, 3, or 4 ring members selected from N, O, S, C(═O), S(═O), or S(═O)2; and the heteroaryl ring contains 1, 2, 3, or 4 ring members selected from N, O, and S; In certain embodiments, ring F is selected from a 3-membered heterocycloalkyl ring; a 4-membered heterocycloalkyl ring; a 5-membered heterocycloalkyl ring; a 6-membered heterocycloalkyl ring; a 7-membered heterocycloalkyl ring; a 3-membered heterocycloalkenyl ring; a 4-membered heterocycloalkenyl ring; a 5-membered heterocycloalkenyl ring; a 6-membered heterocycloalkenyl ring; a 7-membered heterocycloalkenyl ring; a 5-membered heteroaryl ring; a 6-membered heteroaryl ring; a 7-membered heteroaryl ring; an 8-membered heteroaryl ring; a 9-membered heteroaryl ring; or a 10-membered heteroaryl ring; wherein each occurrence of said heterocycloalkyl ring or heterocycloalkenyl ring independently contains one N and optionally further contains 1, 2, 3, or 4 ring members selected from N, O, S, C(═O), S(═O), and S(═O)2; and said heteroaryl ring contains 1, 2, 3, or 4 ring members selected from N, O, or S; In one embodiment, the compound according to any one of [1] to

[50] , wherein ring F is selected from 5-membered heterocycloalkyl rings containing one N.

[0072]

[58] . The compound has the following formula: [ka] Selected from; In certain embodiments, the compound has the following formula: [ka] Select one of the following: In certain embodiments, the compound has the following formula: [ka] Select one of the following: In certain embodiments, the compound has the following formula: [ka] The compound according to

[57] , selected from any one of

[0073]

[59] .The compound has the following formula (X): [ka] Selected from; In the formula, R1, R2, R3, R4, R6, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , Y1, Y2, Y3, X1, X2, X3, X4, X5, Z1, Z2, Z3, Z 16 , ring A, ring B, ring C, m1, m2, m3, m4, t1, t2, t3 or t 16 The definition of is the same as any one of [1] to

[50] ; Ring G is a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, -C 6~10 selected from an aryl ring or a 5- to 20-membered heteroaryl ring; In one embodiment, ring G is a 3- to 10-membered cycloalkyl ring, a 3- to 10-membered cycloalkenyl ring, a 3- to 10-membered heterocycloalkyl ring, a 3- to 10-membered heterocycloalkenyl ring, -C 6~10 selected from an aryl ring or a 5- to 10-membered heteroaryl ring; In certain embodiments, ring G is selected from a 3- to 10-membered heterocycloalkyl ring, a 3- to 10-membered heterocycloalkenyl ring, or a 5- to 10-membered heteroaryl ring; each occurrence of the heterocycloalkyl or heterocycloalkenyl ring contains one O and optionally further contains 1, 2, 3, or 4 ring members selected from N, O, S, C(═O), S(═O), or S(═O)2; and the heteroaryl ring contains 1, 2, 3, or 4 ring members selected from N, O, and S; In certain embodiments, ring G is selected from a 3-membered heterocycloalkyl ring; a 4-membered heterocycloalkyl ring; a 5-membered heterocycloalkyl ring; a 6-membered heterocycloalkyl ring; a 7-membered heterocycloalkyl ring; a 3-membered heterocycloalkenyl ring; a 4-membered heterocycloalkenyl ring; a 5-membered heterocycloalkenyl ring; a 6-membered heterocycloalkenyl ring; a 7-membered heterocycloalkenyl ring; a 5-membered heteroaryl ring; a 6-membered heteroaryl ring; a 7-membered heteroaryl ring; an 8-membered heteroaryl ring; a 9-membered heteroaryl ring; or a 10-membered heteroaryl ring; wherein each occurrence of said heterocycloalkyl ring or heterocycloalkenyl ring independently contains one O and optionally further contains 1, 2, 3, or 4 ring members selected from N, O, S, C(═O), S(═O), and S(═O)2; and said heteroaryl ring contains 1, 2, 3, or 4 ring members selected from N, O, or S; In one embodiment, the compound according to any one of [1] to

[50] , wherein ring G is selected from 5-membered heterocycloalkyl rings containing one O.

[0074]

[60] . The compound has the following formula: [ka] Selected from; In certain embodiments, the compound has the following formula: [ka] Select one of the following: In certain embodiments, the compound has the following formula: [ka] Select one of the following: In certain embodiments, the compound has the following formula: [ka] The compound according to

[59] , selected from any one of:

[0075]

[61] .The compound has the following formula (XI): [ka] Selected from; In the formula, R1, R2, R3, R4, R5, R6, R8, R9, R 10 , R 12 , R 13 , R 14 , R 15 , Y1, Y2, Y3, X1, X2, X3, X4, X5, Z1, Z2, Z3, Z 22 , ring A, ring B, ring C, m1, m2, m3, t1, t2, t3 or t 22 The definition of is the same as any one of [1] to

[50] ; Ring H is a 3- to 20-membered carbocyclic ring, a 3- to 20-membered heterocyclic ring, -C 6~10 selected from an aryl ring or a 5- to 20-membered heteroaryl ring; In one embodiment, ring H is a 3- to 10-membered cycloalkyl ring, a 3- to 10-membered cycloalkenyl ring, a 3- to 10-membered heterocycloalkyl ring, a 3- to 10-membered heterocycloalkenyl ring, -C 6~10 selected from an aryl ring or a 5- to 10-membered heteroaryl ring; In one embodiment, ring H is -C 6~10 an aryl ring or a 5- to 10-membered heteroaryl ring; wherein the heteroaryl ring contains 1, 2, 3, or 4 ring members selected from N, O, and S; In certain embodiments, Ring H is selected from a benzene ring; a naphthalene ring; a 5-membered heteroaryl ring; a 6-membered heteroaryl ring; a 7-membered heteroaryl ring; an 8-membered heteroaryl ring; a 9-membered heteroaryl ring; and a 10-membered heteroaryl ring; wherein the heteroaryl ring contains 1, 2, 3, or 4 ring members selected from N, O, and S; In one embodiment, the compound according to any one of [1] to

[50] , wherein ring H is selected from a benzene ring.

[0076]

[62] . The compound has the following formula: [ka] Selected from; In certain embodiments, the compound has the following formula: [ka] Select one of the following: In certain embodiments, the compound has the following formula: [ka] Select one of the following: In certain embodiments, the compound has the following formula: [ka] The compound according to

[61] , selected from any one of TIFF2024506612000140.tif169170.

[0077]

[63] . The compound has the following formula (XII): [ka] Selected from; In the formula, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , Y1, Y2, Y3, X1, X2, X3, X4, X5, Z1, Z2, Z3, ring A, ring B, ring C, m1, m2, m3, t1, t2, or t3 are defined as any one of [1] to

[50] ; The compound according to any one of [1] to

[50] , wherein m6 is selected from 0, 1, 2, 3, 4, 5, or 6.

[0078]

[64] . The compound has the following formula: [ka] Select one of the following: In certain embodiments, the compound has the following formula: [ka] Select one of the following: TIFF2024506612000144.tif255162TIFF2024506612000145.tif228170TIFF2024506612000146.tif113170; In certain embodiments, the compound has the following formula: [ka] TIFF2024506612000148.tif255170TIFF2024506612000149.tif240170TIFF2024506612000150.tif255159TIFF2024506612000151.tif250170TIFF2024506612000152.tif242170TIFF2024506612000153.tif251170TIFF2024506612000154.tif252170TIFF2024506612000155.tif138170.

[0079]

[65] . Each occurrence of Y2 independently represents -C(R Y2 )2-, -C(=O)-, -O-, -NR Y2 -, -S-, -S(=O)-, -S(=O)2-, -PR Y2 -, -P(=O)R Y2 -, -C(=O)NR Y2 -, -NR Y2 C(=O)-, -S(=O)NR Y2 -, -NR Y2 S(=O)-, -S(=O)2NR Y2 - or -NR Y2 The compound according to any one of [1] to

[64] , selected from S(=O)2-.

[0080]

[66] . Each occurrence of Y2 independently represents -C(R Y2 )2-, -C(=O)-, -O-, -NR Y2 -, -S-, -S(=O)-, -S(=O)2-, -C(=O)NR Y2 -, -NRY2 C(=O)-, -S(=O)NR Y2 -, -NR Y2 S(=O)-, -S(=O)2NR Y2 - or -NR Y2 The compound according to any one of [1] to

[65] , selected from S(=O)2-.

[0081]

[67] . The compound according to any one of [1] to

[66] , wherein Y2, at each occurrence, is independently selected from —CH2—, —CH(CH3)—, —CH(CH2CH3)—, —C(CH3)2—, —O—, —NH—, —N(CH3)—, —N(CH2CH3)—, —N(CH(CH3)2)—, —C(═O)—, —C(═O)NH—, —C(═O)N(CH3)—, —NH—C(═O)—, —N(CH3)—C(═O)—, —S—, —S(═O)—, —NH—S(═O)—, —N(CH3)—S(═O)—, —S(═O)2—, —NH—S(═O)2—, or —N(CH3)—S(═O)2-.

[0082]

[68] The compound according to any one of [1] to

[67] , wherein each occurrence of Y2 is independently selected from -O-, -CO-NH-, or -NH-CO-.

[0083]

[69] The compound according to any one of [1] to

[68] , wherein each occurrence of Y2 is independently selected from -O-.

[0084]

[70] . Each occurrence of Y3 independently represents -C(R Y3 )2-, -C(=O)-, -O-, -NR Y3 -, -S-, -S(=O)-, -S(=O)2-, -PR Y3 -, -P(=O)R Y3 -, -C(=O)NR Y3 -, -NR Y3 C(=O)-, -S(=O)NR Y3 -, -NR Y3 S(=O)-, -S(=O)2NR Y3 - or -NR Y3The compound according to any one of [1] to

[69] , wherein the compound is selected from S(=O)2-.

[0085]

[71] . Each occurrence of Y3 independently represents -C(R Y3 )2-, -C(=O)-, -O-, -NR Y3 -, -S-, -S(=O)-, -S(=O)2-, -C(=O)NR Y3 -, -NR Y3 C(=O)-, -S(=O)NR Y3 -, -NR Y3 S(=O)-, -S(=O)2NR Y3 - or -NR Y3 The compound according to any one of [1] to

[70] , selected from S(=O)2-.

[0086]

[72] . The compound according to any one of [1] to

[71] , wherein Y3, in each occurrence, is independently selected from —CH2—, —CH(CH3)—, —CH(CH2CH3)—, —C(CH3)2—, —O—, —NH—, —N(CH3)—, —N(CH2CH3)—, —N(CH(CH3)2)—, —C(═O)—, —C(═O)NH—, —C(═O)N(CH3)—, —NH—C(═O)—, —N(CH3)—C(═O)—, —S—, —S(═O)—, —NH—S(═O)—, —N(CH3)—S(═O)—, —S(═O)2—, —NH—S(═O)2—, or —N(CH3)—S(═O)2-.

[0087]

[73] . The compound according to any one of [1] to

[72] , wherein each occurrence of Y3 is independently selected from -C(=O)-, -S(=O)2-, -C(=O)-NH-, -NH-C(=O)-, -C(=O)-N(CH3)-, or -N(CH3)-C(=O)-.

[0088]

[74] The compound according to any one of [1] to

[73] , wherein each occurrence of Y3 is independently selected from -C(=O)-.

[0089]

[75] . The compound according to any one of [1] to

[54] and

[61] to

[74] , wherein each occurrence of Y2 is independently selected from -O-, and each occurrence of Y3 is independently selected from -C(=O)-.

[0090]

[76] . R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , or R 12 Each occurrence of represents independently hydrogen, halogen, -C 1~6 Alkyl, -C 1~6 Haloalkyl, -C 1~6 Haloalkoxy, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -CN, oxo, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 alkyl), -OH, -O(C 1~6 alkyl), -SH, -S(C 1~6 alkyl), -S(haloC 1~6 alkyl), -S(=O)(C 1~6 alkyl), -S(=O)2(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -C(=O)OH, -C(=O)(OC 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -C(=O)NH2, -C(=O)NH(C 1~6 alkyl), -C(=O)N(C 1~6 alkyl)2, -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -OC(=O)O(C 1~6 alkyl), -NHC(=O)(OC 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(OC 1~6 alkyl), -OC(=O)NH(C 1~6 alkyl), -OC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH2, -NHC(=O)NH(C 1~6alkyl), -NHC(=O)N(C 1~6 alkyl)2, -N(C 1~6 alkyl)C(=O)NH2, -N(C 1~6 alkyl)C(=O)NH(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)N(C 1~6 alkyl)2, -S(=O)(OC 1~6 alkyl), -OS(=O)(C 1~6 alkyl), -S(=O)NH2, -S(=O)NH(C 1~6 alkyl), -S(=O)N(C 1~6 alkyl)2, -NHS(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)(C 1~6 alkyl), -S(=O)2(OC 1~6 alkyl), -OS(=O)2(C 1~6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1~6 alkyl), -S(=O)2N(C 1~6 alkyl)2, -NHS(=O)2(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2(C 1~6 alkyl), -OS(=O)2O(C 1~6 alkyl), -NHS(=O)2O(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2O(C 1~6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1~6 alkyl), -OS(=O)2N(C 1~6 alkyl)2, -NHS(=O)2NH2, -NHS(=O)2NH(C 1~6 alkyl), -NHS(=O)2N(C 1~6 alkyl)2, -N(C 1~6 alkyl)S(=O)2NH2, -N(C 1~6 alkyl)S(=O)2NH(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2N(C 1~6 alkyl)2, -PH(C 1~6 alkyl), -P(C1~6 alkyl)2, -P(=O)H(C 1~6 alkyl), -P(=O)(C 1~6 alkyl)2, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein said —C 1~6 Alkyl, -C 1~6 Haloalkyl, -C 1~6 Haloalkoxy, -C 2~6 Alkenyl, -C 2~6 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl are independently selected from the group consisting of -F, -Cl, -Br, -C 1~6 Alkyl, -C 1~6 Haloalkyl, -C 1~6 Haloalkoxy, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -CN, oxo, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 alkyl), -OH, -O(C 1~6 alkyl), -SH, -S(C 1~6 alkyl), -S(haloC 1~6 alkyl), -S(=O)(C 1~6 alkyl), -S(=O)2(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -C(=O)OH, -C(=O)(OC 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -C(=O)NH2, -C(=O)NH(C 1~6 alkyl), -C(=O)N(C 1~6 alkyl)2, -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -OC(=O)O(C 1~6 alkyl), -NHC(=O)(OC 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(OC 1~6 alkyl), -OC(=O)NH(C 1~6 alkyl), -OC(=O)N(C1~6 alkyl)2, -NHC(=O)NH2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -N(C 1~6 alkyl)C(=O)NH2, -N(C 1~6 alkyl)C(=O)NH(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)N(C 1~6 alkyl)2, -S(=O)(OC 1~6 alkyl), -OS(=O)(C 1~6 alkyl), -S(=O)NH2, -S(=O)NH(C 1~6 alkyl), -S(=O)N(C 1~6 alkyl)2, -NHS(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)(C 1~6 alkyl), -S(=O)2(OC 1~6 alkyl), -OS(=O)2(C 1~6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1~6 alkyl), -S(=O)2N(C 1~6 alkyl)2, -NHS(=O)2(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2(C 1~6 alkyl), -OS(=O)2O(C 1~6 alkyl), -NHS(=O)2O(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2O(C 1~6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1~6 alkyl), -OS(=O)2N(C 1~6 alkyl)2, -NHS(=O)2NH2, -NHS(=O)2NH(C 1~6 alkyl), -NHS(=O)2N(C 1~6 alkyl)2, -N(C 1~6 alkyl)S(=O)2NH2, -N(C 1~6 alkyl)S(=O)2NH(C 1~6 alkyl), -N(C 1~6alkyl)S(=O)2N(C 1~6 alkyl)2, -PH(C 1~6 alkyl), -P(C 1~6 alkyl)2, -P(=O)H(C 1~6 alkyl), -P(=O)(C 1~6 alkyl) optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from 2, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; m1 is 0, 1, 2, 3, 4, 5, or 6; m2 is 0, 1, 2, 3, 4, 5, or 6; m3 is 0, 1, 2, 3, 4, 5, or 6; The compound according to any one of [1] to

[75] , wherein m4 is 0, 1, 2, 3, 4, 5, or 6.

[0091]

[77] . R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , or R 12 Each occurrence of is independently -H, -D, -F, -Cl, -Br, -C 1~3 Alkyl, -C 1~3 Haloalkyl, -C 1~3 Haloalkoxy, -C 2~3 Alkenyl, -C 2~3 Alkynyl, -CN, oxo, -NH2, -NH(C 1~3 alkyl), -N(C 1~3 alkyl), -OH, -O(C 1~3 alkyl), -SH, -S(C 1~3 alkyl), -S(=O)(C 1~3 alkyl), -S(=O)2(C 1~3 alkyl), -C(=O)(C 1~3 alkyl), -C(=O)OH, -C(=O)(OC 1~3 alkyl), -OC(=O)(C 1~3 alkyl), -C(=O)NH2, -C(=O)NH(C 1~3 alkyl), -C(=O)N(C 1~3 alkyl)2, -NHC(=O)(C1~3 alkyl), -N(C 1~3 alkyl)C(=O)(C 1~3 alkyl), -S(=O)(OC 1~3 alkyl), -OS(=O)(C 1~3 alkyl), -S(=O)NH2, -S(=O)NH(C 1~3 alkyl), -S(=O)N(C 1~3 alkyl)2, -NHS(=O)(C 1~3 alkyl), -N(C 1~3 alkyl)S(=O)(C 1~3 alkyl), -S(=O)2(OC 1~3 alkyl), -OS(=O)2(C 1~3 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1~3 alkyl), -S(=O)2N(C 1~3 alkyl)2, -NHS(=O)2(C 1~3 alkyl), -N(C 1~3 alkyl)S(=O)2(C 1~3 alkyl), -P(=O)H(C 1~3 alkyl), -P(=O)(C 1~3 alkyl)2, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein said —C 1~3 Alkyl, -C 1~3 Haloalkyl, -C 1~3 Haloalkoxy, -C 2~6 Alkenyl, -C 2~6 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl are independently selected from hydrogen, —F, —Cl, —Br, —C 1~3 Alkyl, -C 1~3 Haloalkyl, -C 1~3 Haloalkoxy, -C 2~3 Alkenyl, -C 2~3 Alkynyl, -CN, oxo, -NH2, -NH(C 1~3 alkyl), -N(C 1~3 alkyl), -OH, -O(C1~3 alkyl), -SH, -S(C 1~3 alkyl), -S(=O)(C 1~3 alkyl), -S(=O)2(C 1~3 alkyl), -C(=O)(C 1~3 alkyl), -C(=O)OH, -C(=O)(OC 1~3 alkyl), -OC(=O)(C 1~3 alkyl), -C(=O)NH2, -C(=O)NH(C 1~3 alkyl), -C(=O)N(C 1~3 alkyl)2, -NHC(=O)(C 1~3 alkyl), -N(C 1~3 alkyl)C(=O)(C 1~3 alkyl), -S(=O)(OC 1~3 alkyl), -OS(=O)(C 1~3 alkyl), -S(=O)NH2, -S(=O)NH(C 1~3 alkyl), -S(=O)N(C 1~3 alkyl)2, -NHS(=O)(C 1~3 alkyl), -N(C 1~3 alkyl)S(=O)(C 1~3 alkyl), -S(=O)2(OC 1~3 alkyl), -OS(=O)2(C 1~3 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1~3 alkyl), -S(=O)2N(C 1~3 alkyl)2, -NHS(=O)2(C 1~3 alkyl), -N(C 1~3 alkyl)S(=O)2(C 1~3 alkyl), -P(=O)H(C 1~3 alkyl), -P(=O)(C 1~3 alkyl) optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from 2, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; m1 is 0, 1, 2, or 3; m2 is 0, 1, 2, or 3; m3 is 0, 1, 2, or 3; The compound according to any one of [1] to

[76] , wherein m4 is 0, 1, 2, or 3.

[0092]

[78] . R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , or R 12 each occurrence independently represents -H, -D, -Cl, -F, -Br, -CH3, -CD3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -O-CH2F, -O-CHF2, -O-CF3, -S-CH2F, -S-CHF2, -S-CF3, [ka] -CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CHFCH3、-CF2CH3、-C N、オキソ、-NH2、-NH(CH3)、-N(CH3)2、-NH(CH2CH3)、-OH、-O-CH3、-O-CH2CH3、 -O-CH2CH2CH3、-O-CH(CH3)2、-SH、-S-CH3、-S-CH2CH3、-S-CH2CH2CH3、-S- CH(CH3)2、-S(=O)CH3、-S(=O)(CH2CH3)、-S(=O)(CH2CH2CH3)、-S(=O)(CH( CH3)2)、-S(=O)2CH3、-S(=O)2(CH2CH3)、-S(=O)2(CH2CH2CH3)、-S(=O)2(CH(CH3)2)、-COOH、-C(=O)(CH3)、-C(=O)(CH2CH3)、-C(=O)(CH(CH3)2)、-C(=O)(CF3)、-C(=O)(OCH3)、-C(=O)(OCH2CH3)、-C(=O)(OCH2CH3)、-C(=O)(OCH2CH2CH3)、-C(=O)(OCH(CH3)2)、-OC(=O)(CH3)、-OC(=O)(CH2CH3)、 -OC(=O)(CH(CH3)2)、-C(=O)NH2、-C(=O)NH(CH3)、-C(=O)NH(CH2CH3)、-C(=O)NH(CH2CH2CH3)、-C(=O)NH(CH(CH3)2)、-C(=O)N(CH3)2、-C(=O)N(CH2CH3)2、-NHC(=O)(CH3)、-NHC(=O)(CH2CH3)、-NHC(=O)(CH2CH2CH3)、-NHC(=O)(CH(CH3)2)、-N(CH3)C(=O)(CH3)、-S(=O)(OCH3)、-S(=O)(OCH2CH3)、- S(=O)(OCH2CH2CH3)、-S(=O)(OCH(CH3)2)、-OS(=O)(CH3)、-OS(=O)(CH2CH3)、-OS(=O)(CH2CH2CH3)、-OS(=O)(CH(CH3)2)、-S(=O)NH2、-S(=O)NH(CH3)、-S(=O)NH(CH2CH3)、-S(=O)NH(CH2CH2CH3)、-S(=O)NH(CH(CH3)2)、-S(=O)N(CH3)2、-S(=O)N(CH3)(CH2CH3)、-NHS(=O)(CH3)、-NHS(=O)(CH2CH3)、-NHS(=O)(CH2CH2CH3), -NHS(=O)(CH(CH3)2), -N(CH3)S(=O)(CH3), -S(=O)2(OCH3), -S(=O)2(OCH2CH3), -S(=O)2(OCH2CH2CH3), -S(=O)2(OCH(CH3)2), -OS(=O)2(CH3), -OS(=O)2(CH2CH3), -OS(=O)2(CH2CH2CH3), -OS(=O)2(CH(CH3)2), -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2NH(CH2CH3), -S(=O)2NH(CH2CH2CH3), -S(=O)2NH(CH(CH3)2), -S(=O)2N(CH3)2, -S(=O)2N(CH3)(CH2CH3), -NHS(=O)2(CH3), -NHS(=O)2(CH2CH3), -NHS(=O)2(CH2CH2CH3), -NHS(=O)2(CH(CH3)2), -N(CH3)S(=O)2(CH3), -P(=O)H(CH3), -P(=O)H(CH2CH3), -P(=O)H(CH2CH2CH3), -P(=O)H(CH(CH3)2), -P(=O)(CH3)2, -P(=O)(CH3)(CH2CH3), -CH2-OH, -CH2CH2-OH, -CH(CH3)-OH, -CH2-OCH3, -CH2-OCH2CH3, -CH2-OCH(CH3)2, -CH2-NH2, -CH2CH2-NH2, -CH(CH3)-NH2, -CH2-NH-C(=O)(CH3), -CH2-NH-C(=O)(CH2CH3), -CH2-NH-C(=O)(CH(CH3)2), -CH2-N(CH3)-C(=O)(CH2CH3), -CH2-CN, -CH2CH2-CN, -CH(CH3)-CN, [Chemical formula] A compound according to any one of [1] to

[77] , selected from

[0093]

[79] . R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , or R 12each occurrence independently represents -H, -D, -Cl, -F, -Br, -CH3, -CD3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, -O-CF3, -S-CF3, -CF3, -CN, oxo, -NH2, -NH(CH3), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH(CH3)2, -S(=O)CH3, -S(=O)2CH3, -COOH, -C(=O)(CH3), -C(=O)(CH2CH3), -C(=O)(CF3 ), -C(=O)NH2, -C(=O)NH(CH3), -NHC(=O)(CH3), -S(=O)NH2, -S(=O)NH(CH3), -NHS(=O)(CH3), -S(=O)2NH2, -S(=O)2NH(CH3), -NHS(=O)2(CH3), -CH2-OH, -CH 2CH2-OH, -CH(OH)(CH3), -CH2-OCH3, -CH2-OCH2CH3, -CH2-NH2, -CH2CH2-NH2, -CH(CH3)-NH2, -CH2-NH-C(=O)(CH3), -CH2-CN, -CH2CH2-CN, -CH(CH3)-CN, or [ka] Selected from; m1 is 0 or 1; m2 is 0 or 1; m3 is 0 or 1; The compound according to any one of [1] to

[78] , wherein m4 is 0 or 1.

