Substituted bicyclic heteroaryl sulfonamide derivatives for the treatment of cancer

Abstract

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein X 1 is CR 7 or N and X 2 is CR 8 or N and X 3 is CR 9 or N and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 provides compounds of formula (I) and pharmaceutically acceptable salts thereof, as defined in the claims, and methods of using the compounds in the treatment of neoplastic diseases such as cancer.

Description

[Technical Field]

[0001] The present invention relates to compounds that inhibit poly ADP-ribose glycohydrolase (PARG) and the use of such compounds in the treatment of neoplastic diseases such as cancer. [Background technology]

[0002] Genomic instability and replicative immortality are key hallmarks of cancer (Hanahan D, Cancer Discovery 2022). However, persistent, uncontrolled proliferation driven by oncogenes and the loss of tumor suppressor genes also place a strain on cancer cells' metabolism. For example, constitutive activation of oncogenic pathways forces cells to progress through the cell cycle, which can lead to DNA replication stress (Gaillard H et al., Nature Reviews Cancer 2015). To address the latter and avoid harmful DNA damage, cells activate various complementary DNA damage response and repair (DDR) pathways to resolve stalled replication forks and repair single- and / or double-strand DNA breaks (Brown JS et al., Cancer Discovery 2017).

[0003] Among the tumor suppressor gene functions lost in cancer, multiple components of various DDR pathways may be impaired (e.g., hereditary cancer syndromes). On the one hand, defects in a particular DDR mechanism may be compensated for to some extent by alternative repair pathways (Curtin NJ, Nature Reviews Cancer 2012). On the other hand, these alternative pathways often do not repair DNA damage with the same fidelity as the impaired DDR pathway. Therefore, gaps in repair mechanisms may create vulnerabilities that can be exploited for cancer therapy. This concept is also referred to as synthetic lethality, in which dysfunction of one biological process is still compatible with cell survival, but genetic deficiency or pharmacological inhibition of parallel and / or compensatory processes results in cell death (Hartwell and Friend, Science 1997).

[0004] The discovery and subsequent clinical translation of synthetic lethality in cancer settings associated with defects in homologous recombination repair (HR) through the inhibition of poly(ADP-ribose) polymerases 1 and 2 (PARP1 / 2) represents a scientific and therapeutic breakthrough (Farmer et al., Nature 2005; Bryant et al., Nature 2005). While HR is the most accurate DNA repair pathway, loss of the BRCA1 (BReast cancer gene 1) or BRCA2 (BReast cancer gene 2) tumor suppressor genes in the pathway blunts this pathway, causing affected cells to instead rely on less reliable alternative DDR mechanisms to repair damaged DNA. PARP1 and 2 are DNA damage sensors involved in the alternative non-homologous end joining (alt-NHEJ) and DNA single-strand break (SSB) repair / base excision repair (BER) pathways. Pharmacological inhibition of the PARP1 / 2 enzymes in cancers in which either BRCA1 or BRCA2 is lost, i.e., cancers that exhibit so-called "BRCAness" (Turner N et al, Nature Reviews Cancer 2004), causes the collapse of stalled DNA replication forks, resulting in persistent DNA damage and cancer cell death. PARP1 / 2 enzymes belong to a family of 17 members (Hottiger MO et al., Trends Biochem. Sci. 2010). Upon sensing DNA damage, they rapidly post-translationally modify themselves and other target proteins with ADP-ribose (ADPr) using the coenzyme nicotinamide adenine dinucleotide (NAD+) as a substrate. On receptor proteins, PARP1 / 2 typically form polymers of ADPr, termed polyADP-ribose (PAR) or PARylation, which vary in length and degree of branching. This is thought to facilitate the recruitment of additional DNA repair enzymes at the site of DNA damage (Leung AKL, Trends in Cell Biology 2020). However, to complete DNA damage repair, the PAR chains must be removed from the receptor protein again. Poly(ADP-ribose) glycohydrolase (PARG) balances PARP1 / 2 by degrading the PAR chains. PARG primarily exhibits exoglycohydrolase activity, degrading PAR chains to monomeric ADPr (Barkauskaite E at al, Nature Communications 2013), although endoglycohydrolase activity leading to the release of protein-free PAR chains has also been described (Pourfarjam Y et al, BBRC 2020).

[0005] Preclinical evidence suggests that increased removal of PARG chains promotes cancer growth. Genetically enforced overexpression of PARG has been shown to promote transformation and tumor growth of normal human mammary epithelial cells in mice (Marques M et al., Oncogene 2019). Conversely, shRNA-mediated depletion of PARG led to reduced tumor initiation, growth, and metastasis (Marques M et al., Oncogene 2019). Pharmacological inhibition of PARG has been achieved using cell-permeable tool compounds. Importantly, these studies in cell-based cancer models have demonstrated the potential for PARG inhibitors to act complementary to PARP inhibitors (Pillay N et al., Cancer Cell 2019) and in the setting of acquired PARP inhibitor resistance (Coulson-Gilmer C et al., Journal of Experimental & Clinical Cancer Research 2021). Sensitivity to PARG inhibition has been reported to correlate with markers of DNA replication vulnerability and DNA replication stress, and PARG inhibition resulted in a significant loss of mitotic capacity in sensitive cancer cell lines (Pillay N et al., Cancer Cell 2019; Coulson-Gilmer C et al., Journal of Experimental & Clinical Cancer Research 2021). Furthermore, sustained PARG inhibition is highly toxic to cells (Prokhorova E et al., Molecular Cell 2021). PARG inhibition prolongs PARG inhibition at DNA damage, inhibiting DNA repair factors and suppressing DNA repair (Chen SH & Yu X, Science Advances 2019).As a result, PARG inhibition increases sensitivity to various DNA damaging agents (Slade D, Genes & Development 2020), drugs targeting other DDR enzymes such as checkpoint kinase 1 (CHK1) (Pillay N et al, Cancer Cell 2019), and ionizing radiation-induced DNA damage (Houl JH et al, Nature Communications 2019). In conclusion, PARG inhibition holds promise for the treatment of cancer, both as monotherapy and in combination with other therapies.

[0006] WO 2021 / 055744, WO 2016 / 097749, and WO 2016 / 092326 describe PARG inhibitors. Summary of the Invention [Means for solving the problem]

