Parp1 inhibitors and uses thereof

Abstract

This invention describes PARP1 inhibitors and pharmaceutical compositions comprising such inhibitors. The compounds and compositions of this invention are suitable for the treatment of cancer.

Description

Prior Technology

[0001] Poly(ADP-ribose) polymerase (PARP) or poly(ADP-ribose) synthase (PARS) plays a fundamental role in promoting DNA repair, controlling RNA transcription, mediating cell death, and regulating immune responses. These roles make PARP inhibitors a target for a wide range of diseases. PARP inhibitors have been demonstrated in many disease models, particularly in ischemia-reperfusion injury, inflammatory diseases, degenerative diseases, protection against the adverse effects of cytotoxic compounds, and enhancement of cytotoxic cancer therapies. PARP has also been indicated in retroviral infections, and therefore inhibitors can be used in antiretroviral therapy. PARP inhibitors have been effective in preventing ischemia-reperfusion injury in models of myocardial infarction, stroke, other neurological trauma, organ transplantation, and reperfusion of the eyes, kidneys, intestines, and musculoskeletal system. Inhibitors have been effective in inflammatory diseases such as arthritis, gout, inflammatory bowel disease, CNS inflammation such as MS and allergic encephalitis, sepsis, septic shock, hemorrhagic shock, pulmonary fibrosis, and uveitis. PARP inhibitors have also demonstrated benefits in several models of degenerative diseases, including diabetes (and its complications) and Parkinson's disease. PARP inhibitors have improved hepatotoxicity following acetaminophen overdose, cardiotoxicity and nephrotoxicity caused by doxorubicin and platinum-based antitumor agents, and skin damage secondary to sulfur mustard. In various cancer models, PARP inhibitors have been shown to enhance radiation and chemotherapy by increasing cell death in cancer cells, limiting tumor growth, reducing metastasis, and prolonging survival in tumor-bearing animals.

[0002] PARP1 and PARP2 are the PARPs whose roles in DNA damage repair have been most extensively studied. PARP1 is activated by DNA damage disruption and catalyzes the addition of poly(ADP-ribose) (PAR) chains to target proteins. This post-translational modification (called PARation) mediates the recruitment of additional DNA repair factors to DNA lesions.

[0003] Following this recruitment process, PARP auto-PARation triggers the release of PARP from DNA, allowing it to access other DNA repair proteins to complete the repair. Therefore, PARP binding to the damaged site, its catalytic activity, and its eventual release from DNA are all crucial steps in the response of cancer cells to DNA damage induced by chemotherapy and radiotherapy.

[0004] Inhibition of PARP family enzymes has been used as a strategy to selectively kill cancer cells by activating complementary DNA repair pathways. Numerous preclinical and clinical studies have demonstrated that tumor cells carrying detrimental alterations to BRCA1 or BRCA2 (key tumor suppressor proteins involved in the repair of double-stranded DNA breaks (DSBs) using homologous recombination (HR)) are selectively sensitive to small-molecule inhibitors of the PARP family of DNA repair enzymes. These tumors exhibit a defective homologous recombination repair (HRR) pathway dependent on PARP enzyme viability. Although PARP inhibitor therapy primarily targets SRCA-mutated cancers, PARP inhibitors have been clinically tested in non-SRCA-mutated tumors (those exhibiting homologous recombination deficiency (HRD)).

[0005] It is believed that PARP inhibitors with improved selectivity for PARP1 may offer improved efficacy and reduced toxicity compared to other clinically used PARP1 / 2 inhibitors. It is also believed that strong selective inhibition of PARP1 leads to PARP1 capture on DNA, causing DNA double-strand breaks (DSBs) via replication fork collapse in S phase. Furthermore, it is believed that PARP1-DNA capture is an effective mechanism for selectively killing tumor cells with high erroneous activity (HRD). Therefore, there is an unmet medical need for effective and safe PARP inhibitors, especially PARP inhibitors with selectivity for PARP1. Summary of the Invention

[0006] This article discloses a compound of formula (III"), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Equation (III) in: R C1 represents hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 amylalkyl, C1-C6 heteroalkyl, C2-C 6-alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are, as appropriate and independently, substituted by one or more R Ca; Each RCa is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcd, -NRcRd, -NR bC(=O)NRcd, -NR bC(=O)Ra, -NR bC(=O)ORb, -NR bS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 6-Heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R Ca atoms on the same atom can together form a side oxygen group; R C2 represents hydrogen, deuterium, halogen, -CN, -OH, -OR a, -NR cR d, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, or heterocycloalkyl; R C3 can be hydrogen, deuterium, halogen, -CN, -OH, -OR a, -NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, or heterocycloalkyl; Each R 7 is independently hydrogen, deuterium, halogen, -CN, -OH, -OR a, -NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Or two R7s together form a cycloalkyl or heterocycloalkyl group; each may be substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, depending on the case. Each R 8 is independently a deuterium, halogen, -CN, -NO 2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O) 2R a, -S(=O) 2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O) 2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-Heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R8 atoms on the same carbon atom may together form a side group; Two R8s on the same carbon, adjacent carbon, or opposite carbon may be used together to form a cycloalkyl or heterocycloalkyl group; each may be substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, or C1-C6 heteroalkyl groups, as appropriate. n is between 0 and 6; R 12 is a C1-C6 alkyl, C1-C6 deuterylalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are, as appropriate, derived from one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C 6 heteroalkyl substitutions; Each R11 is independently a deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6. Heteroalkyl, cycloalkyl, or heterocycloalkyl; q is between 0 and 3; Each Ra is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, as appropriate, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O) 2NHCH 3, -S(=O) 2N(CH 3) 2, -NH 2, -NHCH 3, -N(CH 3) 2, -C(=O)CH 3, -C(=O)OH, -C(=O)OCH 3, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 deuteralkyl, C 1-C 6 hydroxyalkyl, C 1-C 6 aminoalkyl, or C 1-C 6 heteroalkyl substitution; Each Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, depending on the case, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH 2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl substitution; and Each Rc and Rd is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, depending on the case, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH 2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl substitution; Alternatively, Rc and Rd together with the atoms they are attached to form heterocyclic alkyl groups, which may be substituted with one or more side oxygen groups, deuterium, halogens, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, or C1-C6 heteroalkyl.

[0007] This article also discloses a pharmaceutical composition comprising the compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0008] This article also discloses a method for treating cancer in an individual in need, comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, or lung cancer.

[0009] This article also discloses a method for treating cancers containing BRCA1 and / or BRCA2 mutations in individuals in need, the method comprising administering a compound of any one of the methods 1 to 70 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the cancer is bladder cancer, brain cancer and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer, or uterine cancer. [References included] []

[0010] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference as if each individual publication, patent or patent application specifically and individually indicated to be incorporated by reference. Implementation

[0011] Cross-reference

[0012] This application claims the benefits of U.S. Provisional Application No. 63 / 176,610, filed April 19, 2021; U.S. Provisional Application No. 63 / 183,563, filed May 3, 2021; and U.S. Provisional Application No. 63 / 254,832, filed October 12, 2021, all of which are incorporated herein by reference in their entirety. [definition] []

[0013] In the following description, certain specific details are set forth to provide a thorough understanding of the various embodiments. However, those skilled in the art will understand that the invention can be practiced without such details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context otherwise requires, throughout this specification and the claims herein, the word "comprise" and its variations (such as "comprises / comprising") should be considered to have an open, inclusive meaning, that is, to include (but not limited to) the endpoints. Furthermore, the headings provided herein are for convenience only and do not constitute an explanation of the scope or meaning of the claimed invention.

[0014] Throughout this specification, references to "some embodiments" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. Therefore, the phrases "in one embodiment" appearing in different places throughout this specification do not necessarily refer to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Additionally, unless the context explicitly specifies otherwise, as used in this specification and the appended claims, the singular forms "a / an" and "the" include a plural of indicators. It should also be noted that unless the context explicitly specifies otherwise, the term "or" is generally used to include the meaning of "and / or".

[0015] Unless otherwise indicated, the following terms have the following meanings as used herein:

[0016] "Side group" refers to =O.

[0017] "Carboxyl group" refers to -COOH.

[0018] "Cyano" refers to -CN.

[0019] "Alkyl" refers to a straight-chain or branched monoalkyl group of a saturated hydrocarbon having one to ten carbon atoms, more preferably one to six carbon atoms. Examples include (but are not limited to) methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl, isopentyl, neopentyl, tertiary pentyl and hexyl, as well as longer alkyl groups such as heptyl, octyl and the like. Whenever it appears herein, numerical ranges such as "C1-C6 alkyl" or "C1-6 alkyl" mean that an alkyl group can consist of 1, 2, 3, 4, 5, or 6 carbon atoms, although the definition of this invention also covers the presence of the term "alkyl" where no numerical range is specified. In some embodiments, the alkyl group is C1-10 alkyl. In some embodiments, the alkyl group is C1-6 alkyl. In some embodiments, the alkyl group is C1-5 alkyl. In some embodiments, the alkyl group is C1-4 alkyl. In some embodiments, the alkyl group is C1-3 alkyl. Unless otherwise specifically stated in this specification, the alkyl group may be substituted as appropriate with, for example, a syl group, halogen, amino group, nitrile group, hydroxyl group, haloalkyl group, alkoxy group, carboxyl group, carboxyl group, aryl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, and the like. In some embodiments, the alkyl group may be substituted as appropriate with a syl group, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl group is substituted with a halogen, -CN, -OH, or -OMe, depending on the specific embodiment. In some embodiments, the alkyl group is substituted with a halogen, depending on the specific embodiment.

[0020] "Alkenyl" refers to a straight-chain or branched hydrocarbon monoradical having one or more carbon-carbon double bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be configured in cis or trans around the double bond and should be understood to include both isomers. Examples include (but are not limited to) vinyl (-CH=CH 2), 1-propenyl (-CH 2CH=CH 2), isopropenyl [-C(CH 3)=CH 2], butenyl, 1,3-butadienyl, and the like. Whenever it appears herein, numerical ranges such as "C 2-C 6 alkenyl" or "C 2-6 alkenyl" mean that the alkenyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, but the definition of this invention also covers the presence of the term "alkenyl" where no numerical range is specified. Unless otherwise specifically stated in this specification, the alkenyl group may be substituted as appropriate with, for example, a syl group, halogen, amino group, nitro group, hydroxyl group, haloalkyl group, alkoxy group, carboxyl group, carboxylate group, aryl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, and the like. In some embodiments, the alkenyl group may be substituted as appropriate with a syl group, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl group may be substituted as appropriate with a halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl group may be substituted as appropriate with a halogen.

[0021] "Alynyl" refers to a straight-chain or branched hydrocarbon monoradical having one or more carbon-carbon triple bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. Examples include (but are not limited to) ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever it appears herein, numerical ranges such as "C 2-C 6 ynyl" or "C 2-6 ynyl" mean that the ynyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, but the definition of this invention also covers the presence of the term "ynyl" where no numerical range is specified. Unless otherwise specifically stated in this specification, the ynyl group may be substituted as appropriate with, for example, a serogroup, halogen, amino group, nitro group, hydroxyl group, haloalkyl group, alkoxy group, carboxyl group, carboxylate group, aryl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, and the like. In some embodiments, the alkynyl group is substituted with a side oxygen, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH₂, or -NO₂, depending on the situation. In some embodiments, the alkynyl group is substituted with a halogen, -CN, -OH, or -OMe, depending on the situation. In some embodiments, the alkynyl group is substituted with a halogen, depending on the situation.

[0022] "Phenylene" refers to a straight-chain or branched divalent hydrocarbon chain. Unless otherwise specifically stated in this specification, alkylene groups may be substituted as appropriate with, for example, oxy-groups, halogens, amino groups, nitriles, hydroxyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxyl groups, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, and the like. In some embodiments, alkylene groups may be substituted as appropriate with oxy-groups, halogens, -CN, -COOH, COOMe, -OH, -OMe, -NH₂, or -NO₂. In some embodiments, alkylene groups may be substituted as appropriate with halogens, -CN, -OH, or -OMe. In some embodiments, alkylene groups may be substituted as appropriate with halogens.

[0023] "Alkoxy" refers to a group of the formula -ORa, where Ra is an alkyl group as defined. Unless otherwise specifically stated in this specification, alkoxy groups may be substituted as appropriate with, for example, alkyl groups, halogens, amino groups, nitriles, hydroxyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxyl groups, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, and the like. In some embodiments, alkoxy groups may be substituted as appropriate with halogens, -CN, -COOH, COOMe, -OH, -OMe, -NH₂, or -NO₂. In some embodiments, alkoxy groups may be substituted as appropriate with halogens, -CN, -OH, or -OMe. In some embodiments, alkoxy groups may be substituted as appropriate with halogens.

[0024] "Aryl" refers to a group derived from a hydrocarbon ring system, comprising 6 to 30 carbon atoms and at least one aromatic ring. Aryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused (when fused with a cycloalkyl or heterocyclic alkyl ring, the aryl group is bonded via aromatic ring atoms) or bridged ring systems. In some embodiments, the aryl group is a 6- to 10-membered aryl group. In some embodiments, the aryl group is a 6-membered aryl (phenyl) group. Aryl groups include (but are not limited to) aryl groups derived from the following hydrocarbon ring systems: anthraceneyl, anthracene-naphthyl, anthracene, azurite, benzene, etc. Arylene, arylene, as-dicyclopentadienzylbenzene, s-dicyclopentadienzylbenzene, indane, indene, naphthalene, fentanyl, pleiadene, pyrene, and terphenylene. Unless otherwise specifically stated in this specification, the aryl group may be substituted as appropriate with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the aryl group may be substituted as appropriate with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl group may be substituted as appropriate with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl group may be substituted as appropriate with halogen.

[0025] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbon ring, which may include fused (when fused with an aryl or heteroaryl ring, the cycloalkyl is bonded via non-aromatic ring atoms) or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyl groups include, but are not limited to, those having the following carbon atoms: three to fifteen carbon atoms (C3-C15 cycloalkyl or C3-C15 cycloalkenyl), three to ten carbon atoms (C3-C10 cycloalkyl or C3-C10 cycloalkenyl), three to eight carbon atoms (C3-C8 cycloalkyl or C3-C8 cycloalkenyl), three to six carbon atoms (C3-C6 cycloalkyl or C3-C6 cycloalkenyl), three to five carbon atoms (C3-C5 cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (C3-C4 cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl group is a 3- to 10-membered cycloalkyl group or a 3- to 10-membered cycloalkenyl group. In some embodiments, the cycloalkyl group is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered cycloalkenyl group. In some embodiments, the cycloalkyl group is a 5- to 6-membered cycloalkyl group or a 5- to 6-membered cycloalkenyl group. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decahydronaphthyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthyl, trans-decahydronaphthyl, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, as well as 7,7-dimethyl-bicyclo[2.2.1]heptyl. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specifically stated in this specification, cycloalkyl groups may be substituted as appropriate with, for example, a syl group, halogen, amino group, nitro group, hydroxyl group, alkyl group, alkenyl group, alkynyl group, haloalkyl group, alkoxy group, carboxyl group, carboxylate group, aryl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, and the like. In some embodiments, the cycloalkyl group may be substituted as appropriate with a syl group, halogen, methyl group, ethyl group, -CN group, -COOH group, COOMe group, -CF3 group, -OH group, -OMe group, -NH2 group, or -NO2 group. In some embodiments, the cycloalkyl group may be substituted as appropriate with a syl group, halogen, methyl group, ethyl group, -CN group, -CF3 group, -OH group, or -OMe group. In some embodiments, the cycloalkyl group may be substituted as appropriate with a halogen.

[0026] "Halogen" or "halogen" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

[0027] "Haloalkyl" means an alkyl group as defined above that has been substituted with one or more halogen groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl and the like.

[0028] "Hydroxyalkyl" refers to an alkyl group as defined above that has been substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0029] "Aminoalkyl" refers to an alkyl group as defined above that is substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl.

[0030] "Cyanoalkyl" means an alkyl group as defined above that has been substituted with one or more cyano groups. In some embodiments, the alkyl group is substituted with one cyano group. In some embodiments, the alkyl group is substituted with one or two cyano groups. Cyanoalkyl includes, for example, cyanomethyl.

[0031] "Deuteryl alkyl" refers to an alkyl group as defined above that is substituted with one or more deuterium groups. In some embodiments, the alkyl group is substituted with one deuterium group. In some embodiments, the alkyl group is substituted with one, two, or three deuterium groups. In some embodiments, the alkyl group is substituted with one, two, three, four, five, or six deuterium groups. Deuteryl alkyl groups include, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteryl alkyl group is CD3.

[0032] "Heteroalkyl" refers to an alkyl group in which one or more alkyl skeleton atoms are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl group is attached to the rest of the molecule at the carbon atom of the heteroalkyl group. In one state, the heteroalkyl group is a C1-C6 heteroalkyl group, wherein the heteroalkyl group consists of 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, wherein the heteroalkyl group is attached to the rest of the molecule at the carbon atom of the heteroalkyl group. Examples of such heteroalkyl groups are, for example, -CH₂OCH₃, -CH₂CH₂OCH₃, -CH₂CH₂OCH₂CH₂OCH₃, -CH(CH₃)OCH₃, -CH₂NHCH₃, -CH₂N(CH₃)₂, -CH₂CH₂NHCH₃, or -CH₂CH₂N(CH₃)₂. Unless otherwise specifically stated in this specification, heteroalkyl groups may be substituted as appropriate with, for example, a syloxy group, halogen, amino group, nitro group, hydroxyl group, alkyl group, alkenyl group, alkynyl group, haloalkyl group, alkoxy group, aryl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, and the like. In some embodiments, heteroalkyl groups may be substituted as appropriate with a syloxy group, halogen, methyl group, ethyl group, -CN group, -CF₃ group, -OH group, -OMe group, -NH₂ group, or -NO₂ group. In some embodiments, the heteroalkyl group is substituted with a side-oxygen group, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe, depending on the situation. In some embodiments, the heteroalkyl group is substituted with a halogen, depending on the situation.

[0033] "Heterocyclic alkyl" refers to a 3- to 24-member partially or fully saturated cyclic group comprising 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the heterocyclic alkyl is fully saturated. In some embodiments, the heterocyclic alkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic alkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocyclic alkyl comprises one to three nitrogen atoms. In some embodiments, the heterocyclic alkyl comprises one or two nitrogen atoms. In some embodiments, the heterocyclic alkyl comprises one nitrogen atom. In some embodiments, the heterocyclic alkyl comprises one nitrogen atom and one oxygen atom. Unless otherwise specifically stated in this specification, the heterocyclic alkyl may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or heteroaryl ring, the heterocyclic alkyl is bonded via non-aromatic ring atoms) or bridged ring system; and the nitrogen, carbon, or sulfur atoms in the heterocyclic alkyl may be oxidized as appropriate; the nitrogen atom may be quaternized as appropriate. Representative heterocyclic alkyl groups include (but are not limited to) heterocyclic alkyl groups having the following: two to fifteen carbon atoms (C2-C15 heterocyclic alkyl or C2-C15 heterocyclic alkenyl), two to ten carbon atoms (C2-C10 heterocyclic alkyl or C2-C10 heterocyclic alkenyl), two to eight carbon atoms (C2-C8 heterocyclic alkyl or C2-C8 heterocyclic alkenyl), two to seven carbon atoms (C2-C7 heterocyclic alkyl or C2-C7 heterocyclic alkenyl), two to six carbon atoms (C2-C6 heterocyclic alkyl or C2-C6 heterocyclic alkenyl), two to five carbon atoms (C2-C5 heterocyclic alkyl or C2-C5 heterocyclic alkenyl), or two to four carbon atoms (C2-C4 heterocyclic alkyl or C2-C4 heterocyclic alkenyl). Examples of such heterocyclic alkyl groups include (but are not limited to) [the following text is incomplete and requires further context to translate accurately.] Aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thiophene[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazodinyl, isothiazolinyl, isozalidinyl, taurinyl, octahydroindolyl, octahydroisoindolyl, 2-side-oxypiperidinyl, 2-side-oxypiperidinyl, 2-side-oxypyrrolidinyl, tauridinyl, piperidinyl, piperidinyl, 4-piperidinoneyl, pyrrolidinyl, pyrazolidinyl The terms pyridyl, thiazolidinyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropiperanyl, thiopyrinyl, thiazolinyl, 1-sideoxy-thiopyrinyl, 1,1-sideoxy-thiopyrinyl, 1,3-dihydroisobenzofuran-1-yl, 3-sideoxy-1,3-dihydroisobenzofuran-1-yl, methyl-2-sideoxy-1,3-m-dioxacyclopenten-4-yl, and 2-sideoxy-1,3-m-dioxacyclopenten-4-yl are used. The term heterocyclic alkyl also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocyclic alkyl groups have 2 to 10 carbons in the ring. It should be understood that when referring to the number of carbon atoms in a heterocyclic alkyl group, the number of carbon atoms in the heterocyclic alkyl group is not the same as the total number of atoms constituting the heterocyclic alkyl group (i.e., the skeletal atoms of the heterocyclic alkyl ring), including heteroatoms. In some embodiments, the heterocyclic alkyl group is 3- to 8-membered heterocyclic alkyl. In some embodiments, the heterocyclic alkyl group is 3- to 7-membered heterocyclic alkyl. In some embodiments, the heterocyclic alkyl group is 3- to 6-membered heterocyclic alkyl. In some embodiments, the heterocyclic alkyl group is 4- to 6-membered heterocyclic alkyl. In some embodiments, the heterocyclic alkyl group is 5- to 6-membered heterocyclic alkyl. In some embodiments, the heterocyclic alkyl group is 3- to 8-membered heterocyclic alkenyl. In some embodiments, the heterocyclic alkyl group is 3- to 7-membered heterocyclic alkenyl. In some embodiments, the heterocyclic alkyl group is 3- to 6-membered heterocyclic alkenyl. In some embodiments, the heterocyclic alkyl group is 4- to 6-membered heterocyclic alkenyl. In some embodiments, the heterocyclic alkyl group is 5- to 6-membered heterocyclic alkenyl. Unless otherwise specifically stated in this specification, heterocyclic alkyl groups may be substituted as described below with, for example, oxy, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocyclic alkyl, heteroaryl, and the like. In some embodiments, the heterocyclic alkyl group may be substituted as described below with oxy, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocyclic alkyl group may be substituted as described below with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocyclic alkyl group may be substituted as described below with halogen.

[0034] "Heteroaryl" refers to a 5- to 14-membered ring system group comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, a heteroaryl group comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heteroaryl group comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heteroaryl group comprises one to three nitrogen atoms. In some embodiments, a heteroaryl group comprises one or two nitrogen atoms. In some embodiments, a heteroaryl group comprises one nitrogen atom. A heteroaryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocyclic alkyl ring, the heteroaryl group is bonded via aromatic ring atoms) or bridged ring system; and the nitrogen, carbon, or sulfur atoms in the heteroaryl group may be oxidized as appropriate; the nitrogen atom may be quaternarily ammonized as appropriate. In some embodiments, a heteroaryl group is a 5- to 10-membered heteroaryl group. In some embodiments, a heteroaryl group is a 5- to 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. Examples include (but are not limited to) aziridine, acridine, benzimidazolyl, benzothiazolyl, benzoindolyl, benzom-dioxacyclopentenyl, benzofuranyl, benzoazirazole, benzothiazolyl, benzo[b][1,4]dioxanyl, 1,4-benzodioxane, benzonaphthuryl, benzoazirazole, benzom-dioxacyclopentenyl, benzom-dioxacyclohexenyl, benzopiperanyl, benzopiperanone, benzofuranyl, benzofuranone, benzothienyl / benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole Alkyl, alkinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanoneyl, isothiazolyl, imidazoyl, indazoleyl, indoleyl, indazoleyl, isoindoleyl, indolinyl, isoindolelinyl, isoquinolinyl, indoleyl, isoazolyl, alkinyl, alkadiazolyl, 2-side-oxy-nitro-pyrrolyl, alkazolyl, ethylene oxide, 1-oxy Ionic groups: pyridyl, 1-oxo-pyrimidinyl, 1-oxo-pyridine, 1-oxo-pyridine, 1-phenyl-1H-pyrroleyl, phenanthioyl, phenanthioyl, phenanthioyl, pyridyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyridyl, pyridyl, pyridine, pyridineyl, pyrimidinyl, pyridineyl, quinazolinyl, quinazolinyl, quinolinyl The heteroaryl group may be substituted with, for example, halogen, amino, nitrile, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, or the like. In some embodiments, the heteroaryl group may be substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, or the like. In some embodiments, the heteroaryl group may be substituted with, for example, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl group may be substituted with, for example, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl group may be substituted with, for example, halogen.

[0035] The terms "as appropriate" or "as appropriate" mean that the event or situation described below may or may not occur, and the description includes both the possibility that the event or situation occurs and the possibility that it does not occur. For example, "as appropriate substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. Furthermore, the group that is substituted as appropriate may be unsubstituted (e.g., -CH 2CH 3), fully substituted (e.g., -CF 2CF 3), monosubstituted (e.g., -CH 2CH 2F), or substituted to any degree between fully substituted and monosubstituted (e.g., -CH 2CHF 2, -CH 2CF 3, -CF 2CH 3, -CFHCHF 2, etc.). Regarding any group containing one or more substituents, those skilled in the art will understand that such groups are not intended to introduce any substitution or substitution pattern that is spatially impractical and / or synthetically infeasible (e.g., substituted alkyl includes, where appropriate, substituted cycloalkyl, which is then defined as including, where appropriate, substituted alkyl, possibly without end). Therefore, any substituent described should generally be understood to have a maximum molecular weight of about 1,000 Daltons and more typically, up to about 500 Daltons.

[0036] "Effective dose" or "therapeutic effective dose" refers to the amount of a compound administered to a mammalian individual as a single dose or as part of a series of doses that effectively produces the desired therapeutic effect.

[0037] "Treatment" of an individual (e.g., a mammal, such as a human) or cell is any type of intervention intended to alter the natural course of disease in an individual or cell. In some embodiments, treatment includes administering a pharmaceutical composition after triggering a pathological event or exposure to a pathogenic agent, and includes stabilizing symptoms (e.g., preventing symptoms from worsening) or alleviating symptoms.

[0038] "Synergy / synergize" refers to the combined effect of a combination of components that is greater than the sum of the effects of the individual components at the same dosage.

[0039] As used in this article, "PARP-related disease or condition" or "PARP-mediated disease or condition" means any disease or other harmful symptom in which PARP or its mutants are known or suspected to be at play.

[0040] As used in this article, "a disease or condition associated with PARP1" or "a disease or condition mediated by PARP1" refers to any disease or other harmful condition in which PARP or its mutants are known or suspected to be at play. [Compound] []

[0041] This article describes compounds of formulas (I), (I'), (II), (III), (III'), (III"), (IV), and (V) suitable for the treatment of cancer, or their pharmaceutically acceptable salts, solvates, or stereoisomers.

[0042] This article discloses a compound of formula (I'), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Formula (I'), in: R1 represents hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, or heterocycloalkyl; X is either N or CR 2; R2 represents hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, or heterocycloalkyl; Z is either N or CR 4; R4 represents hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, or heterocycloalkyl; Y is either N or CR 5; R5 represents hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, or heterocycloalkyl; R6 represents hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, or heterocycloalkyl; Each R 7 is independently hydrogen, deuterium, halogen, -CN, -OH, -OR a, -NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Or two R7s together form a cycloalkyl or heterocycloalkyl group; each may be substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, depending on the case. Each R 8 is independently a deuterium, halogen, -CN, -NO 2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O) 2R a, -S(=O) 2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O) 2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-Heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R8 atoms on the same carbon atom may together form a side group; Two R8s on the same carbon, adjacent carbon, or opposite carbon may be used together to form a cycloalkyl or heterocycloalkyl group; each may be substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, or C1-C6 heteroalkyl groups, as appropriate. n is between 0 and 6; R 12 is a cycloalkyl or heterocycloalkyl group; wherein the cycloalkyl or heterocycloalkyl group is substituted with one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH 3, -S(=O)CH 3, -S(=O) 2CH 3, -S(=O) 2NH 2, -S(=O) 2NHCH 3, -S(=O) 2N(CH 3) 2, -NH 2, -NHCH 3, -N(CH 3) 2, -C(=O)CH 3, -C(=O)OH, -C(=O)OCH 3, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 deuteralkyl, C 1-C 6 hydroxyalkyl, C 1-C 6 aminoalkyl or C 1-C 6 heteroalkyl; Each R11 is independently a deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6. Heteroalkyl, cycloalkyl, or heterocycloalkyl; q is between 0 and 3; Each Ra is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, as appropriate, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O) 2NHCH 3, -S(=O) 2N(CH 3) 2, -NH 2, -NHCH 3, -N(CH 3) 2, -C(=O)CH 3, -C(=O)OH, -C(=O)OCH 3, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 deuteralkyl, C 1-C 6 hydroxyalkyl, C 1-C 6 aminoalkyl, or C 1-C 6 heteroalkyl substitution; Each Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, depending on the case, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH 2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl substitution; and Each Rc and Rd is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, depending on the case, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH 2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl substitution; Alternatively, Rc and Rd together with the atoms they are attached to form heterocyclic alkyl groups, which may be substituted with one or more side oxygen groups, deuterium, halogens, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, or C1-C6 heteroalkyl.