[0094]

[80] . R1 or R2, at each occurrence, is independently selected from -H, -D, -CH3, -CD3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, -CH2-OCH3, -CH2-OCH2CH3, -CH2-OH, -CH2CH2-OH, -CH(OH)(CH3), or -CH2-NH-C(=O)(CH3); m1 is 1; R3, R4, R5, R6, R7, R8, R9, R 10, R 11 , or R 12 is independently selected from -H, -D, -OH, -CH, -CD, -CHCH, -CHCHCH, or -CH(CH); m2 is 0, m3 is 1; The compound according to any one of [1] to

[79] , wherein m4 is 0.

[0095]

[81] . [ka] The part, [ka] Selected from; In the formula, # is [ka] indicates the point of attachment to the moiety, and ## indicates the point of attachment to the moiety [ka] The compound according to any one of [1] to

[80] , wherein the point of attachment to the moiety is

[0096]

[82] . R 13 , R 14 or R 15 Each occurrence of represents independently hydrogen, halogen, -C 1~6 Alkyl, -C 1~6 Haloalkyl, -C 1~6 Haloalkoxy, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -CN, oxo, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 alkyl), -OH, -O(C 1~6 alkyl), -SH, -S(C 1~6 alkyl), -S(haloC 1~6 alkyl), -S(=O)(C 1~6 alkyl), -S(=O)2(C1~6 alkyl), -C(=O)(C 1~6 alkyl), -C(=O)OH, -C(=O)(OC 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -C(=O)NH2, -C(=O)NH(C 1~6 alkyl), -C(=O)N(C 1~6 alkyl)2, -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -OC(=O)O(C 1~6 alkyl), -NHC(=O)(OC 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(OC 1~6 alkyl), -OC(=O)NH(C 1~6 alkyl), -OC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -N(C 1~6 alkyl)C(=O)NH2, -N(C 1~6 alkyl)C(=O)NH(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)N(C 1~6 alkyl)2, -S(=O)(OC 1~6 alkyl), -OS(=O)(C 1~6 alkyl), -S(=O)NH2, -S(=O)NH(C 1~6 alkyl), -S(=O)N(C 1~6 alkyl)2, -NHS(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)(C 1~6 alkyl), -S(=O)2(OC 1~6 alkyl), -OS(=O)2(C 1~6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1~6 alkyl), -S(=O)2N(C 1~6 alkyl)2, -NHS(=O)2(C 1~6 alkyl), -N(C1~6 alkyl)S(=O)2(C 1~6 alkyl), -OS(=O)2O(C 1~6 alkyl), -NHS(=O)2O(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2O(C 1~6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1~6 alkyl), -OS(=O)2N(C 1~6 alkyl)2, -NHS(=O)2NH2, -NHS(=O)2NH(C 1~6 alkyl), -NHS(=O)2N(C 1~6 alkyl)2, -N(C 1~6 alkyl)S(=O)2NH2, -N(C 1~6 alkyl)S(=O)2NH(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2N(C 1~6 alkyl)2, -PH(C 1~6 alkyl), -P(C 1~6 alkyl)2, -P(=O)H(C 1~6 alkyl), -P(=O)(C 1~6 alkyl)2, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein said —C 1~6 Alkyl, -C 1~6 Haloalkyl, -C 1~6 Haloalkoxy, -C 2~6 Alkenyl, -C 2~6 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl are independently selected from the group consisting of -F, -Cl, -Br, -C 1~6 Alkyl, -C 1~6 Haloalkyl, -C 1~6 Haloalkoxy, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -CN, oxo, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 alkyl), -OH, -O(C 1~6 alkyl), -SH, -S(C 1~6alkyl), -S(haloC 1~6 alkyl), -S(=O)(C 1~6 alkyl), -S(=O)2(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -C(=O)OH, -C(=O)(OC 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -C(=O)NH2, -C(=O)NH(C 1~6 alkyl), -C(=O)N(C 1~6 alkyl)2, -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -OC(=O)O(C 1~6 alkyl), -NHC(=O)(OC 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(OC 1~6 alkyl), -OC(=O)NH(C 1~6 alkyl), -OC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -N(C 1~6 alkyl)C(=O)NH2, -N(C 1~6 alkyl)C(=O)NH(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)N(C 1~6 alkyl)2, -S(=O)(OC 1~6 alkyl), -OS(=O)(C 1~6 alkyl), -S(=O)NH2, -S(=O)NH(C 1~6 alkyl), -S(=O)N(C 1~6 alkyl)2, -NHS(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)(C 1~6 alkyl), -S(=O)2(OC 1~6 alkyl), -OS(=O)2(C 1~6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1~6alkyl), -S(=O)2N(C 1~6 alkyl)2, -NHS(=O)2(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2(C 1~6 alkyl), -OS(=O)2O(C 1~6 alkyl), -NHS(=O)2O(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2O(C 1~6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1~6 alkyl), -OS(=O)2N(C 1~6 alkyl)2, -NHS(=O)2NH2, -NHS(=O)2NH(C 1~6 alkyl), -NHS(=O)2N(C 1~6 alkyl)2, -N(C 1~6 alkyl)S(=O)2NH2, -N(C 1~6 alkyl)S(=O)2NH(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2N(C 1~6 alkyl)2, -PH(C 1~6 alkyl), -P(C 1~6 alkyl)2, -P(=O)H(C 1~6 alkyl), -P(=O)(C 1~6 The compound according to any one of [1] to

[81] , optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from alkyl), 2, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl.

[0097]

[83] . R 13 , R 14 or R 15 Each occurrence of is independently -H, -D, -F, -Cl, -Br, -C 1~3 Alkyl, -C 1~3 Haloalkyl, -C 1~3 Haloalkoxy, -C 2~3 Alkenyl, -C 2~3 Alkynyl, -CN, oxo, -NH2, -NH(C 1~3 alkyl), -N(C1~3 alkyl), -OH, -O(C 1~3 alkyl), -SH, -S(C 1~3 alkyl), -S(=O)(C 1~3 alkyl), -S(=O)2(C 1~3 alkyl), -C(=O)(C 1~3 alkyl), -C(=O)OH, -C(=O)(OC 1~3 alkyl), -OC(=O)(C 1~3 alkyl), -C(=O)NH2, -C(=O)NH(C 1~3 alkyl), -C(=O)N(C 1~3 alkyl)2, -NHC(=O)(C 1~3 alkyl), -N(C 1~3 alkyl)C(=O)(C 1~3 alkyl), -S(=O)(OC 1~3 alkyl), -OS(=O)(C 1~3 alkyl), -S(=O)NH2, -S(=O)NH(C 1~3 alkyl), -S(=O)N(C 1~3 alkyl)2, -NHS(=O)(C 1~3 alkyl), -N(C 1~3 alkyl)S(=O)(C 1~3 alkyl), -S(=O)2(OC 1~3 alkyl), -OS(=O)2(C 1~3 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1~3 alkyl), -S(=O)2N(C 1~3 alkyl)2, -NHS(=O)2(C 1~3 alkyl), -N(C 1~3 alkyl)S(=O)2(C 1~3 alkyl), -P(=O)H(C 1~3 alkyl), -P(=O)(C 1~3 alkyl)2, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein said —C 1~3 Alkyl, -C 1~3 Haloalkyl, -C 1~3 Haloalkoxy, -C 2~6Alkenyl, -C 2~6 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl are independently selected from hydrogen, —F, —Cl, —Br, —C 1~3 Alkyl, -C 1~3 Haloalkyl, -C 1~3 Haloalkoxy, -C 2~3 Alkenyl, -C 2~3 Alkynyl, -CN, oxo, -NH2, -NH(C 1~3 alkyl), -N(C 1~3 alkyl), -OH, -O(C 1~3 alkyl), -SH, -S(C 1~3 alkyl), -S(=O)(C 1~3 alkyl), -S(=O)2(C 1~3 alkyl), -C(=O)(C 1~3 alkyl), -C(=O)OH, -C(=O)(OC 1~3 alkyl), -OC(=O)(C 1~3 alkyl), -C(=O)NH2, -C(=O)NH(C 1~3 alkyl), -C(=O)N(C 1~3 alkyl)2, -NHC(=O)(C 1~3 alkyl), -N(C 1~3 alkyl)C(=O)(C 1~3 alkyl), -S(=O)(OC 1~3 alkyl), -OS(=O)(C 1~3 alkyl), -S(=O)NH2, -S(=O)NH(C 1~3 alkyl), -S(=O)N(C 1~3 alkyl)2, -NHS(=O)(C 1~3 alkyl), -N(C 1~3 alkyl)S(=O)(C 1~3 alkyl), -S(=O)2(OC 1~3 alkyl), -OS(=O)2(C 1~3 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1~3 alkyl), -S(=O)2N(C 1~3 alkyl)2, -NHS(=O)2(C 1~3 alkyl), -N(C1~3 alkyl)S(=O)2(C 1~3 alkyl), -P(=O)H(C 1~3 alkyl), -P(=O)(C 1~3 The compound according to any one of [1] to

[82] , optionally substituted by 1, 2, 3, 4, 5, or 6 substituents selected from alkyl), 2, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl.

[0098]

[84] . R 13 , R 14 or R 15 each occurrence independently represents -H, -D, -Cl, -F, -Br, -CH3, -CD3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -O-CH2F, -O-CHF2, -O-CF3, -S-CH2F, -S-CHF2, -S-CF3, [ka] -CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CHFCH3、-CF2CH3、-C N、オキソ、-NH2、-NH(CH3)、-N(CH3)2、-NH(CH2CH3)、-OH、-O-CH3、-O-CH2CH3、 -O-CH2CH2CH3、-O-CH(CH3)2、-SH、-S-CH3、-S-CH2CH3、-S-CH2CH2CH3、-S- CH(CH3)2、-S(=O)CH3、-S(=O)(CH2CH3)、-S(=O)(CH2CH2CH3)、-S(=O)(CH( CH3)2)、-S(=O)2CH3、-S(=O)2(CH2CH3)、-S(=O)2(CH2CH2CH3)、-S(=O)2(CH(CH3)2)、-COOH、-C(=O)(CH3)、-C(=O)(CH2CH3)、-C(=O)(CH(CH3)2)、-C(=O)(CF3)、-C(=O)(OCH3)、-C(=O)(OCH2CH3)、-C(=O)(OCH2CH3)、-C(=O)(OCH2CH2CH3)、-C(=O)(OCH(CH3)2)、-OC(=O)(CH3)、-OC(=O)(CH2CH3)、 -OC(=O)(CH(CH3)2)、-C(=O)NH2、-C(=O)NH(CH3)、-C(=O)NH(CH2CH3)、-C(=O)NH(CH2CH2CH3)、-C(=O)NH(CH(CH3)2)、-C(=O)N(CH3)2、-C(=O)N(CH2CH3)2、-NHC(=O)(CH3)、-NHC(=O)(CH2CH3)、-NHC(=O)(CH2CH2CH3)、-NHC(=O)(CH(CH3)2)、-N(CH3)C(=O)(CH3)、-S(=O)(OCH3)、-S(=O)(OCH2CH3)、- S(=O)(OCH2CH2CH3)、-S(=O)(OCH(CH3)2)、-OS(=O)(CH3)、-OS(=O)(CH2CH3)、-OS(=O)(CH2CH2CH3)、-OS(=O)(CH(CH3)2)、-S(=O)NH2、-S(=O)NH(CH3)、-S(=O)NH(CH2CH3)、-S(=O)NH(CH2CH2CH3)、-S(=O)NH(CH(CH3)2)、-S(=O)N(CH3)2、-S(=O)N(CH3)(CH2CH3)、-NHS(=O)(CH3)、-NHS(=O)(CH2CH3)、-NHS(=O)(CH2CH2CH3), -NHS(=O)(CH(CH3)2), -N(CH3)S(=O)(CH3), -S(=O)2(OCH3), -S(=O)2(OCH2CH3), -S(=O)2(OCH2CH2CH3), -S(=O)2(OCH(CH3)2), -OS(=O)2(CH3), -OS(=O)2(CH2CH3), -OS(=O)2(CH2CH2CH3), -OS(=O)2(CH(CH3)2), -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2NH(CH2CH3), -S(=O)2NH(CH2CH2CH3), -S(=O)2NH(CH(CH3)2), -S(=O)2N(CH3)2, -S(=O)2N(CH3)(CH2CH3), -NHS(=O)2(CH3), -NHS(=O)2(CH2CH3), -NHS(=O)2(CH2CH2CH3), -NHS(=O)2(CH(CH3)2), -N(CH3)S(=O)2(CH3), -P(=O)H(CH3), -P(=O)H(CH2CH3), -P(=O)H(CH2CH2CH3), -P(=O)H(CH(CH3)2), -P(=O)(CH3)2, -P(=O)(CH3)(CH2CH3), -CH2-OH, -CH2CH2-OH, -CH(CH3)-OH, -CH2-OCH3, -CH2-OCH2CH3, -CH2-OCH(CH3)2, -CH2-NH2, -CH2CH2-NH2, -CH(CH3)-NH2, -CH2-NH-C(=O)(CH3), -CH2-NH-C(=O)(CH2CH3), -CH2-NH-C(=O)(CH(CH3)2), -CH2-N(CH3)-C(=O)(CH2CH3), -CH2-CN, -CH2CH2-CN, -CH(CH3)-CN,

Chem.

[83] as described in any one of to .

[0099]

[85] . R 13 、R 14 or R 15each occurrence independently represents -H, -D, -Cl, -F, -Br, -CH3, -CD3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, -O-CF3, -S-CF3, -CF3, -CN, oxo, -NH2, -NH(CH3), -N(CH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH(CH3)2, -S(=O)CH3, -S(=O)2CH3, -COOH, -C(=O)(CH3), -C(=O)(CH2CH3), -C(=O)(CF3 ), -C(=O)NH2, -C(=O)NH(CH3), -NHC(=O)(CH3), -S(=O)NH2, -S(=O)NH(CH3), -NHS(=O)(CH3), -S(=O)2NH2, -S(=O)2NH(CH3), -NHS(=O)2(CH3), -CH2-OH, -CH 2CH2-OH, -CH(OH)(CH3), -CH2-OCH3, -CH2-OCH2CH3, -CH2-NH2, -CH2CH2-NH2, -CH(CH3)-NH2, -CH2-NH-C(=O)(CH3), -CH2-CN, -CH2CH2-CN, -CH(CH3)-CN, or [ka] The compound according to any one of [1] to

[84] , selected from:

[0100]

[86] . R 13 is -F, -Cl, -Br, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -CF3, -C(=O)-CH3, -CO-CF3, -OCH3, [ka] , —S—CH3, —S—CH2CH3, or —S—CH(CH3)2; in some embodiments, R 13 is selected from -CF3; R 14 or R 15is independently selected from -H, -D, -OH, -CH, -CD, -CHCH, -CHCHCH, or -CH(CH); In one embodiment, R 13 is selected from -CF3, and R 14 or R 15 is independently selected from —H at each occurrence.

[0101]

[87] . Each occurrence of Y2 is independently selected from -O-, -CO-NH-, or -NH-CO-; in some embodiments, each occurrence of Y2 is independently selected from -O-; Y3 at each occurrence is independently selected from -C(=O)-, -S(=O)2-, -C(=O)-NH-, -NH-C(=O)-, -C(=O)-N(CH3)-, or -N(CH3)-C(=O)-; in some embodiments, Y3 at each occurrence is independently selected from -C(=O)-; R 13 is -F, -Cl, -Br, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -CF3, -C(=O)-CH3, -C(=O)-CF3, -OCH3, [ka] , —S—CH3, —S—CH2CH3, or —S—CH(CH3)2; in some embodiments, R 13 is selected from -CF3; R1 or R2, at each occurrence, is independently selected from -H, -D, -CH3, -CD3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, -CH2-OCH3, -CH2-OCH2CH3, -CH2-OH, -CH2CH2-OH, -CH(OH)(CH3), or -CH2-NH-C(=O)(CH3); in some embodiments, R1, at each occurrence, is independently selected from -CH3, -CD3, -CH2-O-CH3, -CH(OH)(CH3), or -CH2-NH-C(=O)(CH3); R2, at each occurrence, is independently selected from -H, -D, -CH3, -CD3, -CH2CH3, -CH2CH2CH3; R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 14 or R 15 is independently selected from -H, -D, -OH, -CH, -CD, -CHCH, -CHCH, or -CH(CH); in some embodiments, R, R, R, R, R, R, R, R 10 , R 11 , R 12 , R 14 or R 15 is independently selected from -H, -D, -OH, -CH3, or -CD3; m1 is selected from 1 or 2; m2 is 0 or 1; m3 is 1 or 2; The compound according to any one of [1] to

[86] , wherein m4 is 0 or 1.

[0102]

[88] . each occurrence of Y2 is independently selected from -O-; each occurrence of Y3 is independently selected from -C(=O)-; R 13 is selected from -CF3; R1 at each occurrence is independently selected from -CH3, and R2 at each occurrence is independently selected from -H; R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 14 or R 15 is independently selected from -H; m1 is 1; m2 is 0; m3 is 1; The compound according to any one of [1] to

[87] , wherein m4 is 0.

[0103]

[89] . R 16 or R 17 Each occurrence of represents independently hydrogen, halogen, -C 1~6 Alkyl, -C 1~6 Haloalkyl, -C 1~6 Haloalkoxy, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -CN, oxo, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 alkyl), -OH, -O(C 1~6 alkyl), -SH, -S(C 1~6 alkyl), -S(haloC 1~6 alkyl), -S(=O)(C 1~6 alkyl), -S(=O)2(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -C(=O)OH, -C(=O)(OC 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -C(=O)NH2, -C(=O)NH(C 1~6 alkyl), -C(=O)N(C 1~6 alkyl)2, -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -OC(=O)O(C 1~6 alkyl), -NHC(=O)(OC 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(OC 1~6 alkyl), -OC(=O)NH(C1~6 alkyl), -OC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -N(C 1~6 alkyl)C(=O)NH2, -N(C 1~6 alkyl)C(=O)NH(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)N(C 1~6 alkyl)2, -S(=O)(OC 1~6 alkyl), -OS(=O)(C 1~6 alkyl), -S(=O)NH2, -S(=O)NH(C 1~6 alkyl), -S(=O)N(C 1~6 alkyl)2, -NHS(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)(C 1~6 alkyl), -S(=O)2(OC 1~6 alkyl), -OS(=O)2(C 1~6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1~6 alkyl), -S(=O)2N(C 1~6 alkyl)2, -NHS(=O)2(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2(C 1~6 alkyl), -OS(=O)2O(C 1~6 alkyl), -NHS(=O)2O(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2O(C 1~6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1~6 alkyl), -OS(=O)2N(C 1~6 alkyl)2, -NHS(=O)2NH2, -NHS(=O)2NH(C 1~6 alkyl), -NHS(=O)2N(C 1~6 alkyl)2, -N(C 1~6 alkyl)S(=O)2NH2, -N(C 1~6 alkyl)S(=O)2NH(C 1~6alkyl), -N(C 1~6 alkyl)S(=O)2N(C 1~6 alkyl)2, -PH(C 1~6 alkyl), -P(C 1~6 alkyl)2, -P(=O)H(C 1~6 alkyl), -P(=O)(C 1~6 alkyl)2, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein said —C 1~6 Alkyl, -C 1~6 Haloalkyl, -C 1~6 Haloalkoxy, -C 2~6 Alkenyl, -C 2~6 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl are independently selected from the group consisting of -F, -Cl, -Br, -C 1~6 Alkyl, -C 1~6 Haloalkyl, -C 1~6 Haloalkoxy, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -CN, oxo, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 alkyl), -OH, -O(C 1~6 alkyl), -SH, -S(C 1~6 alkyl), -S(haloC 1~6 alkyl), -S(=O)(C 1~6 alkyl), -S(=O)2(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -C(=O)OH, -C(=O)(OC 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -C(=O)NH2, -C(=O)NH(C 1~6 alkyl), -C(=O)N(C 1~6 alkyl)2, -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -OC(=O)O(C 1~6 alkyl), -NHC(=O)(OC 1~6 alkyl), -N(C1~6 alkyl)C(=O)(OC 1~6 alkyl), -OC(=O)NH(C 1~6 alkyl), -OC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -N(C 1~6 alkyl)C(=O)NH2, -N(C 1~6 alkyl)C(=O)NH(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)N(C 1~6 alkyl)2, -S(=O)(OC 1~6 alkyl), -OS(=O)(C 1~6 alkyl), -S(=O)NH2, -S(=O)NH(C 1~6 alkyl), -S(=O)N(C 1~6 alkyl)2, -NHS(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)(C 1~6 alkyl), -S(=O)2(OC 1~6 alkyl), -OS(=O)2(C 1~6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1~6 alkyl), -S(=O)2N(C 1~6 alkyl)2, -NHS(=O)2(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2(C 1~6 alkyl), -OS(=O)2O(C 1~6 alkyl), -NHS(=O)2O(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2O(C 1~6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1~6 alkyl), -OS(=O)2N(C 1~6 alkyl)2, -NHS(=O)2NH2, -NHS(=O)2NH(C 1~6 alkyl), -NHS(=O)2N(C 1~6 alkyl)2, -N(C 1~6alkyl)S(=O)2NH2, -N(C 1~6 alkyl)S(=O)2NH(C 1~6 alkyl), -N(C 1~6 alkyl)S(=O)2N(C 1~6 alkyl)2, -PH(C 1~6 alkyl), -P(C 1~6 alkyl)2, -P(=O)H(C 1~6 alkyl), -P(=O)(C 1~6 The compound according to any one of [1] to

[88] , optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from alkyl), 2, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl.