[0007] In a first aspect, the present invention provides a compound of formula (I): [ka] and pharmaceutically acceptable salts thereof, During the ceremony, R 1 is hydrogen, cyano, formyl, -CONH2, -CH2OH, -CH2OC 1~2 Alkyl, C 1~2 Alkyl, C 1~2 haloalkyl, or ethynyl; R 2 and R 3 independently, C 1~2 Is it alkyl; or R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl or oxetanyl; X 1 is CR 7 or N; R 7is hydrogen or fluoro; X 2 is CR 8 or N; R 8 is hydrogen or fluoro; X 3 is CR 9 or N; R 9 is hydrogen, halogen, cyano, -N(R m )R n , C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 2~4 Alkynyl, C 3~6 cycloalkyl, phenyl, heteroaryl, heterocyclyl, fused heterocyclyl, spiroheterocyclyl, or bridged heterocyclyl, wherein the cycloalkyl, phenyl, heteroaryl, heterocyclyl, fused heterocyclyl, spiroheterocyclyl, and bridged heterocyclyl are optionally selected from the group consisting of R a , R b , and / or R c is replaced by; R a is hydrogen, -N(R m )R n , C 1~6 Alkyl, hydroxy, C 1~6 Alkoxy, halogen, cyano, oxo, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, Hydroxy C 1~6 Alkyl, C 3~6 Cycloalkyl, heteroaryl, heterocyclyl, -C(O)R d , -C(O)OR e , -C(O)N(R f )R g , -S(O)2N(R h )R i , or C 1~6 Alkyl-N(R j )R k and; R b and R care independently hydrogen, -N(R m )R n , C 1~6 Alkyl, C 1~4 Alkyl-N(R m )R n , hydroxy, C 1~6 Alkoxy, halogen, cyano, C 1~6 Haloalkyl, or C 1~6 haloalkoxy; R d is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 cycloalkyl, phenyl, heteroaryl, or heterocyclyl; R e is hydrogen or C 1~6 is alkyl; R f , R g , R h , R i , R j , R k , R m , and R n are each independently hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, Amino C 1~6 Alkyl or hydroxy C 1~6 is alkyl; or R f and R g , R h and R i , or R j and R k together with the nitrogen atom to which they are attached form a heterocyclyl; where: (i)R a cycloalkyl, heteroaryl, and heterocyclyl; (ii)R d alkyl, haloalkyl, cycloalkyl, phenyl, heteroaryl, and heterocyclyl; (iii)R f and R g , R h and Ri , or R j and R k and the nitrogen to which they are attached to form a heterocyclyl are respectively ((i), (ii), (iii)) optionally, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkyl-NH2, C 1~6 Alkyl-NH(C 1~4 alkyl), C 1~6 Alkyl-N(C 1~4 alkyl)2, hydroxy, oxo, C 1~6 Alkoxy, halogen, cyano, amino-NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, C 1~6 Haloalkyl, and C 1~6 substituted with 1, 2, 3, or 4 substituents independently selected from haloalkoxy; R 4 is hydrogen or -L 1A -L 2A -L 3A It is a base; L 1A does not exist or C 1~2 C optionally substituted with alkyl or oxo 1~3 is alkylene; L 2A is absent or is -O-, -S-, -S(O)-, -S(O)2-, -N(R a1 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a1 )-, -N(R a1 )C(O)-, -N(R a1 )C(O)N(R b1 )-, -S(O)2N(R a1 )- or -N(R a1 )S(O)2-; R a1 and R b1 are each independently hydrogen or C 1~2 is alkyl; L 3A is hydrogen, C 1~6Alkyl, C 3~6 cycloalkyl, phenyl, heterocyclyl, or heteroaryl, where L 3A is optionally halogen, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, -N(R c1 )R d1 , -OR c1 , -C(O)R c1 , -C(O)OR c1 , -OC(O)R c1 , -C(O)N(R d1 )R c1 , -N(R d1 )C(O)R c1 , -S(O) y R c1 , -S(O)2N(R d1 )R c1 , -N(R d1 )S(O)2R c1 , and (CH2) z N(R d1 )R c1 and is substituted with one or more substituents independently selected from: R c1 and R d1 are each independently hydrogen or C 1~4 is alkyl; y is 0, 1, or 2; z is 1, 2, or 3; R 5 is hydrogen or -L 1B -L 2B -L 3B It is a base; L 1B does not exist or C 1~2 C optionally substituted with alkyl or oxo 1~3 is alkylene; L 2B is absent or is -O-, -S-, -S(O)-, -S(O)2-, -N(R a2 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a2)-, -N(R a2 )C(O)-, -N(R a2 )C(O)N(R b2 )-, -S(O)2N(R a2 )- or -N(R a2 )S(O)2-; R a2 and R b2 are each independently hydrogen or C 1~2 is alkyl; L 3B is hydrogen, C 1~6 Alkyl, C 3~6 cycloalkyl, phenyl, heterocyclyl, or heteroaryl, where L 3B is optionally halogen, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, -N(R c2 )R d2 , -OR c2 , -C(O)R c2 , -C(O)OR c2 , -OC(O)R c2 , -C(O)N(R d2 )R c2 , -N(R d2 )C(O)R c2 , -S(O) y’ R c2 , -S(O)2N(R d2 )R c2 , -N(R d2 )S(O)2R c2 , and (CH2) z’ N(R d2 )R c2 and is substituted with one or more substituents independently selected from: R c2 and R d2 are each independently hydrogen or C 1~4 is alkyl; y' is 0, 1, or 2; z' is 1, 2, or 3; R 6 is hydrogen or -L 1C -L 2C-L 3C It is a base; L 1C does not exist or C 1~2 C optionally substituted with alkyl or oxo 1~3 is alkylene; L 2C is absent or is -O-, -S-, -S(O)-, -S(O)2-, -N(R a3 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a3 )-, -N(R a3 )C(O)-, -N(R a3 )C(O)N(R b3 )-, -S(O)2N(R a3 )- or -N(R a3 )S(O)2-; R a3 and R b3 are each independently hydrogen or C 1~2 is alkyl; L 3C is hydrogen, C 1~6 Alkyl, C 3~6 cycloalkyl, phenyl, heterocyclyl, or heteroaryl, where L 3C is optionally halogen, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, -N(R c3 )R d3 , -OR c3 , -C(O)R c3 , -C(O)OR c3 , -OC(O)R c3 , -C(O)N(R d3 )R c3 , -N(R d3 )C(O)R c3 , -S(O) y” R c3 , -S(O)2N(R d3 )R c3 , -N(R d3 )S(O)2R c3 , and (CH2) z” N(Rd3 )R c3 and is substituted with one or more substituents independently selected from: R c3 and R d3 are each independently hydrogen or C 1~4 is alkyl; y" is 0, 1, or 2; z" is 1, 2, or 3; however, -L 1A -L 2A -L 3A group, -L 1B -L 2B -L 3B Groups, and L 1C -L 2C -L 3C the group does not contain an -OO- unit, an -SO- unit, an -OS- unit, or an -SS- unit as a linking unit within the group; -L 1A -L 2A -L 3A The group is R 4 no -ON- or -SN- unit is located adjacent to a ring nitrogen atom connected to -L 1B -L 2B -L 3B The group is R 5 no N atom, O atom, or S atom is located adjacent to the oxime oxygen atom connected to -L 1C -L 2C -L 3C The group is R 6 no -ON- or -SN- unit is located adjacent to a ring nitrogen atom connected to Provided are compounds of formula (I) and pharmaceutically acceptable salts thereof:

[0008] In a further aspect, the present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof for use in the treatment of neoplastic diseases (e.g., cancer) in a subject selected from mammals (particularly a human).

[0009] In a further aspect, the present invention provides the use of compounds of formula (I) and pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of a neoplastic disease (e.g., cancer) in a subject selected from mammals (particularly a human).

[0010] In a further aspect, the present invention provides a method of treating a neoplastic disease (e.g., cancer) in a subject selected from mammals (particularly a human), comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof, e.g., in a therapeutically effective amount.

[0011] In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.

[0012] When a compound of formula (I) contains one, two or more asymmetric centers (e.g., R 1 , R 2 , and R 3 are different moieties), such compounds may be provided as pure enantiomers or pure diastereoisomers, or as mixtures thereof in any ratio, and all such isomers are included within the scope of the compounds of formula (I). Both geometric isomers resulting from the orientation of the bond between the oxime nitrogen atom and the oxygen atom (i.e., compounds (Ia) and (Ib) shown below), and mixtures thereof in any ratio, are included within the scope of the present invention. [ka]

[0013] The compounds of the present invention also include all tautomeric forms of compounds of formula (I) and intermediates thereof (e.g., R 4 is a hydrogen atom and / or R 6 is a hydrogen atom, -N(R 4 )-C(=NOR 5 )-N(R 6 )- moiety). [ka]

[0014] Isotopically labeled compounds (e.g., deuterium substituted and carbon-13 and / or carbon-14 labeled) are also included within the scope of the compounds of formula (I). The compounds of formula (I) may also be solvated, particularly hydrated, and such solvated and hydrated forms of the compounds of formula (I) are also included within the scope of the compounds of formula (I). Solvation and hydration may occur during the preparation process.