[0043] This article discloses a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Formula (I), in: R1 represents hydrogen, deuterium, halogen, -CN, -NO2, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 amylalkyl, C1-C6 cyanoalkyl, C 1-C 6 heteroalkyl, C 2-C 6 alkenyl, C 2-C 6 ynyl, cycloalkyl, or heterocycloalkyl; X is either N or CR 2; R2 represents hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, or heterocycloalkyl; R1 and R2 together form cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups; each may be substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, as appropriate. Z is either N or CR 4; R4 represents hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, or heterocycloalkyl; Y is either N or CR 5; R5 represents hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, or heterocycloalkyl; R6 represents hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, or heterocycloalkyl; Each R 7 is independently hydrogen, deuterium, halogen, -CN, -OH, -OR a, -NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Or two R7s together form a cycloalkyl or heterocycloalkyl group; each may be substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, depending on the case. Each R 8 is independently a deuterium, halogen, -CN, -NO 2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O) 2R a, -S(=O) 2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O) 2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-Heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R8 atoms on the same carbon atom may together form a side group; Two R8s on the same carbon, adjacent carbon, or opposite carbon may be used together to form a cycloalkyl or heterocycloalkyl group; each may be substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, or C1-C6 heteroalkyl groups, as appropriate. n is between 0 and 6; Ring A is a 3- to 16-membered monocyclic, bicyclic, or tricyclic ring, which may contain 1 to 5 heteroatoms selected from the groups of O, N, S, P, or B, depending on the case. Each RA is independently deuterium, halogen, -CN, -NO₂, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)₂R a, -S(=O)₂NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)₂R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-Heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are, as appropriate, and independently substituted by one or more R Aa groups; Or two RA atoms on the same atom can together form a side oxygen group; Each R Aa is independently deuterium, halogen, -CN, -NO 2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O) 2R a, -S(=O) 2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O) 2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-Heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two Ra aa atoms on the same atom can together form a side oxygen group; m ranges from 0 to 6; Each Ra is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, as appropriate, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O) 2NHCH 3, -S(=O) 2N(CH 3) 2, -NH 2, -NHCH 3, -N(CH 3) 2, -C(=O)CH 3, -C(=O)OH, -C(=O)OCH 3, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 deuteralkyl, C 1-C 6 hydroxyalkyl, C 1-C 6 aminoalkyl, or C 1-C 6 heteroalkyl substitution; Each Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, depending on the case, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH 2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl substitution; and Each Rc and Rd is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, depending on the case, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH 2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl substitution; Alternatively, Rc and Rd together with the atoms they are attached to form heterocyclic alkyl groups, which may be substituted with one or more side oxygen groups, deuterium, halogens, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. The constraint is that at least one of X or Y is N; and The constraint is that when n is 0, then Not for .

[0044] In some embodiments of compounds of formula (I) or (I'), R1 is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl.

[0045] In some embodiments of compounds of formula (I) or (I'), R1 is a halogen or cycloalkyl group.

[0046] In some embodiments of compounds of formula (I) or (I'), R1 is a cycloalkyl group.

[0047] In some embodiments of compounds of formula (I) or (I'), R1 is a C1-C6 alkyl group.

[0048] In some embodiments of compounds of formula (I) or (I'), X is N and Y is CR5.

[0049] In some embodiments of the compounds of formula (I) or (I'), R5 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of the compounds of formula (I) or (I'), R5 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compounds of formula (I) or (I'), R5 is hydrogen.

[0050] In some embodiments of compounds of formula (I) or (I'), X is CR 2 and Y is N.

[0051] In some embodiments of the compounds of formula (I) or (I'), R2 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of the compounds of formula (I) or (I'), R2 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compounds of formula (I) or (I'), R2 is hydrogen. In some embodiments of the compounds of formula (I) or (I'), R2 is hydrogen or C1-C6 alkyl. In some embodiments of the compounds of formula (I) or (I'), R2 is C1-C6 alkyl.

[0052] In some embodiments of the compounds of formula (I) or (I'), X is N and Y is N. In some embodiments of the compounds of formula (I) or (I'), Z is N. In some embodiments of the compounds of formula (I) or (I'), Z is CR 4.

[0053] In some embodiments of the compounds of formula (I) or (I'), R4 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of the compounds of formula (I) or (I'), R4 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compounds of formula (I) or (I'), R4 is hydrogen.

[0054] In some embodiments of the compounds of formula (I) or (I'), R6 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of the compounds of formula (I) or (I'), R6 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compounds of formula (I) or (I'), R6 is hydrogen.

[0055] In some embodiments of the compounds of formula (I) or (I'), each R7 is independently hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of formula (I) or (I'), each R7 is hydrogen. In some embodiments of the compounds of formula (I) or (I'), two R7s together form a cycloalkyl group.

[0056] In some embodiments of compounds of formula (I) or (I'), each R8 is a C1-C6 alkyl group; or two R8 groups on the same carbon atom together form a side-oxygen group. In some embodiments of compounds of formula (I) or (I'), two R8 groups on opposite carbon atom together form a cycloalkyl group. In some embodiments of compounds of formula (I) or (I'), two R8 groups on the same carbon atom together form a cycloalkyl group. In some embodiments of compounds of formula (I) or (I'), two R8 groups on adjacent carbon atom together form a cycloalkyl group.

[0057] In some embodiments of the compounds of formula (I) or (I'), n is 0. In some embodiments of the compounds of formula (I) or (I'), n is 1. In some embodiments of the compounds of formula (I) or (I'), n is 2. In some embodiments of the compounds of formula (I) or (I'), n is 3. In some embodiments of the compounds of formula (I) or (I'), n is 4. In some embodiments of the compounds of formula (I) or (I'), n is 5. In some embodiments of the compounds of formula (I) or (I'), n is 6. In some embodiments of the compounds of formula (I) or (I'), n is 0 to 3. In some embodiments of the compounds of formula (I) or (I'), n is 1 to 3. In some embodiments of the compounds of formula (I) or (I'), n is 1 or 2. In some embodiments of the compounds of formula (I) or (I'), n is 1 to 4. In some embodiments of compounds of formula (I) or (I'), n is 2 to 4.

[0058] In some embodiments of the compound of formula (I), ring A is a 3- to 7-membered monocyclic ring, which may contain 1 to 3 heteroatoms selected from the group consisting of O, N or S.

[0059] In some embodiments of the compound of formula (I), ring A is phenyl.

[0060] In some embodiments of the compound of formula (I), ring A is a 5- to 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.

[0061] In some embodiments of the compound of formula (I), ring A is a 5-membered heteroaryl group comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.

[0062] In some embodiments of the compound of formula (I), ring A is a 6-membered heteroaryl group containing 1 to 3 N heteroatoms.

[0063] In some embodiments of the compound of formula (I), ring A is pyridyl.

[0064] In some embodiments of the compound of formula (I), ring A is not pyridyl.

[0065] The compound of any one of technical solutions 1 to 26, or its pharmaceutically acceptable salt, solvate or stereoisomer, wherein ring A is a 3- to 7-membered cycloalkyl group.

[0066] In some embodiments of the compound of formula (I), ring A is a 3- to 7-membered heterocyclic alkyl group comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.

[0067] In some embodiments of the compound of formula (I), ring A is a 6- to 12-membered bicyclic ring, which may contain 1 to 3 heteroatoms selected from the group consisting of O, N or S.

[0068] In some embodiments of the compound of formula (I), ring A is a 6- to 12-membered bicyclic heterocyclic alkyl group comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.

[0069] In some embodiments of the compound of formula (I), ring A is a 6- to 12-membered bicyclic heteroaryl group comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.

[0070] In some embodiments of the compound of formula (I), ring A is a 6- to 12-membered bicyclic partially saturated ring, which may contain 1 to 3 heteroatoms selected from the group consisting of O, N or S.

[0071] In some embodiments of compounds of formula (I), each RA is independently deuterium, halogen, -CN, -OH, -OR a, -S(=O) 2R a, -S(=O) 2NR cR d, -NR cR d, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are, as appropriate and independently, substituted by one or more RAa; or two RAs on the same atom together form a side oxygen group. In some embodiments of compounds of formula (I), each RA is independently deuterium, halogen, -S(=O)₂Ra, -S(=O)₂NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are, as appropriate, independently substituted by one or more RAa; or two RAs on the same atom together form a side oxygen group. In some embodiments of compounds of formula (I), each RA is independently halogen, -C(=O)NRcRd, or C1-C6 alkyl. In some embodiments of compounds of formula (I), each RA is independently -C(=O)NRcRd. In some embodiments of the compounds of formula (I), RA is not -C(=O)NR cR d. In some embodiments of the compounds of formula (I), each RA is independently a heteroaryl group substituted with one or more RAa, depending on the case.

[0072] In some embodiments of compounds of formula (I), each Raa is independently deuterium, halogen, -CN, -OH, -ORa, -NR cRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NR cRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two Raa on the same atom together form a side oxygen group. In some embodiments of compounds of formula (I), each Raa is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl; or two Raa on the same atom together form a side oxygen group.

[0073] In some embodiments of the compound of formula (I), m is 0 to 4. In some embodiments of the compound of formula (I), m is 0 or 1. In some embodiments of the compound of formula (I), m is 2 or 3. In some embodiments of the compound of formula (I), m is 1 or 2. In some embodiments of the compound of formula (I), m is 0. In some embodiments of the compound of formula (I), m is 1. In some embodiments of the compound of formula (I), m is 2. In some embodiments of the compound of formula (I), m is 3. In some embodiments of the compound of formula (I), m is 4. In some embodiments of the compound of formula (I), m is 5. In some embodiments of the compound of formula (I), m is 6.

[0074] In some embodiments of the compound of formula (I), for .

[0075] In some embodiments of the compound of formula (I), for .

[0076] In some embodiments of the compound of formula (I), for or In some embodiments of the compound of formula (I), for In some embodiments of the compound of formula (I), for .

[0077] In some embodiments of compounds of formula (I'), each R 11 is independently deuterium, halogen, -CN, -OH, -OR a, -NR cR d, -C(=O)Ra, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (I'), each R 11 is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterylalkyl. In some embodiments of compounds of formula (I'), each R 11 is independently halogen or C1-C6 alkyl. In some embodiments of the compound of formula (I'), each R 11 is independently a halogen.

[0078] In some embodiments of the compound of formula (I'), q is 0 or 1. In some embodiments of the compound of formula (I'), q is 1 or 2. In some embodiments of the compound of formula (I'), q is 0. In some embodiments of the compound of formula (I'), q is 1. In some embodiments of the compound of formula (I'), q is 2. In some embodiments of the compound of formula (I'), q is 3.

[0079] In some embodiments of the compound of formula (I'), R 12 is a cycloalkyl group.

[0080] In some embodiments of the compound of formula (I), the compound is of the following formula: R1 is C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterylalkyl; Y is N, CH, or CF; each A1 is independently CH, CD, CMe, CCF3, CCl, CF, or N; each RA is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, NHMe, or NHCD3.

[0081] In some embodiments of the compound of formula (I), the compound is of the following formula: R1 is C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterylalkyl; Y is N, CH, or CF; each A1 is independently CH, CD, CMe, CCF3, CCl, CF, or N; each RA is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, NHMe, or NHCD3.

[0082] In some embodiments of the compound of formula (I), the compound is of the following formula: R1 is C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterylalkyl; Y is N, CH, or CF; each A1 is independently CH, CD, CMe, CCF3, CCl, CF, or N; each RA is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, NHMe, or NHCD3; A2 is O, NH, NMe, or NCD3; and A3 is N, CH, CF, or CD.

[0083] In some embodiments of the compound of formula (I), the compound is of the following formula: R1 is C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterylalkyl; Y is N, CH, or CF; each A1 is independently CH, CD, CMe, CCF3, CCl, CF, or N; each RA is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, NHMe, or NHCD3; A2 is O, NH, NMe, or NCD3; and A3 is N, CH, CF, or CD.

[0084] In some embodiments of the compound of formula (I), the compound is of the following formula: R1 is a C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteralkyl; Y is N, CH, or CF; each A is independently CH, CD, CMe, CCF3, CCl, CF, or N; W is CH2, CF2, CD2, CHF, or CHD; each R11 is independently hydrogen, deuterium, or halogen; and R12 is a C1-C6 alkyl or C1-C6 deuteralkyl.

[0085] This article also discloses a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Formula (II), in: R1 represents hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl or C2-C6 ynyl, cycloalkyl or heterocycloalkyl; X is either N or CR 2; R2 represents hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6. Heteroalkyl, cycloalkyl, or heterocycloalkyl; R1 and R2 together form cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups; each may be substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, as appropriate. Z is either N or CR 4; R4 represents hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6. Heteroalkyl, cycloalkyl, or heterocycloalkyl; Y is either N or CR 5; R5 represents hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6. Heteroalkyl, cycloalkyl, or heterocycloalkyl; R6 represents hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6. Heteroalkyl, cycloalkyl, or heterocycloalkyl; W1 does not exist; it is -C(R7)2-, -O-, -S-, -NR W1-, -C(R7)2C(R7)2-, -C(R7)2NR W1-, -NR W1C(R7)2-, -C(R7)2O-, -OC(R7)2-, -C(R7)2S-, or -SC(R7)2-. Each R 7 is independently hydrogen, deuterium, halogen, -CN, -OH, -OR a, -NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Or two R7s together form a cycloalkyl or heterocycloalkyl group; each may be substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, depending on the case. RW1 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterylalkyl; Ring B is a 3- to 16-membered monocyclic, bicyclic, or tricyclic ring, which may contain 1 to 5 heteroatoms selected from the groups of O, N, S, P, or B, depending on the case. Each RB is independently a deuterium, halogen, -CN, -NO₂, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)₂R a, -S(=O)₂NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)₂R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-Heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are, as appropriate, and independently substituted by one or more R Ba groups; Or two RB atoms on the same atom can together form a side oxygen group; Each RBa is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcd, -NRcRd, -NR bC(=O)NRcd, -NR bC(=O)Ra, -NR bC(=O)ORb, -NR bS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-Heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R Ba atoms on the same atom can together form a side oxygen group; p ranges from 0 to 6; W2 does not exist; it is replaced by -C(R9)2-, -O-, -S-, -NR W2-, -C(R9)2C(R9)2-, -C(R9)2NR W2-, -NR W2C(R9)2-, -C(R9)2O-, -OC(R9)2-, -C(R9)2S-, or -SC(R9)2-. Each R9 is independently hydrogen, deuterium, halogen, -CN, -OH, -ORα, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Or two R9s together form a cycloalkyl or heterocycloalkyl group; each may be substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, as appropriate. RW2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterylalkyl; Each R11 is independently a deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6. Heteroalkyl, cycloalkyl, or heterocycloalkyl; q is between 0 and 3; Each Ra is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, as appropriate, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O) 2NHCH 3, -S(=O) 2N(CH 3) 2, -NH 2, -NHCH 3, -N(CH 3) 2, -C(=O)CH 3, -C(=O)OH, -C(=O)OCH 3, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 deuteralkyl, C 1-C 6 hydroxyalkyl, C 1-C 6 aminoalkyl, or C 1-C 6 heteroalkyl substitution; Each Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, depending on the case, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH 2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl substitution; and Each Rc and Rd is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, depending on the case, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH 2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl substitution; Alternatively, Rc and Rd together with the atoms they are attached to form heterocyclic alkyl groups, which may be substituted with one or more side oxygen groups, deuterium, halogens, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. Its restrictions are: Not for .

[0086] In some embodiments of compounds of formula (II), R1 is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl or cycloalkyl. In some embodiments of compounds of formula (II), R1 is a C1-C6 alkyl.

[0087] In some embodiments of the compound of formula (II), X is CR 2 and Y is CR 5.

[0088] In some embodiments of the compound of formula (II), X is N and Y is CR5.

[0089] In some embodiments of compounds of formula (II), R5 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of compounds of formula (II), R5 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of compounds of formula (II), R5 is hydrogen.

[0090] In some embodiments of the compound of formula (II), X is CR 2 and Y is N.

[0091] In some embodiments of compounds of formula (II), R2 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of compounds of formula (II), R2 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of compounds of formula (II), R2 is hydrogen.

[0092] In some embodiments of the compound of formula (II), X is N and Y is N.

[0093] In some embodiments of the compound of formula (II), Z is N. In some embodiments of the compound of formula (II), Z is CR 4.

[0094] In some embodiments of compounds of formula (II), R4 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of compounds of formula (II), R4 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of compounds of formula (II), R4 is hydrogen.

[0095] In some embodiments of compounds of formula (II), R6 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of compounds of formula (II), R6 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of compounds of formula (II), R6 is hydrogen.

[0096] In some embodiments of compounds of formula (II), W1 is -C(R7)2-, -NR W1-, -C(R7)2C(R7)2-, -C(R7)2NR W1-, or -NR W1C(R7)2-. In some embodiments of compounds of formula (II), W1 is -C(R7)2-, -NR W1-, or -C(R7)2NR W1-. In some embodiments of compounds of formula (II), W1 is -C(R7)2-.

[0097] In some embodiments of compounds of formula (II), each R7 is independently hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of formula (II), each R7 is hydrogen. In some embodiments of compounds of formula (II), two R7s together form a cycloalkyl group.

[0098] In some embodiments of compounds of formula (II), RW1 is hydrogen or a C1-C6 alkyl group.

[0099] In some embodiments of the compound of formula (II), W2 is absent and is -C(R9)2-, -NR W2-, -C(R9)2C(R9)2-, -C(R9)2NR W2- or -NR W2C(R9)2-.

[0100] In some embodiments of the compound of formula (II), W1 is absent or is -NR W2-. In some embodiments of the compound of formula (II), W2 is absent. In some embodiments of the compound of formula (II), W2 is -O-.

[0101] In some embodiments of compounds of formula (II), each R9 is independently hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of formula (II), each R9 is hydrogen. In some embodiments of compounds of formula (II), two R9s together form a cycloalkyl group.

[0102] In some embodiments of the compound of formula (II), RW2 is hydrogen or a C1-C6 alkyl group. In some embodiments of the compound of formula (II), RW2 is hydrogen.

[0103] The compound of any one of technical solutions 50 to 81, or its pharmaceutically acceptable salt, solvate or stereoisomer, wherein ring B is a 3- to 7-membered monocyclic ring, which, as appropriate, contains 1 to 3 heteroatoms selected from the group consisting of O, N or S.

[0104] In some embodiments of compounds of formula (II), ring B is a 3- to 7-membered cycloalkyl group.

[0105] In some embodiments of compounds of formula (II), ring B is a 3- to 7-membered heterocyclic alkyl group comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.

[0106] In some embodiments of the compound of formula (II), ring B is piperyl.

[0107] In some embodiments of compounds of formula (II), ring B is not piperyl.

[0108] In some embodiments of the compound of formula (II), ring B is a 6- to 12-membered bicyclic ring, which may contain 1 to 3 heteroatoms selected from the group consisting of O, N or S.

[0109] In some embodiments of compounds of formula (II), ring B is a 6- to 12-membered bicyclic heterocyclic alkyl group comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[0110] In some embodiments of compounds of formula (II), ring B is a 6- to 12-membered bicyclic heterocyclic alkyl group containing 1 to 3 N heteroatoms.

[0111] In some embodiments of the compound of formula (II), ring B is a 6- to 16-membered tricyclic ring, which may contain 1 to 3 heteroatoms selected from the group consisting of O, N or S.

[0112] In some embodiments of compounds of formula (II), ring B is a 6- to 16-membered tricyclic heterocyclic alkyl group comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[0113] In some embodiments of compounds of formula (II), ring B is a 6- to 16-membered tricyclic heterocyclic alkyl group containing 1 to 3 N heteroatoms.

[0114] In some embodiments of compounds of formula (II), each RB is independently deuterium, halogen, -CN, -OH, -OR a, -NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl; or two RBs on the same atom together form a side oxygen group.

[0115] In some embodiments of compounds of formula (II), each RB is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterylalkyl; or two RBs on the same atom together form a side oxygen group.

[0116] In some embodiments of the compound of formula (II), p is 0 to 4. In some embodiments of the compound of formula (II), p is 0 or 1. In some embodiments of the compound of formula (II), p is 1 or 2. In some embodiments of the compound of formula (II), p is 1. In some embodiments of the compound of formula (II), p is 2. In some embodiments of the compound of formula (II), p is 3. In some embodiments of the compound of formula (II), p is 4.

[0117] In some embodiments of the compound of formula (II), for .

[0118] In some embodiments of the compound of formula (II), for .

[0119] In some embodiments of compounds of formula (II), each R11 is independently deuterium, halogen, -CN, -OH, -ORa, -NR cRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NR cRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (II), each R11 is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterylalkyl. In some embodiments of compounds of formula (II), each R11 is independently halogen or C1-C6 alkyl.

[0120] In some embodiments of the compound of formula (II), q is 0 or 1. In some embodiments of the compound of formula (II), q is 1 or 2. In some embodiments of the compound of formula (II), q is 1. In some embodiments of the compound of formula (II), q is 0. In some embodiments of the compound of formula (II), q is 2. In some embodiments of the compound of formula (II), q is 3.

[0121] This article also discloses a compound of formula (III"), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Equation (III) in: R C1 represents hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 amylalkyl, C1-C6 heteroalkyl, C2-C 6-Alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are, depending on the case, and independently substituted by one or more R Ca; Each RCa is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcd, -NRcRd, -NR bC(=O)NRcd, -NR bC(=O)Ra, -NR bC(=O)ORb, -NR bS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 6-Heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R Ca atoms on the same atom can together form a side oxygen group; R C2 represents hydrogen, deuterium, halogen, -CN, -OH, -OR a, -NR cR d, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, or heterocycloalkyl; R C3 can be hydrogen, deuterium, halogen, -CN, -OH, -OR a, -NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, or heterocycloalkyl; Each R 7 is independently hydrogen, deuterium, halogen, -CN, -OH, -OR a, -NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Or two R7s together form a cycloalkyl or heterocycloalkyl group; each may be substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, depending on the case. Each R 8 is independently a deuterium, halogen, -CN, -NO 2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O) 2R a, -S(=O) 2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O) 2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-Heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R8 atoms on the same carbon atom may together form a side group; Two R8s on the same carbon, adjacent carbon, or opposite carbon may be used together to form a cycloalkyl or heterocycloalkyl group; each may be substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, or C1-C6 heteroalkyl groups, as appropriate. n is between 0 and 6; R 12 is a C1-C6 alkyl, C1-C6 deuterylalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are substituted with one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R11 is independently a deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6. Heteroalkyl, cycloalkyl, or heterocycloalkyl; q is between 0 and 3; Each Ra is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, as appropriate, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O) 2NHCH 3, -S(=O) 2N(CH 3) 2, -NH 2, -NHCH 3, -N(CH 3) 2, -C(=O)CH 3, -C(=O)OH, -C(=O)OCH 3, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 deuteralkyl, C 1-C 6 hydroxyalkyl, C 1-C 6 aminoalkyl, or C 1-C 6 heteroalkyl substitution; Each Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, depending on the case, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH 2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl substitution; and Each Rc and Rd is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, depending on the case, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH 2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl substitution; Alternatively, Rc and Rd together with the atoms they are attached to form heterocyclic alkyl groups, which may be substituted with one or more side oxygen groups, deuterium, halogens, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, or C1-C6 heteroalkyl.

[0122] In some embodiments of the compound of formula (III), RC is deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, and heterocycloalkyl are, as appropriate and independently, substituted by one or more RCa. In some embodiments of the compound of formula (III), RC is halogen, C1-C6 haloalkyl, C1-C6 deuterylalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compound of formula (III), RC is halogen, cycloalkyl, or heterocycloalkyl. In some embodiments of the compound of formula (III), RC is halogen or cycloalkyl. In some embodiments of the compound of formula (III), R C1 is a halogen. In some embodiments of the compound of formula (III), R C1 is a cycloalkyl group.

[0123] In some embodiments of the compounds of formula (III), each RCa is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds of formula (III), each RCa is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, or C1-C6 haloalkyl.

[0124] In some embodiments of the compound of formula (III), RC2 is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of formula (III), RC2 is hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of formula (III), RC2 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of formula (III), RC2 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of formula (III), RC2 is hydrogen. In some embodiments of the compound of formula (III), RC2 is C1-C6 alkyl.

[0125] In some embodiments of the compound of formula (III), RC3 is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of formula (III), RC3 is hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of formula (III), RC3 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of formula (III), RC3 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of formula (III), RC3 is hydrogen. In some embodiments of the compound of formula (III), RC3 is C1-C6 alkyl.

[0126] In some embodiments of the compound of formula (III), for .

[0127] In some embodiments of the compound of formula (III), for In some embodiments of the compound of formula (III), for In some embodiments of the compound of formula (III), for In some embodiments of the compound of formula (III), for In some embodiments of the compound of formula (III), for In some embodiments of the compound of formula (III), for In some embodiments of the compound of formula (III), for In some embodiments of the compound of formula (III), for In some embodiments of the compound of formula (III), for In some embodiments of the compound of formula (III), for In some embodiments of the compound of formula (III), for .

[0128] In some embodiments of the compounds of formula (III), each R7 is independently hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of formula (III), each R7 is hydrogen. In some embodiments of the compounds of formula (III), two R7s together form a cycloalkyl group.

[0129] In some embodiments of compounds of formula (III), each R8 is a C1-C6 alkyl group; or two R8 groups on the same carbon atom together form a side-oxygen group. In some embodiments of compounds of formula (III), two R8 groups on opposite carbon atom together form a cycloalkyl group. In some embodiments of compounds of formula (III), two R8 groups on the same carbon atom together form a cycloalkyl group. In some embodiments of compounds of formula (III), two R8 groups on adjacent carbon atom together form a cycloalkyl group.

[0130] In some embodiments of the compound of formula (III), n is 0. In some embodiments of the compound of formula (III), n is 1. In some embodiments of the compound of formula (III), n is 2. In some embodiments of the compound of formula (III), n is 3. In some embodiments of the compound of formula (III), n is 4. In some embodiments of the compound of formula (III), n is 5. In some embodiments of the compound of formula (III), n is 6. In some embodiments of the compound of formula (III), n is 0 to 3. In some embodiments of the compound of formula (III), n is 1 to 3. In some embodiments of the compound of formula (III), n is 1 or 2. In some embodiments of the compound of formula (III), n is 1 to 4. In some embodiments of the compound of formula (III), n is 2 to 4.

[0131] In some embodiments of the compounds of formula (III), each R 11 is independently deuterium, halogen, -CN, -OH, -OR a, -NR cR d, -C(=O)Ra, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds of formula (III), each R 11 is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterylalkyl. In some embodiments of the compounds of formula (III), each R11 is independently a halogen or a C1-C6 alkyl group.

[0132] In some embodiments of the compound of formula (III) , q is 0 or 1. In some embodiments of the compound of formula (III) , q is 1 or 2. In some embodiments of the compound of formula (III) , q is 0. In some embodiments of the compound of formula (III) , q is 1. In some embodiments of the compound of formula (III) , q is 2. In some embodiments of the compound of formula (III) , q is 3.