[0104]

[90] . R 16 or R 17 Each occurrence of is independently -H, -D, -F, -Cl, -Br, -C 1~3 Alkyl, -C 1~3 Haloalkyl, -C 1~3 Haloalkoxy, -C 2~3 Alkenyl, -C 2~3 Alkynyl, -CN, oxo, -NH2, -NH(C 1~3 alkyl), -N(C 1~3 alkyl), -OH, -O(C 1~3 alkyl), -SH, -S(C 1~3 alkyl), -S(=O)(C 1~3 alkyl), -S(=O)2(C 1~3 alkyl), -C(=O)(C 1~3 alkyl), -C(=O)OH, -C(=O)(OC 1~3 alkyl), -OC(=O)(C 1~3 alkyl), -C(=O)NH2, -C(=O)NH(C 1~3 alkyl), -C(=O)N(C 1~3 alkyl)2, -NHC(=O)(C 1~3 alkyl), -N(C 1~3 alkyl)C(=O)(C 1~3 alkyl), -S(=O)(OC 1~3 alkyl), -OS(=O)(C1~3 alkyl), -S(=O)NH2, -S(=O)NH(C 1~3 alkyl), -S(=O)N(C 1~3 alkyl)2, -NHS(=O)(C 1~3 alkyl), -N(C 1~3 alkyl)S(=O)(C 1~3 alkyl), -S(=O)2(OC 1~3 alkyl), -OS(=O)2(C 1~3 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1~3 alkyl), -S(=O)2N(C 1~3 alkyl)2, -NHS(=O)2(C 1~3 alkyl), -N(C 1~3 alkyl)S(=O)2(C 1~3 alkyl), -P(=O)H(C 1~3 alkyl), -P(=O)(C 1~3 alkyl)2, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein said —C 1~3 Alkyl, -C 1~3 Haloalkyl, -C 1~3 Haloalkoxy, -C 2~6 Alkenyl, -C 2~6 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl are independently selected from hydrogen, —F, —Cl, —Br, —C 1~3 Alkyl, -C 1~3 Haloalkyl, -C 1~3 Haloalkoxy, -C 2~3 Alkenyl, -C 2~3 Alkynyl, -CN, oxo, -NH2, -NH(C 1~3 alkyl), -N(C 1~3 alkyl), -OH, -O(C 1~3 alkyl), -SH, -S(C 1~3 alkyl), -S(=O)(C 1~3 alkyl), -S(=O)2(C 1~3 alkyl), -C(=O)(C1~3 alkyl), -C(=O)OH, -C(=O)(OC 1~3 alkyl), -OC(=O)(C 1~3 alkyl), -C(=O)NH2, -C(=O)NH(C 1~3 alkyl), -C(=O)N(C 1~3 alkyl)2, -NHC(=O)(C 1~3 alkyl), -N(C 1~3 alkyl)C(=O)(C 1~3 alkyl), -S(=O)(OC 1~3 alkyl), -OS(=O)(C 1~3 alkyl), -S(=O)NH2, -S(=O)NH(C 1~3 alkyl), -S(=O)N(C 1~3 alkyl)2, -NHS(=O)(C 1~3 alkyl), -N(C 1~3 alkyl)S(=O)(C 1~3 alkyl), -S(=O)2(OC 1~3 alkyl), -OS(=O)2(C 1~3 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1~3 alkyl), -S(=O)2N(C 1~3 alkyl)2, -NHS(=O)2(C 1~3 alkyl), -N(C 1~3 alkyl)S(=O)2(C 1~3 alkyl), -P(=O)H(C 1~3 alkyl), -P(=O)(C 1~3 The compound according to any one of [1] to

[89] , optionally substituted by 1, 2, 3, 4, 5, or 6 substituents selected from alkyl), 2, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl.

[0105]

[91] . R 16 or R 17each occurrence independently represents -H, -D, -Cl, -F, -Br, -CH3, -CD3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -O-CH2F, -O-CHF2, -O-CF3, -S-CH2F, -S-CHF2, -S-CF3, [ka] -CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CHFCH3、-CF2CH3、-C N、オキソ、-NH2、-NH(CH3)、-N(CH3)2、-NH(CH2CH3)、-OH、-O-CH3、-O-CH2CH3、 -O-CH2CH2CH3、-O-CH(CH3)2、-SH、-S-CH3、-S-CH2CH3、-S-CH2CH2CH3、-S- CH(CH3)2、-S(=O)CH3、-S(=O)(CH2CH3)、-S(=O)(CH2CH2CH3)、-S(=O)(CH( CH3)2)、-S(=O)2CH3、-S(=O)2(CH2CH3)、-S(=O)2(CH2CH2CH3)、-S(=O)2(CH(CH3)2)、-COOH、-C(=O)(CH3)、-C(=O)(CH2CH3)、-C(=O)(CH(CH3)2)、-C(=O)(CF3)、-C(=O)(OCH3)、-C(=O)(OCH2CH3)、-C(=O)(OCH2CH3)、-C(=O)(OCH2CH2CH3)、-C(=O)(OCH(CH3)2)、-OC(=O)(CH3)、-OC(=O)(CH2CH3)、 -OC(=O)(CH(CH3)2)、-C(=O)NH2、-C(=O)NH(CH3)、-C(=O)NH(CH2CH3)、-C(=O)NH(CH2CH2CH3)、-C(=O)NH(CH(CH3)2)、-C(=O)N(CH3)2、-C(=O)N(CH2CH3)2、-NHC(=O)(CH3)、-NHC(=O)(CH2CH3)、-NHC(=O)(CH2CH2CH3)、-NHC(=O)(CH(CH3)2)、-N(CH3)C(=O)(CH3)、-S(=O)(OCH3)、-S(=O)(OCH2CH3)、- S(=O)(OCH2CH2CH3)、-S(=O)(OCH(CH3)2)、-OS(=O)(CH3)、-OS(=O)(CH2CH3)、-OS(=O)(CH2CH2CH3)、-OS(=O)(CH(CH3)2)、-S(=O)NH2、-S(=O)NH(CH3)、-S(=O)NH(CH2CH3)、-S(=O)NH(CH2CH2CH3)、-S(=O)NH(CH(CH3)2)、-S(=O)N(CH3)2、-S(=O)N(CH3)(CH2CH3)、-NHS(=O)(CH3)、-NHS(=O)(CH2CH3)、-NHS(=O)(CH2CH2CH3), -NHS(=O)(CH(CH3)2), -N(CH3)S(=O)(CH3), -S(=O)2(OCH3), -S(=O)2(OCH2CH3), -S(=O)2(OCH2CH2CH3), -S(=O)2(OCH(CH3)2), -OS(=O)2(CH3), -OS(=O)2(CH2CH3), -OS(=O)2(CH2CH2CH3), -OS(=O)2(CH(CH3)2), -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2NH(CH2CH3), -S(=O)2NH(CH2CH2CH3), -S(=O)2NH(CH(CH3)2), -S(=O)2N(CH3)2, -S(=O)2N(CH3)(CH2CH3), -NHS(=O)2(CH3), -NHS(=O)2(CH2CH3), -NHS(=O)2(CH2CH2CH3), -NHS(=O)2(CH(CH3)2), -N(CH3)S(=O)2(CH3), -P(=O)H(CH3), -P(=O)H(CH2CH3), -P(=O)H(CH2CH2CH3), -P(=O)H(CH(CH3)2), -P(=O)(CH3)2, -P(=O)(CH3)(CH2CH3), -CH2-OH, -CH2CH2-OH, -CH(CH3)-OH, -CH2-NH2, -CH2CH2-NH2, -CH(CH3)-NH2, -CH2-CN, -CH2CH2-CN, -CH(CH3)-CN, [Chemical formula] A compound according to any one of [1] to

[90] , selected from

[0106]

[92] . R 16 or R 17each occurrence independently represents -H, -D, -Cl, -F, -Br, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -O-CF3, -S-CF3, -CF3, -CN, oxo, -NH2, -NH(CH3), -N(CH3)2, -OH, -O-CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH(CH3)2, -S(=O)CH3, -S(=O)2CH3, -COOH, -C(=O)(CH3), -C(=O)(CH2CH3), -C(=O)(CF3), -C(=O )NH2, -C(=O)NH(CH3), -NHC(=O)(CH3), -S(=O)NH2, -S(=O)NH(CH3), -NHS(=O)(CH3), -S(=O)2NH2, -S(=O)2NH(CH3), -NHS(=O)2(CH3), -P(=O) H(CH3), -P(=O)(CH3)2, -CH2-OH, -CH2CH2-OH, -CH(CH3)-OH, -CH2-NH2, -CH2CH2-NH2, -CH(CH3)-NH2, -CH2-CN, -CH2CH2-CN, -CH(CH3)-CN, or [ka] The compound according to any one of [1] to

[91] , selected from:

[0107]

[93] The compound according to any one of [1] to

[92] , wherein the compound is selected from any one of the following compounds:

[0108] [Table 1] TIFF2024506612000172.tif246170TIFF2024506612000173.tif240170TIFF2024506612000174.tif241170TIFF2024506612000175.tif238170TIFF2024506612000176.tif245170TIFF2024506612000177.tif249170TIFF2024506612000178.tif244170TIFF2024506612000179.tif255169TIFF2024506612000180.tif245170TIFF2024506612000181.tif245170TIFF2024506612000182.tif246170TIFF2024506612000183.tif245170TIFF2024506612000184.tif246170TIFF2024506612000185.tif249170TIFF2024506612000186.tif247170TIFF2024506612000187.tif246170TIFF2024506612000188.tif244170TIFF2024506612000189.tif245170TIFF2024506612000190.tif249170TIFF2024506612000191.tif253170TIFF2024506612000192.tif228170TIFF2024506612000193.tif247170TIFF2024506612000194.tif243170TIFF2024506612000195.tif249170TIFF2024506612000196.tif245170TIFF2024506612000197.tif244170TIFF2024506612000198.tif246170TIFF2024506612000199.tif245170TIFF2024506612000200.tif243170TIFF2024506612000201.tif246170TIFF2024506612000202.tif239170TIFF2024506612000203.tif245170TIFF2024506612000204.tif247170TIFF2024506612000205.tif247170TIFF2024506612000206.tif244170TIFF2024506612000207.tif245170TIFF2024506612000208.tif243170TIFF2024506612000209.tif240170TIFF2024506612000210.tif245170TIFF2024506612000211.tif237170TIFF2024506612000212.tif235170TIFF2024506612000213.tif245170TIFF2024506612000214.tif240170TIFF2024506612000215.tif246170TIFF2024506612000216.tif245170TIFF2024506612000217.tif247170TIFF2024506612000218.tif247170TIFF2024506612000219.tif237170TIFF2024506612000220.tif248170TIFF2024506612000221.tif244170TIFF2024506612000222.tif250170TIFF2024506612000223.tif247170TIFF2024506612000224.tif246170TIFF2024506612000225.tif247170TIFF2024506612000226.tif251170TIFF2024506612000227.tif246170TIFF2024506612000228.tif241170TIFF2024506612000229.tif241170TIFF2024506612000230.tif245170TIFF2024506612000231.tif243170TIFF2024506612000232.tif248170TIFF2024506612000233.tif251170TIFF2024506612000234.tif245170TIFF2024506612000235.tif253170TIFF2024506612000236.tif242170TIFF2024506612000237.tif242170TIFF2024506612000238.tif243170TIFF2024506612000239.tif243170TIFF2024506612000240.tif247170TIFF2024506612000241.tif246170TIFF2024506612000242.tif243170TIFF2024506612000243.tif247170TIFF2024506612000244.tif246170TIFF2024506612000245.tif245170TIFF2024506612000246.tif245170TIFF2024506612000247.tif255170TIFF2024506612000248.tif246170TIFF2024506612000249.tif242170TIFF2024506612000250.tif248170TIFF2024506612000251.tif247170TIFF2024506612000252.tif247170TIFF2024506612000253.tif249170TIFF2024506612000254.tif247170TIFF2024506612000255.tif246170TIFF2024506612000256.tif241170TIFF2024506612000257.tif243170TIFF2024506612000258.tif243170TIFF2024506612000259.tif244170TIFF2024506612000260.tif246170TIFF2024506612000261.tif244170TIFF2024506612000262.tif243170TIFF2024506612000263.tif236170TIFF2024506612000264.tif243170TIFF2024506612000265.tif246170TIFF2024506612000266.tif251170TIFF2024506612000267.tif254170TIFF2024506612000268.tif247170TIFF2024506612000269.tif238170TIFF2024506612000270.tif244170TIFF2024506612000271.tif239170TIFF2024506612000272.tif245170TIFF2024506612000273.tif245170TIFF2024506612000274.tif249170TIFF2024506612000275.tif236170TIFF2024506612000276.tif241170TIFF2024506612000277.tif248170TIFF2024506612000278.tif244170TIFF2024506612000279.tif241170TIFF2024506612000280.tif243170TIFF2024506612000281.tif239170TIFF2024506612000282.tif247170TIFF2024506612000283.tif239170TIFF2024506612000284.tif241170TIFF2024506612000285.tif244170TIFF2024506612000286.tif246170TIFF2024506612000287.tif243170TIFF2024506612000288.tif246170TIFF2024506612000289.tif247170TIFF2024506612000290.tif240170TIFF2024506612000291.tif239170TIFF2024506612000292.tif247170TIFF2024506612000293.tif246170TIFF2024506612000294.tif246170TIFF2024506612000295.tif237170TIFF2024506612000296.tif245170TIFF2024506612000297.tif248170TIFF2024506612000298.tif244170TIFF2024506612000299.tif246170TIFF2024506612000300.tif243170TIFF2024506612000301.tif242170TIFF2024506612000302.tif242170TIFF2024506612000303.tif245170TIFF2024506612000304.tif243170TIFF2024506612000305.tif250170TIFF2024506612000306.tif244170TIFF2024506612000307.tif253170TIFF2024506612000308.tif246170TIFF2024506612000309.tif245170TIFF2024506612000310.tif252170TIFF2024506612000311.tif235170TIFF2024506612000312.tif247170TIFF2024506612000313.tif248170TIFF2024506612000314.tif238170TIFF2024506612000315.tif241170TIFF2024506612000316.tif233170TIFF2024506612000317.tif241170TIFF2024506612000318.tif247170TIFF2024506612000319.tif241170TIFF2024506612000320.tif243170TIFF2024506612000321.tif249170TIFF2024506612000322.tif246170TIFF2024506612000323.tif236170TIFF2024506612000324.tif240170TIFF2024506612000325.tif241170TIFF2024506612000326.tif247170TIFF2024506612000327.tif248170TIFF2024506612000328.tif250170TIFF2024506612000329.tif242170TIFF2024506612000330.tif244170TIFF2024506612000331.tif249170TIFF2024506612000332.tif243170TIFF2024506612000333.tif245170TIFF2024506612000334.tif245170TIFF2024506612000335.tif241170TIFF2024506612000336.tif239170TIFF2024506612000337.tif244170TIFF2024506612000338.tif244170TIFF202450 6612000339.tif243170TIFF2024506612000340.tif235170TIFF2024506612000341.tif94170.

[0109]

[94] .An intermediate selected from any one of the following formulae: [ka] (In the formula, LG1 is a leaving group or a group that can be converted into a leaving group; in certain embodiments, the leaving group is a halogen (such as -Cl, -Br, or -I), -OS(=O)2CH3, or [ka] In some embodiments, the group that can be converted to a leaving group is selected from: When X5 is selected from N, Q1 is selected from -H or a protecting group for N, and in some embodiments, the protecting group for N is selected from -Boc; LG2 is a leaving group or a group that can be converted into a leaving group; in certain embodiments, the leaving group is a halogen (such as -Cl, -Br, or -I), -OS(=O)2CH3, or [ka] In some embodiments, the group that can be converted to a leaving group is selected from: Q2 is selected from -H; Q3 is selected from -H; LG3 is a leaving group or a group that can be converted into a leaving group; in certain embodiments, the leaving group is a halogen (such as -Cl, -Br, or -I), -OS(=O)2CH3, or [ka] Selected from; In certain embodiments, the group that can be converted to a leaving group is selected from —OH; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , Y1, Y2, Y3, X1, X2, X3, X4, X5, ring A, ring B, ring C, Z1, Z2, Z3, m1, m2, m3, m4, t1, t2, or t3, each occurrence of which is the same as any one of [1] to

[93] .

[0110]

[95] .The intermediate is [ka] TIFF2024506612000347.tif226170TIFF2024506612000348.tif244170TIFF2024506612000349.tif248 170TIFF2024506612000350.tif243170TIFF2024506612000351.tif245170TIFF2024506612000352.tif2 38170TIFF2024506612000353.tif231170TIFF2024506612000354.tif245170TIFF2024506612000355.tif245170TIFF2024506612000356.tif249170TIFF2024506612000357.tif193170.

[0111]

[95] . A method for preparing the compound according to any one of [1] to

[93] , comprising the following step A or step B: Step A: Reacting a compound of formula (I-1) with a compound of formula (I-2) by a condensation reaction to obtain a compound of formula (I): [ka] In the compound of formula (I-1), LG1 is a leaving group or a group that can be converted into a leaving group; in some embodiments, the leaving group is a halogen (such as -Cl, -Br, or -I), -OS(=O)2CH3, or [ka] In some embodiments, the group that can be converted to a leaving group is selected from: When X5 is selected from N, Q1 in the compound of formula (I-2) is selected from -H or a protecting group for N, and in some embodiments, the protecting group for N is selected from -Boc; Step B: reacting the compound of formula (I'-1) with the compound of formula (I'-2) by substitution or coupling reaction to obtain the compound of formula (I); [ka] In the compound of formula (I'-1), LG2 is a leaving group or a group that can be converted into a leaving group; in some embodiments, the leaving group is a halogen (such as -Cl, -Br, or -I), -OS(=O)2CH3, or [ka] Selected from; In certain embodiments, the group that can be converted to a leaving group is selected from —OH; Q2 in the compound of formula (I'-2) is selected from -H; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , Y1, Y2, Y3, X1, X2, X3, X4, X5, ring A, ring B, ring C, Z1, Z2, Z3, m1, m2, m3, m4, t1, t2, or t3, each time it appears in formula (I-1), formula (I-2), formula (I-1'), formula (I-2'), or formula (I), is the same as any one of [1] to

[93] ; In some embodiments, the compound of formula (I-1) has the following formula: [ka] Select one of TIFF2024506612000363.tif238170TIFF2024506612000364.tif98170; In some embodiments, the compound of formula (I-2) has the following formula: [ka] TIFF2024506612000366.tif160170, In some embodiments, the compound of formula (I'-1) has the following formula: [ka] Select one of the following: In some embodiments, the compound of formula (I'-1) is [ka] Selected from; In some embodiments, the compound of formula (I'-2) has the following formula: [ka] A method selected from one of TIFF2024506612000370.tif252170TIFF2024506612000371.tif81170.

[0112]

[96] . The compound of formula (I-1) is prepared by the following step C or step D: Process C: [ka] (a) reacting a compound of formula (I'-1) with a compound of formula (I-3) by a substitution reaction or a coupling reaction to obtain a compound of formula (I-4); Q3 in the compounds of formula (I-3) and (I-4) is selected from -H; (b) reacting the compound of formula (I-4) with the compound of formula (I-5) by a substitution or coupling reaction to obtain the compound of formula (I-1); In the compound of formula (I-5), LG3 is a leaving group or a group that can be converted into a leaving group; in some embodiments, the leaving group is a halogen (such as -Cl, -Br, or -I), -OS(=O)2CH3, or [ka] In some embodiments, the group that can be converted to a leaving group is selected from: In some embodiments, the compound of formula (I-3) has the following formula: [ka] Select one of the following: In some embodiments, the compound of formula (I-4) has the following formula: [ka] Select one of TIFF2024506612000376.tif40170; In some embodiments, the compound of formula (I-5) has the following formula: [ka] Select one of the following: Process D: [ka] (a) reacting a compound of formula (I'-1) with a compound of formula (I-6) by a substitution reaction or a coupling reaction to obtain a compound of formula (I-7); (b) reacting the compound of formula (I-7) with the compound of formula (I-8) by an addition reaction to obtain the compound of formula (I-1); In some embodiments, the compound of formula (I-6) has the following formula: [ka] Select one of the following: In some embodiments, the compound of formula (I-7) has the following formula: [ka] Select one of TIFF2024506612000381.tif41170; In some embodiments, the compound of formula (I-8) is independently represented by the following formula: [ka] The method according to

[95] , wherein the method is selected from any one of the following:

[0113]

[97] . The compound of formula (I'-2) is prepared by the following step E or step F: Process E: [ka] (a) reacting a compound of formula (I-2) with a compound of formula (I-5) by a condensation reaction to obtain a compound of formula (I'-3): (b) reacting a compound of formula (I'-3) with a compound of formula (I-3) by substitution or coupling reaction to obtain a compound of formula (I'-2); In some embodiments, the compound of formula (I'-3) has the following formula: [ka] Select one of TIFF2024506612000385.tif232170TIFF2024506612000386.tif89170; Process F: [ka] (a) reacting a compound of formula (I-2) with a compound of formula (I-8) by a condensation reaction to obtain a compound of formula (I'-4); (b) reacting the compound of formula (I'-4) with the compound of formula (I-6) by an addition reaction to obtain the compound of formula (I'-2); In some embodiments, the compound of formula (I'-4) has the following formula: [ka] The method according to

[95] or

[96] , selected from any one of TIFF2024506612000389.tif200170.

[0114]

[98] . Use of a compound of formula (I) according to any one of [1] to

[93] , its stereoisomer, its deuterated derivative, or its pharmaceutically acceptable salt as a targeted PARP7 protein ligand in a PROTAC compound acting as a degradation regulator of PARP7 protein.

[0115]

[99] . A pharmaceutical composition comprising a compound of formula (I) according to any one of [1] to

[93] , its stereoisomer, its deuterated derivative, or its pharmaceutically acceptable salt; and at least one pharmaceutically acceptable excipient.

[0116]

[0100] A method for inhibiting the activity of PARP7, comprising contacting an effective amount of a compound of formula (I) described in any one of [1] to

[93] , its stereoisomer, its deuterated derivative, or a pharmaceutically acceptable salt thereof with PARP7 or a cell in which inhibition of PARP7 is desired.

[0117]

[0101] Use of a compound of formula (I) according to any one of [1] to

[93] , its stereoisomer, its deuterated derivative, or its pharmaceutically acceptable salt; or a pharmaceutical composition according to

[99] , for the manufacture of a medicament for the treatment of cancer; In one embodiment, the cancer is a PARP7-associated cancer; In one embodiment, the cancer is a cancer associated with PARP7 overexpression; In certain embodiments, the cancer is selected from breast cancer, cancer of the central nervous system, endometrial cancer, kidney cancer, colon cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, mesothelioma, melanoma, fibrosarcoma, bladder cancer, rectal cancer, lymphoma, cervical cancer, head and neck cancer, upper aerodigestive tract cancer, colorectal cancer, urinary tract cancer, or colon cancer, more preferably each cancer is independently selected from adenocarcinoma, squamous cell carcinoma, mixed adenosquamous carcinoma, and undifferentiated carcinoma, more preferably ovarian cancer comprises high-grade serous ovarian adenocarcinoma, ovarian mucinous cystadenocarcinoma, or malignant ovarian Brenner tumor; kidney cancer comprises clear cell renal cell carcinoma; tongue cancer comprises tongue squamous cell carcinoma; lung cancer cancers of the central nervous system include glioma, glioblastoma, or glioblastoma multiforme; gastric cancer includes gastric adenocarcinoma; breast cancer includes ductal carcinoma, breast adenocarcinoma, or HR+ breast cancer; bladder cancer includes bladder squamous cell carcinoma; melanoma includes malignant melanoma; colon cancer includes colon adenocarcinoma; and head and neck cancer includes head and neck small cell squamous cell carcinoma; in one embodiment, the cancer is a cancer associated with PARP7 overexpression.

[0118]

[0102] A method for treating a subject having cancer, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) described in any one of [1] to

[93] , its stereoisomer, its deuterated derivative, its tautomer, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition described in

[99] ; In one embodiment, the cancer is a PARP7-associated cancer; In one embodiment, the cancer is a cancer associated with PARP7 overexpression; In certain embodiments, the cancer is selected from breast cancer, cancer of the central nervous system, endometrial cancer, kidney cancer, colon cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, mesothelioma, melanoma, fibrosarcoma, bladder cancer, rectal cancer, lymphoma, cervical cancer, head and neck cancer, upper aerodigestive tract cancer, colorectal cancer, urinary tract cancer, or colon cancer, more preferably each cancer is independently selected from adenocarcinoma, squamous cell carcinoma, mixed adenosquamous carcinoma, and undifferentiated carcinoma, more preferably ovarian cancer comprises high-grade serous ovarian adenocarcinoma, ovarian mucinous cystadenocarcinoma, or malignant ovarian Brenner tumor; kidney cancer comprises clear cell renal cell carcinoma; tongue cancer comprises tongue squamous cell carcinoma; lung cancer wherein the cancer comprises lung adenocarcinoma, lung adenosquamous carcinoma, squamous cell lung carcinoma, large cell lung carcinoma, small cell lung carcinoma, papillary lung adenocarcinoma, or non-small cell lung carcinoma; pancreatic cancer comprises pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma; esophageal cancer comprises esophageal squamous cell carcinoma; mesothelioma comprises biphasic mesothelioma; cancer of the central nervous system comprises glioma, glioblastoma, or glioblastoma multiforme; gastric cancer comprises gastric adenocarcinoma; breast cancer comprises ductal carcinoma, breast adenocarcinoma, or HR+ breast cancer; bladder cancer comprises bladder squamous cell carcinoma; melanoma comprises malignant melanoma; colon cancer comprises colon adenocarcinoma; and head and neck cancer comprises head and neck small cell squamous cell carcinoma; in certain embodiments, the cancer is a cancer associated with PARP7 overexpression.