[0015] Reference to the compounds of the present invention includes pharmaceutically acceptable salts of said compounds. Such salts may also exist as hydrates and solvates. Examples of pharmacologically acceptable salts of compounds of formula (I) include physiologically acceptable mineral acid salts, such as salts of hydrochloric acid, sulfuric acid, and phosphoric acid, or organic acid salts, such as salts of methanesulfonic acid, p-toluenesulfonic acid, lactic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid, and salicylic acid. Further examples of pharmacologically acceptable salts of compounds of formula (I) include alkali metal salts and alkaline earth metal salts, such as sodium salt, potassium salt, lithium salt, calcium salt, or magnesium salt, ammonium salt, or salts of organic bases, such as methylamine salt, dimethylamine salt, triethylamine salt, piperidine salt, ethylenediamine salt, lysine salt, choline hydroxide salt, meglumine salt, morpholine salt, or arginine salt.

[0016] "Alkylene," by itself or as part of another substituent, means a divalent saturated straight or branched chain hydrocarbon having the specified number of carbon atoms (i.e., C 1~6 means 1 to 6 carbons.) Examples of alkylene groups include -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(CH3)-CH2-, -CH(CH2CH3)-, and CH2CH(CH3)CH2-.

[0017] "Alkoxy" and "haloalkoxy" refer to an alkyl group and a haloalkyl group, respectively, attached to the remainder of the molecule through an oxygen atom.

[0018] "Alkyl," alone or as part of another substituent, means a saturated, straight- or branched-chain hydrocarbon radical having the specified number of carbon atoms (i.e., C 1~6 means 1 to 6 carbons.) Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl.

[0019] An "aminoalkyl" is an alkyl group consisting of one N(R)R', where R and R' are independently hydrogen, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, C 1~6 Alkoxy C 1~6 Alkyl, or -C(O)C 1~6 For example, "amino C" refers to an alkyl substituted with an alkyl group. 1~6 "Alkyl" includes NH2methyl, methylaminomethyl, methylaminoethyl, dimethylaminomethyl, diethylaminoethyl, dimethylaminoethyl, acetylaminomethyl, and acetylaminoethyl. In some embodiments, N(R)R' is attached to a carbon atom of the alkyl distal to the point of attachment to the rest of the molecule.

[0020] "Bridged heterocyclyl" refers to a heterocyclic group, unless otherwise specified, consisting of (X1) n"means a saturated 5- to 7-membered monocyclic heterocycle having two non-adjacent ring atoms linked by a group (wherein n is 1, 2, or 3; each X is CRR', NR, S, SO, SO, or O; not more than one X is NR, SO, SO, or O; and R and R' are independently H or methyl). The 5- to 7-membered heterocycle has as ring atoms 1, 2, or 3 heteroatoms independently selected from N, O, and S (the sulfur and nitrogen atoms are optionally oxidized), and the remaining ring atoms are carbon atoms. O and S are not bridgehead atoms, and such a ring does not contain adjacent oxygen atoms, adjacent sulfur atoms, or adjacent oxygen and sulfur atoms within the ring. Examples include 2-azabicyclo[2.2.2]octane, quinuclidine, 7-oxabicyclo[2.2.1]heptane, and 3,8-diazabicyclo[3.2.1]octane.

[0021] "Cycloalkyl" means a saturated hydrocarbon ring having a specified number of ring atoms (e.g., C 3~6 cycloalkyl). Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0022] "Fused heterocyclyl" means, unless otherwise specified, a saturated or partially saturated monocyclic ring of 4 to 7 ring atoms having 1, 2, or 3 heteroatoms independently selected from N, S, and O (the sulfur and nitrogen atoms are optionally oxidized), with the remaining ring atoms being carbon atoms, and the heterocyclyl ring may be substituted with phenyl, 5- or 6-membered heteroaryl, C, or CI, each as defined herein. 3~6"(Cycloalkyl)" refers to a monocyclic ring fused to two adjacent ring members of a cycloalkyl or heterocyclyl. The fused heterocyclyl may be attached to the remainder of the molecule through any ring atom. The number of ring atoms in a saturated or partially saturated monocyclic ring includes the two common ring atoms shared with the fused group. Such a ring does not contain adjacent oxygen atoms, adjacent sulfur atoms, or adjacent oxygen and sulfur atoms within the ring. Examples include 2,3-dihydrobenzo[b][1,4]-dioxinyl and 2-oxabicyclo[3.1.0]hexanyl.

[0023] "Halogen," by itself or as part of another substituent, means a fluorine, chlorine, bromine, or iodine atom.

[0024] "Haloalkyl" means alkyl substituted with 1 to 5 halogen atoms, and includes monohaloalkyl and polyhaloalkyl. For example, "C 1~4 "Haloalkyl" includes trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, and 3-bromopropyl. Similarly, fluoromethyl includes -CHF, -CHF, and CF.

[0025] "Heteroaryl," unless otherwise specified, means a 5- to 10-membered aromatic ring containing, as ring atoms, 1 to 5 heteroatoms independently selected from N, S, and O (wherein the nitrogen and sulfur atoms are optionally oxidized). A heteroaryl group can be attached to the remainder of the molecule through a heteroatom or a carbon atom. Such rings do not contain adjacent oxygen atoms, adjacent sulfur atoms, or adjacent oxygen and sulfur atoms within the ring. Examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, and thienyl.

[0026] "Heterocyclyl," unless otherwise specified, means a saturated or partially unsaturated 4- to 10-membered monocyclic or bicyclic ring having from 1 to 4 heteroatoms independently selected from N, S, and O (the sulfur and nitrogen atoms are optionally oxidized) as ring atoms, with the remaining ring atoms being carbon atoms. Such rings do not include adjacent oxygen atoms, adjacent sulfur atoms, or adjacent oxygen and sulfur atoms within the ring. Examples include: pyrrolidinyl, imidazolidinyl, pyrazolidinyl, butyrolactamyl, valerolactamyl, imidazolidinonyl, hydantoinyl, dioxolanyl, piperidinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl-S-oxide, 1,1-dioxothiomorpholinyl, piperazinyl, pyranyl, pyridonyl, 3-pyrrolinyl, thiopyranyl, pyronyl, tetrahydrofuranyl, and tetrahydrothiophenyl. Heterocycloalkyl groups can be attached to the remainder of the molecule through a ring carbon atom or a heteroatom.

[0027] "Hydroxyalkyl" means an alkyl (as defined above) substituted with one or two hydroxy moieties. For example, "hydroxy C 1~4 "Alkyl" includes hydroxymethyl, 1- or 2-hydroxyethyl, 1,2-dihydroxyethyl, and hydroxypropyl. In some embodiments, one hydroxy moiety is attached to the carbon atom of the alkyl distal from the point of attachment to the rest of the molecule.

[0028] Oxo is the =O group. When a moiety is said to be "oxo-substituted," it is considered to be substituted by one substituent.

[0029] "Spiroheterocyclyl" means a saturated or partially unsaturated bicyclic ring of 5 to 12 ring atoms, in which 1, 2, or 3 ring atoms are heteroatoms independently selected from N, S, and O (the sulfur and nitrogen atoms are optionally oxidized), the remaining ring atoms are carbon atoms, and the two rings are linked to each other by a single common atom. Such rings do not contain adjacent oxygen atoms, adjacent sulfur atoms, or adjacent oxygen and sulfur atoms within the ring. Examples include 6-azaspiro[3.4]octanyl, 2-oxa-6-azaspiro[3.4]octan-6-yl, 4-oxaspiro[2.4]heptanyl, spiro[3.5]non-6-enyl, and 2,7-diazaspiro[4.4]nonanyl.