[0133] In some embodiments of the compounds of formula (III), R12 is a C1-C6 alkyl or cycloalkyl. []

[0134] This article also discloses a compound of formula (III'), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Formula (III'), in: The ring C is a 3- to 16-membered monocyclic, bicyclic, or tricyclic ring, which may contain 1 to 5 heteroatoms selected from the groups of O, N, S, P, or B, depending on the case. Each RC is independently a deuterium, halogen, -CN, -NO₂, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)₂R a, -S(=O)₂NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)₂R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-Heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are, depending on the case, and independently substituted by one or more R Ca; Or two RC atoms on the same atom can together form a side oxygen group; Each RCa is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcd, -NRcRd, -NR bC(=O)NRcd, -NR bC(=O)Ra, -NR bC(=O)ORb, -NR bS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 6-Heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R Ca atoms on the same atom can together form a side oxygen group; r is between 0 and 6; W3 is absent; it is either -C(R7)2- or C2- ynyl group. Each R 7 is independently hydrogen, deuterium, halogen, -CN, -OH, -OR a, -NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Or two R7s together form a cycloalkyl or heterocycloalkyl group; each may be substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, depending on the case. Each R 8 is independently a deuterium, halogen, -CN, -NO 2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O) 2R a, -S(=O) 2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O) 2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-Heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R8 atoms on the same carbon atom may together form a side group; Two R8s on the same carbon, adjacent carbon, or opposite carbon may be used together to form a cycloalkyl or heterocycloalkyl group; each may be substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, or C1-C6 heteroalkyl groups, as appropriate. n is between 0 and 6; A is N, CR, 11, or CH; R12 is a C1-C6 alkyl or a C1-C6 deuterylalkyl; Each R11 is independently a deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6. Heteroalkyl, cycloalkyl, or heterocycloalkyl; q is between 0 and 3; Each Ra is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, as appropriate, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O) 2NHCH 3, -S(=O) 2N(CH 3) 2, -NH 2, -NHCH 3, -N(CH 3) 2, -C(=O)CH 3, -C(=O)OH, -C(=O)OCH 3, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 deuteralkyl, C 1-C 6 hydroxyalkyl, C 1-C 6 aminoalkyl, or C 1-C 6 heteroalkyl substitution; Each Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, depending on the case, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH 2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl substitution; and Each Rc and Rd is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, depending on the case, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH 2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl substitution; Alternatively, Rc and Rd together with the atoms they are attached to form heterocyclic alkyl groups, which may be substituted with one or more side oxygen groups, deuterium, halogens, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. The constraint is that when n is 0, then Not for .

[0135] This article also discloses a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Formula (III), in: The ring C is a 3- to 16-membered monocyclic, bicyclic, or tricyclic ring, which may contain 1 to 5 heteroatoms selected from the groups of O, N, S, P, or B, depending on the case. Each RC is independently a deuterium, halogen, -CN, -NO₂, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)₂R a, -S(=O)₂NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)₂R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-Heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are, depending on the case, and independently substituted by one or more R Ca; Or two RC atoms on the same atom can together form a side oxygen group; Each RCa is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcd, -NRcRd, -NR bC(=O)NRcd, -NR bC(=O)Ra, -NR bC(=O)ORb, -NR bS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 6-Heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R Ca atoms on the same atom can together form a side oxygen group; r is between 0 and 6; W3 is absent; it is either -C(R7)2- or C2- ynyl group. Each R 7 is independently hydrogen, deuterium, halogen, -CN, -OH, -OR a, -NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Or two R7s together form a cycloalkyl or heterocycloalkyl group; each may be substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, depending on the case. Each R 8 is independently a deuterium, halogen, -CN, -NO 2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O) 2R a, -S(=O) 2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O) 2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-Heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R8 atoms on the same carbon atom may together form a side group; Two R8s on the same carbon, adjacent carbon, or opposite carbon may be used together to form a cycloalkyl or heterocycloalkyl group; each may be substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, or C1-C6 heteroalkyl groups, as appropriate. n is between 0 and 6; Each R11 is independently a deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6. Heteroalkyl, cycloalkyl, or heterocycloalkyl; q is between 0 and 3; Each Ra is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, as appropriate, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O) 2NHCH 3, -S(=O) 2N(CH 3) 2, -NH 2, -NHCH 3, -N(CH 3) 2, -C(=O)CH 3, -C(=O)OH, -C(=O)OCH 3, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 deuteralkyl, C 1-C 6 hydroxyalkyl, C 1-C 6 aminoalkyl, or C 1-C 6 heteroalkyl substitution; Each Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, depending on the case, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH 2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl substitution; and Each Rc and Rd is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, depending on the case, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH 2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl substitution; Alternatively, Rc and Rd together with the atoms they are attached to form heterocyclic alkyl groups, which may be substituted with one or more side oxygen groups, deuterium, halogens, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. The constraint is that when n is 0, then Not for .

[0136] In some embodiments of compounds of formula (III) or (III'), the ring C is a 3- to 7-membered monocyclic ring, which may contain 1 to 3 heteroatoms selected from the group consisting of O, N or S.

[0137] In some embodiments of compounds of formula (III) or (III'), the ring C is phenyl.

[0138] In some embodiments of compounds of formula (III) or (III'), the ring C is a 5- to 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[0139] In some embodiments of compounds of formula (III) or (III'), the ring C is a 5-membered heteroaryl group comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.

[0140] In some embodiments of compounds of formula (III) or (III'), the ring C is a 6-membered heteroaryl group comprising 1 to 3 N heteroatoms.

[0141] In some embodiments of compounds of formula (III) or (III'), the ring C is a 3- to 7-membered cycloalkyl group.

[0142] In some embodiments of compounds of formula (III) or (III'), the ring C is a 3- to 7-membered heterocyclic alkyl group comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[0143] In some embodiments of compounds of formula (III) or (III'), the ring C is a 6- to 12-membered bicyclic ring, which may contain 1 to 3 heteroatoms selected from the group consisting of O, N or S.

[0144] In some embodiments of compounds of formula (III) or (III'), the ring C is a 6- to 12-membered bicyclic heterocyclic alkyl group comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[0145] In some embodiments of compounds of formula (III) or (III'), the ring C is a 6- to 12-membered bicyclic heteroaryl group comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[0146] In some embodiments of compounds of formula (III) or (III'), the ring C is an 8- to 16-membered tricyclic ring, which may contain 1 to 3 heteroatoms selected from the group consisting of O, N or S.

[0147] In some embodiments of compounds of formula (III) or (III'), the ring C is an 8- to 16-membered tricyclic heterocyclic alkyl group comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[0148] In some embodiments of compounds of formula (III) or (III'), each RC is independently deuterium, halogen, -CN, -OH, -OR a, -NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; or two RCs on the same atom together form a side oxygen group. In some embodiments of compounds of formula (III) or (III'), each RC is independently deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterylalkyl; or two RCs on the same atom together form a side oxygen group. In some embodiments of compounds of formula (III) or (III'), each RC is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of compounds of formula (III) or (III'), each RC is independently C1-C6 alkyl. In some embodiments of compounds of formula (III) or (III'), the RC is not C1-C6 alkyl. In some embodiments of compounds of formula (III) or (III'), the RC is not C1-C6 haloalkyl.

[0149] In some embodiments of compounds of formula (III) or (III'), r is 0 to 4. In some embodiments of compounds of formula (III) or (III'), r is 1 to 3. In some embodiments of compounds of formula (III) or (III'), r is 0 or 1. In some embodiments of compounds of formula (III) or (III'), r is 0 to 3. In some embodiments of compounds of formula (III) or (III'), r is 1 or 2. In some embodiments of compounds of formula (III) or (III'), r is 1 or 2. In some embodiments of compounds of formula (III) or (III'), r is 1. In some embodiments of compounds of formula (III) or (III'), r is 2. In some embodiments of compounds of formula (III) or (III'), r is 3. In some embodiments of compounds of formula (III) or (III'), r is 4.

[0150] In some embodiments of compounds of formula (III) or (III'), for .

[0151] In some embodiments of compounds of formula (III) or (III'), for .

[0152] In some embodiments of compounds of formula (III) or (III'), W3 is absent. In some embodiments of compounds of formula (III) or (III'), W3 is C2-ynyl. In some embodiments of compounds of formula (III) or (III'), W3 is -C(R7)2-.

[0153] In some embodiments of compounds of formula (III) or (III'), each R7 is independently hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of formula (III) or (III'), each R7 is hydrogen. In some embodiments of compounds of formula (III) or (III'), two R7s together form a cycloalkyl group.

[0154] In some embodiments of compounds of formula (III) or (III'), each R8 is a C1-C6 alkyl group; or two R8 groups on the same carbon atom together form a side-oxygen group. In some embodiments of compounds of formula (III) or (III'), two R8 groups on opposite carbon atom together form a cycloalkyl group. In some embodiments of compounds of formula (III) or (III'), two R8 groups on the same carbon atom together form a cycloalkyl group. In some embodiments of compounds of formula (III) or (III'), two R8 groups on adjacent carbon atom together form a cycloalkyl group.

[0155] In some embodiments of compounds of formula (III) or (III'), n is 0. In some embodiments of compounds of formula (III) or (III'), n is 1. In some embodiments of compounds of formula (III) or (III'), n is 2. In some embodiments of compounds of formula (III) or (III'), n is 3. In some embodiments of compounds of formula (III) or (III'), n is 4. In some embodiments of compounds of formula (III) or (III'), n is 5. In some embodiments of compounds of formula (III) or (III'), n is 6. In some embodiments of compounds of formula (III) or (III'), n is 0 to 3. In some embodiments of compounds of formula (III) or (III'), n is 1 to 3. In some embodiments of compounds of formula (III) or (III'), n is 1 or 2. In some embodiments of compounds of formula (III) or (III'), n is 1 to 4. In some embodiments of compounds of formula (III) or (III'), n is 2 to 4.

[0156] In some embodiments of compounds of formula (III) or (III'), each R 11 is independently deuterium, halogen, -CN, -OH, -OR a, -NR cR d, -C(=O)Ra, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (III) or (III'), each R 11 is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterylalkyl. In some embodiments of compounds of formula (III) or (III'), each R 11 is independently halogen or C1-C6 alkyl.

[0157] In some embodiments of compounds of formula (III) or (III'), q is 0 or 1. In some embodiments of compounds of formula (III) or (III'), q is 1 or 2. In some embodiments of compounds of formula (III) or (III'), q is 0. In some embodiments of compounds of formula (III) or (III'), q is 1. In some embodiments of compounds of formula (III) or (III'), q is 2. In some embodiments of compounds of formula (III) or (III'), q is 3.

[0158] In some embodiments of compounds of formula (III) or (III'), the compound is a compound of the following formula: , where Y is N, CH or CF; A1 is CH2, CF2, CHF, CHCH3, C(CH3)2; B1 is CH2, CF2, CHF, CHCH3, C(CH3)2; and C1 is O or S; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0159] In some embodiments of compounds of formula (III) or (III'), the compound is a compound of the following formula: , where Y is N, CH or CF; A2 is CH2, CF2, CHF, CHCH3, C(CH3)2; B2 is CH2, CF2, CHF, CHCH3, C(CH3)2; and C2 is CH2, CF2, CHF, CHCH3, C(CH3)2; and D2 is O or S; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0160] In some embodiments of compounds of formula (III) or (III'), the compound is a compound of the following formula: , wherein Y is N, CH or CF; A3 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl or, where applicable, halogen-substituted cycloalkyl; B3 is O or S; and C3 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or, where applicable, halogen-substituted cycloalkyl; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0161] In some embodiments of compounds of formula (III) or (III'), the compound is a compound of the following formula: , wherein Y is N, CH or CF; A4 is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl; B4 is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl; and C4 is O or S; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0162] In some embodiments of compounds of formula (III) or (III'), the compound is a compound of the following formula: Y is N, CH or CF; A5 is O or S; B5 is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl; and C5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0163] In some embodiments of compounds of formula (III) or (III'), the compound is a compound of the following formula: , wherein Y is N, CH or CF; A6 is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl; and B6 is O or S; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0164] In some embodiments of compounds of formula (III) or (III'), the compound is a compound of the following formula: , wherein Y is N, CH or CF; A7 is O or S; B7 is CH2, CF2, CHF, CHCH3, C(CH3)2; and C7 is CH2, CF2, CHF, CHCH3, C(CH3)2; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0165] In some embodiments of compounds of formula (III) or (III'), the compound is a compound of the following formula: , wherein Y is N, CH or CF; A8 is O or S; B8 is CH2, CF2, CHF, CHCH3, C(CH3)2; C7 is CH2, CF2, CHF, CHCH3, C(CH3)2; and D8 is CH2, CF2, CHF, CHCH3, C(CH3)2; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0166] In some embodiments of compounds of formula (III) or (III'), the compound is a compound of the following formula: Y is N, CH or CF; A9 is O or S; B9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or, where applicable, a halogen-substituted cycloalkyl; and C9 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl or, where applicable, a halogen-substituted cycloalkyl; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0167] In some embodiments of compounds of formula (III) or (III'), the compound is a compound of the following formula: In this system, Y is N, CH, or CF; A is CH, CMe, CCF3, CCl, CF, or N; R12 is C1-C6 alkyl, C1-C6 deuterylalkyl; each R11 is independently hydrogen, deuterium, or halogen; and A10 is C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterylalkyl.

[0168] This article discloses a compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Formula (IV), in: R1 represents hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, or heterocycloalkyl; X is either N or CR 2; R2 represents hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, or heterocycloalkyl; R1 and R2 together form cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups; each may be substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, as appropriate. Z is either N or CR 4; R4 represents hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, or heterocycloalkyl; Y is either N or CR 5; R5 represents hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, or heterocycloalkyl; R6 represents hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, or heterocycloalkyl; R 7a is deuterium, halogen, -CN, -OH, -OR a, -NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R 7b is hydrogen, deuterium, halogen, -CN, -OH, -OR a, -NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R7a and R7b together may form cycloalkyl or heterocycloalkyl groups; each may be substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, as appropriate. Each R 8 is independently a deuterium, halogen, -CN, -NO 2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O) 2R a, -S(=O) 2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O) 2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-Heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R8 atoms on the same carbon atom may together form a side group; Two R8s on the same carbon, adjacent carbon, or opposite carbon may be used together to form a cycloalkyl or heterocycloalkyl group; each may be substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, or C1-C6 heteroalkyl groups, as appropriate. n is between 0 and 6; Each R11 is independently a deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6. Heteroalkyl, cycloalkyl, or heterocycloalkyl; q is between 0 and 3; Each Ra is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, as appropriate, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O) 2NHCH 3, -S(=O) 2N(CH 3) 2, -NH 2, -NHCH 3, -N(CH 3) 2, -C(=O)CH 3, -C(=O)OH, -C(=O)OCH 3, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 deuteralkyl, C 1-C 6 hydroxyalkyl, C 1-C 6 aminoalkyl, or C 1-C 6 heteroalkyl substitution; Each Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, depending on the case, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH 2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl substitution; and Each Rc and Rd is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, depending on the case, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH 2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl substitution; Alternatively, Rc and Rd together with the atoms they are attached to form heterocyclic alkyl groups, which may be substituted with one or more side oxygen groups, deuterium, halogens, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, or C1-C6 heteroalkyl.

[0169] In some embodiments of compounds of formula (IV), R1 is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, or cycloalkyl. In some embodiments of compounds of formula (IV), R1 is a C1-C6 alkyl.

[0170] In some embodiments of the compound of formula (IV), X is CR 2 and Y is CR 5.

[0171] In some embodiments of the compound of formula (IV), X is N and Y is CR5.

[0172] In some embodiments of compounds of formula (IV), R5 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of compounds of formula (IV), R5 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of compounds of formula (IV), R5 is hydrogen.

[0173] In some embodiments of the compound of formula (IV), X is CR 2 and Y is N.

[0174] In some embodiments of compounds of formula (IV), R2 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of compounds of formula (IV), R2 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of compounds of formula (IV), R2 is hydrogen.

[0175] In some embodiments of the compound of formula (IV), X is N and Y is N.

[0176] In some embodiments of the compound of formula (IV), Z is N. In some embodiments of the compound of formula (IV), Z is CR 4.

[0177] In some embodiments of compounds of formula (IV), R4 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of compounds of formula (IV), R4 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of compounds of formula (IV), R4 is hydrogen.

[0178] In some embodiments of the compound of formula (IV), R6 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of the compound of formula (IV), R6 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compound of formula (IV), R6 is hydrogen.

[0179] In some embodiments of the compound of formula (IV), R 7a is deuterium, a halogen, a C1-C6 alkyl, a C1-C6 haloalkyl, or a C1-C6 deuterylalkyl. In some embodiments of the compound of formula (IV), R 7a is deuterium or a C1-C6 alkyl. In some embodiments of the compound of formula (IV), R 7a is deuterium.

[0180] In some embodiments of the compound of formula (IV), R 7b is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterylalkyl.

[0181] In some embodiments of the compound of formula (IV), R7a and R7b together form a cycloalkyl group. In some embodiments of the compound of formula (IV), R7a and R7b are both deuterium.

[0182] In some embodiments of compounds of formula (IV), each R8 is a C1-C6 alkyl group; or two R8 groups on the same carbon atom together form a side-oxygen group. In some embodiments of compounds of formula (IV), two R8 groups on opposite carbon atom together form a cycloalkyl group. In some embodiments of compounds of formula (IV), two R8 groups on the same carbon atom together form a cycloalkyl group. In some embodiments of compounds of formula (IV), two R8 groups on adjacent carbon atom together form a cycloalkyl group.

[0183] In some embodiments of the compound of formula (IV), n is 0. In some embodiments of the compound of formula (IV), n is 1. In some embodiments of the compound of formula (IV), n is 2. In some embodiments of the compound of formula (IV), n is 3. In some embodiments of the compound of formula (IV), n is 4. In some embodiments of the compound of formula (IV), n is 5. In some embodiments of the compound of formula (IV), n is 6. In some embodiments of the compound of formula (IV), n is 0 to 3. In some embodiments of the compound of formula (IV), n is 1 to 3. In some embodiments of the compound of formula (IV), n is 1 or 2. In some embodiments of the compound of formula (IV), n is 1 to 4. In some embodiments of the compound of formula (IV), n is 2 to 4.

[0184] In some embodiments of compounds of formula (IV), each R11 is independently deuterium, halogen, -CN, -OH, -ORa, -NR cRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NR cRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (IV), each R11 is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterylalkyl. In some embodiments of compounds of formula (IV), each R11 is independently halogen or C1-C6 alkyl.

[0185] In some embodiments of the compound of formula (IV), q is 0 or 1. In some embodiments of the compound of formula (IV), q is 1 or 2. In some embodiments of the compound of formula (IV), q is 0. In some embodiments of the compound of formula (IV), q is 1. In some embodiments of the compound of formula (IV), q is 2. In some embodiments of the compound of formula (IV), q is 3.

[0186] This article discloses a compound of formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Equation (V), in: R1 represents hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, or heterocycloalkyl; X is either N or CR 2; R2 represents hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, or heterocycloalkyl; R1 and R2 together form cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups; each may be substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, as appropriate. Z is either N or CR 4; R4 represents hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, or heterocycloalkyl; Y is either N or CR 5; R5 represents hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, or heterocycloalkyl; R6 represents hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, or heterocycloalkyl; Each R 7 is independently hydrogen, deuterium, halogen, -CN, -OH, -OR a, -NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Or two R7s together form a cycloalkyl or heterocycloalkyl group; each may be substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, depending on the case. Each R 8 is independently a deuterium, halogen, -CN, -NO 2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O) 2R a, -S(=O) 2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O) 2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6-Heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R8 atoms on the same carbon atom may together form a side group; Two R8s on the same carbon, adjacent carbon, or opposite carbon may be used together to form a cycloalkyl or heterocycloalkyl group; each may be substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, or C1-C6 heteroalkyl groups, as appropriate. n is between 1 and 6; Each R11 is independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C 6. Heteroalkyl, cycloalkyl, or heterocycloalkyl; The limiting condition is that one R11 and one R8 together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; each of them may be substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl groups, as appropriate. Each A is independently N or CR 11; R12 is a C1-C6 alkyl or a C1-C6 deuterylalkyl; Each Ra is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, as appropriate, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O) 2NHCH 3, -S(=O) 2N(CH 3) 2, -NH 2, -NHCH 3, -N(CH 3) 2, -C(=O)CH 3, -C(=O)OH, -C(=O)OCH 3, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 deuteralkyl, C 1-C 6 hydroxyalkyl, C 1-C 6 aminoalkyl, or C 1-C 6 heteroalkyl substitution; Each Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, depending on the case, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH 2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl substitution; and Each Rc and Rd is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, depending on the case, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH 2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl substitution; Alternatively, Rc and Rd together with the atoms they are attached to form heterocyclic alkyl groups, which may be substituted with one or more side oxygen groups, deuterium, halogens, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, or C1-C6 heteroalkyl.

[0187] In some embodiments of compounds of formula (V), R1 is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl.

[0188] In some embodiments of compounds of formula (V), R1 is a C1-C6 alkyl group.

[0189] In some embodiments of the compound of formula (V), X is N and Y is CR5.

[0190] In some embodiments of compounds of formula (V), R5 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of compounds of formula (V), R5 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of compounds of formula (V), R5 is hydrogen.

[0191] In some embodiments of the compound of formula (V), X is CR 2 and Y is N.

[0192] In some embodiments of compounds of formula (V), R2 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of compounds of formula (V), R2 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of compounds of formula (V), R2 is hydrogen.

[0193] In some embodiments of the compound of formula (V), X is N and Y is N. In some embodiments of the compound of formula (V), Z is N. In some embodiments of the compound of formula (V), Z is CR 4.

[0194] In some embodiments of compounds of formula (V), R4 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of compounds of formula (V), R4 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of compounds of formula (V), R4 is hydrogen.

[0195] In some embodiments of compounds of formula (V), R6 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of compounds of formula (V), R6 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of compounds of formula (V), R6 is hydrogen.

[0196] In some embodiments of compounds of formula (V), each R7 is independently hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of formula (V), each R7 is hydrogen. In some embodiments of compounds of formula (V), two R7s together form a cycloalkyl group.

[0197] In some embodiments of compounds of formula (V), each R8 is a C1-C6 alkyl group; or two R8 groups on the same carbon atom together form a side-oxygen group. In some embodiments of compounds of formula (V), two R8 groups on opposite carbon atom together form a cycloalkyl group. In some embodiments of compounds of formula (V), two R8 groups on the same carbon atom together form a cycloalkyl group. In some embodiments of compounds of formula (V), two R8 groups on adjacent carbon atom together form a cycloalkyl group.

[0198] In some embodiments of the compound of formula (V), n is 0. In some embodiments of the compound of formula (V), n is 1. In some embodiments of the compound of formula (V), n is 2. In some embodiments of the compound of formula (V), n is 3. In some embodiments of the compound of formula (V), n is 4. In some embodiments of the compound of formula (V), n is 5. In some embodiments of the compound of formula (V), n is 6. In some embodiments of the compound of formula (V), n is 0 to 3. In some embodiments of the compound of formula (V), n is 1 to 3. In some embodiments of the compound of formula (V), n is 1 or 2. In some embodiments of the compound of formula (V), n is 1 to 4. In some embodiments of the compound of formula (V), n is 2 to 4.

[0199] In some embodiments of compounds of formula (V), each R11 is independently deuterium, halogen, -CN, -OH, -ORa, -NR cRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NR cRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (V), each R11 is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterylalkyl. In some embodiments of compounds of formula (V), each R11 is independently halogen or C1-C6 alkyl.

[0200] In some embodiments of the compound of formula (V), one A is CR 11 and the other is N. In some embodiments of the compound of formula (V), both A are CR 11. In some embodiments of the compound of formula (V), both A are N.

[0201] In some embodiments of compounds of formula (V), R12 is a C1-C6 alkyl group. In some embodiments of compounds of formula (V), R12 is a C1-C6 deuterylalkyl group.

[0202] In some embodiments of compounds of formula (V), one R11 together with one R8 forms a cycloalkyl or heterocycloalkyl group; each is, as appropriate, substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, or C1-C6 heteroalkyl groups.

[0203] In some embodiments of compounds of formula (V), an R11 together with an R8 forms a heterocyclic alkyl group, which may be substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, or C1-C6 heteroalkyl groups.

[0204] In some embodiments of compounds of formula (V), an R11 together with an R8 forms a 5- or 6-membered heterocyclic alkyl group, which may be substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, or C1-C6 heteroalkyl groups, depending on the case.

[0205] In some embodiments of compounds of formula (V), one R11 together with one R8 forms a 6-membered heterocyclic alkyl group, which may be substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, or C1-C6 heteroalkyl groups.

[0206] In some embodiments of compounds of formula (V), one R11 together with one R8 forms a 5-membered heterocyclic alkyl group, which may be substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, or C1-C6 heteroalkyl groups.

[0207] In some embodiments of the compound of formula (V), the compound has the following formula: R1 is a C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteralkyl; Y is N, CH, or CF; each A is independently CH, CD, CMe, CCF3, CCl, CF, or N; B1 is O, S, NH, NMe, NCD3, CH2, CHF, CD2, or CDH; R is hydrogen, deuterium, or halogen; and R12 is a C1-C6 alkyl or C1-C6 deuteralkyl.

[0208] In some embodiments of the compounds disclosed herein, each Ra is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, as appropriate, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH 3, -C(=O)OH, -C(=O)OCH 3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl substituted. In some embodiments of the compounds disclosed herein, each Ra is independently a C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently, as appropriate, derived from one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C1-C6 ... 6-aminoalkyl or C1-C6 heteroalkyl substitution. In some embodiments of the compounds disclosed herein, each Ra is independently C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each Ra is independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each Ra is independently C1-C6 alkyl.

[0209] In some embodiments of the compounds disclosed herein, each Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, as appropriate, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH 3, -C(=O)OH, -C(=O)OCH 3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl substituted. In some embodiments of the compounds disclosed herein, each Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently, as appropriate, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxy ... 6-aminoalkyl or C1-C6 heteroalkyl substitution. In some embodiments of the compounds disclosed herein, each Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each Rb is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each Rb is independently hydrogen or C1-C6 alkyl.

[0210] In some embodiments of the compounds disclosed herein, each Rc and Rd is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, as appropriate, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH 3, -C(=O)OH, -C(=O)OCH 3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl substituted. In some embodiments of the compounds disclosed herein, each Rc and Rd is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently, as appropriate, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterylalkyl, C1-C6 hydroxyalkyl, C 1-C6 amine alkyl, C1-C6 heteroalkyl substitution. In some embodiments of the compounds disclosed herein, each Rc and Rd is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each Rc and Rd is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each Rc and Rd is independently hydrogen or C1-C6 alkyl.

[0211] In some embodiments of the compounds disclosed herein, Rc and Rd together with the atoms to which they are attached form heterocyclic alkyl groups, which may be substituted with one or more lateral alkyl groups, deuterium, halogen, -CN, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, or C1-C6 heteroalkyl.

[0212] In some embodiments of the compounds disclosed herein, each RA, RB, RC, Ra, Rb, Rc, Rd, the cycloalkyl or heterocycloalkyl formed when two R7s are bonded together, the cycloalkyl or heterocycloalkyl formed when two R8s are bonded together, and the heterocycloalkyl formed when Rc and Rd are bonded together, is independently substituted with one, two, three, or four substituents as defined herein. In some embodiments of the compounds disclosed herein, each RA, RB, RC, Ra, Rb, Rc, Rd, the cycloalkyl or heterocycloalkyl formed when two R7s are bonded together, the cycloalkyl or heterocycloalkyl formed when two R8s are bonded together, and the heterocycloalkyl formed when Rc and Rd are bonded together, is independently substituted with one or two substituents as defined herein.

[0213] Any combination of the groups described above for various variables is covered herein. Throughout this specification, those skilled in the art will select the groups and their substituents to obtain stable moieties and compounds.

[0214] In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or stereoisomers are selected from the compounds in Table 1. [, , ] [] [surface] [1] []

[0215] In some embodiments, the compound is selected from the group consisting of: Or, a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0216] In some embodiments, the compound is selected from the group consisting of: Or, a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0217] In some embodiments, the compound is selected from the group consisting of: Or, a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0218] In some embodiments, the compound is selected from the group consisting of: Or, a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0219] In some embodiments, the compound is selected from the group consisting of: Or, a pharmaceutically acceptable salt, solvate or stereoisomer thereof. [Other forms of the compounds revealed in this article] [] Isomers / Stereoisomers

[0220] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, engegen (E), and zusammen (Z) isomers and their corresponding mixtures. In some cases, the compounds described herein have one or more palmar centers, each center existing in an R or S configuration. The compounds described herein include all non-mirror image isomers, mirror image isomers, and epimeric forms and their corresponding mixtures. In additional embodiments of the compounds and methods provided herein, mixtures of mirror image isomers and / or non-mirror image isomers produced by a single preparation step, combination, or interconversion are suitable for the applications described herein. In some embodiments, the compounds described herein are prepared in their individual stereoisomer forms by reacting a racemic mixture other than the compound with an optically active resolving agent to form a non-mirror image isomer pair, separating the non-mirror image isomers, and recovering the optically pure mirror image isomers. In some embodiments, a dissociable complex is preferred. In some embodiments, the non-mirror image isomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated using these differences. In some embodiments, the non-mirror image isomers are separated by piezometric chromatography or preferably by separation / resolution techniques based on differences in solubility. In some embodiments, the optically pure mirror image isomers are subsequently recovered along with the eluent using any practical means that do not cause racemization. Labeled compounds

[0221] In some embodiments, the compounds described herein are present in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds in the form of a pharmaceutical composition. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are the same as those listed herein, but in fact have one or more atoms replaced by atomic substitutions that differ from the atomic masses or mass numbers commonly found in nature. Examples of isotopes that may be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such isotopes as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds described herein containing the aforementioned isotopes and / or other isotopes of other atoms, as well as their pharmaceutically acceptable salts, solvates, or stereoisomers, are within the scope of this invention. Certain isotopically labeled compounds (e.g., compounds containing radioactive isotopes such as 3H and 14C) are suitable for pharmaceutical and / or tissue distribution analysis. Tritium (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, substitution with heavy isotopes such as deuterium (i.e., 2H) yields certain therapeutic advantages resulting from greater metabolic stability, such as extended in vivo half-life or reduced dose requirements.