[0119]

[0103] A compound of formula (I) according to any one of [1] to

[93] , its stereoisomer, its deuterated derivative, its tautomer, or its pharmaceutically acceptable salt, for use in the treatment of cancer; or a pharmaceutical composition according to

[99] ; In one embodiment, the cancer is a PARP7-associated cancer; In one embodiment, the cancer is a cancer associated with PARP7 overexpression, In certain embodiments, the cancer is selected from breast cancer, cancer of the central nervous system, endometrial cancer, kidney cancer, colon cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, mesothelioma, melanoma, fibrosarcoma, bladder cancer, rectal cancer, lymphoma, cervical cancer, head and neck cancer, upper aerodigestive tract cancer, colorectal cancer, urinary tract cancer, or colon cancer, more preferably each cancer is independently selected from adenocarcinoma, squamous cell carcinoma, mixed adenosquamous carcinoma, and undifferentiated carcinoma, more preferably ovarian cancer comprises high-grade serous ovarian adenocarcinoma, ovarian mucinous cystadenocarcinoma, or malignant ovarian Brenner tumor; kidney cancer comprises clear cell renal cell carcinoma; tongue cancer comprises tongue squamous cell carcinoma; lung cancer comprises lung adenocarcinoma, lung adenosquamous carcinoma, squamous cell lung carcinoma, large cell lung carcinoma, small cell lung carcinoma, papillary lung adenocarcinoma, or non- pancreatic cancer includes pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma; esophageal cancer includes esophageal squamous cell carcinoma; mesothelioma includes biphasic mesothelioma; cancer of the central nervous system includes glioma, glioblastoma, or glioblastoma multiforme; gastric cancer includes gastric adenocarcinoma; breast cancer includes ductal carcinoma, breast adenocarcinoma, or HR+ breast cancer; bladder cancer includes bladder squamous cell carcinoma; melanoma includes malignant melanoma; colon cancer includes colon adenocarcinoma; head and neck cancer includes head and neck small cell squamous cell carcinoma; in an embodiment, the cancer is a cancer associated with PARP7 overexpression.

[0120] definition The terms "a," "an," "the," and similar terms, as used herein, unless otherwise indicated, should be construed to encompass both the singular and the plural.

[0121] The terms "halogen" or "halo," as used interchangeably herein, mean fluoro, chloro, bromo, or iodo, unless otherwise indicated. Preferred halogen groups include -F, -Cl, and -Br.

[0122] The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched chains. 1~10C in alkyl 1~10 is defined to identify groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms in a linear or branched arrangement. Non-limiting alkyls include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, and 2-methylpentyl.

[0123] The term "haloalkyl," as used herein, unless otherwise indicated, refers to an alkyl as defined above substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) halogens (such as -F, -Cl, or -Br). In certain embodiments, haloalkyl is an alkyl group such as the replaceable -C 1~10 Haloalkyl or HaloC 1~10 alkyl, where -C 1~10 Haloalkyl or HaloC 1~10 C in alkyl 1~10 indicates that the total carbon atoms in the alkyl are 1 to 10. In some embodiments, -C 1~10 Haloalkyl is -C 1~6 In some embodiments, -C is haloalkyl. 1~6 Haloalkyl is -C 1~3 In some embodiments, -C is haloalkyl. 1~3 Haloalkyl is substituted with 1, 2, 3, 4, 5, or 6 -F (methyl, ethyl, propyl, or isopropyl); preferably -C 1~3 Haloalkyl is —CF 3 .

[0124] The term "alkylene," as used herein, unless otherwise indicated, means a difunctional group obtained by removal of an additional hydrogen atom from an alkyl group that is defined above. In certain embodiments, alkylene is a C 0~6 In one embodiment, C is alkylene. 0~6 Alkylene is C 0~3 It is alkylene. C before alkylene 0~6indicates that the total number of carbon atoms in the alkylene is 0 to 6, and C0 indicates that the two ends of the alkylene are directly bonded. Non-limiting examples of alkylene include methylene (i.e., -CH2-), ethylene (i.e., -CH2-CH2- or -CH(CH3)-), and propylene (i.e., -CH2-CH2-CH2-, -CH(-CH2-CH3)-, or -CH2-CH(CH3)-).

[0125] The term "alkenyl," as used herein, unless otherwise indicated, refers to a straight- or branched-chain hydrocarbon radical containing one or more double bonds and typically from 2 to 20 carbon atoms in length. In certain embodiments, alkenyl is defined as -C 2~10 In some embodiments, -C is alkenyl. 2~10 Alkenyl is a group containing 2 to 6 carbon atoms -C 2~6 Alkenyl. Non-limiting examples of alkenyl include ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

[0126] The term "haloalkenyl," as used herein, unless otherwise indicated, refers to an alkenyl as defined above substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) halogens (such as -F, -Cl, or -Br). In certain embodiments, haloalkenyl is an alkenyl group selected from the group consisting of the replaceable -C 2~10 Haloalkenyl or haloC 2~10 alkenyl, where -C 2~10 Haloalkenyl or haloC 2~10 C in alkenyl 2~10 indicates that the total carbon atoms in the alkenyl are 2 to 10. 2~10 Haloalkenyl is -C 2~6 In one embodiment, -C is haloalkenyl. 2~6 Haloalkenyl is -C 2~3 In one embodiment, -C is haloalkenyl. 2~3Haloalkenyl is substituted with 1, 2, 3, 4, 5, or 6 -F (ethenyl or propenyl).

[0127] The term "alkynyl," as used herein, unless otherwise indicated, includes a straight- or branched-chain hydrocarbon radical containing one or more triple bonds and typically from 2 to 20 carbon atoms in length. In certain embodiments, alkynyl is defined as -C 2~10 In one embodiment, -C is alkynyl. 2~10 Alkynyl is a group containing 2 to 6 carbon atoms -C 2~6 Non-limiting examples of alkynyl include ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

[0128] The term "haloalkynyl," as used herein, unless otherwise indicated, refers to an alkynyl as defined above substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) halogens (such as -F, -Cl, or -Br). In certain embodiments, haloalkynyl is an alkynyl group, which may be substituted with an interchangeable -C 2~10 Haloalkynyl or HaloC 2~10 alkynyl, where -C 2~10 Haloalkynyl or HaloC 2~10 C in alkynyl 2~10 indicates that the total carbon atoms in the alkynyl are 2 to 10. 2~10 Haloalkynyl is -C 2~6 In one embodiment, -C is haloalkynyl. 2~6 Haloalkynyl is -C 2~3 In one embodiment, -C is haloalkynyl. 2~3 Haloalkynyl is substituted with 1, 2, 3, 4, 5, or 6 -F (ethynyl or propynyl).

[0129] The term "alkoxy," as used herein, unless otherwise noted, is an oxygen ether formed from an alkyl group as described above.

[0130] The term "haloalkoxy," as used herein, unless otherwise indicated, refers to an alkoxy as defined above substituted with one or more (1, 2, 3, 4, 5, or 6) halogens (-F, -Cl, or -Br). In certain embodiments, haloalkoxy refers to an alkoxy group ... 1~10 Haloalkoxy or HaloC 1~10 In some embodiments, haloalkoxy is an alkoxy group, which is an alkoxy group that is replaceable by -C 1~6 Haloalkoxy or HaloC 1~6 Alkoxy, where -C 1~6 Haloalkoxy or HaloC 1~6 C in alkoxy 1~6 indicates that the total carbon atoms in the alkoxy are 1 to 6. 1~6 Haloalkoxy is -C 1~3 In one embodiment, -C is haloalkoxy. 1~3 Haloalkoxy is substituted with 1, 2, 3, 4, 5, or 6 -F (methoxy, ethoxy, propoxy, or isopropoxy); preferably -C 1~3 Haloalkoxy is -OCF3.

[0131] The term "carbocycle," as used herein, unless otherwise indicated, refers to a fully saturated or partially saturated monocyclic, bicyclic, bridged, fused, or spirocyclic non-aromatic ring containing only carbon atoms as ring members. The term "carbocyclyl," as used herein, unless otherwise indicated, refers to a monovalent group obtained by removing a hydrogen atom on a ring carbon atom from a carbocycle, as defined herein. A carbocycle can be interchangeable with a carbocyclyl ring in the present invention. In some embodiments, a carbocycle is a 3- to 20-membered (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, or 20-membered) carbocycle that is fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, for example, 1, 2, 3, 4, 5, or 6, are included in this definition. Carbocycles include cycloalkyl rings in which all ring carbon atoms are saturated, cycloalkenyl rings containing at least one double bond (preferably one double bond), and cycloalkynyl rings containing at least one triple bond (preferably one triple bond). Exemplary cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and the like. Exemplary cycloalkenyls include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, and the like. Carbocyclyl rings include monocyclic carbocyclyl rings and bicyclic or polycyclic carbocyclyl rings in which one, two, or three or more atoms are shared between the rings. The term "spirocyclic carbocycle" refers to a carbocycle in which each of the rings shares only one ring atom with the other ring. In some embodiments, the spirocyclic ring is a bicyclic spirocyclic ring. Spirocyclic carbocycles include spirocyclic cycloalkyl rings, spirocyclic cycloalkenyl rings, and spirocyclic cycloalkynyl rings. The term "fused carbocycle" refers to a carbocycle in which each ring shares two adjacent ring atoms with the other ring. In some embodiments, the fused ring is a bicyclic fused ring.Fused carbocycles include fused cycloalkyl rings, fused cycloalkenyl rings, and fused cycloalkynyl rings. Monocyclic carbocycles fused to an aromatic ring (such as phenyl) are included in the definition of fused carbocycles. The term "bridged carbocycle" refers to a carbocycle containing at least two bridgehead carbon ring atoms and at least one bridging carbon atom. In certain embodiments, a bridged ring is a bicyclic bridged ring. Bridged carbocycles include bicyclic bridged carbocycles containing two bridgehead carbon atoms and polycyclic bridged carbocycles containing three or more bridgehead carbon atoms. Bridged carbocycles include bridged cycloalkyl rings, bridged cycloalkenyl rings, and bridged cycloalkynyl rings. Examples of monocyclic and bicyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl.

[0132] The term "heterocycle", as used herein, unless otherwise specified, refers to a fully saturated or partially saturated monocyclic, bicyclic, bridged, fused, or spirocyclic non-aromatic ring that contains not only carbon atoms as ring members but also one or more (e.g., 1, 2, 3, 4, 5, or 6) heteroatoms as ring members. Preferred heteroatoms include N, O, S, N-oxide, sulfur oxide, and sulfur dioxide. The term "heterocyclyl", as used herein, unless otherwise specified, refers to a monovalent group obtained by removing a hydrogen atom on a ring carbon atom or ring heteroatom from a heterocycle as defined in this invention. A heterocycle can be interchangeable with a heterocyclyl ring in this invention. In certain embodiments, a heterocycle is a 3- to 20-membered (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, or 20-membered) heterocycle that is fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, e.g., 1, 2, 3, 4, 5, or 6, are included in this definition. Heterocycles include heterocycloalkyl rings in which all ring carbon atoms are saturated, heterocycloalkenyl rings containing at least one double bond (preferably one double bond), and heterocycloalkynyl rings containing at least one triple bond (preferably one triple bond). Heterocyclyl rings include monocyclic heterocyclyl rings and bicyclic or polycyclic heterocyclyl rings in which one, two, or more atoms are shared between the rings. The term "spirocyclic heterocycle" refers to a heterocycle in which each of the rings shares only one ring atom with the other ring. In certain embodiments, the spirocyclic ring is a bicyclic spirocyclic ring. Spirocyclic heterocycles include spirocyclic heterocycloalkyl rings, spirocyclic heterocycloalkenyl rings, and spirocyclic heterocycloalkynyl rings. The term "fused heterocycle" refers to a heterocycle in which each of the rings shares two adjacent ring atoms with the other ring. In certain embodiments, the fused ring is a bicyclic fused ring. Fused heterocycles include fused heterocycloalkyl rings, fused heterocycloalkenyl rings, and fused heterocycloalkynyl rings. Monocyclic heterocycles fused with an aromatic ring (such as phenyl) are included in the definition of fused heterocycle.The term "bridged heterocycle" refers to a heterocycle containing at least two bridgehead ring atoms and at least one bridge atom. In certain embodiments, the bridged ring is a bicyclic bridged ring. Bridged heterocycles include bicyclic bridged heterocycles containing two bridgehead atoms and polycyclic bridged heterocycles containing three or more bridgehead atoms. Bridged heterocycles include bridged heterocycloalkyl rings, bridged heterocycloalkenyl rings, and bridged heterocycloalkynyl rings. Examples of such heterocyclyls include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl.

[0133] The term "aryl," as used herein, unless otherwise indicated, refers to a monocyclic or polycyclic aromatic ring system containing only carbon ring atoms. Preferred aryls are monocyclic or bicyclic 6- to 10-membered aromatic rings. Phenyl and naphthyl are preferred aryls.

[0134] The term "heteroaryl," as used herein, unless otherwise indicated, refers to an aromatic ring containing carbon and one or more (e.g., 1, 2, 3, or 4) heteroatoms selected from N, O, or S. Heteroaryl can be monocyclic or polycyclic. Monocyclic heteroaryl groups can have 1 to 4 heteroatoms in the ring, while polycyclic heteroaryls can contain 1 to 10 heteroatoms. Polycyclic heteroaryl rings can contain fused ring bonds; for example, a bicyclic heteroaryl is a polycyclic heteroaryl. Bicyclic heteroaryl rings can contain 8 to 12 member atoms. Monocyclic heteroaryl rings can contain 5 to 8 member atoms (carbon and heteroatoms), with preferred monocyclic heteroaryls being 5-membered heteroaryls containing 1, 2, 3, or 4 heteroatoms selected from N, O, or S, or 6-membered heteroaryls containing 1 or 2 heteroatoms selected from N. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladeninyl, quinolinyl, or isoquinolinyl.

[0135] The term "one or more," as used herein, unless otherwise indicated, refers to one or more than one. In certain embodiments, "one or more" refers to one, two, three, four, five, or six. In certain embodiments, "one or more" refers to one, two, three, or four. In certain embodiments, "one or more" refers to one, two, or three. In certain embodiments, "one or more" refers to one or two. In certain embodiments, "one or more" refers to one. In certain embodiments, "one or more" refers to two. In certain embodiments, "one or more" refers to three. In certain embodiments, "one or more" refers to four. In certain embodiments, "one or more" refers to five. In certain embodiments, "one or more" refers to six.

[0136] The term "substituted" as used herein, unless otherwise specified, refers to the substitution of hydrogen on a carbon atom or hydrogen on a nitrogen atom with a substituent.When one or more substituents are substituted on a ring in the present invention, it means that each of the substituents can be independently substituted on all ring atoms of the ring, including but not limited to ring carbon atoms or ring nitrogen atoms.Furthermore, when the ring is a polycyclic ring, such as a fused ring, a bridged ring, or a spiro ring, each of the substituents can be independently substituted on all ring atoms of the polycyclic ring.In some embodiments, when the ring is a fused ring, the substitution does not occur on the fused atom.

[0137] The term "oxo" together with the attached carbon atom represents the group [ka] refers to the oxygen atoms that form

[0138] The term "composition," as used herein, is intended to encompass a product containing the specified components in the specified amounts, as well as any product resulting directly or indirectly from combining the specified components in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as active ingredients, as well as methods for preparing the compounds of the present invention, are also part of the present invention. Furthermore, some of the crystalline forms of the compounds may exist as polymorphs, and as such, are intended to be included in the present invention. Furthermore, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of the present invention.

[0139] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When a compound of the present invention is acidic, its corresponding salt can be conveniently prepared from a pharmaceutically acceptable non-toxic base, including inorganic bases and organic bases. When a compound of the present invention is basic, its corresponding salt can be conveniently prepared from a pharmaceutically acceptable non-toxic acid, including inorganic and organic acids. Since the compounds of the present invention are intended for pharmaceutical use, they are preferably provided in a substantially pure form, for example, at least 60% pure, more preferably at least 75% pure, and particularly at least 98% pure (% is weight by weight).

[0140] The present invention includes within its scope prodrugs of the compounds of the present invention. Generally, such prodrugs will be functional derivatives of the compounds that are readily converted in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administering" is intended to encompass treatment of the various disorders described with a specifically disclosed compound or a compound that may not be specifically disclosed, but which is converted to the specified compound in vivo after administration to a subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985.

[0141] It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of the invention can be selected by those skilled in the art to provide chemically stable compounds that can be readily synthesized by techniques known in the art and the methods described herein.

[0142] The present invention includes compounds described that may contain one or more asymmetric centers and may therefore give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.

[0143] The present invention includes all stereoisomers of the compounds and their pharmaceutically acceptable salts. It also includes mixtures of stereoisomers as well as isolated specific stereoisomers. During the synthetic procedures used to prepare such compounds, or when using racemization or epimerization procedures known to those skilled in the art, the products of such procedures may be mixtures of stereoisomers.

[0144] The term "stereoisomer" as used herein refers to isomers in which atoms or groups of atoms in a molecule are bonded to each other in the same order but differ in spatial arrangement, including conformational isomers and configurational isomers. Configurational isomers include geometric isomers and optical isomers, and optical isomers primarily include enantiomers and diastereomers. The present invention includes all possible stereoisomers of a compound.

[0145] The present invention is intended to include all isotopes of atoms occurring in the compounds of the present invention. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example, and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of hydrogen include: 1 H (hydrogen), 2 H (deuterium) and 3H (tritium). They are also commonly represented as D for deuterium and T for tritium. In this application, CD3 represents a methyl group in which all of the hydrogen atoms are deuterium. Carbon isotopes are 13 C and 14 C. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described herein, using an appropriate isotopically labeled reagent in place of an unlabeled reagent.

[0146] The term "deuterated derivative" as used herein, unless otherwise specified, refers to a compound having the same chemical structure as the reference compound, except that one or more hydrogen atoms have been replaced with deuterium atoms ("D"). It will be recognized that some variation in natural isotopic abundance will occur in synthesized compounds depending on the origin of the chemical materials used in their synthesis. Despite this variation, the concentration of naturally abundant stable hydrogen isotopes is low and insignificant compared to the degree of stable isotopic substitution of the deuterated derivatives described herein. Therefore, unless otherwise specified, when a "deuterated derivative" of a compound of the present disclosure is referred to, at least one hydrogen is replaced with deuterium at a level far above its natural isotopic abundance (typically about 0.015%). In certain embodiments, deuterated derivatives of the present disclosure have an isotopic enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium), at least 4500, (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), or at least 6600 (99% deuterium incorporation).

[0147] When tautomers of the compounds of the present invention exist, the present invention includes all possible tautomers and pharmaceutically acceptable salts thereof, as well as mixtures thereof, unless otherwise specified.

[0148] The compounds described herein can also inhibit PARP7 protein function by incorporating them into agents that catalyze the destruction of PARP7 protein. For example, the compounds can be incorporated into proteolysis-targeting chimeric molecules (PROTACs). PROTACs are bifunctional molecules, with one portion capable of engaging an E3 ubiquitin ligase and the other portion capable of binding to a target protein intended for degradation by a cellular protein quality control mechanism. Recruitment of a target protein to a specific E3 ligase results in its tagging for destruction (i.e., ubiquitination) and subsequent degradation by the proteasome. Any E3 ligase can be used. Preferably, the portion of the PROTAC that engages with the E3 ligase is linked to the portion of the PROTAC that engages with the target protein via a linker consisting of a variable chain of atoms. Thus, recruitment of the PARP-7 protein to the E3 ligase will result in the destruction of the PARP-7 protein. The variable chain of atoms can include, for example, a ring, heteroatoms, and / or repeating polymer units. It can be rigid or flexible. It can be attached to the two moieties described above using techniques standard in the art of organic synthesis.

[0149] Pharmaceutical compositions of the present invention comprise a compound of the present invention (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients or adjuvants. Compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host and the nature and severity of the condition for which the active ingredient is administered. Pharmaceutical compositions are conveniently presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

[0150] In practice, the compounds of the present invention, or prodrugs or metabolites of the present invention, or pharmaceutically acceptable salts thereof, can be combined as active ingredients in intimate admixture with pharmaceutical carriers according to conventional pharmaceutical compounding techniques. The carriers can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration, such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient. Furthermore, the compositions can be presented as a powder, granules, a liquid, a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. In addition to the common dosage forms set forth above, the compounds of the present invention or pharmaceutically acceptable salts thereof can also be administered by controlled-release means and / or delivery devices. The compositions can be prepared by any of the methods of pharmacy. In general, such methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredients with liquid carriers or finely divided solid carriers or both, and the product can then be conveniently shaped into the desired presentation.

[0151] Thus, the pharmaceutical compositions of the invention can include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt thereof. The compounds of the invention, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

[0152] The pharmaceutical carrier used can be, for example, solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. When preparing compositions for oral dosage form, any convenient pharmaceutical medium can be used. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc. can be used to form oral liquid preparations such as suspensions, elixirs, and solutions; while carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. can be used to form oral solid preparations such as powders, capsules, and tablets. Due to their ease of administration, tablets and capsules are preferred oral dosage units, whereby solid pharmaceutical carriers are used. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques.

[0153] Tablets containing the compositions of the present invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing the active ingredient into a free-flowing form, such as a powder or granules, mixed with an optional binder, lubricant, inert diluent, surfactant, or dispersing agent in a suitable machine. Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. Each tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient, and each cachet or capsule preferably contains from about 0.05 mg to about 5 g of the active ingredient. For example, a formulation intended for oral administration to humans may contain from about 0.5 mg to about 5 g of the active agent, combined with an appropriate and convenient amount of carrier material, which may vary from about 0.05 to about 95 percent of the total composition. Dosage unit forms will generally contain from about 0.01 mg to about 2 g of active ingredient, typically 0.01 mg, 0.02 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1500 mg or 2000 mg.

[0154] The pharmaceutical composition of the present invention suitable for parenteral administration can be prepared as a solution or suspension of the active compound in water.For example, a suitable surfactant such as hydroxypropyl cellulose can be included.Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and their mixtures in oil.In addition, preservatives can be included to prevent harmful growth of microorganisms.

[0155] Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions may be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and effectively fluid. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, they should preferably be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0156] The pharmaceutical compositions of the present invention can be in a form suitable for topical use, such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Additionally, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared using a compound of the present invention or a pharmaceutically acceptable salt thereof by conventional processing methods. For example, a cream or ointment can be prepared by mixing a hydrophilic material and water together with about 0.05% to about 10% by weight of the compound to produce a cream or ointment having the desired consistency.

[0157] The pharmaceutical composition of the present invention can be in a form suitable for rectal administration, where the carrier is solid.Preferably, the mixture forms unit-dose suppositories.Suitable carriers include cocoa butter and other materials commonly used in the art.Suppositories can be conveniently formed by first mixing the composition with a softened or melted carrier, then cooling and shaping in molds.

[0158] In addition to the above carrier components, the pharmaceutical formulations described above may optionally contain one or more additional carrier components such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc. Furthermore, other adjuvants for rendering the formulation isotonic with the blood of the intended recipient may be included. Compositions containing the compounds described herein or pharmaceutically acceptable salts thereof may also be prepared in powder or liquid concentrate form.

[0159] Generally, dosage levels of about 0.001 mg / kg to about 150 mg / kg body weight / day are useful in treating the above conditions, or about 0.05 mg to about 7 g / patient / day. For example, inflammation, cancer, psoriasis, allergies / asthma, diseases and conditions of the immune system, and diseases and conditions of the central nervous system (CNS) can be effectively treated by administration of about 0.001 to 50 mg of compound per kilogram body weight / day, or about 0.05 mg to about 3.5 g / patient / day.

[0160] However, it will be understood that the specific dose level for any particular patient will depend on a variety of factors, including age, body weight, general health, sex, dietary habits, timing of administration, route of administration, rate of excretion, concurrent medications, and the severity of the particular disease being treated.

[0161] Unless otherwise clear from the context, when a value is expressed as "about" X or "approximately" X, the stated value of X will be understood to be accurate to ±10%, preferably ±5%, ±2%.

[0162] The term "subject" refers to an animal. In certain embodiments, an animal is a mammal. A subject also refers to, for example, a primate (e.g., a human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, etc. In certain embodiments, a subject is a human. A "patient," as used herein, refers to a human subject. As used herein, a subject is "in need of" a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment.