[0030] When a substituent is said to be "optionally substituted," the substituent may be unsubstituted or substituted with the specified substituent (e.g., substituted with 1, 2, or 3 of the specified substituents).

[0031] The following examples of substituent definitions and embodiments may be combined in any combination where possible.

[0032] R 1 is hydrogen, cyano, formyl, -CONH2, -CH2OH, -CH2OC 1~2 Alkyl, C 1~2 Alkyl, C 1~2 haloalkyl, or ethynyl. Preferably, R 1 is cyano, C 1~2 alkyl, or ethynyl. In some embodiments, R 1 is cyano or C 1~2 R is alkyl. 1 Specific examples include cyano and CH3.

[0033] R 2 and R 3 independently, C 1~2 alkyl or R 2 and R3 together with the carbon atom to which they are attached form a cyclopropyl or oxetanyl. Preferably, R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl or oxetanyl (e.g., an oxetanyl in which the oxygen atom is distal from the quaternary carbon atom). Specific examples include cyclopropyl and oxetanyl (e.g., an oxetanyl in which the oxygen atom is distal from the quaternary carbon atom).

[0034] X 1 is CR 7 or N and R 7 is hydrogen or fluoro. In some embodiments, X 1 is CR 7 In some embodiments, X 1 is CR 7 and R 7 is H. X 2 is CR 8 or N and R 8 is hydrogen or fluoro. In some embodiments, X 2 is CR 8 In some embodiments, X 2 is CR 8 and R 8 is H.

[0035] X 3 is CR 9 or N. In some embodiments, X 3 is CR 9 In some embodiments, X 1 , X 2 , and X 3 In some embodiments, no more than two of X are N. 1 is CR 7 and X 2 is CR 8 and X 3 is CR 9 In some embodiments, X 1 is CR7 and X 2 is CR 8 and X 3 is CR 9 and R 7 and R 8 is hydrogen.

[0036] R 9 is hydrogen, halogen, cyano, -N(R m )R n , C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 2~4 Alkynyl, C 3~6 cycloalkyl, phenyl, heteroaryl, heterocyclyl, fused heterocyclyl, spiroheterocyclyl, or bridged heterocyclyl, wherein the cycloalkyl, phenyl, heteroaryl, heterocyclyl, fused heterocyclyl, spiroheterocyclyl, and bridged heterocyclyl are optionally selected from the group consisting of R a , R b , and / or R c is replaced by .

[0037] Preferably, R 9 is hydrogen, halogen, cyano, -N(R m )R n , C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 2~4 Alkynyl, C 3~6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, S, and O as ring atoms, and 5- to 7-membered monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, S, and O as ring atoms, wherein the cycloalkyl, phenyl, heteroaryl, and heterocyclyl are optionally selected from R a , R b, and / or R c is substituted with; or R 9 is spiroheterocyclyl, where X 3 is a 5- to 7-membered monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, S, and O as ring atoms, and a second ring is connected to the first ring by a common carbon atom, the second ring being a 3- to 6-membered monocyclic cycloalkyl or a 3- to 6-membered monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, S, and O as ring atoms, or a spiroheterocyclyl, wherein the spiroheterocyclyl is optionally selected from R a , R b , and / or R c is replaced by .

[0038] For example, R 9 is hydrogen, halogen, cyano, phenyl, 5- to 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N as ring atoms, or 6-membered monocyclic heterocyclyl containing 1 to 2 heteroatoms selected from N and O as ring atoms, wherein phenyl, heteroaryl, and heterocyclyl are optionally selected from R a , R b , and / or R c is substituted with; or R 9 is a spiro ring system, and X 3is a 4- to 6-membered monocyclic heterocyclyl containing 1 to 2 heteroatoms selected from N as ring atoms, and a second ring is connected to the first ring by a common carbon atom, the second ring being a 4- to 6-membered monocyclic heterocyclyl containing 1 heteroatom independently selected from N, O, and S, specifically selected from O as a ring atom, spiro ring system, wherein the first ring of the spiroheterocyclyl is optionally b and / or R c is replaced by .

[0039] For example, R 9 is hydrogen, halogen, cyano, phenyl, 5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from N as ring atoms, wherein phenyl and 6 membered heteroaryl are optionally joined by R a and optionally substituted with R b and the 5-membered heteroaryl is optionally substituted with R at the 3-position distal to its attachment to the rest of the molecule. a and optionally substituted with R b or R 9 is (R 9a ) part or (R 9b )portion: [ka] and During the ceremony, Z 1 is N or CH, and Z 2 is N(R a ), O, S, CH(R a ), or C(R x )(R y ) where R x and R ytogether form a 4- to 6-membered monocyclic heterocyclyl containing one heteroatom selected from N, O, and S as a ring atom; optionally, Z 1 and Z 2 At least one of the a ) for the definition of the heterocyclyl moiety. 9a and R 9b The S and N ring atoms in are optionally oxidized. 9a ) portion and (R 9b ) moiety, the substituent R b occupies one of the two carbon atoms on the left side of the drawing, and R c occupies one of the two carbon atoms on the right side of the drawing.

[0040] (R 9a ) moiety are as follows (the two structures on the bottom right are R c is hydrogen). [ka] Z 1 or Z 2 are CH or CH(R a ), further stereoisomers are possible.

[0041] (R 9b ) moiety are as follows (the two structures on the bottom right are R c is hydrogen). [ka] Z 2 is CH or CH(R a ) in each case, further stereoisomers are possible.

[0042] R when possible a , R b , and / or Rc R may be optionally substituted with 9 Specific examples of include hydrogen, chloro, phenyl, piperidinyl (eg, piperidin-1-yl, piperidin-4-yl), piperazinyl (eg, piperazin-1-yl), and imidazolyl (eg, imidazol-5-yl).

[0043] R a , R b , and / or R c R when replaced by 9 Specific examples of the group include the following: [ka] are listed, R a is hydrogen, -N(R m )R n , C 1~6 Alkyl, hydroxy, C 1~6 Alkoxy, halogen, cyano, oxo, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, Hydroxy C 1~6 Alkyl, C 3~6 Cycloalkyl, heteroaryl, heterocyclyl, -C(O)R d , -C(O)OR e , -C(O)N(R f )R g , -S(O)2N(R h )R i , or C 1~6 Alkyl-N(R j )R k wherein cycloalkyl, heteroaryl, and heterocyclyl are optionally selected from C 1~6 Alkyl, C 1~6 Alkyl-NH2, C 1~6 Alkyl-NH(C 1~4 alkyl), C 1~6 Alkyl-N(C 1~4 alkyl)2, hydroxy, oxo, C 1~6 Alkoxy, halogen, cyano, amino, -NH(C 1~4 alkyl), -N(C1~4 Alkyl)2, C 1~6 Haloalkyl, and C 1~6 and substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl.