[0222] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labeling, or chemiluminescent labeling. Pharmaceutically acceptable salts.

[0223] In some embodiments, the compounds described herein are present in their pharmaceutically acceptable salt form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering a pharmaceutically acceptable salt. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such a pharmaceutically acceptable salt in the form of a pharmaceutical composition.

[0224] In some embodiments, the compounds described herein have acidic or basic groups and thus react with a variety of inorganic or organic bases and any of inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, such salts are prepared in situ during the final isolation and purification of the compounds disclosed herein or their solvates or stereoisomers, or by reacting a purified compound, which is in its free form, with a suitable acid or base alone, and then isolating the resulting salt.

[0225] Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with inorganic, organic acids, or inorganic bases. Such salts include acetates, acrylates, adipates, alginates, aspartates, benzoates, benzenesulfonates, bisulfates, bisulfites, bromides, butyrates, butyn-1,4-dicitates, camphorates, camphorsulfonates, hexanoates, octanoates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, diglucuronates, dihydrophosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfonates, formates, transbutenedioic acid, glucoheptanoates, glycerophosphates, glycolic acid salts, hemisulfates, heptanoates, hexyn-1,6-dicitates, hydroxybenzoates, and gamma-hydroxybutyrates. Hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, amygdalinate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrophosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pentanoate, propionate, pyrosulfonate, pyrophosphate, propynate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, octanoate, sebacic acid salt, sulfonate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and xylenesulfonate.

[0226] Furthermore, the compounds described herein can be prepared in a pharmaceutically acceptable salt form by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, and tartaric acid. Acids, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-en-1-carboxylic acid, glucohepanoic acid, 4,4'-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tributylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, or mucoconic acid. In some embodiments, other acids (such as oxalic acid), although pharmaceutically unacceptable on their own, are used to prepare salts that serve as intermediates in obtaining the compounds disclosed herein, their solvates or stereoisomers, and their pharmaceutically acceptable acid addition salts.

[0227] In some embodiments, the compounds described herein containing free acid groups react with a suitable base (such as hydroxides, carbonates, bicarbonates, and sulfates of pharmaceutically acceptable metal cations), ammonia, or a pharmaceutically acceptable primary, secondary, tertiary, or quaternary organic amine. Representative salts include alkali metal or alkaline earth metal salts, such as lithium, sodium, potassium, calcium, and magnesium salts, as well as aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4 alkyl)4, and the like.

[0228] Representative organic amines suitable for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, and the like. It should be understood that the compounds described herein also include quaternary ammoniation of any basic nitrogen-containing group they contain. In some embodiments, such quaternary ammoniation yields water- or oil-soluble or dispersible products. Solvents

[0229] In some embodiments, the compounds described herein are present in the form of solvates. The present invention provides a method for treating diseases by administering such solvates. The present invention further provides a method for treating diseases by administering such solvates in the form of a pharmaceutical composition.

[0230] The solvates contain stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments, are formed using pharmaceutically acceptable solvents such as water, ethanol, and the like. When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcoholic compound is formed. The solvates of the compounds described herein can suitably be prepared or formed during the processes described herein. By way of example only, the hydrates of the compounds described herein can suitably be prepared from aqueous / organic solvent mixtures using organic solvents including, but not limited to, dialkyl, tetrahydrofuran, or methanol. Furthermore, the compounds provided herein can exist in both solvated and non-solventized forms. Generally, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the non-solventized form. Tautomers

[0231] In some cases, compounds exist as tautomers. The compounds described herein include all possible tautomers of the formulas described herein. Tautomers are compounds that can interconvert through the migration of hydrogen atoms, which involves the conversion of single bonds with adjacent double bonds. A chemical equilibrium of tautomers exists in the bond arrangements in which tautomerization may occur. This covers all tautomer forms of the compounds disclosed herein. The precise ratio of tautomers depends on several factors, including temperature, solvent, and pH. [Treatment methods] []

[0232] This article discloses a method for treating diseases in which inhibition of PARP is beneficial, the method comprising administering a compound disclosed herein. This article also discloses a method for treating diseases in which inhibition of PARP1 is beneficial, the method comprising administering a compound disclosed herein. In some embodiments, the disease is cancer. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer (such as stomach cancer and colorectal cancer), or lung cancer. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer. In some embodiments, the cancer is leukemia, colon cancer, glioblastoma, lymphoma, melanoma, or cervical cancer.

[0233] In some embodiments, the cancer contains BRCA1 and / or BRCA2 mutations.

[0234] In some embodiments, cancers containing BRCA1 and / or BRCA2 mutations include bladder cancer, brain cancer and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer, or uterine cancer.

[0235] In some embodiments, the cancer is a cancer lacking Flomologous recombination (FIR)-dependent DNA DSB repair activity. The FIR-dependent DNA DSB repair pathway repairs double-strand breaks (DSBs) in DNA via homology mechanisms to reform continuous DNA helices. The components of the FIR-dependent DNA DSB repair pathway include (but are not limited to) ATM (NM_000051), RAD51 (NM_002875), RAD51 L1 (NM_002877), RAD51 C (NM_002876), RAD51 L3 (NM_002878), DMC1 (NM_007068), XRCC2 (NM_005431), XRCC3 (NM_005432), RAD52 (NM_002879), RAD54L (NM_003579), RAD54B (NM_012415), BRCA1 (NM_007295), BRCA2 (NM_000059), RAD50 (NM_005732), MRE1 1 A (NM_005590) and NBS1 (NM_002485). Other proteins involved in the FIR-dependent DNA DSB repair pathway include regulators such as EMSY. In some embodiments, cancer lacking FIR-dependent DNA DSB repair comprises one or more cancer cells with reduced or eliminated ability to repair DNA DSBs via this pathway relative to normal cells, i.e., reduced or eliminated activity of the FIR-dependent DNA DSB repair pathway in one or more cancer cells.

[0236] In some embodiments, the activity of one or more components of the FIR-dependent DNA DSB repair pathway is eliminated in one or more cancer cells in an individual suffering from cancer lacking FIR-dependent DNA DSB repair.

[0237] In some embodiments, cancer cells exhibit a BRCA1 and / or BRCA2 deficiency phenotype, meaning that BRCA1 and / or BRCA2 activity is reduced or eliminated in cancer cells. Cancer cells with this phenotype may lack BRCA1 and / or BRCA2, meaning that the expression and / or activity of BRCA1 and / or BRCA2 can be reduced or eliminated in cancer cells, for example, through mutations or polymorphisms encoding nucleic acids or through amplification, mutations, or polymorphisms of genes encoding regulatory factors (e.g., the EMSY gene encoding a BRCA2 regulatory factor). BRCA1 and BRCA2 are known tumor suppressors, and their wild-type counterparts are frequently lost in tumors containing heterozygous conjugate vectors. Amplification of the EMSY gene, encoding a BRCA2 binding factor, is also known to be associated with breast and ovarian cancer. Carriers of mutations in BRCA1 and / or BRCA2 also have a high risk of certain cancers, including breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematologic malignancies, gastrointestinal cancer, and lung cancer.

[0238] To minimize the risk of off-target effects, drug molecules need to be selective for specific targets.

[0239] Avoiding inhibition of PARP family isoforms beyond PARP1 is crucial in minimizing toxicity that can result from inhibition of non-PARP1 isoforms. Pharmacologically, inhibition of PARP isoforms beyond PARP1 can drive toxicity, which reduces the therapeutic index of agents with lower selectivity for PARP1 relative to PARP isoforms. PARP3 (such as PARP1) plays a role in DNA damage, but has also been found to be a key player in the integrity of the mitotic spindle and telomerase (Gauthier, LR., Mortusewicz O. et al. Poly(ADP-ribose) polymerase 3 (PARP3), a newcomer in cellular response to DNA damage and mitotic progression. PNAS, Jan 26, 2011, 108(7) 2783-2788). PARP5A, also known as telomerase 1, plays a crucial role in Wnt signaling and telomere length (Kulak, O., Chen, H., Holohan B. et al. Disruption of Wnt / β-Catenin Signaling and Telomeric Shortening Are Inextricable Consequences of Tankyrase Inhibition in Human Cells. Mol Cell Biol. July 2015; 35(14), 2425-2435). PARP6 is an essential microtubule regulatory gene in mice, and germline mutations in PARP6 that eliminate catalytic activity have a negative impact on neuronal function in humans (Vermehren-Schmaedick, A., Huang JY, Levinson, M. et al. Characterization of PARP6 Function in Knockout Mice and Patients with Developmental Delay. Cells, June 2021; 10(6), 1289).PARP7 catalytic inhibition overstimulates the production of type I interferon, an autoimmune phenotype (Gozgit, JM, Vasbinder, MM, Abo, RP et al. PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition triggers antitumor immunity. Vol. 39, No. 9, September 13, 2021, pp. 1214-1226). Although the exact function of PARP8 has not been established, its gene knockout has been shown to induce mitosis and nuclear morphology defects and reduce cell viability (Vyas, S., Chesarone-Cataldo, M., Todorova, T. et al., A Systematic Analysis of the PARP Protein Family Identifies New Functions Critical for Cell Physiology. Nat. Commun. 2013, 4 (1), 2240). PARP10 has been described as a MYC-interacting protein with tumor suppressor activity (Yu, M., Schreek, S., Cerni, C. et al., PARP-10, a novel Myc-interacting protein with poly(ADP-ribose) polymerase activity, inhibits transformation. Oncogene, 2005, Vol. 24, pp. 1982-1993).

[0240] In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, exhibit higher selectivity for PARP1 than other members of the PARP family, including PARP2, PARP3, PARP6, PARP7, PARP8, PARP10, PARP11, PARP14, PARP15, TNKS1 (PARP5A), and TNKS2 (PARP5B). In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, exhibit higher selectivity for PARP1 than PARP2. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, exhibit higher selectivity for PARP1 than PARP3. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, exhibit higher selectivity for PARP1 than PARP6. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, exhibit higher selectivity for PARP1 than PARP7. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, exhibit higher selectivity for PARP1 than PARP8. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, exhibit higher selectivity for PARP1 than PARP10. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, exhibit higher selectivity for PARP1 than PARP11. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, exhibit higher selectivity for PARP1 than PARP14. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, exhibit higher selectivity for PARP1 than PARP15. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, exhibit higher selectivity for PARP1 than TNKS1 (PARP5A). In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or stereoisomers exhibit higher selectivity for PARP1 than for TNKS2 (PARP5B).

[0241] In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, exhibit selectivity for PARP1 that is more than 10,000 times higher than that for PARP2. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, exhibit selectivity for PARP1 that is more than 9,000 times higher than that for PARP2. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, exhibit selectivity for PARP1 that is more than 8,000 times higher than that for PARP2. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, exhibit selectivity for PARP1 that is more than 7,000 times higher than that for PARP2. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, exhibit selectivity for PARP1 that is more than 6,000 times higher than that for PARP2. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, exhibit selectivity for PARP1 that is more than 5000 times higher than that for PARP2. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, exhibit selectivity for PARP1 that is more than 4000 times higher than that for PARP2. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, exhibit selectivity for PARP1 that is more than 3000 times higher than that for PARP2. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, exhibit selectivity for PARP1 that is more than 2000 times higher than that for PARP2. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, exhibit selectivity for PARP1 that is more than 100 times higher than that for PARP2. In some embodiments, the compounds disclosed herein exhibit at least 400 to 600 times greater selectivity for PARP1 than for PARP2. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, exhibit at least 400 times greater selectivity for PARP1 than for PARP2. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, exhibit at least 500 times greater selectivity for PARP1 than for PARP2.

[0242] In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, exhibit selectivity for PARP1 that is more than 100 times higher than that for PARP3. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, exhibit selectivity for PARP1 that is more than 200 times higher than that for PARP3.

[0243] In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, exhibit at least 200 to 700 times greater selectivity for PARP1 than for PARP3. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, exhibit at least 200 times greater selectivity for PARP1 than for PARP3. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, exhibit at least 650 times greater selectivity for PARP1 than for PARP3.

[0244] In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have a PARP1 selectivity that is more than 1000 times higher than that of PARP6. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have a PARP1 selectivity that is at least 2000 to 3000 times higher than that of PARP6. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have a PARP1 selectivity that is at least 2400 times higher than that of PARP6. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have a PARP1 selectivity that is at least 3000 times higher than that of PARP6.

[0245] In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have a PARP1 selectivity that is more than 500 times higher than that of PARP7. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have a PARP1 selectivity that is at least 600 to 900 times higher than that of PARP7. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have a PARP1 selectivity that is at least 600 times higher than that of PARP7. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have a PARP1 selectivity that is at least 800 times higher than that of PARP7.

[0246] In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have a PARP1 selectivity that is more than 3000 times higher than that of PARP8. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have a PARP1 selectivity that is at least 5000 to 9000 times higher than that of PARP8. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have a PARP1 selectivity that is at least 8000 times higher than that of PARP8. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have a PARP1 selectivity that is at least 5000 times higher than that of PARP8.

[0247] In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have a PARP1 selectivity that is more than 200 times higher than that of PARP10. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have a PARP1 selectivity that is at least 300 to 400 times higher than that of PARP10. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have a PARP1 selectivity that is at least 350 times higher than that of PARP10. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have a PARP1 selectivity that is at least 300 times higher than that of PARP10.

[0248] In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have a PARP1 selectivity that is more than 5 times higher than that of PARP11. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have a PARP1 selectivity that is at least 5 to 270 times higher than that of PARP11. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have a PARP1 selectivity that is at least 6 times higher than that of PARP11. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have a PARP1 selectivity that is at least 270 times higher than that of PARP11.

[0249] In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have PARP1 selectivity that is more than 2000 times higher than that of PARP14. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have PARP1 selectivity that is at least 1400 to 2600 times higher than that of PARP14. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have PARP1 selectivity that is at least 1400 times higher than that of PARP14. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have PARP1 selectivity that is at least 2600 times higher than that of PARP14.

[0250] In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have PARP1 selectivity that is more than 1000 times higher than that of PARP15. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have PARP1 selectivity that is at least 1600 times higher than that of PARP15.

[0251] In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have PARP1 selectivity that is more than 100 times higher than that of TNKS1 (PARP5A). In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have PARP1 selectivity that is at least 100 to 250 times higher than that of TNKS1 (PARP5A). In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have PARP1 selectivity that is at least 100 times higher than that of TNKS1 (PARP5A). In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have PARP1 selectivity that is at least 230 times higher than that of TNKS1 (PARP5A).

[0252] In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have PARP1 selectivity that is more than 100 times higher than that of TNKS2 (PARP5B). In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have PARP1 selectivity that is at least 100 to 150 times higher than that of TNKS2 (PARP5B). In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have PARP1 selectivity that is at least 140 times higher than that of TNKS2 (PARP5B). In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, have PARP1 selectivity that is at least 130 times higher than that of TNKS2 (PARP5B). [Administration]

[0253] In some embodiments, a composition containing the compounds described herein is administered for preventative and / or therapeutic treatment. In some therapeutic applications, the composition is administered to a patient already suffering from the disease or symptom in an amount sufficient to cure or at least partially suppress at least one symptom of the disease or symptom. The effective amount for this purpose depends on the severity and course of the disease or symptom, prior therapy, the patient's health status, weight, and response to the drug, as well as the judgment of the treating physician. The therapeutically effective amount may be determined, as appropriate, by methods including, but not limited to, dose escalation and / or dose range clinical trials.

[0254] In prophylactic use, a composition containing the compound described herein is administered to a patient susceptible to a specific disease, condition, or symptom, or otherwise at risk of such a disease, condition, or symptom. This amount is defined as a "preventatively effective amount or dose." In this use, the precise amount also depends on the patient's health condition, weight, and similar factors. When used on a patient, the effective amount for this purpose will depend on the severity and course of the disease, condition, or symptom, prior treatment, the patient's health condition and response to the drug, and the diagnosis of the treating physician. In one instance, prophylactic treatment comprises administering a pharmaceutical composition containing the compound described herein or a pharmaceutically acceptable salt thereof to a mammal who has previously experienced at least one symptom or risk factor of a treated disease and is currently in remission, to prevent recurrence of symptoms of the disease or symptom.

[0255] In some embodiments where the patient’s condition does not improve, the compound is administered long-term, i.e., for a prolonged period of time, including the entire duration of the patient’s life, in order to improve or otherwise control or limit the symptoms of the patient’s disease or condition, based on the physician’s judgment.

[0256] In some embodiments where the patient's condition improves, the dosage of the administered medication is temporarily reduced or temporarily suspended for a certain period of time (i.e., a "medication holiday"). In specific embodiments, the length of the medication holiday is between 2 days and 1 year, including, for example, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dosage reduction during the medication holiday is, for example, only from 10% to 100%, including, for example, only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0257] Once the patient's condition improves, a maintenance dose is administered if necessary. Subsequently, in certain embodiments, the dose or frequency, or both, is reduced according to symptoms to maintain the improvement in the disease, condition, or symptom. However, in some embodiments, the patient requires long-term intermittent or daily treatment to prevent any recurrence of symptoms.

[0258] The amount of a given drug corresponding to this quantity varies depending on factors such as the specific compound, the disease symptoms and their severity, and the attributes of the individual or host requiring treatment (e.g., weight, sex), but is still determined based on the specific circumstances surrounding the following: such as the specific drug administered, the route of administration, the disease being treated, and the individual or host being treated.

[0259] However, generally, the dosage for adult treatment typically ranges from 0.01 mg to 5000 mg per day. In one embodiment, the dosage for adult treatment is from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is preferably presented as a single dose or as divided doses administered simultaneously or at appropriate intervals (e.g., as sub-dose twice, three, four or more times per day).

[0260] In one embodiment, a suitable daily dose of the compound described herein or a pharmaceutically acceptable salt thereof is about 0.01 to about 50 mg per kilogram of body weight. In some embodiments, the daily dose or amount of the active ingredient in the dosage form may be lower or higher than the range indicated herein, depending on many variables relating to individual treatment regimens. In various embodiments, the daily dose and unit dose may vary depending on many variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the individual's needs, the severity of the disease or condition being treated, and the physician's judgment.

[0261] The toxicity and therapeutic efficacy of such treatment regimens are determined in cell cultures or laboratory animals using standard pharmaceutical procedures, including (but not limited to) the determination of LD10 and ED90. The dose ratio between toxicity and therapeutic effect is the therapeutic index, expressed as the ratio between LD50 and ED50. In some embodiments, data obtained from cell culture analysis and animal studies are used in the formulation for therapeutically effective daily dose ranges and / or therapeutically effective unit doses in mammals, including humans. In some embodiments, the daily doses of the compounds described herein are within a range that includes the cyclic concentration of ED50 with minimal toxicity. In some embodiments, the daily dose range and / or unit dose vary within this range, depending on the dosage form and route of administration used.

[0262] Any of the foregoing embodiments is an alternative example, wherein an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof is: (a) administered systemically to a mammal; and / or (b) administered orally to a mammal; and / or (c) administered intravenously to a mammal; and / or (d) administered to a mammal by injection; and / or (e) administered locally to a mammal; and / or (f) administered to a mammal in a non-systemic or local manner.

[0263] Any of the foregoing embodiments is another example of a compound administered in a single effective dose, including (i) administration of the compound once a day; or (ii) administration of the compound to a mammal multiple times a day.

[0264] Any of the foregoing embodiments is another example of administering an effective amount of the compound multiple times, including (i) administering the compound in a single dose, either continuously or intermittently; (ii) administering the compound every 6 hours; (iii) administering the compound to a mammal every 8 hours; (iv) administering the compound to an individual every 12 hours; and (v) administering the compound to an individual every 24 hours. In other or alternative embodiments, the method includes a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the administered compound is temporarily reduced; and at the end of the drug holiday, administration of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year. [Investment method] []

[0265] Suitable routes of administration include (but are not limited to) oral, intravenous, rectal, aerosol, non-enteral, ocular, pulmonary, mucosal, percutaneous, vaginal, ear, nose, and local administration. Additionally, by way of example only, non-enteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intracardiac, intraperitoneal, intralymphatic, and intranasal injection.

[0266] In some embodiments, the compounds described herein are administered locally rather than systemically, for example, typically in the form of reservoir formulations or sustained-release formulations by direct injection into an organ. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, such as in liposomes coated with organ-specific antibodies. In such embodiments, the liposomes target the organ and are selectively absorbed by the organ. In other embodiments, the compounds described herein are provided in the form of rapid-release formulations, extended-release formulations, or intermediate-release formulations. In yet other embodiments, the compounds described herein are administered locally. [Pharmaceutical Compositions] [ / ] [Ingredients] []

[0267] In accordance with standard pharmaceutical practice, the compounds described herein, alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, are administered to individuals in need as pharmaceutical compositions. In one embodiment, the compounds of the present invention may be administered to animals. These compounds may be administered orally or non-enterally, including via intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and local routes of administration.

[0268] In another embodiment, this document provides a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into a pharmaceutically usable formulation. Suitable formulations depend on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found in, for example, Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L. (eds.), Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

[0269] In some embodiments, pharmaceutically acceptable excipients are selected from carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoamers, antioxidants, preservatives, and any combination thereof.

[0270] The pharmaceutical compositions described herein may be administered to an individual via appropriate routes of administration, including but not limited to oral, non-enteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or percutaneous administration. The pharmaceutical formulations described herein include (but are not limited to) aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid oral dosage forms, powders, immediate-release formulations, controlled-release formulations, rapidly dissolving formulations, tablets, capsules, pills, powders, sugar-coated pills, foaming formulations, lyophilized formulations, delayed-release formulations, extended-release formulations, pulsatile-release formulations, multi-particle formulations, and mixed immediate-release and controlled-release formulations.

[0271] Pharmaceutical compositions including the compounds described herein or their pharmaceutically acceptable salts, solvates or stereoisomers are manufactured in a conventional manner, such as by means of conventional mixing, dissolving, granulation, sugar-coated pilling, water milling, emulsification, encapsulation, coating or compression methods only.

[0272] Pharmaceutical compositions intended for oral use are obtained by mixing one or more solid excipients with one or more compounds described herein, grinding the resulting mixture as appropriate, and, if necessary, treating the granular mixture after adding suitable excipients to obtain a core for a tablet or sugar-coated pill. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or other excipients such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If necessary, disintegrants such as cross-linked sodium carboxymethylcellulose, polyvinylpyrrolidone, agar, or alginate or its salts (such as sodium alginate) are added. In some embodiments, dyes or pigments are added to the coating of the tablet or sugar-coated pill to identify or characterize different combinations of active compound dosages.

[0273] Orally administered pharmaceutical compositions include push-fit capsules made of gelatin and soft-sealable capsules made of gelatin and plasticizers (such as glycerin or sorbitol). Push-fit capsules contain a mixture of the active ingredient and fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and stabilizers as appropriate. In the soft capsules, the active compound is dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added.

[0274] Pharmaceutical compositions intended for non-enteral use are formulated as infusion or injection solutions. In some embodiments, pharmaceutical compositions suitable for injection or infusion include sterile aqueous solutions or dispersions, or sterile powders containing compounds described herein or their pharmaceutically acceptable salts, solvates, or stereoisomers. In some embodiments, the pharmaceutical composition includes a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium comprising, for example, water, saline, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oils, non-toxic glycerides, and any combination thereof. In some embodiments, the pharmaceutical composition further includes a preservative to prevent microbial growth. [combination] []

[0275] This article discloses methods for treating cancer by combining the compounds disclosed herein or their pharmaceutically acceptable salts, solvates, or stereoisomers with additional therapeutic agents.

[0276] In some embodiments, the additional therapeutic agent is an anticancer agent.

[0277] In some embodiments, the additional therapeutic agent is administered simultaneously with the compounds disclosed herein. In some embodiments, the additional therapeutic agent and the compounds disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered before the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered after the compounds disclosed herein. [Example] [] [Example] [1] [step] [1] [:] [preparation] [4-[2-] [Cyano] [-6-(] [Methylaminomethyl] [)] [Pyridine] [-3-] [base] []] [Pipeline] [𠯤] [-1-] [Tributyl carboxylate] [:] []

[0278] Pd(PPh3)4 (0.29 g, 0.25 mmol, 0.10 equivalent) was added to a stirred solution of 4-[2-bromo-6-(methylaminomethyl)pyridin-3-yl]piperazine-1-carboxylic acid tributyl ester (1.00 g, 2.50 mmol, 1.00 equivalent) and Zn(CN)2 (0.44 g, 3.76 mmol, 1.50 equivalent) in DMF (10 mL). The resulting mixture was stirred at 120 °C for 3 h under N2 atmosphere. The reaction was monitored by LCMS. The mixture was diluted with H2O (50 mL). The mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The pure solvent was concentrated under vacuum to give a white solid, 4-[2-cyano-6-(methylaminomethyl)pyridin-3-yl]piperazine-1-carboxylic acid tributyl ester (460 mg, 53.1%). LC-MS: (ES+H, m / z): [M+H]⁺ = 346.2. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (q, 1H), 8.13 (d, 1H), 7.76 (d, 1H), 3.52 (dd, 4H), 3.33 (d, 4H), 2.80 (d, 3H), 1.43 (s, 9H). [Steps] [2] [:] [Preparation] [6-] [Cyano] [-N-] [methyl] [-5-(] [Pipeline] [𠯤] [-1-] [base] [)] [Pyridine] [-2-] [Methionine] [HCl] [Salt:]

[0279] Tributyl 4-[2-cyano-6-(methylaminomethyl)pyridin-3-yl]piperazine-1-carboxylic acid (260 mg, 0.75 mmol, 1.00 equivalent) was added dropwise to a stirred solution of 4-[2-cyano-6-(methylaminomethyl)pyridin-3-yl]piperazine-1-carboxylic acid (2 mL) in dimethyl ether (2 mL) containing HCl (gaseous) in an ice bath. The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The mixture was concentrated under reduced pressure to give 6-cyano-N-methyl-5-(piperazine-1-yl)pyridin-2-methylamine, HCl salt (180 mg, 97.4%). The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] +=245.9. 1H NMR (300 MHz, DMSO-d6) δ 9.32 (brs, 2H), 8.65 (d, 1H), 8.16 (d, 1H), 7.86 (d, 1H), 3.58 (dd, 4H), 3.29 (s, 4H), 2.80 (d, 3H). [step] [3] [:] [preparation] [6-] [Cyano] [-5-{4-[(7-] [Ethyl] [-6-] [Side group] [-5H-1,5-] [Ding] [-3-] [base] [)] [methyl] []] [Pipeline] [𠯤] [-1-] [base] [}-N-] [Methylpyridine] [-2-] [Methamide:] DIEA (145 mg, 1.12 mmol, 5.00 equivalent) was added dropwise to a stirred solution of 7-(chloromethyl)-3-ethyl-1H-1,5-pyridin-2-one (50 mg, 0.22 mmol, 1.00 equivalent), 6-cyano-N-methyl-5-(piperazine-1-yl)pyridin-2-methylamine (60 mg, 0.25 mmol, 1.10 equivalent), and KI (7 mg, 0.04 mmol, 0.20 equivalent) in MeCN (3 mL). The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (3 mL). The crude product was purified by preparative HPLC. The pure solvent was concentrated and lyophilized to obtain 6-cyano-5-{4-[(7-ethyl-6-sideoxy-5H-1,5-diphenyl-3-yl)methyl]piperidin-1-yl}-N-methylpyridin-2-methylamine (12.9 mg, 13.11%) as a white solid. LC-MS: (ES+H, m / z): [M+H] +=431.9. 1H NMR (300 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.58 (d, 1H), 8.42 (s, 1H), 8.11 (d, 1H), 7.74 (d, 2H), 7.62 (s, 1H), 3.68 (s, 2H), 3.37 (d, 4H), 2.79 (d, 3H), 2.60-2.56 (m, 6H), 1.19 (t, 3H). The following examples are created using a similar procedure to that shown in Example 1. [Example] [NMR] [LCMS (ESI) m / z]

[37] 1H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.57 (q, 1H), 8.41 (d, 1H), 8.11 (d, 1H), 7.83 (s, 1H), 7.74 (d, 1H), 7.62 (d, 1H), 3.68 (s, 2H), 3.37 (m, 4H), 2.79 (d, 3H), 2.61 (m, 4H), 2.14 (d, 3H). [M+H] +=418.25