[0163] The terms "inhibition," "inhibiting," or "inhibit" refer to the alleviation or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0164] The terms "treat," "treating," or "treatment" of any disease or disorder, in one embodiment, refer to ameliorating the disease or disorder (i.e., slowing or halting or alleviating the onset of the disease or at least one of its clinical symptoms). In another embodiment, "treat," "treating," or "treatment" refers to alleviating or improving at least one physical parameter, including one that may not be discernible by the patient. In yet another embodiment, "treat," "treating," or "treatment" refers to modulating the disease or disorder physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, "treat," "treating," or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder.

[0165] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. Any examples provided herein, or the use of exemplary language (e.g., "etc.") are intended merely to facilitate a more readily understood understanding of the invention and do not impose limitations on the scope of the invention as otherwise claimed.

[0166] These and other aspects will become apparent from the following specification of the invention.

[0167] Preparation method The compounds of the present invention can be synthesized from commercially available reagents using the synthetic methods and reaction schemes described herein. The examples outlining specific synthetic routes, and the general schemes below, are intended to provide guidance to those skilled in the art of synthetic chemistry, who will readily understand that solvents, concentrations, reagents, protecting groups, order of synthetic steps, times, temperatures, and the like, can be varied as necessary and well within the skill and judgment of the skilled artisan. [Example]

[0168] The following examples are provided to better illustrate the present invention. Unless otherwise specified, all parts and percentages are by weight and all temperatures are in °C. The following abbreviations are used in the examples:

[0169] [Table 2] TIFF2024506612000392.tif58170

[0170] Intermediate A1 (INT A1) [ka] Step 1: A solution of 4,5-dibromopyridazin-3(2H)-one (204.14 g, 0.80 mol, 1.0 equiv) dissolved in DMF (1.0 L) was purged, maintained under an inert atmosphere of nitrogen, and cooled to 0-10 °C. NaH (42.17 g, 1.05 mol, 1.31 equiv) (60% in mineral oil) was then slowly added. The resulting mixture was stirred at 0 °C for 1 h, and then 1-(chloromethyl)-4-methoxybenzene (193.71 g, 1.24 mmol, 1.54 equiv) was added. The reaction mixture was stirred at room temperature for 3 h, quenched with water (1.5 L), and extracted with DCM (1.5 L × 2). The organic layers were combined, dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was dispersed in MeOH (800 mL), stirred at room temperature for 1 hour, and then filtered. The filter cake was dried under reduced pressure to give INT A1-1 (245.01 g, 81% yield) as a solid. LCMS: m / z=375 [M+1] + .

[0171] Step 2: A mixture of INT A1-1 (242.91 g, 0.65 mol, 1.0 equiv.), potassium hydroxide (143.46 g, 2.56 mol, 3.94 equiv.), and MeOH (2.5 L) was stirred at room temperature for 4 hours and then concentrated under reduced pressure to precipitate a solid. The solid was collected by filtration and then dispersed in water (1.8 L) to obtain a suspension, which was stirred at room temperature for 1 hour. The resulting mixture was filtered, and the filter cake was dried under reduced pressure to obtain INT A1-2 (118.86 g, 56% yield) as a solid. LCMS: m / z=325, 327 [M+1] + .

[0172] Step 3: INT A1-2 (80.76 g, 0.25 mol, 1.0 equiv.), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (159.59 g, 0.83 mol, 3.345 equiv.), and CuI (74.04 g, 0.39 mol, 1.57 equiv.) were dispersed in NMP (800 mL). The reaction mixture was purged, maintained under an inert nitrogen atmosphere, stirred at 100 °C for 4.5 h, quenched with water (1.5 L), and then extracted with DCM (500 mL × 3). The organic layers were combined and concentrated under reduced pressure to give a residue. The residue was purified using a silica gel column (eluted with EA / hexane) to give an oil, which was dispersed in HO (1.0 L) to precipitate a solid. The solid was obtained by filtration, washed with MeOH (100 mL), and dried under reduced pressure to give INT A1-3 (67.3 g, 86% yield) as a white solid. LCMS: m / z=315 [M+1] + .

[0173] Step 4: A solution of INT A1-3 (60.34 g, 0.19 mol, 1.0 equiv) dissolved in NMP (600 mL) was purged and maintained under an inert atmosphere of nitrogen, and then TMSI (69.27 g, 0.35 mol, 1.80 equiv) was added dropwise at 20 °C. The reaction mixture was stirred at 85 °C for 20 h, quenched with water (850 ml), and then extracted with EA (500 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give a residue, which was purified using silica gel column chromatography (eluted with Hex / EA) to give INT A1-4 (54.0 g, 94% yield) as a solid. LCMS: m / z = 301 [M+1] + .

[0174] Step 5: A solution of INT A1-4 (27.12 g, 90.33 mmol, 1.0 equiv) dissolved in DMF (250 mL) was purged, maintained under an inert atmosphere of nitrogen, and cooled to 0-5 °C, followed by the dropwise addition of oxalic dichloride (33.25 g, 0.26 mol, 2.90 equiv). The reaction mixture was stirred at room temperature for 3 h, quenched with saturated aqueous sodium carbonate (850 mL), and then extracted with EA (500 mL × 3). The organic layers were combined, dried over anhydrous Na2SO4, and then concentrated under reduced pressure to give a residue that was purified using a silica gel column (eluted with Hex / EA) to give INT A1-5 (18.94 g, 66% yield) as a solid. LCMS: m / z = 319 [M+1] + .

[0175] Step 6: INT A1-5 (10.76 g, 33.76 mmol, 1.0 equiv), S-(+)-2-amino-1-propanol (3.43 g, 45.67 mmol, 1.35 equiv), and TEA (15 mL) were dissolved in CHCN (100 mL). The reaction mixture was stirred at 85 °C for 18 hours and concentrated under reduced pressure. The residue was purified using prep-HPLC (C18 column, eluted with CHCN / HO) to give INT A1-6 (10.29 g, 85% yield) as a solid. LCMS: m / z = 358 [M+1] + .

[0176] Step 7: INT A1-6 (9.15 g, 25.60 mmol, 1.0 equiv), methyl acrylate (15.83 g, 183.88 mmol, 7.18 equiv), and CsCO (42.73 g, 131.15 mmol, 5.12 equiv) were dispersed in CHCN (150 mL). The reaction mixture was stirred at room temperature for 8 hours and then filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified using a silica gel column (eluted with Hex / EA) to give INT A1-7 (4.40 g, 39% yield) as a solid. LCMS: m / z = 444 [M+1] + .

[0177] Step 8: TfOH (45 mL) was added dropwise to a solution of INT A1-7 (32.12 g, 72.44 mmol, 1.0 equiv) dissolved in TFA (200 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, quenched with saturated aqueous sodium bicarbonate (850 mL), and then extracted with EA (500 mL × 3). The organic layers were combined, dried over anhydrous Na2SO4, and then concentrated under reduced pressure to give a residue, which was purified using a silica gel column (eluted with Hex / EA) to give INT A1-8 (14.53 g, 62% yield) as a solid. LCMS: m / z = 324 [M+1] + .

[0178] Step 9: INT A1-8 (2.54 g, 7.86 mmol, 1.0 equiv) and LiOH (0.67 g, 24.98 mmol, 3.56 equiv) were dispersed in THF (50 mL) and water (10 mL). The reaction mixture was stirred at room temperature for 4 h, quenched with aqueous HCl (1 N), and extracted with EA (30 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give a residue, which was purified using Prep-HPLC (C18 column, eluted with HO / CHCN) to give INT A1 (1.86 g, 77% yield). LCMS: m / z = 310 [M+1] + .

[0179] Intermediate A2 (INT A2) [ka] Step 1: 4-Bromo-5-methoxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one (81.14 g, 0.25 mol, 1.0 equiv.), tributyl(1-ethoxyvinyl)stannane (99.34 g, 0.28 mol, 1.12 equiv.), Pd(PPh3)2Cl2 (20.39 g, 28.88 mmol, 0.12 equiv.), and CsF (112.68 g, 0.74 mol, 2.96 equiv.) were dispersed in 1,4-dioxane (600 mL). The reaction mixture was purged, maintained under an inert atmosphere of nitrogen, and stirred at 100 °C for 4.5 h, then filtered. The filtrate was concentrated under reduced pressure to give a residue that was purified using a silica gel column (eluted with Hex / EA) to give INT A2-1 (66.66 g, 84% yield). LCMS: m / z=317[M+1] + .

[0180] Step 2: 6N aqueous hydrochloric acid (200 mL) was added to a solution of INT A2-1 (66.66 g, 0.21 mol, 1.0 equiv.) dissolved in THF (600 mL) at room temperature. The reaction mixture was stirred for 3 h, quenched with sodium bicarbonate solution (800 mL), and then extracted with EA (800 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give INT A2-2 (57.35 g, 94% yield). LCMS: m / z = 289 [M+1] + .

[0181] Step 3: Aqueous NaOH (4N, 100 mL, 0.40 mol, 2.0 equiv.) was added to a solution of INT A2-2 (57.35 g, 0.20 mmol, 1.0 equiv.) dissolved in THF (800 mL). The reaction mixture was stirred at 85° C. for 3 h, cooled to room temperature, quenched with HCl (2N, aq.), and then extracted with EA (500 mL×3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give a residue, which was purified using a silica gel column (eluted with Hex / EA) to give INT A2-3 (50.51 g, 92% yield). LCMS: m / z=275 [M+1] + .

[0182] Step 4: A mixture of INT A2-3 (50.51 g, 0.18 mol, 1.0 equiv) and POCl (100 mL) was stirred at 95 °C for 2 h, cooled to room temperature, quenched with aqueous NaHCO, and extracted with EA (500 mL x 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give a residue, which was purified using a silica gel column (eluted with Hex / EA) to give INT A2-4 (32.80 g). LCMS: m / z = 293 [M+1] + .

[0183] Step 5: INT A2-4 (32.80 g, 112.05 mmol, 1.0 equiv.), S-(+)-2-amino-1-propanol (17.80 g, 236.99 mmol, 2.12 equiv.), and TEA (35.60 g, 351.82 mmol, 3.14 equiv.) were dispersed in CH3CN (200 mL). The reaction mixture was stirred at 85 °C for 18 hours, cooled to room temperature, and concentrated under reduced pressure to give a residue, which was purified using Prep-HPLC (C18 column, eluted with HO / CH3CN) to give INT A2-5 (36.08 g, 97% yield). LCMS: m / z = 332 [M+1] + .

[0184] Step 6: INT A2-5 (36.08 g, 108.88 mmol, 1.0 equiv.), tert-butyl acrylate (65.20 g, 508.71 mmol, 4.67 equiv.), and CsCO (96.70 g, 296.79 mmol, 2.73 equiv.) were dispersed in CHCN (500 mL). The reaction mixture was stirred at room temperature for 8 hours and then filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified using a silica gel column (eluted with Hex / EA) to give INT A2-6 (38.87 g, 84% yield). LCMS: m / z = 460 [M+1] + .

[0185] Step 7: TFA (8 mL) was added dropwise to a solution of INT A2-6 (2.83 g, 6.16 mmol, 1.0 equiv) dissolved in DCM (30 mL) at room temperature. The reaction mixture was stirred at room temperature for 5 hours, quenched with saturated aqueous NaHCO (100 mL), and then extracted with EA (100 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product of INT A2 (2.60 g) as a yellow oil, which was used in the next step without further purification. LCMS: m / z = 404 [M + 1] + .

[0186] Intermediate A3 (INT A3) [ka] Step 1: TfOH (10 mL) was added dropwise to a solution of INT A2-6 (43.4 g, 75.30 mmol, 1.0 equiv) dissolved in TFA (100 mL) at room temperature. The reaction mixture was stirred at room temperature for 7 hours, quenched with saturated aqueous NaHCO (850 mL), and extracted with EA (500 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and concentrated under reduced pressure to give a residue, which was purified using Prep-HPLC (C18 column, eluted with HO / CHCN) to give INT A3 (21.10 g, 98% yield). LCMS: m / z = 284 [M+1] + .

[0187] Intermediate A4 (INT A4) [ka] Step 1: 2-(benzyloxy)propan-1-ol (21.33 g, 128.33 mmol, 1.0 equiv), tert-butyl acrylate (70.84 g, 552.71 mmol, 4.31 equiv), and CsCO (125.61 g, 385.52 mmol, 3.00 equiv) were dispersed in DMSO (210 mL). The reaction mixture was stirred at room temperature for 3 hours, poured into water (200 mL), and extracted with EA (200 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give a residue, which was purified using prep-HPLC (C18 column, eluted with HO / CHCN) to give INT A4-1 (26.52 g). LCMS: m / z = 295 [M+1] + .

[0188] Step 2: A mixture of INT A4-1 (10.71 g, 36.38 mmol, 1.0 equiv.), Pd / C (1.02 g, 9.58 mmol, 0.26 equiv.) and MeOH (10 mL) was purged, maintained under an inert atmosphere of hydrogen, stirred at room temperature for 48 hours, and then filtered. The filtrate was concentrated under reduced pressure to give a crude product (9.15 g) containing INT A4-2, which was used in the next step without further purification. LCMS: m / z=205 [M+1] + .

[0189] Step 3: In a nitrogen atmosphere, INT A4-2 (9.15 g, 44.80 mmol, 1.09 equiv.), 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (13.11 g, 41.14 mmol, 1.0 equiv.), and t-BuONa (5.52 g, 57.44 mmol, 1.40 equiv.) were dispersed in DCM (50 mL). The reaction mixture was stirred at room temperature for 2 hours, washed with NH4Cl (aq.), and then extracted with DCM (50 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, and then concentrated under reduced pressure to give a residue, which was purified using prep-HPLC (C18 column, eluted with HO / CH3CN) to give INT A4-3 (12.81 g). LCMS: m / z=487[M+1] + .

[0190] Step 4: TFA (10 mL) was added dropwise to a solution of INT A4-3 (12.81 g, 26.33 mmol, 1.0 equiv) dissolved in DCM (40 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, quenched with saturated aqueous NaHCO3 (50 mL), and extracted with EA (100 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, and then concentrated under reduced pressure to give the crude product of INT A4-4 (11.33 g), which was used in the next step without further purification. LCMS: m / z = 431 [M+1] + .

[0191] Step 5: TfOH (30 mL) was added dropwise to a solution of INT A4-4 (12.81 g, crude product) dissolved in TFA (200 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, quenched with saturated aqueous NaHCO (850 mL), and then extracted with EA (500 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give a residue, which was purified using Prep-HPLC (C18 column, eluted with HO / CHCN) to give INT A4 (5.23 g, 64% yield). LCMS: m / z = 311 [M+1] + .

[0192] The following intermediates were synthesized using the corresponding starting materials and procedures described above.

[0193] [Table 3]

[0194] Intermediate A7 (INT A7) [ka] Step 1: Tert-butyl (R)-(1-hydroxy-3-methoxypropan-2-yl)carbamate (19.29 g, 93.98 mmol, 1.0 equiv), tert-butyl acrylate (57.36 g, 447.54 mmol, 4.76 equiv), and CsCO (100.01 g, 306.95 mmol, 3.27 equiv) were dispersed in CHCN (500 mL). The reaction mixture was stirred at room temperature for 16 hours, poured into water (200 mL), and extracted with EA (200 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give a residue, which was purified using a silica gel column (eluted with Hex / EA) to give INT A7-1 (20.76 g, 66% yield). LCMS: m / z = 334 [M+1] + .

[0195] Step 2: TFA (10 mL) was added dropwise to a solution of INT A7-1 (20.66 g, 61.96 mmol, 1.0 equiv.) dissolved in DCM (200 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give the crude product of INT A7-2 (23.38 g), which was used in the next step without further purification. LCMS: m / z=178 [M+1] + .

[0196] Step 3: Under a nitrogen atmosphere, the crude product of INT A7-2 (1.01 g), 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (1.13 g, 3.55 mol, 1.32 equiv.), and EtN (2.88 g, 28.50 mmol, 10.63 equiv.) were dispersed in CHCN (10 mL). The reaction mixture was stirred at 70 °C for 5 hours, cooled to room temperature, and then concentrated under reduced pressure to give a residue, which was purified using prep-HPLC (C18 column, eluted with HO / CHCN) to give INT A7 (0.92 g, 75% yield). LCMS: m / z = 460 [M+1] + .

[0197] Intermediate A8 (INT A8) [ka] Step 1: 5-Chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (10.00 g, 31.38 mmol, 1.0 equiv.), (S)-2-aminobutan-1-ol (4.07 g, 45.66 mmol, 1.46 equiv.), and TEA (15 mL) were dissolved in CHCN (100 mL). The reaction mixture was stirred at 70 °C for 4 hours, cooled to room temperature, and concentrated under reduced pressure to give a residue. The residue was purified using prep-HPLC (C18 column, eluted with CHCN / HO) to give INT A8-1 (11.05 g, 94% yield). LCMS: m / z = 372 [M+1] + .

[0198] Step 2: INT A8-1 (11.05 g, 29.78 mmol, 1.0 equiv), tert-butyl acrylate (19.74 g, 154.02 mmol, 5.17 equiv), and CsCO (29.13 g, 89.41 mmol, 3.00 equiv) were dispersed in DMSO (100 mL). The reaction mixture was stirred at room temperature for 3 hours, poured into water (100 mL), and extracted with EA (100 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and concentrated under reduced pressure to give a residue, which was purified using a silica gel column (eluted with Hex / EA) to give INT A8-2 (5.58 g, 37% yield). LCMS: m / z = 500 [M+1] + .

[0199] Step 3: TFA (10 mL) was added dropwise to a solution of INT A8-2 (5.47 g, 10.95 mmol, 1.0 equiv) dissolved in DCM (50 mL) at room temperature. The reaction mixture was stirred at room temperature for 5 hours, quenched with aqueous NaHCO (50 mL), and then extracted with EA (100 mL x 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give the crude product of INT A8-3 (4.85 g), which was used in the next step without further purification. LCMS: m / z = 444 [M + 1] + .

[0200] Step 4: The crude product of INT A8-3 (4.85 g) was dissolved in TFA (60 mL) to obtain a solution, and then TfOH (6 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 2 hours, quenched with saturated aqueous NaHCO (200 mL), and then extracted with EA (200 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to obtain a residue, which was purified using Prep-HPLC (C18 column, eluted with HO / CHCN) to obtain INT A8 (1.41 g, 39% yield). LCMS: m / z = 324 [M+1] + .

[0201] Intermediate A9 (INT A9) [ka] Step 1: 5-Chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (12.60 g, 39.54 mmol, 2.11 equiv.), 2-amino-3,3,3-trifluoropropan-1-ol hydrochloride (3.10 g, 18.73 mmol, 1.0 equiv.), and CsCO (18.0 g, 55.25 mmol, 2.95 equiv.) were dissolved in CHCN (100 mL). The reaction mixture was stirred at room temperature for 16 hours and then filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified using prep-HPLC (C18 column, eluted with CHCN / HO) to give INT A9-1 (0.82 g, 10% yield). LCMS: m / z = 412 [M+1] + .

[0202] Step 2: INT A9-1 (0.80 g, 1.95 mmol, 1.0 equiv), tert-butyl acrylate (2.56 g, 19.97 mmol, 10.27 equiv), and CsCO (3.24 g, 9.94 mmol, 5.11 equiv) were dispersed in DMSO (8 mL). The reaction mixture was stirred at room temperature for 5 hours, poured into water (50 mL), and extracted with EA (50 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give a residue, which was purified using a silica gel column (eluted with Hex / EA) to give INT A9-2 (0.32 g, 30% yield). LCMS: m / z = 540 [M+1] + .

[0203] Step 3: TFA (2 mL) was added dropwise to a solution of INT A9-2 (0.32 g, 0.59 mmol, 1.0 equiv) dissolved in DCM (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours, quenched with aqueous NaHCO (50 mL), and then extracted with EA (50 mL x 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give the crude product of INT A9 (0.27 g), which was used in the next step without further purification. LCMS: m / z = 484 [M + 1] + .

[0204] Intermediate A10 (INT A10) [ka] Step 1: Ethyl oxirane-2-carboxylate (27.84 g, 239.76 mmol, 2.10 equiv.), tert-butyl (S)-(1-hydroxypropan-2-yl)carbamate (20.03 g, 114.31 mmol, 1.0 equiv.), and Mg(ClO4)2 (49.69 g, 222.62 mmol, 1.95 equiv.) were dispersed in EA (200 mL). The reaction mixture was stirred at room temperature for 64 h and then filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified using a silica gel column (eluted with Hex / EA) to give INT A10-1 (1.10 g, 3% yield). LCMS: m / z = 292 [M+1]+ .

[0205] Step 2: A solution of INT A10-1 (0.99 g, 3.40 mmol, 1.0 equiv) dissolved in HCl / 1,4-dioxane (10 mL, 1N) was stirred at room temperature for 2 hours and concentrated under reduced pressure to give crude INT A10-2 (0.96 g), which was used in the next step without further purification. LCMS: m / z=192 [M+1] + .

[0206] Step 3: 5-Chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (1.40 g, 4.39 mmol, 1.29 equiv.), INT A10-2 (0.96 g, 3.40 mmol, 1.0 equiv.), and TEA (3 mL) were dissolved in CHCN (10 mL). The reaction mixture was stirred at 60 °C for 2 hours and then concentrated under reduced pressure to give a residue, which was purified using prep-HPLC (C18 column, eluted with CHCN / HO) to give INT A10-3 (1.20 g, 62% yield). LCMS: m / z = 474 [M+1] + .

[0207] Step 4: INT A10-3 (1.20 g, 2.53 mmol, 1.0 equiv) and LiOH (0.18 g, 7.52 mmol, 2.97 equiv) were dispersed in a mixed solvent of THF (10 mL) and water (3 mL). The reaction mixture was stirred at room temperature for 3 hours, quenched with aqueous HCl (1N), and extracted with EA (30 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and concentrated under reduced pressure to give a residue, which was purified using prep-HPLC (C18 column, eluted with HO / CHCN) to give INT A10-4 (0.40 g, 35% yield). LCMS: m / z = 446 [M+1] + .

[0208] Step 5: TfOH (1 mL) was added dropwise to a solution of INT A10-4 (0.40 g, 0.90 mmol, 1.0 equiv.) dissolved in TFA (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, quenched with saturated aqueous NaHCO3 (850 mL), and then extracted with EA (500 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, and then concentrated under reduced pressure to give the crude product of INT A10 (0.40 g), which was used in the next step without further purification. LCMS: m / z = 326 [M+1] + .

[0209] Intermediate A11 (INT A11) [ka] Step 1: Dess-Martin periodinane (13.76 g, 32.44 mmol, 1.25 equiv) was added to a solution of tert-butyl (1-hydroxypropan-2-yl)carbamate (4.53 g, 25.85 mmol, 1.0 equiv) dissolved in DCM (90 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h, and then saturated aqueous NaHCO3 (50 mL) was added. The resulting mixture was extracted with EA (100 mL x 3). The organic layers were combined and concentrated under reduced pressure to give a residue that was purified using a silica gel column (eluted with Hex / EA) to give INT A11-1 (3.82 g, 85% yield). LCMS: m / z = 174 [M+1] + .

[0210] Step 2: INT A11-1 (3.82 g, 25.85 mmol, 1.0 equiv) and tert-butyl pyrrolidine-3-carboxylate (4.34 g, 25.35 mmol, 1.15 equiv) were dissolved in DCM (80 mL), and then STAB (6.97 g, 33.04 mmol, 1.50 equiv) was added. The reaction mixture was stirred at room temperature for 4 hours, and then saturated aqueous NaHCO3 (50 mL) was added. The resulting mixture was extracted with EA (100 mL x 3), and the combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified using a silica gel column (eluted with Hex / EA) to give INT A11-2 (4.07 g, 56% yield). LCMS: m / z = 329 [M+1] + .

[0211] Step 3: TFA (8 mL) was added dropwise to a solution of INT A11-2 (4.07 g, 12.39 mmol, 1.00 equiv) dissolved in DCM (40 mL) at room temperature. The reaction mixture was stirred at room temperature for 8 hours, quenched with aqueous NaHCO (50 mL), and extracted with EA (50 mL x 3). The organic layers were combined, dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product of INT A11-3 (2.13 g), which was used in the next step without further purification. LCMS: m / z = 173 [M+1] + .