[0044] Preferably, R a is hydrogen, -N(R m )R n , C 1~6 Alkyl, oxo, -C(O)R d , -C(O)N(R f )R g , or C 1~6 Alkyl-N(R j )R k is. For example, R a is hydrogen, -NH2, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, C 1~6 Alkyl, C 3~6 Cycloalkyl, oxo, -C(O)-C 1~4 Alkyl-C 3~6 Cycloalkyl, -C(O)-C 1~4 Haloalkyl-C 3~6 Cycloalkyl, -C(O)-C 3~6 Cycloalkyl, -C(O)-C 3~6 Cycloalkyl-NH2, -C(O)-C 3~6 Cycloalkyl-NH(C 1~4 alkyl), -C(O)-C 3~6 Cycloalkyl-N(C 1~4 alkyl)2, -C(O)-C 3~6 Cycloalkyl-C 1~4 Alkyl, -C(O)-C 3~6 Cycloalkyl-C 1~4 Alkyl-NH2, -C(O)-C 3~6 Cycloalkyl-C 1~4 Alkyl-NH(C 1~4 alkyl), -C(O)-C 3~6 Cycloalkyl-C 1~4 Alkyl-N(C 1~4 alkyl)2, -C(O)NH2, -C(O)NH(C 1~4alkyl), -C(O)N(C 1~4 alkyl)2, -C(O)N(C 1~4 Alkyl)(C 3~6 cycloalkyl), C 1~6 Alkyl-NH2, C 1~6 Alkyl-NH(C 1~4 alkyl), C 1~6 Alkyl-N(C 1~4 alkyl)2, -C(O)-C 1~6 Alkyl, -C(O)-C 1~6 Alkyl-NH2, -C(O)-C 1~6 Alkyl-NH(C 1~4 alkyl), -C(O)-C 1~6 Alkyl-N(C 1~4 alkyl)2, -C(O)-heterocyclyl, -C(O)-heterocyclyl-NH2, -C(O)-heterocyclyl-NH(C 1~4 alkyl), -C(O)-heterocyclyl-N(C 1~4 alkyl)2, -C(O)-heterocyclyl-C 1~4 Alkyl, -C(O)-heterocyclyl-C 1~4 Alkyl-NH2, -C(O)-heterocyclyl-C 1~4 Alkyl-NH(C 1~4 alkyl), or -C(O)-heterocyclyl-C 1~4 Alkyl-N(C 1~4 alkyl), wherein each heterocyclyl is a 4-6 membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from N, O, and S as ring atoms (e.g., pyrrolidinyl or morpholinyl), the heterocyclyl is optionally connected to a carbonyl moiety through a nitrogen atom, and the alkyl, haloalkyl, cycloalkyl, heteroaryl, and heterocyclyl are optionally C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkyl-NH2, C 1~6 Alkyl-NH(C 1~4 alkyl), C 1~6 Alkyl-N(C 1~4 alkyl)2, hydroxy, oxo, C 1~6Alkoxy, halogen, cyano, amino, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, C 1~6 Haloalkyl, and C 1~6 and substituted with 1, 2, 3, or 4 substituents independently selected from haloalkoxy.

[0045] For example, R a is hydrogen, C 1~4 Alkyl, -C(O)-C 1~4 Alkyl-C 3~6 Cycloalkyl, -C(O)-C 1~4 Haloalkyl-C 3~6 Cycloalkyl, -C(O)-C 3~6 Cycloalkyl, -C(O)-C 3~6 Cycloalkyl-C 1~4 Alkyl, -C(O)-C 3~6 Cycloalkyl-NH2, -C(O)-C 3~6 Cycloalkyl-NH(C 1~4 alkyl), -C(O)-C 3~6 Cycloalkyl-NH(C 1~4 alkyl)2, -C(O)NH2, -C(O)NH(C 1~4 alkyl), -C(O)N(C 1~4 alkyl)2, -C(O)N(C 1~4 Alkyl)(C 3~6 cycloalkyl), C 1~4 Alkyl-NH2, C 1~4 Alkyl-NH(C 1~4 alkyl), or C 1~4 Alkyl-N(C 1~4 alkyl)2.

[0046] R a Specific examples of include hydrogen, -CH3, -C(O)-CH3, -C(O)-C(CH2-CH2)-CH3, -C(O)-C(CH2-CH2)-NH2, -C(O)-NH2, -C(O)-N(CH3)2, and CH2-NH2. The -C(O)-C(CH2-CH2)-CH3 moiety and the C(O)-C(CH2-CH2)-NH2 moiety are, respectively: [ka] It is depicted as follows.

[0047] R b is hydrogen, -N(R m )R n , C 1~6 Alkyl, C 1~4 Alkyl-N(R m )R n , hydroxy, C 1~6 Alkoxy, halogen, cyano, C 1~6 Haloalkyl, or C 1~6 haloalkoxy. Preferably, R b is hydrogen, amino, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, C 1~4 Alkyl, C 1~4 Alkyl-NH2, C 1~4 Alkyl-NH(C 1~4 alkyl), C 1~4 Alkyl-N(C 1~4 alkyl)2.

[0048] In some embodiments, R b is hydrogen or C 1~4 R is alkyl. b Specific examples include hydrogen and CH3.

[0049] R c is hydrogen, -N(R m )R n , C 1~6 Alkyl, C 1~4 Alkyl-N(R m )R n , hydroxy, C 1~6 Alkoxy, halogen, cyano, C 1~6 Haloalkyl, or C 1~6 haloalkoxy. Preferably, R c is hydrogen or C 1~4 R is alkyl. c Specific examples include hydrogen and CH3.

[0050] R d is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 cycloalkyl, phenyl, heteroaryl, or heterocyclyl, wherein alkyl, haloalkyl, cycloalkyl, phenyl, heteroaryl, and heterocyclyl are optionally selected from the group consisting of C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkyl-NH2, C 1~6 Alkyl-NH(C 1~4 alkyl), C 1~6 Alkyl-N(C 1~4 alkyl)2, hydroxy, oxo, C 1~6 Alkoxy, halogen, cyano, amino, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, C 1~6 Haloalkyl, and C 1~6 and substituted with 1, 2, 3, or 4 substituents independently selected from haloalkoxy.

[0051] Preferably, R d is hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 cycloalkyl, or a 4- to 7-membered monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, S, and O as ring atoms, wherein the alkyl, haloalkyl, cycloalkyl, and heterocyclyl are optionally selected from C 1~4 Alkyl, C 3~6 Cycloalkyl, amino, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, C 1~6 Alkyl-NH2, C 1~6 Alkyl-NH(C 1~4 alkyl), C 1~6 Alkyl-N(C 1~4 alkyl)2, and C 1~4 and substituted with 1 or 2 substituents independently selected from haloalkyl.

[0052] For example, R d is hydrogen, C 1~4 Alkyl or C 3~6 cycloalkyl, where cycloalkyl is optionally selected from C 1~4 Alkyl, amino, -NH(C 1~4 alkyl), -N(C 1~4 alkyl)2, and C 1~4 and substituted with 1 or 2 substituents independently selected from haloalkyl.

[0053] For example, R d is hydrogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkyl-C 3~6 Cycloalkyl, C 1~6 Haloalkyl-C 3~6 Cycloalkyl, C 3~6 Cycloalkyl-NH2, C 3~6 Cycloalkyl-NH(C 1~4 alkyl), C 3~6 Cycloalkyl-N(C 1~4 Alkyl)2, C 3~6 Cycloalkyl-C 1~4 Alkyl, C 3~6 Cycloalkyl-C 1~4 Alkyl-NH2, C 3~6 Cycloalkyl-C 1~4 Alkyl-NH(C 1~4 alkyl), C 3~6 Cycloalkyl-C 1~4 Alkyl-N(C 1~4 alkyl)2, heterocyclyl, heterocyclyl-NH2, heterocyclyl-NH(C 1~4 alkyl), heterocyclyl-N(C 1~4 alkyl)2, heterocyclyl-C 1~4 Alkyl, heterocyclyl-C 1~4 Alkyl-NH2, Heterocyclyl-C 1~4 Alkyl-NH(C 1~4 alkyl), heterocyclyl-C 1~4 Alkyl-N(C 1~4alkyl), wherein each heterocyclyl is a 4- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from N, O, and S as ring atoms (e.g., pyrrolidinyl or morpholinyl).

[0054] R d Specific examples include hydrogen, -CH3, -C(CH2-CH2)-NH2, and C(CH2-CH2)-CH3.

[0055] R e is hydrogen or C 1~6 It is alkyl.