[97] 1H NMR (300 MHz, DMSO-d6) δ 11.90 (s, 1H), 8.58 (d, 1H), 8.40 (d, 1H), 8.11 (d, 1H), 7.75 (d, 1H), 7.60 (s, 1H), 7.43 (s, 1H), 3.67 (s, 2H), 3.41 - 3.35 (m, 4H), 2.79 (d, 3H), 2.61 (t, 4H), 2.18 - 2.11 (m, 1H), 1.03 - 0.93 (m, 2H), 0.84-0.81 (m, 2H). [M+H] +=444.2 [Example] [2] [step] [1] [:preparation] [(3R)-4-[6-(] [Methoxycarbonyl] [)] [Pyridine] [-3-] [base] []-3-] [Methylpiperazine] [𠯤] [-1-] [Tributyl carboxylate:] []

[0280] A mixture of (3R)-3-methylpiperazine-1-carboxylic acid tributyl ester (5.00 g, 24.96 mmol, 1.00 equivalent, [a]26D (c = 1.0, CHCl3): +14.75), methyl 5-bromopyridine-2-carboxylic acid (5.66 g, 26.21 mmol, 1.05 equivalent), Cs₂CO₃ (16.27 g, 49.93 mmol, 2.00 equivalent), and RuPhos Palladacycle Gen.3 (1.04 g, 1.25 mmol, 0.05 equivalent) in 1,4-dimethylacetate (50 mL) was stirred overnight at 120 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (100 mL) and then extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tributyl (3R)-4-[6-(methoxycarbonyl)pyridin-3-yl]-3-methylpiperyl-1-carboxylic acid (5.00 g, 59.71%) as a white solid. LC-MS: (ES+H, m / z): [M+H]⁺ = 336.1. [step] [2] [:preparation] [(3R)-3-] [methyl] [-4-[6-(] [Methylaminomethyl] [)] [Pyridine] [-3-] [base] []] [Pipeline] [𠯤] [-1-] [Tributyl carboxylate:]

[0281] A solution of (3R)-4-[6-(methoxycarbonyl)pyridin-3-yl]-3-methylpiperyl-1-carboxylic acid tributyl ester (2.00 g, 5.96 mmol, 1.00 equivalent) and methylamine (8 mL, 25-30 wt% solution in water) in CH3OH (7 mL) was stirred at room temperature for 3 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reactants were quenched with saturated NH4Cl (30 mL) at room temperature. The resulting mixture was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain (3R)-3-methyl-4-[6-(methylaminomethyl)pyridin-3-yl]piperazine-1-carboxylic acid tributyl ester (1.70 g, 85.25%), which was a pale yellow oil. LC-MS: (ES+H, m / z): [M+H]+=335.3. [step] [3] [:preparation] [N-] [methyl] [-5-[(2R)-2-] [Methylpiperazine] [𠯤] [-1-] [base] []] [Pyridine] [-2-] [Methionine] [HCl] [Salt:]

[0282] A mixture of (3R)-3-methyl-4-[6-(methylaminomethyl)pyridin-3-yl]piperazine-1-carboxylic acid tributyl ester (500 mg, 1.50 mmol, 1.00 equivalent) and 1,4-dimethylalkanes containing HCl (gas) (3.7 mL, 14.95 mmol, 10.00 equivalent, 4.0 M) was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was concentrated under reduced pressure to give N-methyl-5-[(2R)-2-methylpiperazine-1-yl]pyridin-2-methylamine, HCl salt (400 mg, crude product), as a yellow solid. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H]+=234.9. [step] [4] [:preparation] [5-[(2R)-4-[(7-] [Ethyl] [-6-] [Side group] [-5H-1,5-] [Ding] [-3-] [base] [)] [methyl] []-2-] [Methylpiperazine] [𠯤] [-1-] [base] []-N-] [Methylpyridine] [-2-] [Methamide:]

[0283] A mixture of N-methyl-5-[(2R)-2-methylpiperidin-1-yl]pyridin-2-methylamine, HCl salt (128 mg, crude), 7-(chloromethyl)-3-ethyl-1H-1,5-pyridin-2-one (100 mg, 0.45 mmol, 1.00 equivalent), KI (15 mg, 0.09 mmol, 0.20 equivalent), and DIEA (290 mg, 2.24 mmol, 5.00 equivalent) in MeCN (10 mL) was stirred at 80 °C for 3 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silicone column chromatography to obtain a crude product. The crude product was further purified by preparative HPLC. The purified fraction was concentrated under reduced pressure and lyophilized to give 5-[(2R)-4-[(7-ethyl-6-sideoxy-5H-1,5-diphenyl-3-yl)methyl]-2-methylpiperazine-1-yl]-N-methylpyridin-2-methylamine (90 mg, 46.89%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=421.2. 1H NMR (400 MHz, DMSO- d 6) δ 11.90 (s, 1H), 8.42 (d, 1H), 8.37 (d, 1H), 8.21 (d, 1H), 7.82 (d, 1H), 7.76 (s, 1H), 7.67 (d, 1H), 7.33 (dd, 1H), 4.23 (s, 1H), 3.71 (d, 1H), 3.65 - 3.52 (m, 2H), 3.14 - 3.03 (m, 1H), 2.93 (d, 1H), 2.78 (d, 3H), 2.72 (d, 1H), 2.58 - 2.53 (m, 2H), 2.33 (dd, 1H), 2.29 - 2.15 (m, 1H), 1.19 (t, 3H), 1.13 (d, 3H). The following examples are obtained using a similar procedure to that shown in Example 2. [Example] [NMR] [LCMS (ESI) m / z]

[27] 1H NMR (300 MHz, DMSO-d6) δ 11.91 (s, 1H), 8.42 (d, 1H), 8.38 (d, 1H), 8.21 (d, 1H), 7.83 (d, 1H), 7.76 (s, 1H), 7.69 (s, 1H), 7.33 (dd, 1H), 4.22 (brs, 1H), 3.72 (d, 1H), 3.65 - 3.53 (m, 2H), 3.15-3.03 (m, 1H), 2.94 (d, 1H), 2.78 (d, 3H), 2.72 (d, 1H), 2.60 - 2.53 (m, 2H), 2.34-2.22 (m, 2H), 1.26 - 1.04 (m, 6H)。 [M+H] +=420.95

[30] 1H NMR (300 MHz, DMSO- d 6) δ 11.85 (s, 1H), 8.43 - 8.35 (m, 2H), 7.75 (s, 1H), 7.62 (d, 1H), 7.13 (s, 1H), 3.66 (s, 2H), 3.24-3.20 (m, 4H), 2.74 (d, 3H), 2.61-2.52 (m, 6H), 1.19 (t, 3H)。 [M+H] +=413.25

[33] 1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.44 - 8.36 (m, 2H), 8.27 (d, 1H), 7.85 - 7.80 (m, 2H), 7.62 (s, 1H), 7.39 (dd, 1H), 3.65 (s, 2H), 2.56 (t, 4H), 2.78 (d, 3H), 2.56 (t, 4H), 2.14 (d, 3H)。 [M+H] +=393.2

[34] 1H NMR (300 MHz, DMSO-d6): δ 11.89 (s, 1H), 8.45 - 8.36 (m, 2H), 7.84 (dd, J = 8.0, 1.5 Hz, 1H), 7.62 -7.52 (m, 2H), 7.42 (s, 1H), 3.64 (s, 2H), 3.31 - 3.13 (m, 4H), 2.76 (d, J = 4.8 Hz, 3H), 2.61-2.53 (m, 4H), 2.20 - 2.07 (m, 1H), 1.03 - 0.91 (m, 2H), 0.87 - 0.75 (m, 2H)。 19F NMR (282 MHz, DMSO-d6) δ -72.53。 [M+H] +=437. 15.

[35] 1H NMR (300 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.41 (d, 1H), 8.27 (q, 1H), 8.13 (s, 1H), 7.76 (s, 1H), 7.62 (d, 1H), 7.22 (dd, 1H), 3.39 (m, 4H), 2.75 (d, 3H), 2.60 - 2.52 (m, 6H), 1.19 (t, 3H)。 19F NMR (282 MHz, DMSO) δ-120.39。 [M+H] +=427.15

[38] 1H NMR (300 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.47- 8.45(m, 2H), 8.12 (d, 1H), 8.03 (q, 1H), 7.84 (s, 1H), 7.62 (s, 1H), 7.20 (d, 1H), 3.68 (s, 2H), 3.34-3.29 (m, 4H), 2.77 (s, 3H), 2.66-2.58 (m, 4H), 2.15 (s, 3H)。 [M+H] +=417.25

[39] 1H NMR (300 MHz, DMSO-d6, D2O exchange) δ 8.41 (s, 1H), 8.18 (br s), 8.02 (s, 1H), 7.78 (s, 1H), 7.73 (s, 1H), 7.04 (dd, 1H), 4.23 - 4.08 (m, 1H), 3.71 (d, 1H), 3.56 (d, 2H), 3.16 - 3.05 (m, 1H), 2.95 - 2.82 (m, 1H), 2.73 - 2.64 (m, 4H), 2.57 - 2.50 (m, 2H), 2.35 - 2.11 (m, 2H), 1.22 - 1.05 (m, 6H). 19F NMR (282 MHz, DMSO) δ -120.36. [M + H]+ = 439.1

[51] 1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 8.45 - 8.41 (m, 2H), 7.92 (s, 1H), 7.77 (s, 1H), 7.66 (s, 1H), 6.75 (d, 1H), 4.81 - 3.41 (m, 6H), 2.75 (d, 3H), 2.61 - 2.50 (m, 6H), 1.19 (t, 3H). 19F NMR (282 MHz, DMSO) δ -73.47. [M + H]+ = 425.2

[61] 1H NMR (300 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.78 (d, 1H), 8.41 (d, 1H), 7.83 (d, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.34 (d, 1H), 3.73 - 3.69 (m, 4H), 3.66 (s, 2H), 2.81 (d, 3H), 2.58 - 2.52 (m, 6H), 1.18 (t, 3H). [M + H]+ = 408.15

[63] 1H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.42-8.33 (m, 2H), 8.23 (d, 1H), 7.85-7.80 (m, 2H), 7.62 (s, 1H), 7.39 (dd, 1H), 3.65(s, 2H), 3.34-3.31 (m, 4H), 2.89-2.80 (m, 1H), 2.55 (m, 4H), 2.14 (s 3H), 0.70-0.58 (m, 4H)。 [M+H] +=419.10

[66] 1H NMR (300 MHz, DMSO-d6) δ 11.91 (s, 1H), 8.60 (d, 1H), 8.41 (d, 1H), 8.12 (d, 1H), 7.86 - 7.78 (m, 2H), 7.65 (s, 1H), 4.02 (s, 1H), 3.65 (q, 2H), 3.47 (m, 1H), 3.22 (m, 1H), 2.90 - 2.76 (m, 4H), 2.55 (m, 2H), 2.42 (m, 1H), 2.14 (d, 3H), 1.13 (d, 3H)。 [M+H] +=432.2

[67] 1H NMR (300 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.38 - 8.22 (m, 3H), 7.83 (d, 1H), 7.61 (s, 1H), 7.39 (m, 2H), 3.64 (s, 2H),3.32 - 3.24 (m, 4H), 2.53 - 2.43 (m, 4H), 2.25 - 2.10 (m, 1H),1.08 - 0.90 (m, 2H), 0.89 - 0.73 (m, 2H)。 [M+H] +=422.2

[68] 1H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.44 - 8.33 (m, 2H), 8.27 (d, 1H), 7.81 (d, 1H), 7.76 (s, 1H), 7.64 (d, 1H), 7.39 (dd, 1H), 4.77 (dd, 1H), 4.65 (dd, 1H), 4.51 (s, 1H), 3.76 - 3.63 (m, 2H), 3.59 (d, 1H), 3.26 - 3.14 (m, 1H), 2.92 (t, 2H), 2.78 (d, 3H), 2.59 - 2.53 (m, 2H), 2.38 - 2.15 (m, 2H), 1.19 (t, 3H)。 19F NMR (377 MHz, DMSO) δ-223.51。 [M+H] +=439.15

[74] 1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.41 - 8.35 (m, 2H), 8.20 (d, 1H), 7.82 (d, 1H), 7.65 (s, 1H), 7.42 (s, 1H), 7.33 (dd, 1H), 4.26 - 4.17 (m, 1H), 3.70 (d, 1H), 3.64 - 3.51 (m, 2H), 3.08 (td, 1H), 2.93 (d, 1H), 2.78 (d, 3H), 2.71 (d, 1H), 2.32 (dd, 1H), 2.28 - 2.09 (m, 2H), 1.12 (d, 3H), 1.01 - 0.93 (m, 2H), 0.85 - 0.78 (m, 2H)。 [M+H] +=433.30

[79] 1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 9.06 (d, 1H), 8.42 (d, 1H), 8.24 (d, 1H), 7.82 (d, 1H), 7.76 (s, 1H), 7.70-7.65 (m, 1H), 7.34 (dd, 1H), 5.08-4.95 (m, 1H), 4.75-4.68 (m, 4H), 4.30-4.24 (m, 1H), 3.75-3.54 (m, 3H), 3.14-3.04 (m, 1H), 2.95-2.92 (m, 1H), 2.74-2.71(m, 1H), 2.58-2.53 (m, 2H), 2.37-2.19 (m, 2H), 1.26-1.11 (m, 6H)。 [M+H] +=463.10

[93] 1H NMR (300 MHz, DMSO-d6) δ 11.90 (s, 1H), 8.57 (s, 1H), 8.42 (d, 1H), 8.12 (d, 1H), 7.85 - 7.72 (m, 2H), 7.65 (d, 1H), 4.09 - 3.94 (m, 1H), 3.76 - 3.55 (m, 2H), 3.43-3.23 (m, 2H), 2.78 (m, 1H), 2.60 - 2.52 (m, 4H), 2.42 (t, 1H), 1.24 - 1.09 (m, 6H)。 [M+H] +=449.2

[0100] 1H NMR (300 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.38 (d, 1H), 8.26 (dd, 1H), 8.12 (s, 1H), 7.60 (d, 1H), 7.42 (s, 1H), 7.21 (dd, 1H), 3.63 (s, 2H), 3.41-3.35 (m, 4H), 2.74 (d, 3H), 2.56-2.52 (m, 4H), 2.19-2.09 (m, 1H), 1.01-0.94 (m, 2H), 0.85-0.79 (m, 2H)。 19F NMR (282 MHz, DMSO) δ -120.40。 [M+H] +=437.25

[0105] 1H NMR (300 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.40 (d, 1H), 8.25 (d, 1H), 8.11 (s, 1H), 7.76 (s, 1H), 7.62 (d, 1H), 7.22 (dd, 1H), 3.65 (s, 2H), 3.41-3.35 (m, 4H), 2.85 - 2.74 (m, 1H), 2.60 - 2.52 (m, 6H), 1.19 (t, 3H), 0.72-0.62 (m, 2H), 0.54-0.61 (m, 2H)。 19F NMR (282 MHz, DMSO) δ -120.46 [M+H] +=451.4

[0108] 1H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.39 (d, 1H), 8.25 (d, 1H), 8.10 (t, 1H), 7.83 (d, 1H), 7.61 (d, 1H), 7.22 (dd, 1H), 3.65 (s, 2H), 3.41-3.34 (m, 4H), 2.86-2.74 (m, 1H), 2.57-2.51(m, 4H), 2.14 (d, 3H), 0.70-0.63 (m, 2H), 0.61-0.54 (m, 2H)。 19F NMR (282 MHz, DMSO) δ-120.46。 [M+H] +=437.20

[0115] 1H NMR (300 MHz, DMSO-d6) δ 8.39 (d, 2H), 8.25 (s, 1H), 7.83 (d, 1H), 7.61 (s, 1H), 7.46-7.26 (m, 2H), 3.51-3.32 (m, 4H), 2.78 (d, 3H), 2.78-2.54 (m,4H),2.14-2.13 (m,1H), 0.97-0.96 (m, 2H), 0.87-0.76 (m, 2H)。 [M+H] +=421.2

[0116] 1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.38-8.36 (m, 2H), 8.26 (d, 1H), 7.83 (d, 1H), 7.60 (d, 1H), 7.44-7.35 (m, 2H), 3.36-3.30 (m, 4H), 2.55-2.53 (m, 4H), 2.15-2.13 (m, 1H), 1.00-0.94 (m, 2H), 0.86-0.78 (m, 2H) [M+H] +=424.25

[0117] 1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 8.37 (dd, 2H), 8.23 (d, 1H), 7.83 (d, 1H), 7.60 (d, 1H), 7.45 -7.35 (m, 2H), 3.33-3.26 (m, 4H), 2.90-2.80 (m, 1H), 2.61-2.52 (m, 4H), 2.20-2.09 (m, 1H), 1.04-0.91 (m, 2H), 0.88-0.77 (m, 2H), 0.70-0.56 (m, 4H)。 [M+H] +=447.30

[0119] 1H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.39 (d, 2H), 8.26 (d, 1H), 7.83 (d, 1H), 7.61 (d, 1H), 7.45 - 7.34 (m, 2H), 3.64 (s, 2H), 3.41 - 3.32 (m, 4H), 2.59 - 2.52 (m, 4H), 2.19 - 2.10 (m, 1H), 1.01 - 0.93 (m, 2H), 0.85 - 0.79 (m, 2H)。 [M+H] +=438.15.

[0134] 1H NMR (300 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.40 (d, 1H), 7.85 (t, 1H), 7.76 (s, 1H), 7.62 (d, 1H), 7.48 (t, 1H), 6.81 - 6.69 (m, 2H), 3.64 (s, 2H), 3.28 (d, 4H), 2.80 (tt, 1H), 2.56 (dd, 6H), 1.19 (t, 3H), 0.66 (td, 2H), 0.56 - 0.49 (m, 2H)。 19F NMR (282 MHz, DMSO) δ -111.70。 [M+H] +=450.15

[0137] 1H NMR (300 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.43 - 8.39 (m, 2H), 8.26 (d, 1H), 7.83 (d, 1H), 7.61 (d, 1H), 7.42 - 7.37 (m, 2H), 3.64 (s, 2H), 3.33 - 3.29 (m, 2H), 3.27 - 3.24 (m, 4H), 2.56 (s, 4H), 2.20 - 2.10 (m, 1H), 1.10 (t, 3H), 1.00 - 0.94 (m, 2H), 0.85 (d, 2H)。 [M+H] +=433.15

[0139] 1H NMR (300 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.55 (d, 1H), 8.42 (d, 1H), 8.10 (d, 1H), 7.74 (d, 2H), 7.62 (d, 1H), 3.69 (s, 2H), 3.42 - 3.33 (m, 4H) 2.93-2.81 (m, 1H), 2.64 - 2.51 (m, 6H), 1.19 (t, 3H), 0.73 - 0.64 (m, 4H)。 [M+H] +=458.20

[0145] 1H NMR (300 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.45 - 8.36 (m, 1H), 8.18 (s, 1H), 7.89 - 7.74 (m, 2H), 7.62 (s, 1H), 7.00 (d, J = 8.9 Hz, 1H), 3.67 (s, 2H), 3.36-3.33 (m, 4H), 2.77 (d, J = 4.5 Hz, 3H), 2.58-2.50 (m, 6H), 1.19 (t, J = 7.4 Hz, 3H)。 19F NMR (282 MHz, DMSO) δ -106.65。 [M+H] +=449.10

[0158] 1H NMR (300 MHz, DMSO-d6) δ 11.90 (s, 1H), 8.40-8.33 (m, 2H), 7.84 (d, J = 7.9 Hz, 1H), 7.63 - 7.51 (m, 2H), 7.42 (s, 1H), 3.64 (s, 2H), 3.19 - 3.14 (m, 4H), 2.87 - 2.84 (m, 1H), 2.59 - 2.54 (m, 4H), 2.17 - 2.14 (m, 1H), 0.99 - 0.95 (m, 2H), 0.86 - 0.77 (m, 2H), 0.69 - 0.62 (m, 4H). 19F NMR (282 MHz, DMSO) δ -72.41. [M+H] +=463.20

[0161] 1H NMR (300 MHz, DMSO-d6) δ 11.82 (s, 1H), 8.40-8.37 (m, 2H), 8.27 (d, 1H), 7.82 (d, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 7.39 (dd, 1H), 4.11 (d, 1H), 3.71 (d, 1H), 3.60 (d, 1H), 3.41 - 3.36 (m, 1H) 2.96 (t, 1H), 2.84 - 2.70 (m, 5H), 2.64 - 2.53 (m, 3H), 2.28 (t, 1H), 1.25 - 1.09 (m, 6H). [M+H] +=420.90 [] [Example] [3A] [and] [3B] [Steps] [1] [Preparation] [5-[6-(] [Methoxycarbonyl] [)] [Pyridine] [-3-] [base] []-2,5-] [Dazabicyclo] [[4.1.0]] [Heptane] [-2-] [Tributyl carboxylate:] []

[0284] At room temperature under a nitrogen atmosphere, RuPhos Palladacycle Gen.3 (0.48 g, 0.57 mmol, 1 equivalent) and Cs₂CO₃ (7.54 g, 23.14 mmol, 2.00 equivalent) were added to a stirred mixture of methyl 5-bromopyridine-2-carboxylate (2.5 g, 11.57 mmol, 1 equivalent) and 2,5-diazabicyclo[4.1.0]heptane-2-carboxylate tributyl ester (2.41 g, 12.15 mmol, 1.05 equivalent) in dimethyl methacrylate (25 mL) and dimethyl methacrylate (2.41 g, 12.15 mmol, 1.05 equivalent) in dimethyl methacrylate (25 mL) and dimethyl methacrylate (2.05 equivalent) in dimethyl methacrylate (2.5 g, 11.57 mmol, 1 equivalent) in ... The combined organic layers were washed with saturated NaCl (aqueous solution) (200 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1.1 g (Y = 28.4%) of 5-[6-(methoxycarbonyl)pyridin-3-yl]-2,5-diazabicyclo[4.1.0]heptane-2-carboxylic acid tributyl ester, a yellow solid. LC-MS: (ES+H, m / z): [M+H]⁺ = 334.1 [step] [2] [:preparation] [5-[6-(] [Methylaminomethyl] [)] [Pyridine] [-3-] [base] []-2,5-] [Dazabicyclo] [[4.1.0]] [Heptane] [-2-] [Tributyl carboxylate:] []

[0285] A mixture of 5-[6-(methoxycarbonyl)pyridin-3-yl]-2,5-diazabicyclo[4.1.0]heptane-2-carboxylic acid tributyl ester (1 g, 3.00 mmol, 1 equivalent) and CH3NH2 (2.33 g, 75.03 mmol, 25.01 equivalent, 40% in H2O) in MeOH (15 ml) was stirred at room temperature for 3 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (40 mL). The mixture was acidified to pH 6 with saturated NH4Cl (aqueous solution). The resulting mixture was extracted with CH2Cl2 (3 × 100 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain 1.2 g (crude substance) of 5-[6-(methylaminomethyl)pyridin-3-yl]-2,5-diazabicyclo[4.1.0]heptane-2-carboxylic acid tributyl ester, which was a yellow crude oil. LC-MS: (ES+H, m / z): [M+H]+=333.1 [step] [3] [:preparation] [5-{2,5-] [Dazabicyclo] [[4.1.0]] [Geng] [-2-] [base] [}-N-] [Methylpyridine] [-2-] [Methamide:]

[0286] Under a nitrogen atmosphere at room temperature, 1,4-dimethylalkanes (6 mL) containing HCl (gas) was added dropwise to a stirred mixture of 5-[6-(methylaminomethyl)pyridin-3-yl]-2,5-diazabicyclo[4.1.0]heptane-2-carboxylic acid tributyl ester (1.2 g, 3.61 mmol, 1 equivalent) in MeOH (10 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by grinding with diethyl ether (40 mL). The resulting mixture was concentrated under reduced pressure to give 5-{2,5-diazabicyclo[4.1.0]hept-2-yl}-N-methylpyridin-2-methylamine (1 g, crude substance) as a yellow crude oil. LC-MS: (ES+H, m / z): [M+H]+=232.9 [step] [4] [:preparation] [5-{5-[(7-] [Ethyl] [-6-] [Side group] [-5H-1,5-] [Ding] [-3-] [base] [)] [methyl] []-2,5-] [Dazabicyclo] [[4.1.0]] [Geng] [-2-] [base] [}-N-] [Methylpyridine] [-2-] [Methamide:]

[0287] KI (52.19 mg, 0.31 mmol, 0.20 equivalent) was added to a stirred mixture of 5-{2,5-diazabicyclo[4.1.0]hept-2-yl}-N-methylpyridin-2-methylamine (547.67 mg, 2.35 mmol, 1.5 equivalent) and 7-(chloromethyl)-3-ethyl-1H-1,5-pyridin-2-one (350 mg, 1.57 mmol, 1.00 equivalent) in acetonitrile (5 ml). The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was concentrated under reduced pressure. The residue was purified by silicone column chromatography to give 5-{5-[(7-ethyl-6-sideoxy-5H-1,5-diphenyl-3-yl)methyl]-2,5-diazabicyclo[4.1.0]hept-2-yl}-N-methylpyridin-2-methylamine (180 mg, Y=21.3%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=419.0 [step] [5] [:preparation] [rel-5-[(1R,6S)-5-[(7-] [Ethyl] [-6-] [Side group] [-5H-1,5-] [Ding] [-3-] [base] [)] [methyl] []-2,5-] [Dazabicyclo] [[4.1.0]] [Geng] [-2-] [base] []-N-] [Methylpyridine] [-2-] [Methionine] [(] [Example] [3A)] [and] [rel-5-[(1R,6S)-5-[(7-] [Ethyl] [-6-] [Side group] [-5H-1,5-] [Ding] [-3-] [base] [)] [methyl] []-2,5-] [Dazabicyclo] [[4.1.0]] [Geng] [-2-] [base] []-N-] [Methylpyridine] [-2-] [Methionine] [(] [Example] [3B)] [:] []

[0288] Rel-5-[(1R,6S)-5-[(7-ethyl-6-sideoxy-5H-1,5-diphenyl-3-yl)methyl]-2,5-diazabicyclo[4.1.0]hept-2-yl]-N-methylpyridin-2-methylamine was purified by preparative, palmitic HPLC to yield rel-5-[(1R,6S)-5-[(7-ethyl-6-sideoxy-5H-1,5-diphenyl-3-yl)methyl]-2,5-diazabicyclo[4.1.0]hept-2-yl]-N-methylpyridin-2-methylamine (Example 3A, 54.8). mg, Y=30.4%, ee=99.28%) and rel-5-[(1R,6S)-5-[(7-ethyl-6-sideoxy-5H-1,5-diphenyl-3-yl)methyl]-2,5-diazabicyclo[4.1.0]hept-2-yl]-N-methylpyridin-2-methylamine (Example 3B, 39.0 mg, Y=21.6%, ee=98.42%). Note: The stereochemical partitions of Examples 3A and 3B are arbitrary. [Example] [3A] [:] []

[0289] LC-MS: (ES+H, m / z): [M+H] +=419.2. 1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.44 (d, 1H), 8.37 - 8.32 (m, 1H), 8.19 (d, 1H), 7.85 (d, 1H), 7.75 (s, 1H), 7.69 - 7.65 (m, 1H), 7.27 (dd, 1H), 3.89 (q, 2H), 3.54 - 3.46 (m, 1H), 3.24 - 3.16 (m, 1H), 2.81 - 2.69 (m, 5H), 2.57 - 2.52 (m, 4H), 1.18 (t, 3H), 0.83 - 0.74 (m, 1H), 0.44 - 0.34 (m, 1H). [Example] [3B] [:] []

[0290] LC-MS: (ES+H, m / z): [M+H] +=419.1. 1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.46 - 8.40 (m, 1H), 8.38 - 8.31 (m, 1H), 8.19 (d, 1H), 7.85 (d, 1H), 7.75 (s, 1H), 7.67 (s, 1H), 7.27 (dd, 1H), 3.99 - 3.81 (m, 2H), 3.56 - 3.47 (m, 1H), 3.24 - 3.18 (m, 1H), 2.85 - 2.70 (m, 5H), 2.58 - 2.52 (m, 4H), 1.18 (t, 3H), 0.83 - 0.74 (m, 1H), 0.44 - 0.34 (m, 1H). The following examples in Table 3 were obtained using similar procedures to those shown in Examples 3A and 3B. Table 3: [Example] [NMR] [LCMS (ESI) m / z]

[28] 1H NMR (400 MHz, DMSO- d 6) δ 11.83 (s, 1H), 8.43 (d, 1H), 8.35 (d, 1H), 8.19 (d, 1H), 7.85 (d, 1H), 7.75 (s, 1H), 7.66 (s, 1H), 7.27 (dd, 1H), 3.99 - 3.80 (m, 2H), 3.60 - 3.45 (m, 1H), 3.27 - 3.14 (m, 1H), 2.84 - 2.75 (m, 4H), 2.74 - 2.66 (m, 1H), 2.59 - 2.52 (m, 4H), 1.18 (t 3H), 0.84 - 0.69 (m, 1H), 0.49 - 0.28 (m, 1H)。 [M+H] +=419.2

[69] 1H NMR (300 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.43 (d, 1H), 8.25 (q, 1H), 8.06 (t, 1H), 7.75 (q, 1H), 7.66 (d, 1H), 7.05 (dd, 1H), 3.97 - 3.80 (m, 2H), 3.60-3.45 (m, 1H), 3.26 - 3.15 (m, 1H), 2.83 - 2.69 (m, 5H), 2.57-2.52 (m, 4H), 1.18 (t, 3H), 0.79 (q, 1H), 0.41 (q, 1H)。 19F NMR (282 MHz, DMSO) δ -120.44。 [M+H] +=437.20.