[0212] Step 4: 5-Chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (4.44 g, 13.93 mmol, 1.0 equiv.), INT A11-3 (2.13 g, crude product), and TEA (10 mL) were dissolved in CHCN (60 mL). The reaction mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure to give a residue, which was purified using prep-HPLC (C18 column, eluted with CHCN / HO) to give INT A11 (0.97 g, 17% yield). LCMS: m / z = 455 [M+1] + .

[0213] Intermediate A12 (INT A12) [ka] Step 1: 4-Bromo-5-methoxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one (10.12 g, 31.12 mmol, 1.0 equiv.), Zn(CN) (5.51 g, 46.92 mmol, 1.51 equiv.), and Pd(PPh) (10.31 g, 8.92 mmol, 0.29 equiv.) were dispersed in DMF (100 mL). The reaction mixture was purged, maintained under an inert atmosphere of nitrogen, stirred at 130 °C for 4 h, cooled to room temperature, diluted with brine (100 mL), and then extracted with EA (100 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give a residue that was purified by Prep-HPLC (C 18 Purification using a column eluted with CHCN / H0 gave INT A12-1 (7.83 g, 92% yield). LCMS: m / z=272 [M+1] + .

[0214] Step 2: A mixture of INT A12-1 (7.83 g, 28.86 mol, 1.0 equiv) and DMF (80 mL) was purged and maintained under an inert atmosphere of nitrogen, then TMSI (11.47 g, 57.32 mol, 1.99 equiv) was added dropwise at room temperature. The reaction mixture was stirred at 85 °C for 3 hours, cooled to room temperature, quenched with water (100 mL), and then extracted with EA (100 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and concentrated under reduced pressure to give a residue, which was purified using Prep-HPLC (C18 column, eluted with CHCN / HO) to give INT A12-2 (4.25 g, 57% yield). LCMS: m / z = 258 [M+1] + .

[0215] Step 3: A mixture of INT A12-2 (4.25 g, 16.52 mmol, 1.0 equiv) and DMF (50 mL) was purged, maintained under an inert atmosphere of nitrogen, and cooled to 0-5 °C, followed by the dropwise addition of oxalyl dichloride (4.10 g, 32.30 mol, 1.96 equiv). The reaction mixture was stirred at room temperature for 6 h, quenched with saturated aqueous Na2CO3 (100 mL), and then extracted with EA (150 mL × 3). The organic layers were combined, dried over anhydrous Na2SO4, and then concentrated under reduced pressure to give the crude product of INT A12-3 (4.49 g), which was used in the next step without further purification. LCMS: m / z = 276 [M+1] + .

[0216] Step 4: INT A12-3 (4.49 g, 16.29 mmol, 1.0 equiv.), S-(+)-2-amino-1-propanol (2.50 g, 33.28 mmol, 2.04 equiv.), and TEA (4.97 g, 49.12 mmol, 3.02 equiv.) were dispersed in CHCN (100 mL). The reaction mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure to give a residue, which was purified using prep-HPLC (C18 column, eluted with CHCN / HO) to give INT A12-4 (4.57 g, 89% yield). LCMS: m / z = 315 [M+1] + .

[0217] Step 5: INT A12-4 (2.10 g, 6.68 mmol, 1.0 equiv), tert-butyl acrylate (10.0 g, 78.02 mmol, 11.68 equiv), and CsCO (3.24 g, 9.94 mmol, 1.49 equiv) were dispersed in DMSO (30 mL). The reaction mixture was stirred at room temperature for 16 h, poured into water (50 mL), and extracted with EA (50 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give a residue, which was purified using prep-HPLC (C18 column, eluted with CHCN / HO) to give INT A12-5 (2.21 g, 74% yield). LCMS: m / z = 443 [M+1] + .

[0218] Step 6: TFA (10 mL) was added dropwise to a solution of INT A12-5 (4.38 g, 9.90 mmol, 1.0 equiv) dissolved in DCM (50 mL) at room temperature. The reaction mixture was stirred at room temperature for 6 hours, quenched with saturated aqueous NaHCO (20 mL), and extracted with EA (50 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product of INT A12-6 (4.27 g) as a yellow oil, which was used in the next step without further purification. LCMS: m / z = 387 [M + 1] + .

[0219] Step 7: TfOH (8 mL) was added dropwise to a solution of INT A12-6 (4.12 g, 10.66 mmol, 1.0 equiv) dissolved in TFA (30 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 h, quenched with saturated aqueous NaHCO (100 mL), and then extracted with EA (100 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and concentrated under reduced pressure to give a residue, which was purified by Prep-HPLC (C 18 Purification using a column eluted with CHCN / H0 gave INT A12 (1.78 g, 62% yield). LCMS: m / z=267 [M+1] + .

[0220] Intermediate A13 (INT A13) [ka] Step 1: A solution of 4,5-dichloropyridazin-3(2H)-one (5.02 g, 30.43 mmol, 1.0 equiv) dissolved in DMF (1.0 L) was purged, maintained under an inert atmosphere of nitrogen, and cooled to 0-10 °C. NaH (1.32 g, 32.75 mmol, 1.08 equiv) (60% in mineral oil) was then slowly added. The resulting mixture was stirred at 0 °C for 1 h, and then 1-(chloromethyl)-4-methoxybenzene (6.76 g, 43.16 mmol, 1.42 equiv) was added. The reaction mixture was stirred at room temperature for 2 h, quenched with water (50 mL), and extracted with EA (50 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give a residue. A mixture of the residue and MeOH (10 mL) was stirred at room temperature for 1 h and then filtered. The filter cake was dried under reduced pressure to give INT A13-1 (5.01 g, 57% yield) as a solid. LCMS: m / z=285 [M+1] + .

[0221] Step 2: INT A13-1 (2.21 g, 7.75 mmol, 1.0 equiv), S-(+)-2-amino-1-propanol (1.78 g, 23.70 mmol, 3.06 equiv), and TEA (2.03 g, 20.06 mmol, 2.59 equiv) were dissolved in CHCN (15 mL). The reaction mixture was stirred at 80 °C for 18 hours and concentrated under reduced pressure to give a residue, which was purified using prep-HPLC (C18 column, eluted with CHCN / HO) to give INT A13-2 (1.58 g, 62% yield) as a solid. LCMS: m / z = 324 [M+1] + .

[0222] Step 3: INT A13-2 (1.36 g, 4.20 mmol, 1.0 equiv), tert-butyl acrylate (2.96 g, 23.09 mmol, 5.50 equiv), and CsCO (4.29 g, 13.17 mmol, 3.13 equiv) were dispersed in DMSO (10 mL). The reaction mixture was stirred at room temperature for 3 hours, poured into water (50 mL), and extracted with EA (50 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and concentrated under reduced pressure to give a residue, which was purified using a silica gel column (eluted with Hex / EA) to give INT A13-3 (1.14 g, 60%). LCMS: m / z = 452 [M+1] + .

[0223] Step 4: TFA (2 mL) was added dropwise to a solution of INT A13-3 (1.14 g, 2.52 mmol, 1.0 equiv) dissolved in DCM (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, quenched with saturated aqueous NaHCO3 (20 mL), and extracted with EA (50 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product of INT A13 (0.99 g) as a yellow oil, which was used in the next step without further purification. LCMS: m / z = 396 [M + 1] + .

[0224] Intermediate A14 (INT A14) [ka] Step 1: 4,5-Dibromo-2-(4-methoxybenzyl)pyridazin-3(2H)-one (2.56 g, 6.84 mmol, 1.0 equiv.), S-(+)-2-amino-1-propanol (1.92 g, 25.56 mmol, 3.74 equiv.), and TEA (4 mL) were dispersed in CHCN (15 mL). The reaction mixture was stirred at 80 °C for 18 hours, cooled to room temperature, and concentrated under reduced pressure to give a residue, which was purified using prep-HPLC (C18 column, eluted with CHCN / HO) to give INT A14-1 (1.46 g, 57% yield) as a solid. LCMS: m / z = 368, 370 [M+1] +.

[0225] Step 2: INT A14-1 (1.36 g, 3.69 mmol, 1.0 equiv), tert-butyl acrylate (3.75 g, 29.26 mmol, 5.50 equiv), and CsCO (2.40 g, 7.37 mmol, 1.99 equiv) were dispersed in DMSO (15 mL). The reaction mixture was stirred at room temperature for 3 hours, poured into water (50 mL), and extracted with EA (50 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give a residue, which was purified using prep-HPLC (C18 column, eluted with CHCN / HO) to give INT A14-2 (0.83 g, 45% yield). LCMS: m / z = 496, 498 [M+1] + .

[0226] Step 3: TFA (2 mL) was added dropwise to a solution of INT A14-2 (0.83 g, 1.67 mmol, 1.0 equiv) dissolved in DCM (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, quenched with saturated aqueous NaHCO (20 mL), and extracted with EA (50 mL x 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give the crude product of INT A14 (0.74 g) as a yellow oil, which was used in the next step without further purification. LCMS: m / z = 440, 442 [M+1] + .

[0227] Intermediate A15 (INT A15) [ka] Step 1: HCl / 1,4-dioxane (100 mL, 1N) was added to a solution of tert-butyl (S)-2-(hydroxymethyl)azetidine-1-carboxylate (9.93 g, 53.03 mmol, 1.0 equiv.) dissolved in 1,4-dioxane (10 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give the crude product of INT A15-1 (8.49 g) as a yellow oil, which was used in the next step without further purification. LCMS: m / z=88 [M+1]+ .

[0228] Step 2: INT A15-1 (8.49 g, 97.45 mmol, 1.0 equiv) and 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (17.82 g, 55.91 mmol, 0.57 equiv) were dissolved in CHCN (120 mL), followed by the addition of TEA (30.31 g, 0.29 mol, 3.07 equiv). The reaction mixture was stirred at 90 °C for 4 h, quenched with water (200 mL), and extracted with EA (200 mL × 3). The organic layers were combined and concentrated under reduced pressure to give a residue, which was purified by Prep-HPLC (C 18 Purification using a column (eluted with H2O / CH3CN) gave INT A15-2 (10.47 g, 29% yield) as a yellow oil. LCMS: m / z = 370 [M+1] + .

[0229] Step 3: INT A15-2 (10.36 g, 28.05 mmol, 1.0 equiv.), tert-butyl acrylate (19.93 g, 155.49 mmol, 5.51 equiv.), and CsCO (27.64 g, 84.83 mmol, 3.02 equiv.) were dispersed in DMSO (100 mL). The reaction mixture was stirred at room temperature for 8 hours and then filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by Prep-HPLC (C 18 Purification using a column (eluted with H2O / CH3CN) gave INT A15-3 (6.51 g, 46% yield) as a yellow oil. LCMS: m / z = 498 [M+1] + .

[0230] Step 4: TFA (14 mL) was added dropwise to a solution of INT A15-3 (6.51 g, 13.09 mmol, 1.0 equiv.) dissolved in DCM (70 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure to give a residue, which was purified using Prep-HPLC (C18 column, eluted with HO / CHCN) to give INT A15 (4.60 g, 80% yield). LCMS: m / z=442 [M+1] + .

[0231] Intermediate A16 (INT A16) [ka] Step 1: 4-Acetyl-5-chloro-2-(4-methoxybenzyl)pyridazin-3(2H)-one (2.16 g, 7.38 mmol, 1.0 equiv), (S)-azetidin-2-ylmethanol (1.0 g, 11.48 mmol, 1.56 equiv), and TEA (2.8 mL) were dispersed in CHCN (20 mL). The reaction mixture was stirred at 80 °C for 2 hours, poured into water (50 mL), and extracted with EA (50 mL × 3). The organic layers were combined and concentrated under reduced pressure to give a residue, which was purified using prep-HPLC (C18 column, eluted with HO / CHCN) to give INT A16-1 (1.59 g, 62% yield). LCMS: m / z = 344 [M+1] + .

[0232] Step 2: INT A16-1 (1.46 g, 4.25 mmol, 1.0 equiv), tert-butyl acrylate (3.50 g, 27.31 mmol, 6.42 equiv), and CsCO (4.01 g, 12.31 mmol, 2.89 equiv) were dispersed in DMSO (15 mL). The reaction mixture was stirred at room temperature for 2 hours, poured into water (50 mL), and extracted with EA (50 mL × 3). The organic layers were combined and concentrated under reduced pressure to give a residue, which was purified using Prep-HPLC (C18 column, eluted with HO / CHCN) to give INT A16-2 (1.06 g, 52% yield). LCMS: m / z = 472 [M+1] + .

[0233] Step 3: TFA (2 mL) was added dropwise to a solution of INT A16-2 (1.06 g, 2.25 mmol, 1.0 equiv) dissolved in DCM (20 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours, quenched with saturated aqueous NaHCO (20 mL), and extracted with EA (50 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give a residue, which was purified using Prep-HPLC (C18 column, eluted with HO / CHCN) to give INT A16 (0.91 g, 97% yield). LCMS: m / z = 416 [M+1] + .

[0234] Intermediate A17 (INT A17) [ka] Step 1: 5-Chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (9.66 g, 30.31 mmol, 1.0 equiv.), (S)-morpholin-3-ylmethanol (4.13 g, 35.26 mmol, 1.16 equiv.), and TEA (9.94 g, 98.23 mmol, 2.79 equiv.) were dispersed in CHCN (150 mL). The reaction mixture was stirred at 80 °C for 2 hours, cooled to room temperature, and concentrated under reduced pressure to give a residue, which was purified using prep-HPLC (C18 column, eluted with HO / CHCN) to give INT A17-1 (1.26 g, 10% yield). LCMS: m / z = 400 [M+1] + .

[0235] Step 2: INT A17-1 (1.12 g, 2.80 mmol, 1.0 equiv), tert-butyl acrylate (2.07 g, 16.15 mmol, 5.76 equiv), and CsCO (3.21 g, 9.85 mmol, 3.51 equiv) were dispersed in DMF (50 mL). The reaction mixture was stirred at room temperature for 4.5 h, poured into water (100 mL), and extracted with EA (100 mL × 3). The organic layers were combined and concentrated under reduced pressure to give a residue, which was purified using Prep-HPLC (C18 column, eluted with HO / CHCN) to give INT A17-2 (200 mg, 13% yield). LCMS: m / z = 528 [M+1] + .

[0236] Step 3: TFA (2 mL) was added dropwise to a solution of INT A17-2 (210 mg, 0.40 mmol, 1.0 equiv.) dissolved in DCM (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours and concentrated under reduced pressure to give crude INT A17 (200 mg), which was used in the next step without further purification. LCMS: m / z=472 [M+1] + .

[0237] Intermediate A18 (INT A18) [ka] Step 1: 5-Chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (1.50 g, 4.71 mmol, 1.29 equiv.), (S)-3,3-dimethylazetidine-2-carboxylic acid (0.47 g, 3.64 mmol, 1.0 equiv.), and TEA (3 mL) were dispersed in CHCN (20 mL). The reaction mixture was stirred at 80 °C for 16 hours, cooled to room temperature, and concentrated under reduced pressure to give a residue, which was purified using prep-HPLC (C18 column, eluted with HO / CHCN) to give INT A18-1 (1.22 g, 81% yield). LCMS: m / z = 412 [M+1] + .

[0238] Step 2: BH3-THF (8 mL) was added to a solution of INT A18-1 (868 mg, 2.11 mmol, 1.0 equiv) dissolved in THF (15 mL) at 0 °C. The reaction mixture was stirred at room temperature for 5 h, quenched with MeOH, and concentrated under reduced pressure to give a residue, which was purified using Prep-HPLC (C18 column, eluted with HO / CH3CN) to give INT A18-2 (498 mg, 59% yield). LCMS: m / z = 398 [M+1] + .

[0239] Step 3: INT A18-2 (444 mg, 1.12 mmol, 1.0 equiv), tert-butyl acrylate (2.05 g, 15.99 mmol, 14.32 equiv), and CsCO (1.20 g, 3.68 mmol, 3.30 equiv) were dispersed in DMSO (10 mL). The reaction mixture was stirred at room temperature for 7 hours, poured into water (20 mL), and extracted with EA (50 mL × 3). The organic layers were combined and concentrated under reduced pressure to give a residue, which was purified using prep-HPLC (C18 column, eluted with HO / CHCN) to give INT A18-3 (541 mg, 92% yield). LCMS: m / z = 526 [M+1] + .

[0240] Step 4: TFA (1 mL) was added dropwise to a solution of INT A18-3 (505 mg, 0.96 mmol, 1.0 equiv.) dissolved in DCM (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours and concentrated under reduced pressure to give crude INT A18 (581 mg), which was used in the next step without further purification. LCMS: m / z=470 [M+1] + .

[0241] Intermediate A19 (INT A19) [ka] Step 1: Dess-Martin periodinane (2.78 g, 6.55 mmol, 1.31 equiv) was added to a solution of (S)-5-(2-(hydroxymethyl)azetidin-1-yl)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (1.85 g, 5.01 mmol, 1.0 equiv) dissolved in DCM (20 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h, and then saturated aqueous NaHCO (20 mL) was added. The resulting mixture was extracted with EA (50 mL × 3), and the combined organic layers were concentrated under reduced pressure to give a residue that was purified using prep-HPLC (C18 column, eluted with HO / CHCN) to give INT A19-1 (1.71 g, 92% yield). LCMS: m / z = 368 [M+1] + .

[0242] Step 2: Under nitrogen atmosphere, MgMeBr (7.5 mL, 22.5 mmol, 6.30 equiv) was added to a solution of INT A19-1 (1.31 g, 3.57 mmol, 1.0 equiv) dissolved in THF (10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 3 h, quenched with saturated aqueous NH4Cl (20 mL), and then extracted with EA (20 mL × 3). The combined organic layers were concentrated under reduced pressure to give a residue, which was purified using Prep-HPLC (C18 column, eluted with HO / CH3CN) to give INT A19-2 (0.43 g, 31% yield). LCMS: m / z = 384 [M+1] + .

[0243] Step 3: INT A19-2 (0.43 g, 1.12 mmol, 1.0 equiv), tert-butyl acrylate (718.8 mg, 5.61 mmol, 5.0 equiv), and CsCO (1.09 g, 3.55 mmol, 2.98 equiv) were dispersed in DMSO (5 mL). The reaction mixture was stirred at room temperature for 3 hours, poured into water (20 mL), and extracted with EA (50 mL × 3). The organic layers were combined and concentrated under reduced pressure to give a residue, which was purified using Prep-HPLC (C18 column, eluted with HO / CHCN) to give INT A19-3 (0.24 g, 41% yield). LCMS: m / z = 512 [M+1] + .

[0244] Step 4: TFA (3 mL) was added dropwise to a solution of INT A19-3 (0.24 g, 0.47 mmol, 1.0 equiv.) dissolved in DCM (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to give the crude product of INT A19 (0.35 g), which was used in the next step without further purification. LCMS: m / z=456 [M+1] + .

[0245] Intermediate A20 (INT A20) [ka] Step 1: 5-Chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (10.0 g, 31.38 mmol, 1.0 equiv.), (S)-pyrrolidin-2-ylmethanol (3.82 g, 37.77 mmol, 1.20 equiv.), and TEA (7.20 g, 71.15 mmol, 2.27 equiv.) were dispersed in CH3CN (60 mL). The reaction mixture was stirred at 80 °C for 3.5 hours, cooled to room temperature, and concentrated under reduced pressure to give a residue. The residue was purified using prep-HPLC (C18 column, eluted with HO / CH3CN) to give INT A20-1 (11.16 g, 92% yield). LCMS: m / z = 384 [M+1] + .

[0246] Step 2: INT A20-1 (11.16 g, 29.11 mmol, 1.0 equiv), tert-butyl acrylate (22.79 g, 177.81 mmol, 6.11 equiv), and CsCO (28.34 g, 86.98 mmol, 2.99 equiv) were dispersed in DMSO (100 mL). The reaction mixture was stirred at room temperature for 3.5 hours, poured into water (100 mL), and extracted with EA (100 mL × 3). The organic layers were combined and concentrated under reduced pressure to give a residue, which was purified using Prep-HPLC (C18 column, eluted with HO / CHCN) to give INT A20-2 (6.20 g, 41% yield). LCMS: m / z = 512 [M+1] + .

[0247] Step 3: TFA (10 mL) was added dropwise to a solution of INT A20-2 (6.20 g, 12.12 mmol, 1.0 equiv.) dissolved in DCM (100 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure to give the crude product of INT A20-3 (6.12 g), which was used in the next step without further purification. LCMS: m / z=456 [M+1] + .

[0248] Step 4: TfOH (2 mL) was added dropwise to a solution of INT A20-3 (6.12 g, crude product) dissolved in TFA (20 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours, quenched with aqueous NaHCO (100 mL), and then extracted with EA (100 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and concentrated under reduced pressure to give a residue, which was purified using Prep-HPLC (C18 column, eluted with CHCN / HO) to give INT A20 (2.66 g, 65% yield for two steps). LCMS: m / z = 336 [M+1] + .

[0249] Intermediate A21 (INT A21) [ka] Step 1: Dess-Martin periodinane (13.76 g, 32.44 mmol, 1.25 equiv) was added to a solution of tert-butyl (S)-(1-hydroxypropan-2-yl)carbamate (4.53 g, 25.85 mmol, 1.0 equiv) dissolved in DCM (90 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h, and then saturated aqueous NaSO (50 mL) was added. The resulting mixture was extracted with DCM (100 mL × 3). The combined organic layers were concentrated under reduced pressure to give a residue, which was purified using prep-HPLC (C18 column, eluted with CHCN / HO) to give INT A21-1 (3.82 g, 85% yield). LCMS: m / z = 174 [M+1] + .

[0250] Step 2: INT A21-1 (883 mg, 25.85 mmol, 1.0 equiv) and tert-butyl piperidine-4-carboxylate (1.13 g, 5.10 mmol, 1.0 equiv) were dissolved in DCM (15 mL), and then STAB (1.69 g, 8.01 mmol, 1.57 equiv) was added. The reaction mixture was stirred at room temperature for 2 hours, and saturated aqueous NaHCO3 (50 mL) was added. The resulting mixture was extracted with EA (100 mL x 3). The organic layers were combined and concentrated under reduced pressure to give a residue, which was purified using a silica gel column (eluted with Hex / EA) to give INT A21-2 (1.50 g, 85% yield). LCMS: m / z = 343 [M+1] + .

[0251] Step 3: TFA (3 mL) was added dropwise to a solution of INT A21-2 (1.13 g, 3.30 mmol, 1.00 equiv) dissolved in DCM (15 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure to give crude INT A21-3 (2.75 g), which was used in the next step without further purification. LCMS: m / z=187 [M+1] + .

[0252] Step 4: 5-Chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (1.41 g, 4.42 mmol, 1.34 equiv.), the crude product of INT A21-3 (2.75 g), and TEA (5 mL) were dissolved in CHCN (20 mL). The reaction mixture was stirred at room temperature for 2.5 hours and concentrated under reduced pressure to give a residue, which was purified using prep-HPLC (C18 column, eluted with CHCN / HO) to give INT A21 (1.01 g, 65% yield). LCMS: m / z = 469 [M+1] + .

[0253] Intermediate B1 (INT B1) [ka] Step 1: 2-(4-(Tert-butoxycarbonyl)piperazin-2-yl)acetic acid (5.25 g, 23.17 mmol, 1.1 equiv) and 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (5.13 g, 21.00 mmol, 1.0 equiv) were dissolved in a mixture of DMF (20 mL) and THF (60 mL), and then TEA (10.53 g, 104.04 mmol, 4.95 equiv) was added at room temperature. The reaction mixture was stirred at 55° C. for 4 hours, quenched with water (20 mL), and extracted with DCM (50 mL×3). The organic layers were combined and concentrated under reduced pressure to give a residue, which was purified using a silica gel column (eluted with Hex / EA) to give INT B1-1 (6.45 g, 71% yield). LCMS: m / z=435[M+1] + .

[0254] Step 2: INT B1-1 (5.13 g, 11.78 mmol, 1.0 equiv.) and Pd / C (2.22 g, 20.86 mmol, 1.77 equiv.) were dispersed in MeOH (40 mL). The reaction mixture was purged, maintained under an inert atmosphere of hydrogen, stirred at room temperature for 4 hours, and then filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified using a silica gel column (eluted with Hex / EA) to give INT B1-2 (5.2 g, 93% yield). LCMS: m / z=405 [M+1]+ .