[0056] R f is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, Amino C 1~6 Alkyl or hydroxy C 1~6 Preferably, R f is hydrogen or C 1~4 R is alkyl. f A specific example of this is hydrogen.

[0057] R g is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, Amino C 1~6 Alkyl or hydroxy C 1~6 Preferably, R g is hydrogen or C 1~4 R is alkyl. g A specific example of this is hydrogen.

[0058] Or, R f and R g together with the nitrogen atom to which they are attached form a heterocyclyl, where the heterocyclyl is optionally selected from the group consisting of C 1~6 Alkyl, C 1~6 Alkyl-NH2, C 1~6 Alkyl-NH(C1~4 alkyl), C 1~6 Alkyl-N(C 1~4 Alkyl)2, Hydroxy, C 1~6 Alkoxy, halogen, cyano, amino, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, C 1~6 Haloalkyl, and C 1~6 Substituted with 1, 2, or 3 substituents independently selected from haloalkoxy.

[0059] R h is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, Amino C 1~6 Alkyl or hydroxy C 1~6 R is alkyl. i is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, Amino C 1~6 Alkyl or hydroxy C 1~6 It is alkyl.

[0060] Or, R h and R i together with the nitrogen atom to which they are attached form a heterocyclyl, where the heterocyclyl is optionally selected from the group consisting of C 1~6 Alkyl, C 1~6 Alkyl-NH2, C 1~6 Alkyl-NH(C 1~4 alkyl), C 1~6 Alkyl-N(C 1~4 Alkyl)2, Hydroxy, C 1~6 Alkoxy, halogen, cyano, amino, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, C 1~6 Haloalkyl, and C 1~6 Substituted with 1, 2, or 3 substituents independently selected from haloalkoxy.

[0061] R j is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, Amino C1~6 Alkyl or hydroxy C 1~6 Preferably, R j is hydrogen or C 1~4 R is alkyl. j A specific example of this is hydrogen.

[0062] R k is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, Amino C 1~6 Alkyl or hydroxy C 1~6 Preferably, R k is hydrogen or C 1~4 R is alkyl. k A specific example of this is hydrogen.

[0063] Or, R j and R k together with the nitrogen atom to which they are attached form a heterocyclyl, where the heterocyclyl is optionally selected from the group consisting of C 1~6 Alkyl, C 1~6 Alkyl-NH2, C 1~6 Alkyl-NH(C 1~4 alkyl), C 1~6 Alkyl-N(C 1~4 Alkyl)2, Hydroxy, C 1~6 Alkoxy, halogen, cyano, amino, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, C 1~6 Haloalkyl, and C 1~6 Substituted with 1, 2, or 3 substituents independently selected from haloalkoxy.

[0064] Each R m are independently hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, Amino C 1~6 Alkyl or hydroxy C 1~6 Preferably, each R m are independently hydrogen or C 1~4 It is alkyl.

[0065] Each R n are independently hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, Amino C 1~6 Alkyl or hydroxy C 1~6 Preferably, each R n are independently hydrogen or C 1~4 It is alkyl.

[0066] R 4 is hydrogen or -L 1A -L 2A -L 3A In some embodiments, R 4 -L 1A -L 2A -L 3A It is a group. R 4 Specific examples include -CH2-(methylpyrazol-4-yl) (e.g., -CH2-(1-methylpyrazol-4-yl), -CH2-(trifluoromethylpyrazol-4-yl) (e.g., -CH2-(1-trifluoromethylpyrazol-4-yl), and CH2-(methylthiazol-5-yl) (e.g., -CH2-(2-methylthiazol-5-yl)).

[0067] L 1A does not exist or C 1~2 C optionally substituted with alkyl or oxo 1~3 In some embodiments, L is alkylene. 1A is C 1~3 In some embodiments, L is alkylene. 1A does not exist. 1A A specific example of this is -CH2-.

[0068] L 2A is absent or is -O-, -S-, -S(O)-, -S(O)2-, -N(R a1 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a1 )-, -N(R a1 )C(O)-, -N(Ra1 )C(O)N(R b1 )-, -S(O)2N(R a1 )- or -N(R a1 )S(O)2-. In some embodiments, L 2A does not exist.

[0069] R a1 is hydrogen or C 1~2 R is alkyl. b1 is hydrogen or C 1~2 It is alkyl.

[0070] L 3A is hydrogen, C 1~6 Alkyl, C 3~6 cycloalkyl, phenyl, heterocyclyl, or heteroaryl, where L 3A is optionally halogen, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, -N(R c1 )R d1 , -OR c1 , -C(O)R c1 , -C(O)OR c1 , -OC(O)R c1 , -C(O)N(R d1 )R c1 , -N(R d1 )C(O)R c1 , -S(O) y R c1 , -S(O)2N(R d1 )R c1 , -N(R d1 )S(O)2R c1 , and (CH2) z N(R d1 )R c1 and is substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from:

[0071] In some embodiments, L 3A is hydrogen, C 1~6 Alkyl, C 3~6cycloalkyl, phenyl, 5- to 7-membered monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, S, and O as ring atoms, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, S, and O as ring atoms, wherein L 3A is optionally selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, C 1~4 Alkyl, -N(R c1 )R d1 , -OR c1 , -C(O)R c1 , -C(O)OR c1 , -OC(O)R c1 , -C(O)N(R d1 )R c1 , -N(R d1 )C(O)R c1 , -S(O) y R c1 , -S(O)2N(R d1 )R c1 , -N(R d1 )S(O)2R c1 , and (CH2) z N(R d1 )R c1 and is substituted with 1, 2, or 3 substituents independently selected from:

[0072] In some embodiments, L 3A is phenyl or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, S, and O as ring atoms, wherein L 3A is optionally selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, C 1~4 Alkyl, -N(R c1 )R d1 , -OR c1 , -C(O)R c1 , -C(O)OR c1, -OC(O)R c1 , -C(O)N(R d1 )R c1 , -N(R d1 )C(O)R c1 , -S(O) y R c1 , -S(O)2N(R d1 )R c1 , -N(R d1 )S(O)2R c1 , and (CH2) z N(R d1 )R c1 In some embodiments, L is substituted with 1, 2, or 3 substituents independently selected from 3A is phenyl or a 5- to 6-membered heteroaryl containing, as ring atoms, 1 or 2 heteroatoms independently selected from N, S, and O, where at least one heteroatom is N; L 3A is optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methyl, and trifluoromethyl.

[0073] L 3A Specific examples include methylpyrazol-4-yl (e.g., 1-methylpyrazol-4-yl), trifluoromethylpyrazol-4-yl (e.g., 1-trifluoromethylpyrazol-4-yl), and methylthiazol-5-yl (e.g., —CH—(2-methylthiazol-5-yl)).

[0074] R c1 is hydrogen or C 1~4 R is alkyl. d1 is hydrogen or C 1~4 It is alkyl.

[0075] y is 0, 1, or 2. z is 1, 2, or 3.

[0076] In some embodiments, L 1A is C 1~3 is alkylene; L2A does not exist, L 3A is phenyl or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring atoms, wherein L 3A is optionally selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, C 1~4 Alkyl, -N(R c1 )R d1 , -OR c1 , -C(O)R c1 , -C(O)OR c1 , -OC(O)R c1 , -C(O)N(R d1 )R c1 , -N(R d1 )C(O)R c1 , -S(O) y R c1 , -S(O)2N(R d1 )R c1 , -N(R d1 )S(O)2R c1 , and (CH2) z N(R d1 )R c1 substituted with 1, 2, or 3 substituents independently selected from R c1 is hydrogen or C 1~4 is alkyl; R d1 is hydrogen or C 1~4 is alkyl; y is 0, 1, or 2; and z is 1, 2, or 3.