[88] 1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 9.04 (d, 1H), 8.44 (d, 1H), 8.23 (d, 1H), 7.84 (d, 1H), 7.75 (s, 1H), 7.66 (d, 1H), 7.28 (dd, 1H), 5.01 (q, 1H), 4.79 - 4.57 (m, 4H), 3.97 - 3.81 (m, 2H), 3.56 - 3.47 (m, 1H), 3.27 - 3.19 (m, 1H), 2.84 - 2.70 (m, 2H), 2.58 - 2.52 (m, 4H), 1.18 (t, 3H), 0.78 (q, 1H), 0.38 (q, 1H)。 [M+H] +=461.2

[90] 1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.44 (d, 1H), 8.33 (s, 1H), 8.19 (d, 1H), 7.85 (d, 1H), 7.76 (q, 1H), 7.69 - 7.64 (m, 1H), 7.27 (dd, 1H), 3.88 (q, 2H), 3.56 - 3.48 (m, 1H), 3.25 - 3.17 (m, 1H), 2.85 - 2.67 (m, 2H), 2.58 - 2.52 (m, 4H), 1.18 (t, 3H), 0.78 (q, 1H), 0.39 (q, 1H)。 [M+H] +=422.1

[96] 1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.44 (d, 1H), 8.33 (s, 1H), 8.19 (d, 1H), 7.85 (d, 1H), 7.76 (q, 1H), 7.69 - 7.64 (m, 1H), 7.27 (dd, 1H), 3.88 (q, 2H), 3.56 - 3.48 (m, 1H), 3.25 - 3.17 (m, 1H), 2.85 - 2.67 (m, 2H), 2.58 - 2.52 (m, 4H), 1.18 (t, 3H), 0.78 (q, 1H), 0.39 (q, 1H)。 [M+H] +=422.3

[99] 1H NMR (300 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.55 - 8.37 (m, 2H), 8.26 (d, 1H), 7.98 - 7.88 (m, 2H), 7.66 (s, 1H), 7.34 (dd, 1H), 4.05 - 3.86 (m, 2H), 3.66 - 3.51 (m, 1H), 3.29 (td, 1H), 2.95 - 2.72 (m, 5H), 2.67-2.60 (m, 2H), 2.21 (d, 3H), 0.84 (q, 1H), 0.46 (q, 1H)。 [M+H] +=405.35

[0107] 1H NMR (300 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.41 (d, 1H), 8.33 (s, 1H), 8.19 (d, 1H), 7.85 (d, 1H), 7.65 (d, 1H), 7.42 (s, 1H), 7.27 (dd, 1H), 3.96 - 3.80 (m, 2H), 3.51 (dd, 1H), 3.27 - 3.16 (m, 1H), 2.84 - 2.67 (m, 2H), 2.59 - 2.52 (m, 2H), 2.16-2.11(m, 1H), 1.02 - 0.91 (m, 2H), 0.89 - 0.75 (m, 3H), 0.38 (q, 1H)。 [M+H]+=434.25

[0109] 1H NMR (300 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.43 (d, 1H), 8.30 (d, 1H), 8.17 (d, 1H), 7.89 - 7.81 (m, 2H), 7.66 (d, 1H), 7.28 (dd, 1H), 3.98 - 3.81 (m, 2H), 3.57 - 3.44 (m, 1H), 3.28 - 3.16 (m, 1H), 2.89 - 2.68 (m, 3H), 2.60 - 2.49 (m, 2H), 2.14 (s, 3H), 0.77 (q, 1H), 0.70 - 0.59 (m, 4H), 0.38 (q, 1H)。 [M+H] +=431.10

[0110] 1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.41 (d, 1H), 8.34 (q, 1H), 8.18 (d, 1H), 7.85 (d, 1H), 7.64 (d, 1H), 7.42 (s, 1H), 7.27 (dd, 1H), 3.94 - 3.80 (m, 2H), 3.50 (td, 1H), 3.25 - 3.17 (m, 1H), 2.81 - 2.68 (m, 5H), 2.57 - 2.51 (m, 2H), 2.14 (tt, 1H), 1.00 - 0.91 (m, 2H), 0.86 - 0.73 (m, 3H), 0.38 (q, 1H)。 [M+H] +=431.25

[0111] 1H NMR (300 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.43 (d, 1H), 8.29 (d, 1H), 8.16 (d, 1H), 7.85 (d, 1H), 7.75 (s, 1H), 7.66 (s, 1H), 7.27-7.24 (m, 1H), 3.99 - 3.78 (m, 2H), 3.57 - 3.42 (m, 1H), 3.27 - 3.13 (m, 1H), 2.91 - 2.64 (m, 3H), 2.57-2.51 (m, 4H), 1.18 (t, 3H), 0.83 - 0.55 (m, 5H), 0.37 (q, 1H)。 [M+H] +=445.15

[0112] 1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.41 (d, 1H), 8.30 (d, 1H), 8.16 (d, 1H), 7.85 (d, 1H), 7.64 (d, 1H), 7.42 (s, 1H), 7.27 (dd, 1H), 3.95 - 3.77 (m, 2H), 3.53-3.43 (m, 1H), 3.25-3.14 (m, 1H), 2.90 - 2.64 (m, 3H), 2.58-2.52 (m, 2H), 2.19-2.08 (m, 1H), 1.04 - 0.92 (m, 2H), 0.86 - 0.57 (m, 7H), 0.36 (q, 1H). [M+H] +=457.25

[0113] 1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.41 (d, 1H), 8.24 (q, 1H), 8.06 - 8.05(m, 1H), 7.63 (d, 1H), 7.42 (s, 1H), 7.04 (dd, 1H), 4.02 - 3.76 (m, 2H), 3.59 - 3.43 (m, 1H), 3.24-3.15 (m, 1H), 3.06 - 2.63 (m,5H), 2.59 - 2.51 (m, 2H), 2.21 - 2.11 (m, 1H), 1.02 - 0.91 (m, 2H), 0.87 - 0.74 (m, 3H), 0.40 (q, 1H). 19F NMR (282 MHz, DMSO-d 6) δ -120.45. [M+H] +=449.20 [] [, , ] [] [Example] [4] [Steps] [1] [Preparation] [(3R)-4-[2-] [bromine] [-6-(] [Methylaminomethyl] [)] [Pyridine] [-3-] [base] []-3-] [Methylpiperazine] [𠯤] [-1-] [Tributyl carboxylate:] []

[0291] NBS (1.29 g, 7.24 mmol, 1.10 equivalent) was added to a stirred solution of (3R)-3-methyl-4-[6-(methylaminomethyl)pyridin-3-yl]piperyl-1-carboxylic acid tributyl ester (2.20 g, 6.58 mmol, 1.00 equivalent) in DMF (30 mL) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 h. The desired product was detectable by LCMS. The reactants were quenched by adding saturated NaHCO3 (aqueous solution) (30 mL) at 0 °C. The resulting mixture was poured into water (100 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 × 150 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica chromatography to give (3R)-4-[2-bromo-6-(methylaminomethyl)pyridin-3-yl]-3-methylpiperazine-1-carboxylic acid tributyl ester (1.77 g, 65%), which was a pale yellow oil. LC-MS: (ES+H, m / z): [M+H]⁺ = 413.0 / 415.0. 1H NMR (300 MHz, DMSO-d6) δ 8.47 (d, 1H), 7.97 (d, 1H), 7.75 (d, 1H), 3.66 - 3.48 (m, 4H), 3.27-3.18(m, 2H), 2.80 (d, 3H), 2.73 - 2.60 (m, 1H), 1.43 (s, 9H), 0.84 (d, 3H). [Steps] [2] [Preparation] [(3R)-4-[2-] [Cyano] [-6-(] [Methylaminomethyl] [)] [Pyridine] [-3-] [base] []-3-] [Methylpiperazine] [𠯤] [-1-] [Tributyl carboxylate:] []

[0292] A mixture of (3R)-4-[2-bromo-6-(methylaminomethyl)pyridin-3-yl]-3-methylpiperazine-1-carboxylic acid tributyl ester (500 mg, 1.21 mmol, 1.00 equivalent), Zn(CN)₂ (156 mg, 1.33 mmol, 1.10 equivalent), and Pd(PPh₃)₄ (140 mg, 0.12 mmol, 0.10 equivalent) in DMF (8 mL) was stirred overnight at 120 °C under nitrogen. The desired product was detectable by LCMS. The mixture was cooled to room temperature. The resulting mixture was poured into water (100 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give a yellow solid, (3R)-4-[2-cyano-6-(methylaminomethyl)pyridin-3-yl]-3-methylpiperazine-1-carboxylic acid tributyl ester (428 mg, 98%). LC-MS: (ES-H, m / z): [MH] = 358.1. 1H NMR (400 MHz, DMSO-d6) δ 8.60 (d,1H), 8.12 (d,1H), 7.81 (d,1H), 3.41 - 3.33 (m, 4H), 3.21 (d,2H), 2.80 (d,3H),2.52-2.51(m,1H), 1.43 (s, 9H), 1.02 (d, 3H). [Steps] [3] [Preparation] [6-] [Cyano] [-N-] [methyl] [-5-[(2R)-2-] [Methylpiperazine] [𠯤] [-1-] [base] []] [Pyridine] [-2-] [Methionine] [HCl] [salt:] []

[0293] A solution of (3R)-4-[2-cyano-6-(methylaminomethyl)pyridin-3-yl]-3-methylpiperazine-1-carboxylic acid tributyl ester (135 mg, 0.38 mmol, 1.00 equivalent) and 1,4-dimethylalkanes containing HCl (gas) (5 mL, 4 M) in DCM (5 mL) was stirred at room temperature under nitrogen atmosphere for 3 h. The desired product was detectable by LCMS. The mixture was concentrated under reduced pressure to give a pale yellow solid of 6-cyano-N-methyl-5-[(2R)-2-methylpiperazine-1-yl]pyridin-2-methylamine, HCl salt (310 mg, crude). The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] += 260.2 [Steps] [4] [Preparation] [6-] [Cyano] [-5-[(2R)-4-[(7-] [Ethyl] [-6-] [Sidekyl group] [-5H-1,5-] [Ding] [-3-] [base] [)] [methyl] []-2-] [Methylpiperazine] [𠯤] [-1-] [base] []-N-] [Methylpyridine] [-2-] [Methamide:]

[0294] At room temperature, 7-(chloromethyl)-3-ethyl-1H-1,5-pyridin-2-methylamine, HCl salt (250 mg, crude), and DIEA (498 mg, 3.86 mmol, 5.00 equivalent) were added to a stirred mixture in MeCN (8 mL) containing 6-cyano-N-methyl-5-[(2R)-2-methylpiperidin-1-yl]pyridin-2-one (172 mg, 0.77 mmol, 1.00 equivalent) and KI (26 mg, 0.15 mmol, 0.20 equivalent). The resulting mixture was stirred at 80 °C for 4 h under a nitrogen atmosphere. The desired product was detected by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, and the pure solvent was concentrated under reduced pressure to obtain 6-cyano-5-[(2R)-4-[(7-ethyl-6-sideoxy-5H-1,5-diphenyl-3-yl)methyl]-2-methylpiperazine-1-yl]-N-methylpyridin-2-methylamine (135.4 mg, 39%, ee=97.6%), a pale yellow solid. LC-MS: (ES+H, m / z): [M+H]+= 446.1. 1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.58 (d, 1H), 8.42 (d, 1H), 8.12 (d, 1H), 7.81 (d, 1H), 7.75 (s, 1H), 7.65 (d, 1H), 4.02 (m, 1H), 3.74 - 3.58 (m, 2H), 3.47-3.39 (m, 1H), 3.28-3.20 (m, 1H) 2.79 (m, 4H), 2.58 - 2.53 (m, 4H), 2.42 (t, 1H), 1.19 (t, 3H), 1.13 (d, 3H). [Example] [5] [step] [1] [:preparation] [4-(5-)] [fluorine] [-6-(] [Methoxycarbonyl] [)] [Pyridine] [-3-] [base] [)] [Pipeline] [𠯤] [-1-] [Tributyl carboxylate:] []

[0295] A mixture of methyl 5-bromo-3-fluoropyridine-2-carboxylate (1.00 g, 4.27 mmol, 1.00 equivalent), tributyl piperidine-1-carboxylate (0.84 g, 4.48 mmol, 1.05 equivalent), RuPhos Palladacycle Gen.3 (0.36 g, 0.43 mmol, 0.10 equivalent), and Cs₂CO₃ (2.78 g, 8.55 mmol, 2.00 equivalent) in 1,4-dimethylamine (16 mL) was stirred overnight at 110 °C under nitrogen. The reaction was monitored by LCMS. The mixture was then cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give a white solid, 4-[5-fluoro-6-(methoxycarbonyl)pyridin-3-yl]piperazine-1-carboxylic acid tributyl ester (1.00 g, 68.96%). LC-MS: (ES+H, m / z): [M+H]+=339.9. 1H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.23 (dd, 1H), 3.81 (s, 3H), 3.56 - 3.36 (m, 8H), 1.43 (s, 9H). [Steps] [2] [Preparation] [4-(5-)] [fluorine] [-6-(] [Methylaminomethyl] [)] [Pyridine] [-3-] [base] [)] [Pipeline] [𠯤] [-1-] [Tributyl carboxylate:]

[0296] At room temperature, ethyl 4-[5-fluoro-6-(methoxycarbonyl)pyridin-3-yl]piperazine-1-carboxylate (1.20 g, 3.86 mmol, 1.00 equivalent) in methanol (8 mL) was added to a stirred solution of 4-[5-fluoro-6-(methoxycarbonyl)pyridin-3-yl]piperazine-1-carboxylate (8 mL, 25% to 30% in water). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction was monitored by LC-MS. The reactants were quenched at 0 °C with saturated NH4Cl (100 mL aqueous solution). The mixture was extracted with CH2Cl2 (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give a crude product (1.22 g) as a white solid. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H]+ = 338.9. 1H NMR (400 MHz, DMSO-d6) δ 8.29 (q, 1H), 8.14 (d, 1H), 7.23 (d, 1H), 3.55 - 3.34 (m, 8H), 2.75 (d, 3H), 1.42 (s, 9H). [step] [3] [:preparation] [3-] [fluorine] [-N-] [methyl] [-5-(] [Pipeline] [𠯤] [-1-] [base] [)] [Pyridinemethylamine] [:] []

[0297] Under a nitrogen atmosphere, 1,4-dimethylamine (1.22 g, 5.12 mmol, 1.00 equivalent) containing HCl (gaseous) was added dropwise to a stirred solution of 3-fluoro-N-methyl-5-(piperazine-1-yl)pyridin-2-methylamine (5 mL) in 1,4-dimethylamine (1.22 g, 5.12 mmol, 1.00 equivalent) at 0 °C. The resulting mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by grinding with hexane:diethyl ether = 1:1 (10 mL × 3) to give a crude product (1.22 g, HCl salt) as a white solid. The crude product was used directly in the next step. LC-MS: (ES+H, m / z): [M+H]+ = 238.9. [step] [4] [:preparation] [5-(4-((7-] [Ethyl] [-6-] [side] [Oxygen group] [-5,6-] [Dihydrogen] [-] [1,5-] [Ding] [-3-] [base] [)] [methyl] [)] [Pipeline] [𠯤] [-1-] [base] [)-3-] [fluorine] [-N-] [Methylpyridinemethylamine] [:] []

[0298] At room temperature, KI (7 mg, 0.04 mmol, 0.20 equivalent) and DIEA (145 mg, 1.12 mmol, 5.00 equivalent) were added to a stirred solution of 3-fluoro-N-methyl-5-(piperazine-1-yl)pyridin-2-methylamine (80 mg, assuming 100% yield, 0.34 mmol, 1.50 equivalent) and 7-(chloromethyl)-3-ethyl-1H-1,5-pyridin-2-one (50 mg, 0.22 mmol, 1.00 equivalent) in ACN (5 mL). The resulting mixture was stirred at 80 °C for 3 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC. The purified fraction was concentrated and lyophilized to give 5-(4-((7-ethyl-6-sideoxy-5,6-dihydro-1,5-diphenyl-3-yl)methyl)piperidin-1-yl)-3-fluoro-N-methylpyridinecarboxamide (34 mg, 34.24%, obtained through three steps) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=424.90. 1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.40 (s, 1H), 8.27 (q, 1H), 8.13 (s, 1H), 7.75 (s, 1H), 7.62 (s, 1H), 7.22 (dd, 1H), 3.65 (s, 2H), 3.45 - 3.34 (m, 4H), 2.74 (d, 3H), 2.58 - 2.51 (m, 6H), 1.18 (t, 3H). 19F NMR (377 MHz, DMSO) δ -120.40. [Example] [6] [step] [1] [:preparation] [4-(2-)] [bromine] [-6-(] [Methylaminomethyl] [)] [Pyridine] [-3-] [base] [)] [Pipeline] [𠯤] [-1-] [Tributyl carboxylate:] []

[0299] NBS (1.22 g, 6.87 mmol, 1.10 equivalent) was added fractionally to a stirred solution of 4-[6-(methylaminomethyl)pyridin-3-yl]piperyl-1-carboxylic acid tributyl ester (2.00 g, 6.24 mmol, 1.00 equivalent) in DMF (10 ml) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reactants were quenched by adding saturated NaHCO3 (aqueous solution) (5 mL) at 0 °C. The resulting mixture was concentrated under vacuum. The residue was purified by silicone column chromatography to give 4-(2-bromo-6-(methylaminomethyl)pyridin-3-yl)piperyl-1-carboxylic acid tributyl ester (2.40 g, 96.29%) as a colorless oil. LC-MS: (ES+H, m / z): [M+H] +=399.1 / 401.1. 1H NMR (400 MHz, DMSO-d6) δ 8.44 (q, 1H), 7.96 (d, 1H), 7.65 (d, 1H), 3.60 - 3.41 (m, 4H), 3.10 - 2.98 (m, 4H), 2.80 (d, 3H), 1.43 (s, 9H). [step] [2] [:preparation] [4-(2-)] [Cyclopropyl] [-6-(] [Methylaminomethyl] [)] [Pyridine] [-3-] [base] [)] [Pipeline] [𠯤] [-1-] [Tributyl carboxylate:] []

[0300] A mixture of 4-[2-bromo-6-(methylaminomethyl)pyridin-3-yl]piperidin-1-carboxylic acid tributyl ester (1.20 g, 3.00 mmol, 1.00 equivalent), Pd(dppf)Cl₂ (0.22 g, 0.30 mmol, 0.10 equivalent), Cs₂CO₃ (1.96 g, 6.01 mmol, 2.00 equivalent), and cyclopropylboronic acid (0.26 g, 3.00 mmol, 1.00 equivalent) in toluene / H₂O (10 mL / 1 mL) was stirred at 100 °C for 1.5 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silicone column chromatography to give 4-(2-cyclopropyl-6-(methylaminomethyl)pyridin-3-yl)piperazine-1-carboxylic acid tributyl ester (900 mg, 83.08%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=361.1. 1H NMR (300 MHz, DMSO-d6) δ 8.28 (q, 1H), 7.71 (d, 1H), 7.44 (d, 1H), 3.64 - 3.43 (m, 4H), 3.06 - 2.89 (m, 4H), 2.80 (d, 3H), 2.45 - 2.32 (m, 1H), 1.43 (s, 9H), 1.22 - 1.13 (m, 2H), 1.07 - 0.88 (m, 2H). [step] [3] [:preparation] [6-] [Cyclopropyl] [-N-] [methyl] [-5-(] [Pipeline] [𠯤] [-1-] [base] [)] [Pyridinemethylamine] [,] [HCl] [Salt:] []

[0301] Under a nitrogen atmosphere at 0 °C, 10.00 mL (4 M) of 1,4-dimethylamine (containing HCl gas) was added dropwise to a stirred solution of 4-[2-cyclopropyl-6-(methylaminomethyl)pyridin-3-yl]piperazine-1-carboxylic acid tributyl ester (900 mg, 2.50 mmol, 1.00 equivalent) in 1,4-dimethylamine (3 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by grinding with hexane:diethyl ether = 1:1 (10 mL × 3) to give 6-cyclopropyl-N-methyl-5-(piperazine-1-yl)pyridinylmethylamine, HCl salt (900 mg, crude substance), as a white solid. LC-MS: (ES+H, m / z): [M+H] +=261.2. [step] [4] [:preparation] [6-] [Cyclopropyl] [-5-(4-((7-] [Ethyl] [-6-] [Side group] [-5,6-] [Dihydrogen] [-1,5-] [Ding] [-3-] [base] [)] [methyl] [)] [Pipeline] [𠯤] [-1-] [base] [)-N-] [Methylpyridinemethylamine] [:] []

[0302] At room temperature, KI (15 mg, 0.09 mmol, 0.20 equivalent) and DIEA (290 mg, 2.25 mmol, 5.00 equivalent) were added to a stirred mixture of 7-(chloromethyl)-3-ethyl-1H-1,5-pyridin-2-one (100 mg, 0.45 mmol, 1.00 equivalent) and 6-cyclopropyl-N-methyl-5-(piperazine-1-yl)pyridin-2-methylamine, HCl salt (200 mg, 0.67 mmol, 1.50 equivalent) in MeCN (10 mL). The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC. The purified solvent was concentrated and lyophilized to give 6-cyclopropyl-5-(4-((7-ethyl-6-sideoxy-5,6-dihydro-1,5-diphenyl-3-yl)methyl)piperidin-1-yl)-N-methylpyridinecarboxamide (31 mg, 15.51%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=447.0. 1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.41 (d, 1H), 8.32 - 8.21 (m, 1H), 7.75 (s, 1H), 7.70 (d, 1H), 7.62 (s, 1H), 7.43 (d, 1H), 3.68 (s, 2H), 3.15 - 2.90 (m, 4H), 2.78 (d, 3H), 2.69 - 2.54 (m, 6H), 2.36 - 2.29 (m, 1H), 1.22 - 1.10 (m, 5H), 1.01 - 0.91 (m, 2H). [Example] [7] [step] [1] [:preparation] [4-[3-] [fluorine] [-4-(] [Methoxycarbonyl] [)] [Phenyl] []] [Pipeline] [𠯤] [-1-] [Tributyl carboxylate:] []

[0303] At room temperature, Cs₂CO₃ (2.80 g, 8.58 mmol, 2.00 equivalent) and RuPhos Palladacycle Gen. 3 (0.18 g, 0.22 mmol, 0.05 equivalent) were added to a stirred mixture of methyl 4-bromo-2-fluorobenzoate (1.00 g, 4.29 mmol, 1.00 equivalent) and dimethyl benzoate (0.84 g, 4.51 mmol, 1.05 equivalent) in dimethyl benzoate (100 mL). The resulting mixture was stirred at 120 °C for 6 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silicone column chromatography to give tributyl 4-[3-fluoro-4-(methoxycarbonyl)phenyl]piperazine-1-carboxylic acid (1.30 g, 89%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=339.2. 1H NMR (300 MHz, DMSO-d6) δ 7.72 (t, 1H), 6.84 - 6.69 (m, 2H), 3.77 (s, 3H), 3.48 - 3.33 (m, 8H), 1.43 (s, 9H). [step] [2] [:preparation] [4-[3-] [fluorine] [-4-(] [Methylaminomethyl] [)] [Phenyl] []] [Pipeline] [𠯤] [-1-] [Tributyl carboxylate:] []

[0304] Methylamine (3.5 mL, 25-30 wt% in water) was added dropwise to a mixture of tributyl 4-[3-fluoro-4-(methoxycarbonyl)phenyl]piperazine-1-carboxylic acid (1.3 g, 3.84 mmol, 1.00 equivalent) in MeOH (5 mL). The mixture was stirred overnight at 50 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (100 mL). The mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse combi-flash chromatography. Concentration of the mixture under reduced pressure yielded a white solid, 4-[3-fluoro-4-(methylaminomethyl)phenyl]piperazine-1-carboxylic acid tributyl ester (1.00 g, 77%). LC-MS: (ES+H, m / z): [M+H]+=338.2. 1H NMR (300 MHz, DMSO-d6) δ 7.78 (d, 1H), 7.58 (t, 1H), 6.85 - 6.68 (m, 2H), 3.45-3.40 (m, 4H), 3.27 (dd, 4H), 2.76 (d, 3H), 1.43 (s, 9H). [Steps] [3] [Preparation] [2-] [fluorine] [-N-] [methyl] [-4-(] [Pipeline] [𠯤] [-1-] [base] [)] [Benzylamine] [,] [HCl] [salt:] []

[0305] At room temperature under a nitrogen atmosphere, 1,4-dimethylamine (2 mL, 4 M) containing HCl (gas) was added dropwise to a stirred mixture of 4-[3-fluoro-4-(methylaminomethyl)phenyl]piperazine-1-carboxylic acid tributyl ester (500 mg, 1.48 mmol, 1.00 equivalent) in DCM (4 mL). The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by grinding with hexane:diethyl ether = 1:1 (4 mL). The resulting mixture was concentrated under reduced pressure to give 2-fluoro-N-methyl-4-(piperazine-1-yl)benzamide, HCl salt (500 mg, crude substance), as a white solid. LC-MS: (ES+H, m / z): [M+H]+ = 237.9. 1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 2H), 7.92 - 7.79 (m, 1H), 7.60 (t, 1H), 6.91 - 6.72 (m, 2H), 3.54 (m, 4H), 3.17 (m, 4H), 2.75 (d, 3H). [step] [4] [:preparation] [4-{4-[(7-] [Ethyl] [-6-] [Side group] [-5H-1,5-] [Ding] [-3-] [base] [)] [methyl] []] [Pipeline] [𠯤] [-1-] [base] [}-2-] [fluorine] [-N-] [methylbenzamide] [:] []

[0306] KI (15 mg, 0.09 mmol, 0.20 equivalent) and DIEA (290 mg, 2.24 mmol, 5.00 equivalent) were added to a stirred mixture of 7-(chloromethyl)-3-ethyl-1H-1,5-diphenyl-2-one, HCl salt (100 mg, 0.45 mmol, 1.00 equivalent) and 2-fluoro-N-methyl-4-(piperazine-1-yl)benzamide hydrochloride (123 mg, 0.45 mmol, 1.00 equivalent) in MeCN (5 mL). The resulting mixture was stirred at 80 °C for 3 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC, and the purified solvent was concentrated and lyophilized to obtain 4-{4-[(7-ethyl-6-sideoxy-5H-1,5-diphenyl-3-yl)methyl]piperidin-1-yl}-2-fluoro-N-methylbenzamide (14 mg, 7%) as a grayish-white solid. LC-MS: (ES+H, m / z): [M+H]+=423.90. 1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.40 (d, 1H), 7.76 (d, 2H), 7.66 - 7.48 (m, 2H), 6.86 - 6.66 (m, 2H), 3.64 (s, 2H), 3.30 (d, 4H), 3.28 (d, 4H), 2.74 (d, 3H), 2.56 - 2.53 (m, 2H), 1.18 (t, 3H). 19F NMR (377 MHz, DMSO) δ -111.58. [Example] [8] [step] [1] [:preparation] [3',6'-] [Dihydrogen] [-[3,4'-] [Bipyridine] []-1',6(2'H)-] [Dicarboxylic acid] [1'-(] Grade III butyl acetate [)6-] [Methyl acetate] [:] []