[0255] Step 3: INT B1-2 (5.2 g, 12.87 mmol, 1.0 equiv) and TEA (5.07 g, 50.10 mmol, 3.89 equiv) were dissolved in DCM (250 mL), and then HATU (7.35 g, 19.33 mmol, 1.5 equiv) was added. The reaction mixture was stirred at room temperature for 2 hours, quenched with water (20 mL), and extracted with DCM (50 mL x 3). The organic layers were combined and concentrated under reduced pressure to give a residue, which was purified using a silica gel column (eluted with Hex / EA) to give INT B1 (3.26 g, 58% yield). LCMS: m / z = 387 [M+1] + .

[0256] Intermediate B2 (INT B2) [ka] Step 1: 4-(tert-Butoxycarbonyl)piperazine-2-carboxylic acid (47.15 g, 0.20 mol, 1.25 eq) and 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (37.15 g, 0.16 mol, 1.0 eq) were dissolved in DMF (300 mL) and THF (1000 mL), and then TEA (109.67 g, 1.08 mol, 6.61 eq) was added at room temperature. The reaction mixture was stirred at 55 °C for 4 hours, poured into water (1000 mL), and extracted with EA (500 mL x 3). The organic layers were combined and concentrated under reduced pressure to give a residue, which was purified using a silica gel column (eluted with Hex / EA) to give INT B2-1 (63.95 g, 92% yield). LCMS: m / z = 421 [M+1] + .

[0257] Step 2: INT B2-1 (28.38 g, 67.52 mmol, 1.0 equiv.) and Fe powder (22.48 g, 402.54 mmol, 5.96 equiv.) were dispersed in HOAc (400 mL). The reaction mixture was stirred at room temperature for 16 hours and then filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified using a silica gel column (eluted with Hex / EA) to give INT B2 (9.63 g, 38% yield). LCMS: m / z=373 [M+1] + .

[0258] The following intermediates were synthesized using the above procedure with the corresponding starting materials.

[0259] [Table 4]

[0260] Intermediate B6 (INT B6) [ka] Step 1: A mixture of 5-chloro-4-methyl-3-nitropyridin-2-amine (1.09 g, 5.81 mmol, 1.0 equiv.) dispersed in concentrated HCl (10 mL) was cooled to 0 °C, and then NaNO (0.83 g, 12.03 mmol, 2.07 equiv.) was added. The reaction mixture was stirred at room temperature for 16 h and then extracted with EA (50 mL × 3). The organic layers were combined and concentrated under reduced pressure to give a residue that was purified using a silica gel column (eluted with Hex / EA) to give INT B6-1 (1.03 g, 85% yield). LCMS: m / z = 207 [M+1] + .

[0261] Step 2: 2-(4-(Tert-butoxycarbonyl)piperazin-2-yl)acetic acid (1.21 g, 5.25 mmol, 1.1 equiv) and INT B6-1 (1.03 g, 4.98 mmol, 1.0 equiv) were dissolved in DMF (20 mL), and then EtN (1.56 g, 15.42 mmol, 3.10 equiv) was added at room temperature. The reaction mixture was stirred at 100 °C for 16 h, poured into water (50 mL), and then extracted with EA (50 mL × 3). The organic layers were combined and concentrated under reduced pressure to give a residue that was purified using a silica gel column (eluted with Hex / EA) to give INT B6-2 (1.17 g, 58% yield). LCMS: m / z = 401 [M+1] + .

[0262] Step 3: INT B6-2 (1.17 g, 2.92 mmol, 1.0 equiv) and iron powder (0.82 g, 14.68 mmol, 5.03 equiv) were dispersed in HOAc (15 mL). The reaction mixture was stirred at room temperature for 4 hours and then filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified using a silica gel column (eluted with Hex / EA) to give INT B6-3 (0.76 g, 73% yield). LCMS: m / z=353 [M+1] + .

[0263] Step 4: NaH (0.10 g, 4.17 mmol, 2.23 equiv) (60% in mineral oil) was added to a solution of INT B6-3 dissolved in THF (5 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min, and then CHCl (0.71 g, 5.00 mmol, 2.67 equiv) was added. The reaction mixture was stirred at room temperature for 2 h, quenched with water (20 mL), and then extracted with EA (50 mL × 3). The organic layers were combined and concentrated under reduced pressure to give a residue that was purified using a silica gel column (eluted with Hex / EA) to give INT B6 (0.53 g, 77% yield). LCMS: m / z = 367 [M+1] + .

[0264] Intermediate B7 (INT B7) [ka] Step 1: 2,3-Difluoro-5-(trifluoromethyl)pyridine (1.06 g, 5.79 mmol, 1.0 equiv.), tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (1.27 g, 5.87 mmol, 1.0 equiv.), and TEA (3 mL) were dissolved in CHCN (8 mL). The reaction mixture was stirred at 80 °C overnight and then concentrated under reduced pressure to give a residue, which was purified using a silica gel column (eluted with Hex / EA) to give INT B7-1 (1.38 g, 68% yield). LCMS: m / z = 380 [M+1] + .

[0265] Step 2: A mixture of INT B7-1 (230 mg, 0.61 mmol, 1.0 equiv), t-BuOK (255 mg, 2.27 mmol, 3.72 equiv), and t-BuOH (5 mL) was stirred at 80° C. for 2 hours and then concentrated under reduced pressure to give a residue. The residue was purified using a silica gel column (eluted with Hex / EA) to give INT B7 (180 mg, 83% yield). LCMS: m / z=360 [M+1] + .

[0266] The following intermediates were synthesized using the above procedure with the corresponding starting materials.

[0267] [Table 5]

[0268] Intermediate B11 (INT B11) [ka] Step 1: 5-Chloro-2,3-difluoropyridine (1.31 g, 8.76 mmol, 1.75 equiv), tert-butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate (1.10 g, 4.99 mmol, 1.0 equiv), and DIPEA (2 mL) were dissolved in DMSO (10 mL). The reaction mixture was stirred at 130 °C overnight, quenched with water (20 mL), and then extracted with EA (50 mL × 3). The organic layers were combined and concentrated under reduced pressure to give a residue that was purified using a silica gel column (eluted with Hex / EA) to give INT B11-1 (0.96 g, 53% yield). LCMS: m / z = 360 [M+1] + .

[0269] Step 2: INT B11-1 (530 mg, 1.47 mmol, 1.0 equiv) and t-BuOK (570 mg, 5.08 mmol, 3.45 equiv) were dispersed in t-BuOH (10 mL). The reaction mixture was stirred at 120° C. overnight and then concentrated under reduced pressure to give a residue which was purified using a silica gel column (eluted with Hex / EA) to give INT B11 (300 mg, 59% yield). LCMS: m / z=340 [M+1] + .

[0270] The following intermediates were synthesized using the above procedure with the corresponding starting materials.

[0271] [Table 6]

[0272] Intermediate B13 (INT B13) [ka] Step 1: INT B11 (250 mg, 0.74 mmol, 1.0 equiv), Zn(CN) (230 mg, 1.96 mmol, 2.66 equiv), and Pd(PPh) (180 mg, 0.16 mmol, 0.21 equiv) were dispersed in DMF (10 mL). The reaction mixture was purged, maintained under an inert atmosphere of nitrogen, stirred at 130 °C for 4 h, cooled to room temperature, diluted with brine, and extracted with EA (50 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give a residue that was purified using Prep-HPLC (C18 column, eluted with HO / CHCN) to give INT B13 (160 mg, 65% yield). LCMS: m / z = 331 [M+1] + .

[0273] Intermediate B14 (INT B14) [ka] Step 1: INT B12 (340 mg, 0.88 mmol, 1.0 equiv.), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (190 mg, 1.51 mmol, 1.71 equiv.), Pd(dppf)Cl (200 mg, 0.27 mmol, 0.31 equiv.), and NaCO (240 mg, 1.74 mmol, 1.96 equiv.) were dispersed in a mixture of 1,4-dioxane and HO (v / v = 20 mL:2 mL). The reaction mixture was purged, maintained under an inert atmosphere of nitrogen, stirred at 120 °C for 1 h, cooled to room temperature, diluted with brine, and extracted with EA (50 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified using a silica gel column (eluted with Hex / EA) to give INT B14 (240 mg, 84% yield) as a white solid. LCMS: m / z=320 [M+1] + .

[0274] Intermediate B15 (INT B15) [ka] Step 1: INT B12 (1.30 g, 3.38 mmol, 1.0 equiv.), tributyl(1-ethoxyvinyl)stannane (1.70 g, 4.70 mmol, 1.39 equiv.), Pd(PPh3)2Cl2 (0.39 g, 0.55 mmol, 0.16 equiv.), and CsF (1.09 g, 7.18 mmol, 2.12 equiv.) were dispersed in 1,4-dioxane (20 mL). The reaction mixture was purged, maintained under an inert atmosphere of nitrogen, stirred at 90 °C for 2 h, and then filtered. The filtrate was concentrated under reduced pressure to give crude INT B15-1 (1.27 g), which was used in the next step without further purification. LCMS: m / z = 376 [M+1] + .

[0275] Step 2: The crude product of INT B15-1 (1.27 g) was dissolved in THF (20 mL), and then HCl (12 mL, 6N, aq.) was added at room temperature. The reaction mixture was stirred for 3 hours, quenched with aqueous NaHCO (100 mL), and then extracted with EA (50 mL x 3). The organic layers were combined, dried over anhydrous NaSO, and then filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified using a silica gel column (eluted with Hex / EA) to give INT B15 (0.37 g, 31% yield). LCMS: m / z = 348 [M+1] + .

[0276] Intermediate B16 (INT B16) [ka] Step 1: 4-Bromo-2,3-difluoropyridine (4.81 g, 24.80 mmol, 1.75 equiv), tert-butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate (6.48 g, 28.14 mmol, 1.13 equiv), and KCO (7.13 g, 51.59 mmol, 2.08 equiv) were dispersed in NMP (60 mL). The reaction mixture was stirred at 120 °C overnight, poured into water (100 mL), and then extracted with EA (100 mL × 3). The organic layers were combined and concentrated under reduced pressure to give a residue that was purified using a silica gel column (eluted with Hex / EA) to give INT B16-1 (1.60 g, 15% yield). LCMS: m / z = 404, 406 [M+1] + .

[0277] Step 2: A mixture of INT B16-1 (1.53 g, 3.78 mmol, 1.0 equiv.), t-BuOK (1.34 g, 11.94 mmol, 3.16 equiv.), and t-BuOH (30 mL) was stirred at 120 °C for 3 hours and then concentrated under reduced pressure to give a residue. The residue was purified using Prep-HPLC (C18 column, eluted with HO / CHCN) to give INT B16-2 (0.91 g, 62% yield). LCMS: m / z = 384, 386 [M+1] + .

[0278] Step 3: INT B16-2 (2.01 g, 5.23 mmol, 1.0 equiv), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (2.04 g, 8.13 mmol, 1.55 equiv), Pd(dppf)Cl (2.06 g, 2.82 mmol, 0.54 equiv), and NaCO (1.80 g, 13.02 mmol, 2.49 equiv) were dispersed in a mixture of 1,4-dioxane and HO (v / v = 40 mL:4 mL). The reaction mixture was purged, maintained under an inert atmosphere of nitrogen, stirred at 90 °C for 3 h, cooled to room temperature, diluted with brine, and extracted with EA (100 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give a residue, which was purified using a silica gel column (eluted with Hex / EA) to give INT B16-3 (1.07 g, 64% yield) as a white solid. LCMS: m / z=320 [M+1] + .

[0279] Step 4: INT B16-3 (0.87 g, 2.72 mmol, 1.0 equiv) and NCS (0.55 g, 4.12 mmol, 1.51 equiv) were dispersed in CHCN (20 mL). The reaction mixture was purged, maintained under an inert atmosphere of nitrogen, stirred at 80 °C for 3 h, cooled to room temperature, diluted with brine, and extracted with EA (100 mL × 3). The organic layers were combined, dried over anhydrous NaSO, filtered, and then concentrated under reduced pressure to give a residue that was purified using Prep-HPLC (C18 column, eluted with HO / CHCN) to give INT B16 (0.50 g, 51% yield). LCMS: m / z = 354 [M+1] + .

[0280] Intermediate B17 (INT B17) [ka] Step 1: 2,3-Difluoro-5-(trifluoromethyl)pyridine (11.91 g, 65.05 mmol, 1.89 equiv.), tert-butyl 3-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (8.90 g, 34.45 mmol, 1.0 equiv.), and DIPEA (15 mL) were dissolved in DMSO (70 mL). The reaction mixture was stirred at 130 °C overnight, poured into water (100 mL), and then extracted with EA (100 mL × 3). The organic layers were combined and concentrated under reduced pressure to give a residue, which was purified using prep-HPLC (C18 column, eluted with HO / CHCN) to give INT B17-1 (13.59 g, 93% yield). LCMS: m / z = 422 [M+1] + .

[0281] Step 2: INT B17-1 (13.59 g, 32.25 mmol, 1.0 equiv) and LiOH (2.82 g, 117.71 mmol, 3.65 equiv) were dispersed in a mixed solvent of THF (100 mL) and water (30 mL). The reaction mixture was stirred at room temperature for 3 hours, quenched with aqueous HCl (1N), and extracted with EA (100 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give the crude product of INT B17-2 (16.78 g), which was used in the next step without further purification. LCMS: m / z = 408 [M+1] + .

[0282] Step 3: The crude product of INT B17-2 (16.37 g), N,O-dimethylhydroxylamine hydrochloride (8.90 g, 91.24 mmol, 2.83 equiv.), and DIPEA (20 mL) were dissolved in CHCN (200 mL), and then HATU (17.66 g, 46.45 mmol, 1.44 equiv.) was added. The reaction mixture was stirred at room temperature for 4 hours, poured into water (200 mL), and extracted with EA (200 mL × 3). The organic layers were combined and concentrated under reduced pressure to give a residue, which was purified using prep-HPLC (C18 column, eluted with HO / CHCN) to give INT B17-3 (13.05 g, 89% yield). LCMS: m / z = 451 [M+1] + .

[0283] Step 4: Under a nitrogen atmosphere, MgMeBr (15 mL, 45 mmol, 1.56 equiv) was added to a solution of INT B17-3 (12.98 g, 28.82 mmol, 1.0 equiv) dissolved in THF (300 mL) at 0 °C. The reaction solution was stirred at room temperature for 2 h, quenched with saturated aqueous NH4Cl (200 mL), and then extracted with EA (200 mL x 3). The organic layers were combined and then concentrated under reduced pressure to give a residue that was purified using Prep-HPLC (C18 column, eluted with HO / CH3CN) to give INT B17-4 (9.99, 85% yield). LCMS: m / z = 406 [M+1] + .

[0284] Step 5: INT B17-4 (9.63 g, 23.75 mmol, 1.0 equiv) was dissolved in THF (150 mL), and NaBH (10.94 g, 28.77 mmol, 1.21 equiv) was added at room temperature. The reaction mixture was stirred at room temperature for 5 hours, poured into water (200 mL), and extracted with EA (200 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give a residue that was purified using prep-HPLC (C18 column, eluted with HO / CHCN) to give INT B17-5 (9.20 g, 95% yield). LCMS: m / z = 408 [M+1] + .

[0285] Step 6: INT B17-5 (4.15 g, 10.19 mmol, 1.0 equiv) and t-BuOK (3.12 g, 27.80 mmol, 2.73 equiv) were dispersed in t-BuOH (40 mL). The reaction mixture was stirred at 120 °C for 3 h and then concentrated under reduced pressure to give a residue which was purified using Prep-HPLC (C18 column, eluted with HO / CHCN) to give INT B17 (2.40 g, 60% yield). LCMS: m / z = 388 [M+1] + .

[0286] Intermediate B18 (INT B18) [ka] Step 1: 2,3-Difluoro-5-(trifluoromethyl)pyridine (6.92 g, 37.80 mmol, 1.15 equiv), tert-butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate (7.54 g, 32.74 mmol, 1.0 equiv), and TEA (14.84 g, 146.66 mmol, 4.48 equiv) were dissolved in DMF (100 mL). The reaction mixture was stirred at 85 °C overnight and then concentrated under reduced pressure to give a residue, which was purified using prep-HPLC (C18 column, eluted with HO / CHCN) to give INT B18-1 (11.33 g, 87% yield). LCMS: m / z = 394 [M+1] + .

[0287] Step 2: A mixture of INT B18-1 (4.03 g, 10.24 mmol, 1.0 equiv), triphenylphosphine (9.32 g, 35.54 mmol, 3.47 equiv), and THF (80 mL) was purged, maintained under an inert atmosphere of nitrogen, and cooled to −10° C., followed by the dropwise addition of diisopropyl azodicarboxylate (6.15 g, 30.41 mmol, 2.97 equiv). The resulting mixture was stirred at −10° C. for 30 minutes, followed by the dropwise addition of ethanethioic acid (1.75 g, 22.99 mmol, 2.25 equiv) at −10° C. The reaction mixture was stirred at −10° C. for 2 hours, quenched with water (20 mL), and then extracted with EA (100 mL×3). The organic layers were combined and concentrated under reduced pressure to give a residue, which was purified using a silica gel column (eluted with Hex / EA) to give INT B18-2 (4.45 g, 96% yield). LCMS: m / z=452 [M+1] + .

[0288] Step 3: INT B18-2 (7.28 g, 16.12 mmol, 1.0 equiv) and NaOH (1.95 g, 48.75 mmol, 3.02 equiv) were dispersed in a mixed solvent of MeOH (70 mL) and water (10 mL). The reaction mixture was stirred at room temperature for 30 min, quenched with aqueous HCl (1 N), and extracted with EA (100 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give the crude product of INT B18-3 (6.60 g), which was used in the next step without further purification. LCMS: m / z = 410 [M+1] + .

[0289] Step 4: The crude product of INT B18-3 (6.60 g) and LiOH (1.22 g, 50.94 mmol, 3.06 equiv.) were dispersed in a mixture of DMF (10 mL) and THF (30 mL). The reaction mixture was purged, maintained under an inert atmosphere of nitrogen, and stirred at 80 °C for 3 h. It was then concentrated under reduced pressure to give a residue that was purified using prep-HPLC (C18 column, eluted with HO / CHCN) to give INT B18 (4.65 g, 72% yield). LCMS: m / z = 390 [M+1] + .

[0290] The following intermediates were synthesized using the above procedure with the corresponding starting materials.

[0291] [Table 7]

[0292] Intermediate B21 (INT B21) [ka] Step 1: m-CPBA (150 mg, 0.87 mmol, 1.14 equiv) was added to a mixture of INT B18 (296 mg, 0.76 mmol, 1.0 equiv) and DCM (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h, quenched with saturated aqueous NaSO (20 mL), and extracted with EA (50 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give a residue that was purified using a silica gel column (eluted with Hex / EA) to give INT B21 (250 mg, 81% yield). LCMS: m / z = 406 [M+1] + .

[0293] Intermediate B22 (INT B22) [ka] Step 1: m-CPBA (559 mg, 3.24 mmol, 4.21 equiv) was added to a mixture of INT B18 (300 mg, 0.77 mmol, 1.0 equiv) and DCM (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h, quenched with saturated aqueous NaSO (20 mL), and extracted with EA (50 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give a residue that was purified using a silica gel column (eluted with Hex / EA) to give INT B22 (305 mg, 94% yield). LCMS: m / z = 422 [M+1] + .

[0294] Intermediate B23 (INT B23) [ka] Step 1: Ethyl 5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (10.01 g, 38.77 mmol, 1.0 equiv) and t-BuOK (4.80 g, 42.78 mmol, 1.10 equiv) were dispersed in DMF (200 mL) at 0 °C. The resulting mixture was stirred for 1 h, and then tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (9.58 g, 42.91 mmol, 1.11 equiv) was added. The reaction mixture was stirred at room temperature for 2 h, quenched with water (100 mL), and extracted with EA (100 mL × 3). The organic layers were combined and concentrated under reduced pressure to give a residue, which was purified using Prep-HPLC (C18 column, eluted with H2O / CH3CN) to give INT B23-1 (14.17 g). LCMS: m / z = 402 [M+1] + .

[0295] Step 2: TFA (10 mL) was added dropwise to a solution of INT B23-1 (13.16 g, 32.79 mmol, 1.0 equiv) dissolved in DCM (80 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, quenched with saturated aqueous NaHCO3 (50 mL), and extracted with EA (100 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, and then concentrated under reduced pressure to give the crude product of INT B23-2 (9.57 g), which was used in the next step without further purification. LCMS: m / z = 302 [M + 1] + .

[0296] Step 3: Under a nitrogen atmosphere, INT B23-2 (9.60 g, 31.87 mmol, 1.0 equiv) and K2CO3 (22.23 g, 160.85 mmol, 5.05 equiv) were dispersed in MeOH (150 mL). The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure to give a residue. A mixture of the residue and water (100 mL) was stirred and then filtered. The filter cake was washed with water (100 mL x 3) and dried to give the crude product of INT B23-3 (8.24 g), which was used in the next step without further purification. LCMS: m / z = 256 [M + 1] + .

[0297] Step 4: INT B23-3 (2.08 g, 8.15 mmol, 1.0 equiv) was dispersed in MTBE (50 mL), and then LiAlH (640 mg, 16.86 mmol, 2.07 equiv) was added at room temperature. The reaction mixture was stirred at 55 °C for 2 h, quenched with water (50 mL), and extracted with EA (100 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give a residue that was purified using Prep-HPLC (C18 column, eluted with HO / CHCN) to give INT B23 (950 mg). LCMS: m / z = 242 [M + 1] + .

[0298] Intermediate B24 (INT B24) [ka] Step 1: 4-(Tert-butoxycarbonyl)piperazine-2-carboxylic acid (21.59 g, 93.76 mmol, 1.0 equiv.), N,O-dimethylhydroxylamine hydrochloride (21.55 g, 220.93 mmol, 2.36 equiv.), DIPEA (42.43 g, 328.30 mmol, 3.50 equiv.), and HATU (43.87 g, 115.38 mmol, 1.23 equiv.) were dispersed in CH3CN (200 mL). The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure to give a residue which was purified using prep-HPLC (C18 column, eluted with HO / CH3CN) to give INT B24-1 (12.68 g, 49% yield). LCMS: m / z = 274 [M+1] + .

[0299] Step 2: 3-Bromo-2-fluoro-5-(trifluoromethyl)pyridine (19.09 g, 78.24 mmol, 1.25 equiv), INT B24-1 (17.10 g, 62.56 mmol, 1.0 equiv), and DIPEA (9.22 g, 71.34 mmol, 1.14 equiv) were dispersed in DMF (100 mL) at room temperature. The reaction mixture was stirred at 80 °C for 16 hours, poured into water (100 mL), and extracted with DCM (100 mL × 3). The organic layers were combined and concentrated under reduced pressure to give a residue that was purified using a silica gel column (eluted with Hex / EA) to give INT B24-2 (15.59 g, 50% yield). LCMS: m / z = 497, 499 [M+1] + .

[0300] Step 3: Under a nitrogen atmosphere, MeMgBr (14 mL, 42 mmol, 1.54 equiv) was added to a solution of INT B24-2 (13.59 g, 27.33 mmol, 1.0 equiv) dissolved in THF (140 mL) at −20° C. The reaction mixture was stirred at −20° C. for 3 h, quenched with saturated aqueous NH4Cl (200 mL), and extracted with EA (200 mL × 3). The organic layers were combined and then concentrated under reduced pressure to give a residue that was purified using Prep-HPLC (C18 column, eluted with HO / CH3CN) to give INT B24-3 (10.9 g, 88% yield). LCMS: m / z = 452, 454 [M+1] + .

[0301] Step 4: Under a nitrogen atmosphere, n-BuLi (14 mL, 42.0 mmol, 1.74 equiv) was added dropwise to a solution of INT B24-3 (10.9 g, 24.10 mmol, 1.0 equiv) dissolved in THF (100 mL) at −78° C. The reaction mixture was stirred at −78° C. for 1 h, quenched with saturated aqueous NH4Cl (200 mL), and then extracted with EA (200 mL × 3). The organic layers were combined and then concentrated under reduced pressure to give a residue that was purified using Prep-HPLC (C18 column, eluted with HO / CH3CN) to give INT B24 (2.76 g, 30% yield). LCMS: m / z = 374 [M+1] + .