[0077] In some embodiments, L 1A is C 1~3 is alkylene; L 2A does not exist; and L 3Ais phenyl or a 5- to 6-membered heteroaryl containing, as ring atoms, 1 or 2 heteroatoms independently selected from N, S, and O, where at least one heteroatom is N, wherein L 3A is optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methyl, and trifluoromethyl.

[0078] R 5 is hydrogen or -L 1B -L 2B -L 3B In some embodiments, R 5 -L 1B -L 2B -L 3B In some embodiments, R 5 is hydrogen or -L 1B -L 2B -L 3B is a group, where -L 1B -L 2B -L 3B The group is C 1~6 R is alkyl. 5 Specific examples include -CH3, -CH2CH3, -CH(CH3)(CH3), and CH2-(dimethylthiazol-5-yl) (e.g., -CH2-(2,4-dimethylthiazol-5-yl)).

[0079] L 1B does not exist or C 1~2 C optionally substituted with alkyl or oxo 1~3 In some embodiments, L is alkylene. 1B is C 1~3 In some embodiments, L is alkylene. 1B does not exist. 1B A specific example of this is -CH2-.

[0080] L 2B is absent or is -O-, -S-, -S(O)-, -S(O)2-, -N(R a2)-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a2 )-, -N(R a2 )C(O)-, -N(R a2 )C(O)N(R b2 )-, -S(O)2N(R a2 )- or -N(R a2 )S(O)2-. In some embodiments, L 2B does not exist.

[0081] R a2 is hydrogen or C 1~2 R is alkyl. b2 is hydrogen or C 1~2 It is alkyl.

[0082] L 3B is hydrogen, C 1~6 Alkyl, C 3~6 cycloalkyl, phenyl, heterocyclyl, or heteroaryl, where L 3B is optionally selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, -N(R c2 )R d2 , -OR c2 , -C(O)R c2 , -C(O)OR c2 , -OC(O)R c2 , -C(O)N(R d2 )R c2 , -N(R d2 )C(O)R c2 , -S(O) y’ R c2 , -S(O)2N(R d2 )R c2 , -N(R d2 )S(O)2R c2 , and (CH2) z’ N(R d2 )R c2 and is substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from:

[0083] In some embodiments, L 3B is hydrogen, C 1~6 Alkyl, C 3~6 cycloalkyl, phenyl, 5- to 7-membered monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, S, and O as ring atoms, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, S, and O as ring atoms, wherein L 3B is optionally selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, C 1~4 Alkyl, -N(R c1 )R d1 , -OR c1 , -C(O)R c1 , -C(O)OR c1 , -OC(O)R c1 , -C(O)N(R d1 )R c1 , -N(R d1 )C(O)R c1 , -S(O) y’ R c1 , -S(O)2N(R d1 )R c1 , -N(R d1 )S(O)2R c1 , and (CH2) z’ N(R d1 )R c1 and is substituted with 1, 2, or 3 substituents independently selected from:

[0084] In some embodiments, L 3B is phenyl or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, S, and O as ring atoms, wherein L 3B is optionally selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, C 1~4 Alkyl, -N(Rc1 )R d1 , -OR c1 , -C(O)R c1 , -C(O)OR c1 , -OC(O)R c1 , -C(O)N(R d1 )R c1 , -N(R d1 )C(O)R c1 , -S(O) y’ R c1 , -S(O)2N(R d1 )R c1 , -N(R d1 )S(O)2R c1 , and (CH2) z’ N(R d1 )R c1 and is substituted with 1, 2, or 3 substituents independently selected from:

[0085] In some embodiments, L 3B is phenyl or a 5- to 6-membered heteroaryl containing, as ring atoms, 1 or 2 heteroatoms independently selected from N, S, and O, where at least one heteroatom is N; 3B is optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methyl, and trifluoromethyl.

[0086] L 3B Specific examples include -CH3, -CH2CH3, -CH(CH3)(CH3), and dimethylthiazol-5-yl (e.g., 2,4-dimethylthiazol-5-yl).

[0087] R c2 is hydrogen or C 1~4 R is alkyl. d2 is hydrogen or C 1~4 It is alkyl.

[0088] y' is 0, 1, or 2. z' is 1, 2, or 3.

[0089] In some embodiments, L1B is C 1~3 is alkylene; L 2B does not exist; L 3B is phenyl or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms, where L 3B is optionally selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, C 1~4 Alkyl, -N(R c2 )R d2 , -OR c2 , -C(O)R c2 , -C(O)OR c2 , -OC(O)R c2 , -C(O)N(R d2 )R c2 , -N(R d2 )C(O)R c2 , -S(O) y’ R c2 , -S(O)2N(R d2 )R c2 , -N(R d2 )S(O)2R c2 , and (CH2) z’ N(R d2 )R c2 substituted with 1, 2, or 3 substituents independently selected from R c2 is hydrogen or C 1~4 is alkyl; R d2 is hydrogen or C 1~4 is alkyl; y' is 0, 1, or 2; and z' is 1, 2, or 3.

[0090] In some embodiments, L 1B is C 1~3 is alkylene; L 2B does not exist; and L 3Bis phenyl or a 5- to 6-membered heteroaryl containing, as ring atoms, 1 or 2 heteroatoms independently selected from N, S, and O, where at least one heteroatom is N, wherein L 3B is optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methyl, and trifluoromethyl. In some embodiments, -L 1B -L 2B -L 3B is C 1~6 It is alkyl.

[0091] R 6 is hydrogen or -L 1C -L 2C -L 3C In some embodiments, R 6 is hydrogen or -L 1C -L 2C -L 3C is a group, where -L 1C -L 2C -L 3C The group is C 1~6 R is alkyl. 6 A specific example of this is hydrogen.

[0092] L 1C does not exist or C 1~2 C optionally substituted with alkyl or oxo 1~3 In some embodiments, L is alkylene. 1C is C 1~3 In some embodiments, L is alkylene. 1C does not exist.

[0093] L 2C is absent or is -O-, -S-, -S(O)-, -S(O)2-, -N(R a3 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a3 )-, -N(R a3 )C(O)-, -N(R a3 )C(O)N(R b3)-, -S(O)2N(R a3 )- or -N(R a3 )S(O)2-. In some embodiments, L 2C does not exist.

[0094] R a3 is hydrogen or C 1~2 R is alkyl. b3 is hydrogen or C 1~2 It is alkyl.

[0095] L 3C is hydrogen, C 1~6 Alkyl, C 3~6 cycloalkyl, phenyl, heterocyclyl, or heteroaryl, where L 3C is optionally selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, -N(R c3 )R d3 , -OR c3 , -C(O)R c3 , -C(O)OR c3 , -OC(O)R c3 , -C(O)N(R d3 )R c3 , -N(R d3 )C(O)R c3 , -S(O) y” R c3 , -S(O)2N(R d3 )R c3 , -N(R d3 )S(O)2R c3 , and (CH2) z” N(R d3 )R c3 and is substituted with one or more substituents independently selected from:

[0096] In some embodiments, L 3C is hydrogen, C 1~6 Alkyl, C 3~6cycloalkyl, phenyl, 5- to 7-membered monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, S, and O as ring atoms, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, S, and O as ring atoms, wherein L 3C is optionally selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, C 1~4 Alkyl, -N(R c1 )R d1 , -OR c1 , -C(O)R c1 , -C(O)OR c1 , -OC(O)R c1 , -C(O)N(R d1 )R c1 , -N(R d1 )C(O)R c1 , -S(O) y” R c1 , -S(O)2N(R d1 )R c1 , -N(R d1 )S(O)2R c1 , and (CH2) z” N(R d1 )R c1 and is substituted with 1, 2, or 3 substituents independently selected from:

[0097] In some embodiments, L 3C is phenyl or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, S, and O as ring atoms, wherein L 3C is optionally selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, C 1~4 Alkyl, -N(R c1 )R d1 , -OR c1 , -C(O)R c1 , -C(O)OR c1, -OC(O)R c1 , -C(O)N(R d1 )R c1 , -N(R d1 )C(O)R c1 , -S(O) y” R c1 , -S(O)2N(R d1 )R c1 , -N(R d1 )S(O)2R c1 , and (CH2) z” N(R d1 )R c1 and is substituted with 1, 2, or 3 substituents independently selected from:

[0098] In some embodiments, L 3C is phenyl or a 5- to 6-membered heteroaryl containing, as ring atoms, 1 or 2 heteroatoms independently selected from N, S, and O, where at least one heteroatom is N, wherein L 3C is optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methyl, and trifluoromethyl.