[0307] A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tributyl ester (859 mg, 2.78 mmol, 1.20 equivalents), methyl 5-bromopyridine-2-carboxylic acid (500 mg, 2.31 mmol, 1.00 equivalents), K₂CO₃ (640 mg, 4.63 mmol, 2.00 equivalents), and Pd(dppf)Cl₂ (339 mg, 0.46 mmol, 0.2 equivalents) in 1,4-dimethylalkanes (10 mL) and H₂O (2 mL) was stirred overnight at 80 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to RT. The resulting mixture was diluted with H₂O (50 mL). The mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3',6'-dihydro-[3,4'-bipyridine]-1',6(2'H)-dicarboxylic acid 1'-(tertiary butyl ester) 6-methyl ester (260 mg, 29.41%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]⁺=319.1. 1H NMR (300 MHz, DMSO-d6) δ 8.82 (dd, 1H), 8.02 (t, 2H), 6.46 (s, 1H), 4.06 (d, 2H), 3.88 (s, 3H), 3.57 (t, 2H), 2.54 (s, 2H), 1.44 (s, 9H). [step] [2] [:preparation] [6-(] [Methylaminomethyl] [)-3',6'-] [Dihydrogen] [-[3,4'-] [Bipyridine] []-1'(2'H)-] [Tributyl carboxylate:] []

[0308] At room temperature, CH₃NH₂ (3 mL, 25–30 wt% in water) was added to a stirred solution of 3',6'-dihydro-[3,4'-bipyridine]-1',6(2'H)-dicarboxylic acid 1'-(tert-butyl) 6-methyl ester (210 mg, 0.66 mmol, 1.00 equivalent) in methanol (3 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The reactants were quenched by adding saturated NH₄Cl (aqueous solution) (50 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were concentrated under reduced pressure to give 6-(methylaminomethyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylic acid tributyl ester (190 mg, 90.76%) as a purple solid. LC-MS: (ES+H, m / z): [M+H] +=318.2. 1H NMR (400 MHz, DMSO-d6) δ 8.76 - 8.68 (m, 2H), 8.08 - 7.86 (m, 2H), 6.34 (d, 1H), 4.05 (d, 2H), 3.56 (t, 2H), 2.82 (d, 4H), 2.54 (d, 1H), 1.43 (s, 9H). [step] [3] [:preparation] [N-] [methyl] [-1',2',3',6'-] [Tetrahydrogen] [-[3,4'-] [Bipyridine] []-6-] [Methionine] [,] [TFA] [Salt:] []

[0309] TFA (1 mL) was added dropwise to a stirred solution of 6-(methylaminomethyl)-3',6'-dihydro-2'H-[3,4'-bipyridine]-1'-carboxylic acid tributyl ester (170 mg, 0.54 mmol, 1 equivalent) in DCM (5 mL) under air at room temperature. The resulting mixture was stirred at room temperature under nitrogen for 1 h. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H]+=218.1 [step] [4] [:preparation] [1'-((7-] [Ethyl] [-6-] [Side group] [-5,6-] [Dihydrogen] [-1,5-] [Ding] [-3-] [base] [)] [methyl] [)-N-] [methyl] [-1',2',3',6'-] [Tetrahydrogen] [-[3,4'-] [Bipyridine] []-6-] [Methamide:] []

[0310] At room temperature, KI (17 mg, 0.10 mmol, 0.20 equivalent) and DIEA (323 mg, 2.50 mmol, 5.00 equivalent) were added to a stirred mixture of N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-methamide (101 mg, 0.50 mmol, 1.00 equivalent) and 7-(chloromethyl)-3-ethyl-1,5-diphenyl-2(1H)-one (111 mg, 0.50 mmol, 1.00 equivalent) in MeCN (5 mL). The resulting mixture was stirred at 80 °C for 1 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC. The purified solvent was concentrated and lyophilized to give 1'-((7-ethyl-6-sideoxy-5,6-dihydro-1,5-dipyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-methylamine (39.6 mg, 18.49%, obtained in two steps) as a pale yellow solid. LC-MS: (ES+H, m / z): [M+H]+=404.2. ¹H NMR (400 MHz, DMSO-d⁶) δ 11.85 (s, ¹H), 8.70 (t, 2H), 8.42 (s, ¹H), 8.05 - 7.93 (m, 2H), 7.76 (s, ¹H), 7.65 (s, 1H), 6.42 (s, 1H), 3.73 (s, 2H), 3.16 (s, 2H), 2.81 (d, 3H), 2.71 (s, 2H), 2.60 - 2.52 (m, 4H), 1.19 (t, 3H). The following examples were prepared using a similar procedure to that shown in Example 8. [Example] [NMR] [LCMS (ESI) m / z]

[64] 1H NMR (300 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.72 (d, 2H), 8.40 (d, 1H), 7.98 (s, 2H), 7.63 (s, 1H), 7.43 (s, 1H), 6.43 (s, 1H), 3.72 (s, 2H), 3.16 (d, 2H), 2.82 (d, 3H), 2.70 (d, 2H), 2.56 (m, 2H), 2.16 (dt, 1H), 1.03 - 0.93 (m, 2H), 0.85-0.82 (m, 2H). [M+H] +=416.25 [Example] [9] [step] [1] [:preparation] [7-(] [Chloromethyl] [)-3-] [Ethyl] [-1H-] [Quinoline] [-2-] [ketone] [:] []

[0311] SOCl₂ (1.76 g, 14.76 mmol, 3.00 equivalent) was added dropwise to a stirred mixture of 3-ethyl-7-(hydroxymethyl)-1H-quinoline-2-one (1.00 g, 4.92 mmol, 1.00 equivalent) and DMF (18 mg, 0.25 mmol, 0.05 equivalent) in DCM (20 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was concentrated under reduced pressure to give 7-(chloromethyl)-3-ethyl-1H-quinoline-2-one (1.00 g, 91.68%) as a grayish-white solid. MS: (ES+H, m / z): [M+H]⁺=222.1 [step] [2] [:preparation] [6-{4-[(3-] [Ethyl] [-2-] [Side group] [-1H-] [Quinoline] [-7-] [base] [)] [methyl] []] [Pipeline] [𠯤] [-1-] [base] [}] [Pyridine] [-3-] [Formonitrile] [:] []

[0312] DIEA (243 mg, 1.88 mmol, 5.00 equivalent) was added to a stirred mixture of 7-(chloromethyl)-3-ethyl-1H-quinolin-2-one (100 mg, 0.45 mmol, 1.20 equivalent), 6-(piperazine-1-yl)pyridin-3-carboxynitrile (71 mg, 0.38 mmol, 1.00 equivalent), and KI (12 mg, 0.08 mmol, 0.20 equivalent) in MeCN (5 mL). The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC to obtain 6-{4-[(3-ethyl-2-sideoxy-1H-quinolin-7-yl)methyl]piperazine-1-yl}pyridine-3-carboxylonitrile (35.2 mg, 25.07%) as a grayish-white solid. MS: (ES+H, m / z): [M+H] +=374.2. 1H NMR (300 MHz, DMSO-d6) δ 11.68 (s, 1H), 8.48 (d, 1H), 7.84 (dd, 1H), 7.70 (s, 1H), 7.57 (d, 1H), 7.27 (s, 1H), 7.13 (d, 1H), 6.92 (d, 1H), 3.67 (s, 4H), 3.57 (s, 2H), 2.50-2.47 (m, 6H), 1.16 (t, 3H). [Example]

[10] [step] [1] [:preparation] [N-(3-)] [Bromophenyl] [)-2-] [Side-oxycyclopentane] [-1-] [Methamide:] []

[0313] A solution of 4-(cyclopent-1-en-1-yl)oline (3.60 g, 23.49 mmol, 1.00 equivalent) and 1-bromo-3-isocyanophenyl (5.58 g, 28.19 mmol, 1.20 equivalent) in CHCl3 (100 mL) was stirred at room temperature for 4 h under a nitrogen atmosphere. The reaction was monitored by LC-MS. The resulting mixture was concentrated under vacuum. The residue was purified by silicone column chromatography, and the pure solvent was concentrated under vacuum to give N-(3-bromophenyl)-2-sideoxycyclopentane-1-methylamine (3.9 g, 58.8%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=281.9 / 283.9. 1H NMR (300 MHz, chloroform-d) δ 8.83 (s, 1H), 7.84 (t, 1H), 7.45-7.41 (m, 1H), 7.29 - 7.15 (m, 2H), 3.20 - 3.11 (m, 1H), 2.51 - 2.33 (m, 4H), 2.17-2.05 (m, 1H), 1.96-1.83 (m, 1H). [step] [2] [:preparation] [7-] [bromine] [-1H,2H,3H,5H-] [Cyclopenta] [[c]] [Quinoline] [-4-] [ketone:]

[0314] N-(3-bromophenyl)-2-sideoxycyclopentane-1-methylamine (3.3 g, 11.69 mmol, 1.00 equivalent) was slowly added to a stirred solution of H₂SO₄ (10 mL) at 0 °C. The resulting mixture was stirred at room temperature for 4 h. The reaction was monitored by LCMS. The mixture was alkalized with an aqueous solution of Na₂CO₃ (200 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give 7-bromo-1H,2H,3H,5H-cyclopentano[c]quinoline-4-one (2.10 g, 67.9%) as a white solid. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] +=264.0 / 266.0. 1H NMR (300 MHz, DMSO-d6) δ 11.66 (s, 1H), 7.52 - 7.43 (m, 2H), 7.33 (dd, 1H), 3.06 (t, 2H), 2.74 (t, 2H), 2.14-1.99 (m, 2H). [step] [3] [:preparation] [4-] [Side group] [-1H,2H,3H,5H-] [Cyclopenta] [[c]] [Quinoline] [-7-] [Ethyl carboxylate:] []

[0315] In a pressure vessel, Pd(PPh3)2Cl2 (797 mg, 1.13 mmol, 0.20 equivalent) was added to a solution of 7-bromo-1H,2H,3H,5H-cyclopentano[c]quinoline-4-one (1.50 g, 5.67 mmol, 1.00 equivalent) and Et3N (1.15 g, 11.35 mmol, 2.00 equivalent) in EtOH (20 mL). The mixture was purged with nitrogen for 3 min and then pressurized to 40 atm with carbon monoxide overnight at 120 °C. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The residue was purified by silicone column chromatography, and the pure solvent was concentrated under vacuum to give ethyl 4-sideoxy-1H,2H,3H,5H-cyclopentano[c]quinoline-7-carboxylate (750 mg, 51.33%) as a pale yellow solid. LC-MS: (ES+H, m / z): [M+H]+=258.2 [step] [4] [:preparation] [7-(] [Hydroxymethyl] [)-1H,2H,3H,5H-] [Cyclopenta] [[c]] [Quinoline] [-4-] [ketone:] []

[0316] Under a nitrogen atmosphere at 0 °C, ethyl 4-sidekto-1H,2H,3H,5H-cyclopentano[c]quinoline-7-carboxylate (650 mg, 2.52 mmol, 1.00 equivalent) was added dropwise to a stirred solution of 4-sidekto-1H,2H,3H,5H-cyclopentano[c]quinoline-7-carboxylate (3 mL) in THF (2.02 mL, 5.05 mmol, 2.00 equivalent, 2.5 M in THF) over 3 min at 0 °C. The resulting mixture was stirred at room temperature for another 2 h. The reaction was monitored by LCMS. The reactants were quenched by adding 0.3 mL of H₂O at 0 °C. Then, 1.4 mL of NaOH (15 wt%) was added, and the mixture was stirred at room temperature for 10 min. 0.3 mL of H₂O was added to the reactants, and the mixture was stirred for another 10 min. The resulting mixture was filtered, the filter cake was washed with THF (3 × 5 mL), and dried over anhydrous Na₂SO₄. The residue was purified by silicone column chromatography, and the pure solvent was concentrated under vacuum to give 7-(hydroxymethyl)-1H,2H,3H,5H-cyclopenta[c]quinoline-4-one (300 mg, 55.1%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=216.2. 1H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H), 7.47 (d, 1H), 7.33 (s, 1H), 7.12 - 7.08 (m, 1H), 5.34 (t, 1H), 4.57 (d, 2H), 3.07 (t, 2H), 2.75 (t, 2H), 2.13 - 2.06 (m, 2H). [step] [5] [:preparation] [7-(] [Chloromethyl] [)-1H,2H,3H,5H-] [Cyclopenta] [[c]] [Quinoline] [-4-] [ketone:] []

[0317] At 0 °C, SOCl₂ (967 mg, 8.13 mmol, 5.00 equivalent) was added dropwise to a stirred solution of 7-(hydroxymethyl)-1H,2H,3H,5H-cyclopentano[c]quinoline-4-one (350 mg, 1.62 mmol, 1.00 equivalent) and DMF (12 mg, 0.16 mmol, 0.10 equivalent) in DCM (2 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by LC-MS. The resulting mixture was washed with DCM (3 × 30 mL). The mixture was concentrated under vacuum to give 7-(chloromethyl)-3-ethyl-4-fluoro-1H-quinoline-2-one (390 mg, crude) as an orange solid. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H]⁺=234.0 [step] [6] [:preparation] [N-] [methyl] [-5-[4-({4-] [Side group] [-1H,2H,3H,5H-] [Cyclopenta] [[c]] [Quinoline] [-7-] [base] [}] [methyl] [)] [Pipeline] [𠯤] [-1-] [base] []] [Pyridine] [-2-] [Methamide:] []

[0318] DIEA (415 mg, 3.21 mmol, 5.00 equivalent) was added dropwise to a stirred solution of 7-(chloromethyl)-1H,2H,3H,5H-cyclopentano[c]quinoline-4-one (150 mg, 0.64 mmol, 1.00 equivalent) and N-methyl-5-(piperazine-1-yl)pyridin-2-methylamine (148 mg, 0.67 mmol, 1.05 equivalent) in MeCN (3 mL). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silicone column chromatography, and the pure solvent was concentrated under vacuum to give N-methyl-5-[4-({4-sideoxy-1H,2H,3H,5H-cyclopentano[c]quinolin-7-yl}methyl)piperazine-1-yl]pyridin-2-methylamine (34.1 mg, 12.1%), a light brown solid. LC-MS: (ES+H, m / z): [M+H]+=418.2. 1H NMR (300 MHz, DMSO-d6) δ 11.55 (s, 1H), 8.41 (d, 1H), 8.27 (d, 1H), 7.83 (d, 1H), 7.50 (d, 1H), 7.42 - 7.30 (m, 2H), 7.17 (d, 1H), 3.59 (s, 2H), 3.34-3.32 (m, 4H) 3.08 (t, 2H), 2.78-2.74 (m, 5H), 2.55-2.54 (d, 4H), 2.15-2.05 (m, 2H). [Example]

[11] [step] [1] [:preparation] [3-(] [Furran] [-3-] [Venenomide] [)-4-] [Methyl iodobenzoate] [:] []

[0319] A mixture of methyl 3-amino-4-iodobenzoate (10.00 g, 36.09 mmol, 1.00 equivalent), 3-furoic acid (8.09 g, 72.18 mmol, 2.00 equivalent), T3P (114.84 g, 180.46 mmol, 5.00 equivalent, 50 wt% in EA) and DIEA (23.32 g, 180.46 mmol, 5.00 equivalent) in DCM (100 mL) was stirred overnight at 60 °C under a nitrogen atmosphere. The mixture was then cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (150 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silicone column chromatography to give methyl 3-(furan-3-amino)-4-iodobenzoate (6.80 g, 50.76%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=372.0. [step] [2] [:preparation] [3-[N-(] [Tertiary butoxycarbonyl] [)] [Furran] [-3-] [Venenomide] []-4-] [Methyl iodobenzoate] [:]

[0320] A solution of methyl 3-(furan-3-amino)-4-iodobenzoate (6.00 g, 16.167 mmol, 1.00 equivalent), (Boc)₂O (7.06 g, 32.34 mmol, 2.00 equivalent), and DMAP (1.98 g, 16.17 mmol, 1.00 equivalent) in a DCE (100 mL) was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with EtOAc (250 mL) and washed with water (2 × 200 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silicone column chromatography to give methyl 3-[N-(tert-butoxycarbonyl)furan-3-amino]-4-iodobenzoate (5.00 g, 65.63%) as a white solid. ¹H NMR (300 MHz, DMSO-d6) δ 8.31 (dd, 1H), 8.13 (d, 1H), 7.90 (d, 1H), 7.79 (t, 1H), 7.69 (dd, 1H), 6.79 (dd, 1H), 3.87 (s, 3H), 1.34 (s, 9H). [step] [3] [:preparation] [4-] [Side group] [-5H-] [furano] [[3,2-c]] [Quinoline] [-7-] [carboxylic acid] [First] [ester:]

[0321] At room temperature under a nitrogen atmosphere, Pd(OAc)₂ (38 mg, 0.17 mmol, 0.20 equivalent) and K₂CO₃ (235 mg, 1.70 mmol, 2.00 equivalent) were added to a mixture of methyl 3-[N-(tributoxycarbonyl)furan-3-amino]-4-iodobenzoate (400 mg, 0.85 mmol, 1.00 equivalent) and PCy₃ (48 mg, 0.17 mmol, 0.20 equivalent) in DMF (12 mL). The final reaction mixture was irradiated with microwave at 100 °C for 2 h. The mixture was then cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with EtOAc (50 mL). The mixture was washed with water (2 × 25 mL). The combined organic layers were washed with brine (2 × 25 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silicone column chromatography to give methyl 4-sideoxy-5H-furano[3,2-c]quinoline-7-carboxylic acid (120 mg, 58.13%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=244.0. [step] [4] [:preparation] [7-(] [Hydroxymethyl] [)-5H-] [furano] [[3,2-c]] [Quinoline] [-4-] [ketone:]

[0322] Under a nitrogen atmosphere, methyl 4-(hydroxymethyl)-5H-furano[3,2-c]quinoline-7-carboxylic acid (300 mg, 1.23 mmol, 1.00 equivalent) was added dropwise to a stirred mixture of 4-sidekoxy-5H-furano[3,2-c]quinoline-7-carboxylic acid (2 mL) in THF (0 °C). The resulting mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. The reaction was monitored by LC-MS. The reactants were quenched by adding 1 M HCl aqueous solution (1.2 mL) at 0 °C. The residue was purified by silicone column chromatography to give 7-(hydroxymethyl)-5H-furano[3,2-c]quinoline-4-one (220 mg, 82.88%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=216.1. [step] [5] [:preparation] [7-(] [Chloromethyl] [)-5H-] [furano] [[3,2-c]] [Quinoline] [-4-] [ketone:]

[0323] SOCl₂ (995 mg, 8.36 mmol, 6.00 equivalent) was added dropwise to a stirred mixture of 7-(hydroxymethyl)-5H-furano[3,2-c]quinoline-4-one (300 mg, 1.39 mmol, 1.00 equivalent) and DMF (10 mg, 0.14 mmol, 0.10 equivalent) in DCM (5 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred overnight at 0 °C under a nitrogen atmosphere. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silicone column chromatography to give 7-(chloromethyl)-5H-furano[3,2-c]quinoline-4-one (240 mg, 73.69%) as a white solid. LC-MS: (ES+H, m / z): [M+H]⁺ = 234.0. [step] [6] [:preparation] [N-] [methyl] [-5-[4-({4-] [Side group] [-5H-] [furano] [[3,2-c]] [Quinoline] [-7-] [base] [}] [methyl] [)] [Pipeline] [𠯤] [-1-] [base] []] [Pyridine] [-2-] [Methamide:]

[0324] A mixture of 7-(chloromethyl)-5H-furano[3,2-c]quinoline-4-one (100 mg, 0.43 mmol, 1.00 equivalent), N-methyl-5-(piperazine-1-yl)pyridinecarboxamide, HCl salt (110 mg, 0.43 mmol, 1.00 equivalent), KI (14 mg, 0.09 mmol, 0.20 equivalent), and DIEA (276 mg, 2.14 mmol, 5.00 equivalent) in MeCN (10 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silicone column chromatography to give N-methyl-5-[4-({4-sideoxy-5H-furano[3,2-c]quinolin-7-yl}methyl)piperazine-1-yl]pyridin-2-methylamine (95 mg, 51.63%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=418.20. 1H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 8.40 (q, 1H), 8.27 (d, 1H), 8.08 (d, 1H), 7.89 (d, 1H), 7.83 (d, 1H), 7.46 (s, 1H), 7.39 (dd, 1H), 7.28 (dd, 1H), 7.06 (d, 1H), 3.63 (s, 2H), 3.39 - 3.34 (m, 4H), 2.78 (d, 3H), 2.56 (m, 4H). [Example]

[12] [step] [1] [:preparation] [5-{4-[(7-] [Ethyl] [-6-] [Side group] [-5H-1,5-] [Ding] [-3-] [base] [)] [methyl] []] [Pipeline] [𠯤] [-1-] [base] [}] [Pyridine] [-2-] [carboxylic acid:] []

[0325] At room temperature under a nitrogen atmosphere, methyl 5-{4-[(7-ethyl-6-sideoxy-5H-1,5-diphenyl-3-yl)methyl]piperidin-1-yl}pyridine-2-carboxylic acid (120 mg, 0.29 mmol, 1.00 equivalent) in EtOH / THF (1:1, 5 mL) was added to a stirred solution of NaOH (3.0 mL, 1N). The resulting mixture was stirred at room temperature for another 1 h. The reaction was monitored by LCMS. Then, 1(N) HCl aqueous solution (3.0 mL) was added. The reactants were concentrated under reduced pressure to give 150 mg of 5-{4-[(7-ethyl-6-sideoxy-5H-1,5-diphenyl-3-yl)methyl]piperidin-1-yl}pyridine-2-carboxylic acid as a white solid (used without further purification). LC-MS: (ES+H, m / z): [M+H] +=394.2. [step] [2] [:preparation] [N-] [Cyclopropyl] [-5-{4-[(7-] [Ethyl] [-6-] [Side group] [-5H-1,5-] [Ding] [-3-] [base] [)] [methyl] []] [Pipeline] [𠯤] [-1-] [base] [}] [Pyridine] [-2-] [Methamide:]

[0326] HATU (174 mg, 0.46 mmol, 1.50 equivalent) was added to a stirred solution of 5-{4-[(7-ethyl-6-sideoxy-5H-1,5-diphenyl-3-yl)methyl]piperidin-1-yl}pyridine-2-carboxylic acid (120 mg, 0.30 mmol, 1.00 equivalent) and DIEA (158 mg, 1.22 mmol, 4.00 equivalent) in DMF (4 mL). Aminocyclopropane (35 mg, 0.61 mmol, 2.00 equivalent) was added to the mixture and stirred overnight at room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (10 mL). The mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (1 × 5 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse combination rapid chromatography, and the pure solvent was concentrated and lyophilized to give N-cyclopropyl-5-{4-[(7-ethyl-6-sideoxy-5H-1,5-diphenyl-3-yl)methyl]piperidin-1-yl}pyridin-2-methylamine (23.1 mg, 17%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=433.2. 1H NMR (300 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.41 (s, 1H), 8.35 (s, 1H), 8.24 (s, 1H), 7.83 (d, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.40 (d, 1H), 3.65 (s, 2H), 3.30 - 3.14 (m, 6H), 2.85 (s, 1H), 2.65 - 2.53 (m, 4H), 1.18 (t, 3H), 0.69 - 0.57 (m, 4H). [Example]

[13] [step] [1] [:preparation] [5-{4-[(7-] [Ethyl] [-6-] [Side group] [-5H-1,5-] [Ding] [-3-] [base] [)] [methyl] []] [Pipeline] [𠯤] [-1-] [base] [}] [Pyridine] [-2-] [Methyl carboxylate:] []

[0327] At room temperature under a nitrogen atmosphere, 7-(chloromethyl)-3-ethyl-1H-1,5-pyridin-2-carboxylic acid methyl ester (280 mg, 1.26 mmol, 1.00 equivalent) and DIEA (818 mg, 6.32 mmol, 5.00 equivalent) were added to a stirred mixture in MeCN (6 mL) containing methyl 5-(piperidin-1-yl)pyridine-2-one (282 mg, 1.26 mmol, 1.00 equivalent) and KI (42 mg, 0.25 mmol, 0.20 equivalent). The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silicone column chromatography to give methyl 5-{4-[(7-ethyl-6-sideoxy-5H-1,5-diphenyl-3-yl)methyl]piperidin-1-yl}pyridine-2-carboxylic acid (300 mg, 58%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+ = 408.1. [Steps] [2] [Preparation] [5-(4-((7-] [Ethyl] [-6-] [Sidekyl group] [-5,6-] [Dihydrogen] [-1,5-] [Ding] [-3-] [base] [)] [methyl] [)] [Pipeline] [𠯤] [-1-] [base] [)] [Pyridinecarboxylic acid] [:]

[0328] At room temperature under a nitrogen atmosphere, 5.0 mL of 1(N) NaOH aqueous solution was added to a stirred solution of methyl 5-{4-[(7-ethyl-6-sideoxy-5H-1,5-diphenyl-3-yl)methyl]piperidin-1-yl}pyridine-2-carboxylic acid (200 mg, 0.49 mmol, 1.00 equivalent) in EtOH / THF (5 mL / 5 mL). The resulting mixture was stirred at room temperature for another 2 hours. The reaction solution was neutralized with 1 mol / L hydrochloric acid, and then the organic solvent was distilled off under reduced pressure. After filtering off the residue, it was washed with water and concentrated under reduced pressure to give the title compound (140 mg, 73%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+ = 394.2. [step] [3] [:preparation] [N-(2,2-] [Difluoroethyl] [)-5-{4-[(7-] [Ethyl] [-6-] [Side group] [-5H-1,5-] [Ding] [-3-] [base] [)] [methyl] []] [Pipeline] [𠯤] [-1-] [base] [}] [Pyridine] [-2-] [Methamide:]

[0329] At room temperature under a nitrogen atmosphere, EDCI (536 mg, 2.80 mmol, 5.00 equivalent) and HOBT (227 mg, 1.68 mmol, 3.00 equivalent) were added to a stirred solution of 5-{4-[(7-ethyl-6-sideoxy-5H-1,5-diphenyl-3-yl)methyl]piperidin-1-yl}pyridine-2-carboxylic acid (220 mg, 0.56 mmol, 1.00 equivalent) and DIEA (361 mg, 2.80 mmol, 5.00 equivalent) in DMF (5 mL). The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (10 mL). The mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (1 × 5 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (80 mg, 94% purity) as a white solid. The crude material was purified by reverse combination rapid chromatography, and the pure solvent was concentrated and lyophilized to give N-(2,2-difluoroethyl)-5-{4-[(7-ethyl-6-sideoxy-5H-1,5-diphenyl-3-yl)methyl]piperidin-1-yl}pyridin-2-methylamine (46 mg, 18%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=457.2. ¹H NMR (400 MHz, DMSO-d⁶) δ 11.86 (s, ¹H), 8.70 (t, ¹H), 8.41 (s, ¹H), 8.30 (d, ¹H), 7.86 (d, ¹H), 7.76 (s, ¹H), 7.63 (s, ¹H), 7.41 (dd, ¹H), 6.25–5.97 (m, ¹H), 3.73–3.60 (m, 4H), 3.37 (s, 4H), 2.61–2.52 (m, 6H), 1.18 (t, 3H). The following examples were prepared using a similar procedure to that shown in Example 13. [Example] [NMR] [LCMS (ESI) m / z]

[40] 1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.58 (t, 1H), 8.41 (d, 1H), 8.28 (d, 1H), 7.83 (d, 1H), 7.76 (s, 1H), 7.63 (d, 1H), 7.40 (dd, 1H), 3.77 - 3.54 (m, 5H), 3.45 (dd, 1H), 3.45 - 3.26 (m, 4H), 3.26 (t, 2H), 2.59 - 2.51 (m, 7H), 1.95 - 1.82 (m, 1H), 1.58 (m, 1H), 1.26 - 1.16 (m, 3H) [M+H] +=477.35

[41] 1H NMR (300 MHz, DMSO-d 6) δ 11.86 (s, 1H), 8.58 (t, 1H), 8.41 (d, 1H), 8.28 (d, 1H), 7.84 (d, 1H), 7.76 (s, 1H), 7.63 (d, 1H), 7.40 (dd, 1H), 3.78-3.54 (m, 5H), 3.45 (dd, 1H), 3.41-3.34 (m, 4H), 3.30-3.22 (m, 2H), 2.65-2.52 (m, 6H), 2.49-2.42 (m, 1H), 1.97-1.80 (m, 1H), 1.66-1.52 (m, 1H), 1.23-1.14 (m, 3H)。 [M+H] +=477.3

[42] 1H NMR (300 MHz, DMSO-d 6) δ 11.86 (s, 1H), 8.45-8.25 (m, 3H), 7.84 (d, 1H), 7.77 (s, 1H),7.62 (s,1H), 7.40 (dd, 1H), 3.66 (s, 2H), 3.47-3.42 (m, 4H), 3.39-3.36 (m, 2H), 3.33-3.30 (m, 2H), 3.26 (s, 3H), 2.62-2.53 (m, 6H), 1.19 (t, 3H)。 [M+H] +=451.0