[0302] Intermediate B25 (INT B25) [ka] Step 1: A mixture of INT B24 (6.19 g, 16.58 mmol, 1.0 equiv), EtN (3.69 g, 36.47 mmol, 2.20 equiv), DMAP (122 mg, 0.99 mmol, 0.06 equiv), and DCM (100 mL) was cooled to 0 °C, and then MsCl (2.94 g, 25.67 mmol, 1.55 equiv) was added dropwise. The reaction mixture was stirred at 0 °C for 1 h, poured into saturated aqueous NaHCO (100 mL), and then extracted with DCM (100 mL × 3). The organic layers were combined and then concentrated under reduced pressure to give a residue that was purified using a silica gel column (eluted with Hex / EA) to give INT B25-1 (5.40 g, 91% yield). LCMS: m / z = 356 [M+1] + .

[0303] Step 2: A mixture of INT B25-1 (5.05 g, 14.21 mmol, 1.0 equiv) and HCl / 1,4-dioxane (100 mL, 1N) was stirred at room temperature for 3 hours and then concentrated under reduced pressure to give the crude product of the hydrochloride salt of INT B25 (6.72 g), which was used in the next step without further purification. LCMS: m / z=256 [M+1] + .

[0304] Intermediate B26 and Intermediate B27 (INT B26 and INT B27) [ka] Step 1: 2-Chloro-3-nitro-5-(trifluoromethyl)pyridine (10.1 g, 44.58 mmol, 1.0 equiv.), tert-butyl (2-aminoethyl)carbamate (7.15 g, 44.58 mmol, 1.0 equiv.), and TEA (9.02 g, 89.17 mmol, 2.0 equiv.) were dispersed in CHCN (100 mL) at room temperature. The reaction mixture was stirred at 110° C. for 4 hours, cooled to room temperature, and concentrated under reduced pressure to give a residue. A mixture of the residue and EA (5 mL) was stirred and then filtered. The filter cake was washed with EA (1 mL) and dried under reduced pressure to give INT B26-1 (11.20 g, 71% yield). LCMS: m / z=351 [M+1] + .

[0305] Step 2: INT B26-1 (11.73 g, 33.49 mmol, 1.0 equiv.), Pd / C (2.10 g, 0.18 w / w) were dispersed in MeOH (40 mL). The reaction mixture was purged, maintained under an inert atmosphere of hydrogen, stirred at room temperature for 2 hours, and then filtered. The filtrate was concentrated under reduced pressure to give the crude product of INT B26-2 (5.42 g), which was used in the next step without further purification. LCMS: m / z=321 [M+1] +

[0306] Step 3: The crude product of INT B26-2 (5.41 g), ethyl 2-chloro-2-oxoacetate (2.98 g, 21.83 mmol, 1.29 equiv.), and EtN (3.94 g, 38.94 mmol, 2.31 equiv.) were dispersed in DCM (70 mL). The reaction mixture was stirred at room temperature for 1 hour, poured into water (70 mL), and extracted with EA (100 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give a residue. A mixture of the residue and toluene (70 mL) was stirred at 110 °C for 16 hours, cooled to room temperature, and then concentrated under reduced pressure to give the crude product, which was purified using prep-HPLC (C18 column, eluted with HO / CHCN) to give INT B26-3 (0.56 g, 8% yield). LCMS: m / z=403[M+1] + .

[0307] Step 4: TFA (3 mL) was added dropwise to a solution of INT B26-3 (0.55 g, 1.37 mmol, 1.0 equiv) dissolved in DCM (12 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to give the crude product of INT B26-4 (0.40 g), which was used in the next step without further purification. LCMS: m / z=303 [M+1] + .

[0308] Step 5: The crude product of INT B26-4 (0.40 g) (0.40 g, 1.32 mmol, 1.0 equiv) and K2CO3 (0.96 g, 6.95 mmol, 5.25 equiv) were dispersed in MeOH (30 mL). The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure to give a residue. A mixture of the residue and water (20 mL) was stirred and then filtered. The filter cake was washed with water (10 mL) and dried under reduced pressure to give INT B26-5 (0.22 g, 64% yield). LCMS: m / z = 257 [M+1] + .

[0309] Step 6: INT B26-5 (0.42 g, crude product) was dispersed in MTBE (20 mL), and LiAlH (0.11 g, 2.90 mmol, 1.77 equiv) was added at room temperature. The reaction mixture was stirred at 55 °C for 2 h, quenched with water (50 mL), and extracted with EA (100 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give a residue, which was purified using Prep-HPLC (C18 column, eluted with HO / CHCN) to give INT B26 (20 mg), LCMS: m / z = 243 [M+1]. + and INT B27 (200 mg), LCMS: m / z = 245 [M+1] + obtained.

[0310] Intermediate B28 (INT B28) [ka] Step 1: 2-(4-(Tert-butoxycarbonyl)piperazin-2-yl)acetic acid (6.39 g, 28.37 mmol, 1.0 equiv.), 3-bromo-2-fluoro-5-(trifluoromethyl)pyridine (11.19 g, 45.86 mmol, 1.62 equiv.), and TEA (17 mL) were dispersed in CHCN (120 mL) at room temperature. The reaction mixture was stirred at 90° C. for 16 hours, cooled to room temperature, and concentrated under reduced pressure to give a residue, which was purified using Prep-HPLC (C18 column, eluted with HO / CHCN) to give INT B28-1 (12.54 g, 94% yield). LCMS: m / z=468, 470 [M+1] + .

[0311] Step 2: INT B28-1 (12.54 g, 26.78 mmol, 1.0 equiv.), N,O-dimethylhydroxylamine hydrochloride (3.86 g, 39.57 mmol, 1.48 equiv.), TEA (12.72 g, 125.70 mmol, 4.69 equiv.), and HATU (13.79 g, 32.27 mmol, 1.21 equiv.) were dispersed in DCM (100 mL). The reaction mixture was stirred at room temperature for 3 hours, washed with water (100 mL), and then concentrated under reduced pressure to give a residue, which was purified using prep-HPLC (C18 column, eluted with HO / CHCN) to give INT B28-2 (7.99 g, 58% yield). LCMS: m / z = 511, 513 [M+1] + .

[0312] Step 3: Under a nitrogen atmosphere, n-BuLi (8 mL, 24.0 mmol, 3.31 equiv) was added dropwise to a solution of INT B28-2 (3.7 g, 7.24 mmol, 1.0 equiv) dissolved in THF (40 mL) at −78° C. The reaction mixture was stirred at −78° C. for 2.5 h, quenched with saturated aqueous NH4Cl (100 mL), and then extracted with EA (100 mL × 3). The organic layers were combined and concentrated under reduced pressure to give a residue that was purified using Prep-HPLC (C18 column, eluted with HO / CH3CN) to give INT B28 (2.20 g, 81% yield). LCMS: m / z = 372 [M+1] + .

[0313] Intermediate B29 (INT B29) [ka] Step 1: Under a nitrogen atmosphere, MgMeBr (1 mL, 3.0 mmol, 1.40 equiv) was added to a solution of INT B28-2 (1.10 g, 2.15 mmol, 1.0 equiv) dissolved in THF (20 mL) at −20° C. The reaction mixture was stirred at −20° C. for 4.5 h, quenched with saturated aqueous NH4Cl (50 mL), and then extracted with EA (50 mL × 3). The organic layers were combined and concentrated under reduced pressure to give a residue that was purified using Prep-HPLC (C18 column, eluted with HO / CH3CN) to give INT B29-1 (0.68 g, 67% yield). LCMS: m / z = 466, 468 [M+1] + .

[0314] Step 2: Under a nitrogen atmosphere, n-BuLi (0.6 mL, 1.8 mmol, 1.23 equiv) was added dropwise to a solution of INT B29-1 (0.68 g, 1.46 mmol, 1.0 equiv) dissolved in THF (10 mL) at −78° C. The reaction mixture was stirred at −78° C. for 1 h, quenched with saturated aqueous NH4Cl (10 mL), and then extracted with EA (20 mL × 3). The organic layers were combined and concentrated under reduced pressure to give a residue that was purified using Prep-HPLC (C18 column, eluted with HO / CH3CN) to give INT B29 (0.19 g, 33% yield). LCMS: m / z = 388 [M+1] + .

[0315] Intermediate B30 (INT B30) [ka] Step 1: INT B28 (332.6 mg, 0.90 mmol, 1.0 equiv.) and DAST (1.44 g, 8.93 mmol, 9.97 equiv.) were dispersed in CHCl3 (3 mL) at room temperature. The reaction mixture was stirred at 70 °C for 5 hours, cooled to room temperature, and concentrated under reduced pressure to give a residue, which was purified using a silica gel column (eluted with Hex / EA) to give INT B30 (331 mg, 93% yield). LCMS: m / z = 394 [M+1] + .

[0316] Intermediate B31 (INT B31) [ka] Step 1: INT B28 (1.01 g, 2.72 mmol, 1.0 equiv) and NaBH4 (0.57 g, 15.07 mmol, 5.54 equiv) were dispersed in THF (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h, poured into water (10 mL), and extracted with EA (20 mL x 3). The organic layers were combined and concentrated under reduced pressure to give the crude product of INT B31 (1.02 g), which was used in the next step without further purification. LCMS: m / z = 374 [M+1] + .

[0317] Intermediate B32 (INT B32) [ka] Step 1: A mixture of 5-bromo-4-methyl-3-nitropyridin-2-amine (2.03 g, 8.75 mmol, 1.0 equiv.) dispersed in concentrated HCl (50 mL) was cooled to 0 °C, and then NaNO (1.43 g, 20.73 mmol, 2.37 equiv.) was added. The reaction mixture was stirred at room temperature for 16 h and then extracted with EA (100 mL × 3). The organic layers were combined and concentrated under reduced pressure to give a residue that was purified using a silica gel column (eluted with Hex / EA) to give INT B32-1 (1.32 g, 60% yield). LCMS: m / z = 251, 253 [M+1] + .

[0318] Step 2: 2-(4-(Tert-butoxycarbonyl)piperazin-2-yl)acetic acid (2.67 g, 11.60 mmol, 1.39 equiv), INT B32-1 (2.10 g, 8.35 mmol, 1.0 equiv), and EtN (2.69 g, 26.58 mmol, 3.18 equiv) were dispersed in DMF (50 mL) at room temperature. The reaction mixture was stirred at 100° C. for 16 hours, poured into water (50 mL), and then extracted with EA (50 mL×3). The organic layers were combined and concentrated under reduced pressure to give a residue that was purified using a silica gel column (eluted with Hex / EA) to give INT B32-2 (1.07 g, 28% yield). LCMS: m / z=445, 447 [M+1] + .

[0319] Step 3: INT B32-2 (1.02 g, 2.29 mmol, 1.0 equiv.) and Fe powder (0.49 g, 8.77 mmol, 3.83 equiv.) were dispersed in HOAc (20 mL). The reaction mixture was stirred at room temperature for 16 hours and then filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified using a silica gel column (eluted with Hex / EA) to give INT B32-3 (0.21 g, 23% yield). LCMS: m / z = 397, 399 [M+1] + .

[0320] Step 4: INT B32-3 (1.14 g, 2.87 mmol, 1.0 equiv), KCO (0.70 g, 5.06 mmol, 1.77 equiv), and CHI (0.91 g, 6.41 mmol, 2.23 equiv) were dispersed in DMF (30 mL). The reaction mixture was stirred at 60 °C for 1 h, poured into water (50 mL), and extracted with EA (50 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give a residue that was purified using silica gel column chromatography (eluted with Hex / EA) to give INT B32 (0.94 g, 79% yield). LCMS: m / z = 411, 413 [M+1] + .

[0321] Intermediate B33 (INT B33) [ka] Step 1: A mixture of 5-bromo-6-chloro-3-nitropyridin-2-amine (2.02 g, 8.00 mmol, 1.0 equiv) dispersed in concentrated HCl (50 mL) was cooled to 0 °C, and then NaNO (1.10 g, 15.94 mmol, 1.99 equiv) was added. The reaction mixture was stirred at room temperature for 16 h and then extracted with EA (100 mL × 3). The organic layers were combined and concentrated under reduced pressure to give a residue that was purified using a silica gel column (eluted with Hex / EA) to give INT B33-1 (1.59 g, 73% yield). LCMS: m / z = 271, 273 [M+1] + .

[0322] Step 2: 2-(4-(Tert-butoxycarbonyl)piperazin-2-yl)acetic acid (2.07 g, 8.99 mmol, 1.06 equiv), INT B33-1 (2.31 g, 8.50 mmol, 1.0 equiv), and TEA (6 mL) were dispersed in DMF (20 mL) at room temperature. The reaction mixture was stirred at 60° C. for 1 hour, poured into water (50 mL), and then extracted with EA (50 mL×3). The organic layers were combined and concentrated under reduced pressure to give a residue that was purified using Prep-HPLC (C18 column, eluted with HO / CHCN) to give INT B33-2 (3.75 g, 94% yield). LCMS: m / z=465, 467 [M+1] + .

[0323] Step 3: INT B33-2 (3.75 g, 8.05 mmol, 1.0 equiv) and iron powder (2.77 g, 49.60 mmol, 6.16 equiv) were dispersed in HOAc (50 mL). The reaction mixture was stirred at room temperature for 16 hours and then filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified using a silica gel column (eluted with Hex / EA) to give INT B33-3 (1.31 g, 38% yield). LCMS: m / z = 417, 419 [M+1] + .

[0324] Step 4: A mixture of INT B33-3 (1.2 g, 2.87 mmol, 1.0 equiv) and THF (20 mL) was purged, maintained under an inert atmosphere of nitrogen, and cooled to 0-10 °C, then NaH (0.29 g, 7.25 mmol, 2.52 equiv) (60% in mineral oil) was slowly added. The resulting mixture was stirred for 0.5 h, then CHI (1.24 g, 8.74 mmol, 3.04 equiv) was added. The reaction mixture was warmed to room temperature, stirred for 3 h, quenched with water (20 mL), and then extracted with EA (50 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and concentrated under reduced pressure to give a residue that was purified using silica gel column chromatography (eluted with Hex / EA) to give INT B33 (0.89 g, 71% yield). LCMS: m / z=431, 433 [M+1] + .

[0325] Intermediate B34 (INT B34) [ka] Step 1: 2-(4-(Tert-butoxycarbonyl)piperazin-2-yl)acetic acid (3.09 g, 13.42 mmol, 0.98 equiv.), 2,6-difluoro-3-nitropyridine (2.17 g, 13.56 mmol, 1.0 equiv.), and TEA (4 mL) were dispersed in DMF (20 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, poured into water (50 mL), and then extracted with EA (50 mL × 3). The organic layers were combined and concentrated under reduced pressure to give a residue, which was purified using Prep-HPLC (C18 column, eluted with HO / CHCN) to give INT B34-1 (4.66 g, 92% yield). LCMS: m / z = 371 [M+1] + .

[0326] Step 2: INT B34-1 (3.20 g, 8.64 mmol, 1.0 equiv.) and Pd / C (0.45 g, 0.14 w / w) were dispersed in MeOH (40 mL). The reaction mixture was purged, maintained under an inert atmosphere of hydrogen, stirred at room temperature for 24 hours, and then filtered. The filtrate was concentrated under reduced pressure to give crude INT B34-2 (2.10 g). LCMS: m / z=323 [M+1] + .

[0327] Step 3: A mixture of INT B34-2 (2.10 g, 6.52 mmol, 1.0 equiv) dissolved in THF (30 mL) was purged, maintained under an inert atmosphere of nitrogen, and cooled to 0-10 °C, followed by the slow addition of NaH (0.32 g, 13.33 mmol, 2.05 equiv) (60% in mineral oil). The resulting mixture was stirred for 0.5 h, followed by the addition of CHI (4.13 g, 29.10 mmol, 4.47 equiv). The reaction mixture was stirred at room temperature for 2 h, quenched with water (20 mL), and extracted with EA (50 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give a residue that was purified using Prep-HPLC (C18 column, eluted with HO / CHCN) to give INT B34-3 (1.14 g, 52% yield). LCMS: m / z=337[M+1] + .

[0328] Step 4: INT B34-3 (1.14 g, 3.39 mmol, 1.0 equiv) and NCS (0.60 g, 4.49 mmol, 1.33 equiv) were dispersed in DMF (15 mL). The reaction mixture was stirred at room temperature for 1 h, diluted with brine (50 mL), and then extracted with EA (50 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give a residue, which was purified using Prep-HPLC (C18 column, eluted with HO / CHCN) to give INT B34 (0.88 g, 70% yield). LCMS: m / z = 371 [M+1] + .

[0329] Intermediate B35 (INT B35) [ka] Step 1: INT B33 (0.50 g, 1.16 mmol, 1.0 equiv), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (1.06 g, 8.44 mmol, 7.29 equiv), Pd(dppf)Cl (0.30 g, 0.41 mmol, 0.35 equiv), and KCO (0.82 g, 5.93 mmol, 5.12 equiv) were dispersed in a mixture of 1,4-dioxane and HO (v / v = 5 mL:1 mL). The reaction mixture was purged, maintained under an inert atmosphere of nitrogen, stirred at 100 °C for 4 h, cooled to room temperature, diluted with brine, and then extracted with EA (50 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give a residue which was purified using Prep-HPLC (C18 column, eluted with HO / CHCN) to give INT B35 (0.21 g, 49% yield) as a white solid. LCMS: m / z=367 [M+1] + .

[0330] Intermediate B36 (INT B36) [ka] Step 1: INT B32 (410 mg, 1.00 mmol, 1.0 equiv), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (260 mg, 2.07 mmol, 2.07 equiv), Pd(dppf)Cl (260 mg, 0.36 mmol, 0.36 equiv), and KCO (310 mg, 2.24 mmol, 2.24 equiv) were dispersed in a mixture of 1,4-dioxane and HO (v / v = 5 mL:1 mL). The reaction mixture was purged, maintained under an inert atmosphere of nitrogen, stirred at 120 °C for 2 h, cooled to room temperature, diluted with brine, and then extracted with EA (50 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give a residue which was purified using Prep-HPLC (C18 column, eluted with HO / CHCN) to give INT B36 (220 mg, 66% yield) as a white solid. LCMS: m / z=347 [M+1] +.

[0331] Intermediate B37 (INT B37) [ka] Method A: NaH (2.31 g, 57.75 mmol, 2.05 equiv) (60% in mineral oil) was slowly added to a solution of INT B2 (10.48 g, 28.14 mmol, 1.0 equiv) dissolved in THF (100 mL) at 0-10 °C. The resulting mixture was stirred for 0.5 h, and then CHCl (8.41 g, 59.25 mmol, 2.11 equiv) was added. The reaction mixture was stirred at room temperature for 3 h, quenched with water (200 mL), and extracted with DCM (200 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and then concentrated under reduced pressure to give a residue that was purified using silica gel column chromatography (eluted with Hex / EA) to give INT B37 (6.20 g, 57% yield). LCMS: m / z = 387 [M+1] + .

[0332] Method B: INT B2 (10.26 g, 27.56 mmol, 1.0 equiv), methyl iodide (28.01 g, 197.34 mmol, 7.16 equiv), and K2CO3 (7.91 g, 57.23 mmol, 2.08 equiv) were dispersed in DMF (100 mL). The reaction mixture was stirred at 65 °C for 2 h, quenched with water (200 mL), and then extracted with EA (200 mL × 3). The organic layers were combined and concentrated under reduced pressure to give a residue that was purified using Prep-HPLC (C18 column, eluted with HO / CH3CN) to give INT B37 (10.40 g, 97% yield). LCMS: m / z = 387 [M+1] + .

[0333] Intermediate B38 (INT B38) [ka] Step 1: INT B2 (0.61 g, 1.64 mmol, 1.0 equiv), 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.22 g, 5.26 mmol, 3.21 equiv), and CsCO (2.20 g, 6.75 mmol, 4.12 equiv) were dispersed in DMF (10 mL). The reaction mixture was stirred at room temperature for 2 hours, poured into water (20 mL), and then extracted with EA (20 mL × 3). The organic layers were combined and concentrated under reduced pressure to give a residue that was purified using prep-HPLC (C18 column, eluted with HO / CHCN) to give INT B38 (0.48 g, 64% yield). LCMS: m / z = 455 [M+1] + .

[0334] Intermediate B39 (INT B39) [ka] Step 1: INT B2 (2.01 g, 5.40 mmol, 1.0 equiv), potassium trifluoro(vinyl)borate (3.03 g, 22.62 mmol, 4.19 equiv), pyridine (2.85 g, 36.03 mmol, 6.67 equiv), and Cu(OAc)2 (4.44 g, 24.44 mmol, 4.53 equiv) were dispersed in 1,4-dioxane (100 mL). The reaction mixture was stirred at 110 °C for 18 h and then filtered. The filtrate was concentrated under reduced pressure to give a residue that was purified using a silica gel column (eluted with Hex / EA) to give INT B39 (0.85 g, 39% yield). LCMS: m / z = 399 [M+1] + .

[0335] Intermediate B40 (INT B40) [ka] Step 1: In a nitrogen atmosphere, a mixture of 1-(tert-butyl)-3-methyl 4-oxopiperidine-1,3-dicarboxylate (2.03 g, 7.48 mmol, 1.0 equiv.) dissolved in toluene (20 mL) was cooled to -70 °C, and then DIPEA (3.68 g, 28.47 mmol, 3.81 equiv.) and trifluoromethanesulfonic anhydride (3.31 g, 11.73 mmol, 1.57 equiv.) were added. The reaction mixture was stirred at room temperature for 1 hour, quenched with saturated aqueous Na2CO3 (20 mL), and then extracted with EA (50 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, and then concentrated under reduced pressure to give a residue, which was purified using a silica gel column (eluted with Hex / EA) to give INT B40-1 (3.08 g). LCMS: m / z=390[M+1] + .

[0336] Step 2: 4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi(1,3,2-dioxaborolane) (6.45 g, 25.40 mmol, 1.28 equiv.), INT B40-1 (8.01 g, 19.86 mmol, 1.0 equiv.), Pd(dppf)Cl (2.81 g, 3.84 mmol, 0.19 equiv.), and KOAc (5.88 g, 59.91 mmol, 3.02 equiv.) were dispersed in 1,4-dioxane (150 mL). The reaction mixture was purged, maintained under an inert atmosphere of nitrogen, stirred at 80 °C for 16 h, cooled to room temperature, and concentrated under reduced pre...

Claims

1. A compound, a stereoisomer thereof, a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof; the compound is selected from any one of the following compounds: 【Chemistry 1】 【change】 【change】

2. 10. A pharmaceutical composition comprising the compound of claim 1, a stereoisomer thereof, a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof; and at least one pharma- ceutically acceptable excipient.

3. The pharmaceutical composition of claim 2 for use in the treatment of cancer associated with PARP7.

4. The pharmaceutical composition of claim 3 , wherein the cancer is a cancer associated with PARP7 overexpression.

5. 4. The pharmaceutical composition of claim 3, wherein the cancer is selected from breast cancer, cancer of the central nervous system, endometrial cancer, kidney cancer, colon cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, mesothelioma, melanoma, fibrosarcoma, bladder cancer, rectal cancer, lymphoma, cervical cancer, head and neck cancer, upper aerodigestive tract cancer, colorectal cancer, urinary tract cancer, or colon cancer.

6. The pharmaceutical composition of claim 3, wherein the cancer is independently selected from adenocarcinoma, squamous cell carcinoma, mixed adenosquamous carcinoma, or undifferentiated carcinoma.

7. The ovarian cancer is selected from high-grade serous ovarian adenocarcinoma, ovarian mucinous cystadenocarcinoma, or malignant ovarian Brenner tumor; the renal cancer is clear cell renal cell carcinoma; the tongue cancer is tongue squamous cell carcinoma; the lung cancer is selected from lung adenocarcinoma, lung adenosquamous carcinoma, squamous cell lung carcinoma, large cell lung carcinoma, small cell lung carcinoma, papillary adenocarcinoma, or non-small cell lung carcinoma; the pancreatic cancer is selected from pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma; the esophageal cancer is esophageal squamous cell carcinoma; the mesothelioma is biphasic mesothelioma; the cancer of the central nervous system is selected from glioma, glioblastoma, or glioblastoma multiforme; the gastric cancer is gastric adenocarcinoma; the breast cancer is selected from ductal carcinoma, adenocarcinoma, or HR+ breast cancer; the bladder cancer is bladder squamous cell carcinoma; the melanoma is malignant melanoma; the colon cancer is colon adenocarcinoma; The head and neck cancer is head and neck small cell squamous cell carcinoma. The pharmaceutical composition according to claim 5.

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