[43] 1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.41 (d, 1H), 8.27 (d, 1H), 8.08 (d, 1H), 7.83 (d, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.40 (dd, 1H), 4.13 - 4.00 (m, 1H), 3.66 (s, 2H), 3.35 - 3.32 (m, 4H), 2.60 - 2.51 (m, 6H), 1.26 - 1.13 (m, 9H) [M+H] +=434.9

[44] 1H NMR (300 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.41 (d,1H), 8.30 - 8.23 (m, 2H), 7.84 (d,1H), 7.76 (s, 1H), 7.63 (s, 1H), 7.41 (dd, 1H), 4.06-3.92 (m, 1H), 3.91 - 3.80 (m, 2H), 3.66 (s, 2H), 3.44 - 3.34 (m, 6H), 2.61 - 2.52 (m, 6H), 1.77 - 1.57 (m, 4H), 1.19 (t, 3H)。 [M+H] +=477.20

[45] 1H NMR (300 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.41 (d, 1H), 8.33 (d, 1H), 8.28 (d, 1H), 7.82 (d, 1H), 7.76 (s, 1H), 7.63 (s, 1H), 7.40 (dd, 1H), 4.93 (s, 1H), 4.02 (p, 1H), 3.66 (s, 2H), 3.35-3.33 (m, 4H) 2.64 - 2.53 (m, 6H), 2.25 - 2.39 (m, 2H), 2.19 - 2.01 (m, 2H), 1.28 - 1.11 (m, 6H)。 [M+H] +=477.3

[46] 1H NMR (300 MHz, DMSO-d6) δ 11.87 (s, 1H), 9.10 (d, 1H), 8.41 (s, 1H), 8.30 (d, 1H), 7.86 - 7.71 (m, 2H), 7.63 (s, 1H), 7.42 - 7.36 (m, 1H), 5.01 (q, 1H), 4.71 - 4.63 (m, 4H), 3.66 (s, 2H), 3.37-3.33 (m, 4H), 2.56 (m, 6H), 1.18 (t, 3H)。 [M+H] +=449.15

[47] 1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.40 (d, 1H), 8.36 (d, 1H), 8.27 (d, 1H), 7.83 (d, 1H), 7.75 (s, 1H), 7.63 (d, 1H), 7.40 (dd, 1H), 4.51 - 4.40 (m, 1H), 3.89-3.78 (m, 2H), 3.74-3.68 (m, 1H), 3.65 (s, 2H), 3.60-3.54 (m, 1H), 3.39-3.35 (m, 4H), 2.60 - 2.52 (m, 6H), 2.19-2.09 (m, 1H), 1.99 - 1.89 (m, 1H), 1.18 (t, 3H)。 [M+H] +=463.20

[48] 1H NMR (300 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.45 - 8.33 (m, 2H), 8.28 (d, 1H), 7.84 (d, 1H), 7.76 (s, 1H), 7.63 (s, 1H), 7.41 (dd, 1H), 4.45 (m, 1H), 3.92 - 3.78 (m, 2H), 3.78 - 3.65 (m, 1H), 3.66 (s, 2H), 3.57 (dd, 1H), 3.39 - 3.36 (m, 4H),2.58-2.54 (m, 6H), 2.24 - 2.06 (m, 1H), 2.02-1.86 (m, 1H), 1.19 (t, 3H)。 [M+H] +=463.30

[49] 1H NMR (300 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.41 (s, 1H), 8.27 (s, 1H), 8.14 (d, 1H), 7.84 (d, 1H), 7.76 (s, 1H), 7.63 (s, 1H), 7.41 (d, 1H), 4.82 (d, 1H), 4.01-3.96 (m, 2H), 3.66 (s, 2H), 3.33-3.29 (m, 4H), 2.57-2.54 (m, 6H), 2.06-1.92 (m, 1H), 1.91 - 1.77 (m, 1H), 1.70-1.58 (m, 2H), 1.53-1.37 (m, 2H), 1.19 (t, 3H)。 [M+H] +=477.20

[50] 1H NMR (300 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.84 (t, 1H), 8.48 (s, 1H), 8.37 (d, 1H), 7.92 (d, 1H), 7.83 (s, 1H), 7.70 (s, 1H), 7.48 (dd, 1H), 3.73 (s, 2H), 3.58 (d, 2H), 3.43-3.40 (m, 4H), 2.85 (t, 2H), 2.64 (m, 6H), 1.26 (t, 3H)。 [M+H] +=445.90

[52] 1H NMR (400 MHz, DMSO- d 6) δ 11.86 (s, 1H), 8.41 (d, 1H), 8.31 (d, 1H), 8.20 (t, 1H), 7.85 (d, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.41 (dd, 1H), 4.68 (s, 1H), 3.65 (s, 2H), 3.36 - 3.34 (m, 4H), 3.25 (d, 2H), 2.58 - 2.56 (m, 6H), 1.19 (t, 3H), 1.09 (s, 6H)。 [M+H] +=465.2

[53] 1H NMR (300 MHz, DMSO- d 6) δ 11.87 (s, 1H), 8.41 (s, 1H), 8.29 (s, 1H), 8.21 (d, 1H), 7.84 (d, 1H), 7.76 (s, 1H), 7.63 (s, 1H), 7.41 (d, 1H), 3.93-3.87 (m, 1H), 3.76 - 3.63 (m, 4H), 3.40 -3.32 (m, 6H), 2.61 - 2.52 (m, 6H),1.87-1.83 (m, 1H), 1.75 - 1.49 (m, 3H), 1.19 (t, 3H)。 [M+H] +=477.3

[54] 1H NMR (300 MHz, DMSO- d 6) δ 11.87 (s, 1H), 8.41 (s, 1H), 8.29 (d, 1H), 8.22 (d, 1H), 7.84 (d, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.41 (dd, 1H), 3.93-3.87 (m, 1H), 3.76 - 3.63 (m, 4H), 3.40 -3.32 (m, 6H), 2.61 - 2.52 (m, 6H), 1.87-1.83 (m, 1H), 1.77 - 1.51 (m, 3H), 1.18 (t, 3H)。 [M+H] +=477.3

[55] 1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.41 (d, 1H), 8.32 (d, 1H), 8.28 (d, 1H), 7.81 (d, 1H), 7.76 (t, 1H), 7.63 (d, 1H), 7.39 (dd, 1H), 4.92 (s, 1H), 4.02-3.96 (m, 1H), 3.66 (s, 2H), 3.36 - 3.33 (m, 4H), 2.61 - 2.52 (m, 6H), 2.37 - 2.24 (m, 2H), 2.14 - 2.02 (m, 2H), 1.24 (s, 3H), 1.18 (t, 3H)。 [M+H] +=477.35

[56] 1H NMR (300 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.41 (d, 1H), 8.28 (d, 1H), 8.13 (d, 1H), 7.84 (d, 1H), 7.76 (s, 1H), 7.63 (s, 1H), 7.41 (dd, 1H), 4.07 - 4.21 (m, 1H),3.45 (s, 2H), 3.70-3.62(m, 2H), 3.40-3.31 (m, 4H), 3.27 (s, 3H), 2.57-2.55 (m, 6H), 1.28 - 1.06 (m, 6H)。 [M+H] +=465.2

[57] 1H NMR (300 MHz, DMSO-d 6) δ 11.87 (s, 1H), 8.41 (d, 1H), 8.34 - 8.25 (m, 2H), 7.85 (d, 1H), 7.76 (s, 1H), 7.63 (d, 1H), 7.41 (dd, 1H), 4.84 (d, 1H), 3.85 - 3.71 (m, 1H), 3.66 (s, 2H), 3.40-3.16 (m, 1H) 3.34 - 3.27 (m, 4H), 3.21 - 3.04 (m, 1H), 2.65 - 2.53 (m, 6H), 1.19 (t, 3H), 1.05 (d, 3H)。 [M+H] +=451.2

[58] 1H NMR (300 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.92 (d, 1H), 8.41 (d, 1H), 8.28 (d, 1H), 7.82 (d, 1H), 7.76 (s, 1H), 7.63 (d, 1H), 7.39 (dd, 1H), 4.53 - 4.46 (m, 1H), 3.66 (s, 2H),3.40 - 3.36 (m, 4H), 3.12 - 2.94 (m, 1H), 2.61 - 2.53 (m, 10H), 1.19 (t, 3H)。 [M+H] +=472.15

[59] 1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.41 (d, 1H), 8.28 (d, 1H), 8.10 (d, 1H), 7.84 (d, 1H), 7.76 (s, 1H), 7.63 (d, 1H), 7.40 (dd, 1H), 4.85 (t, 1H), 3.99-3.95 (m, 1H), 3.65 (s, 2H), 3.46-3.40 (m, 2H), 3.34-3.45 (m, 4H), 2.57 - 2.49 (m, 6H), 1.21 - 1.11 (m, 6H)。 [M+H] +=451.2

[60] 1H NMR (300 MHz, DMSO- d 6) δ 11.84 (s, 1H), 8.41 (d, 1H), 8.33 - 8.22 (m, 2H), 7.84 (d, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.40 (dd, 1H), 3.65 (s, 2H), 3.50 - 3.44 (m, 1H), 3.42 - 3.36 (m, 3H), 3.35 -3.29 (m, 3H), 3.28 (s, 3H), 2.59 - 2.54 (m, 6H), 1.18 (t, 3H), 1.06 (d, 3H)。 [M+H] +=465.2

[80] 1H NMR (400 MHz, DMSO-d 6) δ 11.86 (s, 1H), 8.51 (dd, 1H), 8.39 (d, 1H), 7.83 (d, 1H), 7.60 (d, 1H), 7.53 (t, 1H), 6.83 - 6.71 (m, 2H), 5.01 - 4.90 (m, 1H), 4.76 - 4.71 (m, 2H), 4.58 - 4.51 (m, 2H), 3.64 (s, 2H), 3.32 - 3.27 (m, 4H), 2.55 - 2.51 (m, 4H), 2.14 (d, 3H)。 19F NMR (377 MHz, DMSO) δ -111.19. [M+H] +=452.05

[81] 1H NMR (300 MHz, DMSO-d6) δ 11.97 (s, 1H), 9.15(d, 1H), 8.45(d, 2H), 7.78 (d, 1H), 7.62(d, 1H), 7.49 (d, 2H), 5.13-5.03 (m, 1H),4.79-4.46 (m, 4H), 3.71 (s, 2H), 3.51-3.42(m, 4H), 2.62 - 2.57 (m, 4H), 2.21- 2.08 (m, 1H), 0.91- 0.90(m, 2H), 0.88 - 0.80 (m, 2H). [M+H] +=461.30 [Example]

[14] [] [step] [1] [:preparation] [4-[2-] [Formaldehyde] [-6-(] [Methylaminomethyl] [)] [Pyridine] [-3-] [base] []] [Pipeline] [𠯤] [-1-] [Tributyl carboxylate:] []

[0330] In a nitrogen atmosphere at room temperature, bis(adamantane-1-yl)(butyl)phosphine (311 mg, 0.87 mmol, 0.20 equivalent) and Pd(OAc)₂ (97 mg, 0.43 mmol, 0.10 equivalent) were added to a stirred solution of 4-[2-bromo-6-(methylaminomethyl)pyridin-3-yl]piperazine-1-carboxylic acid tributyl ester (1.73 g, 4.33 mmol, 1.00 equivalent) and TMEDA (604 mg, 5.20 mmol, 1.20 equivalent) in toluene (60 ml). The resulting mixture was stirred overnight at 100 °C under a CO / H₂ atmosphere (1:1, 30 atm). The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silicone column chromatography to obtain 1.50 g of 4-[2-methoxy-6-(methylaminomethoxy)pyridin-3-yl]piperazine-1-carboxylic acid tributyl ester, a yellow solid. LC-MS: (ES-H, m / z): [MH] = 346.8. [step] [2] [:preparation] [4-[2-(] [Difluoromethyl] [)-6-(] [Methylaminomethyl] [)] [Pyridine] [-3-] [base] []] [Pipeline] [𠯤] [-1-] [Tributyl carboxylate:] []

[0331] BAST (1.20 mL, 6.44 mmol, 1.50 equivalent) was added to a stirred solution of 4-[2-methoxy-6-(methylaminomethoxy)pyridin-3-yl]piperyl-1-carboxylic acid tributyl ester (1.50 g, 4.29 mmol, 1.00 equivalent) in DCM (8 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 h. The reaction was monitored by LCMS. The reactants were quenched with ice water (40 mL) at room temperature. The resulting mixture was extracted with CH₂Cl₂ (3 × 40 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silicone column chromatography to give a grayish-white solid, 4-[2-(difluoromethyl)-6-(methylaminomethyl)pyridin-3-yl]piperazine-1-carboxylic acid tributyl ester (580 mg, 36.05%, two steps). LC-MS: (ES+H, m / z): [M+H]+= 371.1. 1H NMR (300 MHz, chloroform-d) δ 8.29 (d, 1H), 7.94 (d, 1H), 7.63 (d, 1H), 7.21–6.80 (m, 1H), 3.69–3.61 (m, 4H), 3.06 (d, 3H), 3.03–2.98 (m, 4H), 1.51 (s, 9H). 19F NMR (282 MHz, CDCl3) δ-116.99. [step] [3] [:preparation] [6-(] [Difluoromethyl] [)-N-] [methyl] [-5-(] [Pipeline] [𠯤] [-1-] [base] [)] [Pyridine] [-2-] [Methionine] [HCl] [Salt:] []

[0332] 1,4-dimethylalkanes (4 mL, 4 M) containing HCl (gas) was added to a stirred solution of 4-[2-(difluoromethyl)-6-(methylaminomethyl)pyridin-3-yl]piperidin-1-carboxylic acid tributyl ester (570 mg, 1.54 mmol, 1.00 equivalent) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 min. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. This produced a red solid, 6-(difluoromethyl)-N-methyl-5-(piperidin-1-yl)pyridin-2-methylamine, HCl salt (610 mg, crude). LC-MS: (ES+H, m / z): [M+H]+= 270.9. 1H NMR (300 MHz, DMSO-d6) δ 9.39 (s, 2H), 8.50-8.40 (m, 1H), 8.14 (d, 1H), 7.93 (d, 1H), 7.52-7.06 (m, 1H), 3.31-3.27 (m, 4H), 3.22-3.18 (m, 4H), 2.84 (d, 3H). [step] [4] [:preparation] [6-(] [Difluoromethyl] [)-5-{4-[(7-] [Ethyl] [-6-] [Side group] [-5H-1,5-] [Ding] [-3-] [base] [)] [methyl] []] [Pipeline] [𠯤] [-1-] [base] [}-N-] [Methylpyridine] [-2-] [Methamide:] []

[0333] At room temperature under a nitrogen atmosphere, DIEA (377 mg, 2.92 mmol, 5.00 equivalents) and KI (2 mg, 0.01 mmol, 0.02 equivalents) were added to a stirred solution of 6-(difluoromethyl)-N-methyl-5-(piperazine-1-yl)pyridin-2-methylamine, HCl salt (250 mg, 0.82 mmol, 1.40 equivalents) and 7-(chloromethyl)-3-ethyl-1H-1,5-pyridin-2-one (130 mg, 0.58 mmol, 1.00 equivalents) in MeCN (5 mL). The resulting mixture was stirred at 80 °C for 1 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was concentrated under reduced pressure. The crude product (366 mg) was purified by preparative HPLC to give 6-(difluoromethyl)-5-{4-[(7-ethyl-6-sideoxy-5H-1,5-diphenyl-3-yl)methyl]piperidin-1-yl}-N-methylpyridin-2-methylamine (76.0 mg, 29.92%, two steps) as a grayish-white solid. LC-MS: (ES+H, m / z): [M+H]+= 457.2. 1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.44-8.36 (m, 2H), 8.10 (d, 1H), 7.86 (d, 1H), 7.75 (s, 1H), 7.62 (d, 1H), 7.32-6.99 (m, 1H), 3.68 (s, 2H), 3.06-2.98 (m, 4H), 2.83 (d, 3H), 2.66-2.53 (m, 6H), 1.22-1.15 (m, 3H). 19F NMR (377 MHz, DMSO) δ-115.95. [Example]

[15] [step] [1] [:preparation] [2-] [bromine] [-2-] [Ethyl cyclopropyltriethyl acetate]: []

[0334] Under a nitrogen atmosphere at -78°C, LDA (42.9 mL, 85.82 mmol, 1.10 M in THF) was added dropwise to a stirred solution of ethyl 2-cyclopropylacetate (10.00 g, 78.02 mmol, 1.00 equivalent) in 100 mL of THF. The reaction mixture was stirred for 1 hour, followed by the dropwise addition of TMSCl (8.48 g, 78.02 mmol, 1.00 equivalent) while stirring for 3 hours as the mixture was warmed to room temperature. The reaction mixture was then cooled to -78°C and 50 mL of THF containing NBS (15.28 g, 85.82 mmol, 1.10 equivalent) was added dropwise. The mixture was then stirred for 2 hours and warmed to room temperature. The reaction was monitored by LCMS. The reaction mixture was quenched by adding 50 mL of saturated NH4Cl (aqueous solution) at 0°C. The mixture was extracted with Et₂O (3 × 200 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse combination rapid chromatography to give ethyl 2-bromo-2-cyclopropyl acetate (5.00 g, 30.95%) as a yellow liquid. ¹H NMR (300 MHz, chloroform-d) δ 4.25 (q, 2H), 3.58 (d, 1H), 1.65–1.55 (m, 1H), 1.31 (t, 3H), 0.92–0.76 (m, 2H), 0.61–0.53 (m, 1H), 0.48–0.40 (m, 1H). [step] [2] [:preparation] [2-] [Cyclopropyl] [-2-(] [diethoxyphosphoyl] [)] [Ethyl acetate:]

[0335] A solution of ethyl 2-bromo-2-cyclopropylacetate (5.00 g, 24.14 mmol, 1.00 equivalent) and triethyl phosphite (5.22 g, 31.39 mmol, 1.30 equivalent) was stirred at 130 °C for 24 hours under a nitrogen atmosphere. The residue was purified by reverse combination rapid chromatography to give ethyl 2-cyclopropyl-2-(diethoxyphosphatidyl)acetate (2.40 g, 37.61%) as a yellow liquid. 1H NMR (300 MHz, chloroform-d) δ 4.26 - 4.07 (m, 6H), 2.19 (dd, 1H), 1.30 (dt, 10H), 0.71 (dddd, 1H), 0.60 (ddddd, 1H), 0.47 - 0.37 (m, 1H), 0.24 (ddtd, 1H). [step] [3] [:preparation] [6-[(1Z)-2-] [Cyclopropyl] [-3-] [Ethoxy] [-3-] [Side-oxypropyl] [-1-] [ene] [-1-] [base] []-5-] [Nitro] [Pyridine] [-3-] [Methyl carboxylate:]

[0336] Under a nitrogen atmosphere, ethyl 2-cyclopropyl-2-(diethoxyphosphatidyl)acetate (1.89 g, 7.14 mmol, 1.50 equivalence) was added dropwise to a stirred mixture of NaH (0.29 g, 7.14 mmol, 1.50 equivalence) in 20 mL of THF. The resulting mixture was stirred at 0 °C for 10 min and then heated to 40 °C and stirred for 10 min under a nitrogen atmosphere. The resulting mixture was cooled to -78 °C, and then methyl 6-methoxy-5-nitropyridine-3-carboxylic acid (1.00 g, 4.76 mmol, 1.00 equivalence) in 20 mL of THF was added dropwise. The resulting mixture was stirred at -78 °C for 30 min under a nitrogen atmosphere. The reaction was monitored by LCMS. The reactants were quenched by adding saturated NH₄Cl (aqueous solution) (5 mL) at 0 °C. Add 20 mL of water to the resulting mixture and extract with EtOAc (3 × 20 mL). Wash the combined organic layers with brine (1 × 50 mL) and dry over anhydrous Na₂SO₄. After filtration, concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography to give methyl 6-[(1Z)-2-cyclopropyl-3-ethoxy-3-t-oxypropyl-1-en-1-yl]-5-nitropyridine-3-carboxylic acid (700 mg, 45.93%) as a brown oil. LC-MS: (ES+H, m / z): [M+H]⁺ = 320.8. [step] [4] [:preparation] [7-] [Cyclopropyl] [-6-] [Side group] [-5H-1,5-] [Ding] [-3-] [Ethyl carboxylate:]

[0337] At room temperature under a nitrogen atmosphere, CaCl₂ (1.24 g, 11.24 mmol, 6.00 equivalent) was added to a stirred mixture of methyl 6-[(1Z)-2-cyclopropyl-3-ethoxy-3-t-oxypropyl-1-en-1-yl]-5-nitropyridine-3-carboxylic acid (600 mg, 1.87 mmol, 1.00 equivalent) and Fe (1.04 g, 18.73 mmol, 10.00 equivalent) in EtOH (10 mL). The resulting mixture was stirred overnight at 90 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was filtered, and the filter cake was washed with EtOAc (2 × 50 mL). The filtrate was concentrated under reduced pressure. 50 mL of water was added to the resulting mixture, and the mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 7-cyclopropyl-6-sideoxy-5H-1,5-isodimidine-3-carboxylate (200 mg, 41.34%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]⁺ = 259.0. [step] [5] [:preparation] [3-] [Cyclopropyl] [-7-(] [Hydroxymethyl] [)-1H-1,5-] [Ding] [-2-] [ketone:]

[0338] Under a nitrogen atmosphere, ethyl 7-cyclopropyl-6-sideoxy-5H-1,5-diphenyl-3-carboxylate (160 mg, 0.62 mmol, 1.00 equivalent) was added dropwise to a stirred solution of 7-cyclopropyl-6-sideoxy-5H-1,5-diphenyl-3-carboxylate (2.5 M in THF, 0.50 mL). The resulting mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. The reaction was monitored by LC-MS. The reactants were quenched by adding 1 M HCl aqueous solution (1 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silicone column chromatography to give 100 mg, 74.65% 3-cyclopropyl-7-(hydroxymethyl)-1H-1,5-diphenyl-2-one (100 mg, 74.65%) as a pale yellow solid. LC-MS: (ES+H, m / z): [M+H]+=217.2. [step] [6] [:preparation] [7-(] [Chloromethyl] [)-3-] [Cyclopropyl] [-1H-1,5-] [Ding] [-2-] [ketone:]

[0339] SOCl₂ (264 mg, 2.22 mmol, 6.00 equivalent) was added dropwise to a stirred mixture of 3-cyclopropyl-7-(hydroxymethyl)-1H-1,5-diphenyl-2-one (80 mg, 0.37 mmol, 1.00 equivalent) and DMF (3 mg, 0.04 mmol, 0.10 equivalent) in DCM (10 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was concentrated under reduced pressure to give 7-(chloromethyl)-3-cyclopropyl-1H-1,5-diphenyl-2-one as a yellow solid. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H]⁺ = 235.0. [step] [7] [:preparation] [5-{4-[(7-] [Cyclopropyl] [-6-] [Side group] [-5H-1,5-] [Ding] [-3-] [base] [)] [methyl] []] [Pipeline] [𠯤] [-1-] [base] [}-N-] [Methylpyridine] [-2-] [Methamide:]

[0340] A mixture of 7-(chloromethyl)-3-cyclopropyl-1H-1,5-pyridin-2-one (80 mg, 0.34 mmol, 1.00 equivalent), N-methyl-5-(piperazine-1-yl)pyridin-2-methylamine (75 mg, 0.34 mmol, 1.00 equivalent), KI (11 mg, 0.07 mmol, 0.20 equivalent), and DIEA (220 mg, 1.71 mmol, 5.00 equivalent) in MeCN (10 mL) was stirred at 80 °C for 2 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silicone column chromatography to give 5-{4-[(7-cyclopropyl-6-sideoxy-5H-1,5-diphenyl-3-yl)methyl]piperidin-1-yl}-N-methylpyridin-2-methylamine (85 mg, 58.57%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=419.3. 1H NMR (300 MHz, DMSO- d 6) δ 11.89 (s, 1H), 8.43 - 8.36 (m, 2H), 8.26 (d, 1H), 7.83 (d, 1H), 7.61 (d, 1H), 7.44 - 7.35 (m, 2H), 3.64 (s, 2H), 3.34 - 3.28 (m, 4H), 2.78 (d, 3H), 2.56 (d, 4H), 2.21 - 2.07 (m, 1H), 0.97 (dt, 2H), 0.86 - 0.77 (m, 2H). [Example]

[16] [step] [1] [:preparation] [6-(] [Methylaminomethyl] [)-3',6'-] [Dihydrogen] [-[3,4'-] [Bipyridine] []-1'(2'H)-] [Tributyl carboxylate:] []

[0341] At room temperature, Pd(dppf)Cl₂ (102 mg, 0.14 mmol, 1.00 equivalent) and K₂CO₃ (386 mg, 2.79 mmol, 2.00 equivalent) were added to a stirred mixture of 5-bromo-N-methylpyridin-2-methylamine (300 mg, 1.40 mmol, 1.00 equivalent) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentan-2-yl)-3,6-dihydro-2H-pyridin-1-carboxylic acid tributyl ester (518 mg, 1.67 mmol, 1.20 equivalent) in 1,4-dimethylalkanes / H₂O (4 / 1, 5 mL). The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silicone column chromatography to give tributyl 6-(methylaminomethyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylic acid (330 mg, 74.53%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=318.2. 1H NMR (400 MHz, DMSO-d6) δ 8.75 - 8.67 (m, 2H), 8.04 - 7.95 (m, 2H), 6.41 (s, 1H), 4.08 - 4.00 (m, 2H), 3.56 (t, 2H), 2.82 (d, 3H), 2.53 (d, 2H), 1.43 (s, 9H). [step] [2] [:preparation] [4-(6-(] [Methylaminomethyl] [)] [Pyridine] [-3-] [base] [)] [piperidine] [-1-] [Tributyl carboxylate:]

[0342] Pd / C (33 mg, 10 wt%) was added to a stirred solution of 6-(methylaminomethyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylic acid tributyl ester (330 mg, 1.04 mmol, 1.00 equivalent) in methanol (20 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction was monitored by LC-MS. The resulting mixture was filtered, and the filter cake was washed with MeOH (5 × 10 mL). The filtrate was concentrated under reduced pressure to give 4-(6-(methylaminomethyl)pyridine-3-yl)piperidine-1-carboxylic acid tributyl ester (320 mg, 96.36%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=320.2. 1H NMR (400 MHz, DMSO-d6) δ 8.70 (d, 1H), 8.53 (d, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 4.09 (d, 2H), 2.81 (d, 6H), 1.78 (d, 2H), 1.55 (qd, 2H), 1.42 (s, 9H). [step] [3] [:preparation] [N-] [methyl] [-5-(] [piperidine] [-4-] [base] [)] [Pyridinemethylamine] [,] [TFA] [Salt:] []

[0343] TFA (2 mL) was added dropwise to a stirred solution of 4-(6-(methylaminomethyl)pyridin-3-yl)piperidine-1-carboxylic acid tributyl ester (310 mg, 0.97 mmol, 1.00 equivalent) in DCM (5 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. The crude product N-methyl-5-(piperidine-4-yl)pyridinylmethylamine, TFA salt (510 mg, crude product), was used directly in ...

Claims

1. A compound or a pharmaceutically acceptable salt, hydrate or stereoisomer thereof, selected from the group consisting of: , ...

2. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate or stereoisomer thereof is: or a pharmaceutically acceptable salt, hydrate or stereoisomer thereof.

3. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate or stereoisomer thereof is: or a pharmaceutically acceptable salt, hydrate or stereoisomer thereof.

4. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate or stereoisomer thereof is: or a pharmaceutically acceptable salt, hydrate or stereoisomer thereof.

5. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate or stereoisomer thereof is: or a pharmaceutically acceptable salt, hydrate or stereoisomer thereof.

6. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate or stereoisomer thereof is: or a pharmaceutically acceptable salt, hydrate or stereoisomer thereof.

7. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate or stereoisomer thereof is: or a pharmaceutically acceptable salt, hydrate or stereoisomer thereof.

8. A pharmaceutical composition comprising a compound as claimed in claim 1 or a pharmaceutically acceptable salt, hydrate or stereoisomer thereof, and a pharmaceutically acceptable excipient.

9. Use of a compound as claimed in claim 1 or a pharmaceutically acceptable salt, hydrate or stereoisomer thereof for the preparation of a medicine for treating cancer.

10. As claimed in claim 9, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, or lung cancer.

11. Use of a compound as claimed in claim 1 or a pharmaceutically acceptable salt, hydrate or stereoisomer thereof for the preparation of a pharmaceutical product for treating cancers containing BRCA1 and / or BRCA2 mutations.

12. As claimed in claim 11, wherein the cancer is bladder cancer, brain cancer and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer, or uterine cancer.