[0099] R c3 is hydrogen or C 1~4 R is alkyl. d3 is hydrogen or C 1~4 It is alkyl.

[0100] y" is 0, 1, or 2; z" is 1, 2, or 3.

[0101] In compounds of formula (I), -L 1A -L 2A -L 3A group, -L 1B -L 2B -L 3B Groups, and L 1C -L 2C -L 3CThe group does not include -OO-, -SO-, -OS- or -SS- units as linking units within the group. For the avoidance of doubt, this does not exclude oxidized forms of sulfur where the oxygen atom is not part of the linking unit (e.g., -S(O)-, -S(O)2-).

[0102] In compounds of formula (I), -L 1A -L 2A -L 3A The group is R 4 -ON- or -SN- unit is not located adjacent to the ring nitrogen atom connected to -L 1B -L 2B -L 3B The group is R 5 No N atom, O atom, or S atom is located adjacent to the oxime oxygen atom connected to -L 1C -L 2C -L 3C The group is R 6 No -ON- or -SN- unit is located adjacent to the ring nitrogen atom connected to

[0103] In some embodiments, the compound of Formula (I) is a compound of Formula (Ia): In some embodiments, the compound of Formula (I) is a compound of Formula (Ib):

[0104] In some embodiments, R 1 is methyl or cyano; and R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl or oxetanyl.

[0105] In some embodiments, R 9 is C 3~6cycloalkyl, phenyl, heteroaryl (specifically, a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, S, and O as ring atoms), heterocyclyl (specifically, a 5- to 7-membered monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, S, and O as ring atoms), wherein the cycloalkyl, phenyl, heteroaryl, and heterocyclyl are optionally selected from R a , R b , and / or R c Is it replaced by; or R 9 is a spiroheterocyclyl (specifically a spiro ring system in which X 3 is a 5- to 7-membered monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, S, and O as ring atoms (specifically, 1 to 2 heteroatoms selected from N as ring atoms), and a second ring is connected to the first ring by a common carbon atom, and the second ring is a 3- to 6-membered monocyclic cycloalkyl or a 3- to 6-membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, S, and O as ring atoms (specifically, 1 heteroatom selected from O and S as ring atoms, specifically selected from O), a spiro ring system), wherein the spiroheterocyclyl is optionally selected from R a , R b , and / or R c is replaced by .

[0106] In some embodiments, R 9is phenyl, 5- to 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N as ring atoms, or 6-membered monocyclic heterocyclyl containing 1 to 2 heteroatoms selected from N and O as ring atoms, wherein phenyl, heteroaryl, and heterocyclyl are optionally selected from R a , R b , and / or R c is substituted with; or

[0107] R 9 is a spiro ring system, and X 3 is a 4- to 6-membered monocyclic heterocyclyl containing 1 to 2 heteroatoms selected from N as ring atoms, and a second ring is connected to the first ring by a common carbon atom, and the second ring is a 4- to 6-membered monocyclic heterocyclyl containing 1 heteroatom independently selected from N, O, and S, specifically selected from O, as a ring atom, in a spiro ring system, and the first ring of the spiroheterocyclyl is optionally connected to R b and / or R c is replaced by .

[0108] In some embodiments, R 9 is phenyl, 5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from N as ring atoms, wherein the phenyl and 6 membered heteroaryl are optionally joined by R a and optionally substituted with R b and the 5-membered heteroaryl is optionally substituted with R at the 3-position distal to its attachment to the rest of the molecule. a and optionally substituted with R b is substituted with; or R 9 is shown above (R 9a ) part or part (R9b ) in which Z 1 is N or CH, and Z 2 is N(R a ), O, S, CH(R a ), or C(R x )(R y ) where R x and R y together form a 4- to 6-membered monocyclic heterocyclyl containing one heteroatom selected from N, O, and S; optionally, Z 1 and Z 2 At least one of the groups is N or N(R a ) and; And R a is C 1~4 Alkyl, -C(O)R d , -C(O)N(R f )R g , or C 1~6 Alkyl-N(R j )R k It can be, Optionally, R d is C 1~4 Alkyl or C 3~6 cycloalkyl, where cycloalkyl is optionally C 1~4 Alkyl, amino, -NH(C 1~4 alkyl), -N(C 1~4 alkyl)2, and C 1~4 and substituted with 1 or 2 substituents independently selected from haloalkyl.

[0109] In some embodiments, R a is hydrogen, -N(R m )R n , C 1~6 Alkyl, oxo, -C(O)R d , -C(O)N(R f )R g , or C 1~6 Alkyl-N(R j )R k and R bis hydrogen, amino, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, C 1~4 Alkyl, C 1~4 Alkyl-NH2, C 1~4 Alkyl-NH(C 1~4 alkyl), or C 1~4 Alkyl-N(C 1~4 alkyl)2; R c is hydrogen or C 1~4 is alkyl; R d is hydrogen, C 1~4 Alkyl, C 3~6 cycloalkyl, or a 4- to 7-membered monocyclic heterocyclyl containing, as ring atoms, 1, 2, or 3 heteroatoms independently selected from N, S, and O, wherein the cycloalkyl and heterocyclyl are optionally selected from C 1~4 Alkyl, amino, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, C 1~6 Alkyl-NH2, C 1~6 Alkyl-NH(C 1~4 alkyl), C 1~6 Alkyl-N(C 1~4 alkyl)2, and C 1~4 substituted with 1 or 2 substituents independently selected from haloalkyl; R f is hydrogen or C 1~4 is alkyl; R g is hydrogen or C 1~4 is alkyl; R j is hydrogen or C 1~4 is alkyl; R k is hydrogen or C 1~4 is alkyl; R m is hydrogen or C 1~4 is alkyl; and R n is hydrogen or C 1~4 It is alkyl.

[0110] In some embodiments, R 9 When L is cycloalkyl, phenyl, heteroaryl, heterocyclyl, fused heterocyclyl, spiroheterocyclyl, or bridged heterocyclyl (each optionally substituted), then L 3C is not cycloalkyl, phenyl, heterocyclyl, or heteroaryl (each of which is optionally substituted).

[0111] In some embodiments, L 3A , L 3B , and L 3C Not more than two of are cycloalkyl, phenyl, heterocyclyl, or heteroaryl (each optionally substituted).

[0112] In some embodiments, L 3A , L 3B , and L 3C no more than two of are cycloalkyl, phenyl, heterocyclyl, or heteroaryl (each optionally substituted), and R 9 When L is cycloalkyl, phenyl, heteroaryl, heterocyclyl, fused heterocyclyl, spiroheterocyclyl, or bridged heterocyclyl (each optionally substituted), then L 3C is not cycloalkyl, phenyl, heterocyclyl, or heteroaryl (each of which is optionally substituted).

[0113] In some embodiments, L 3A , L 3B , and L 3C is present and is cycloalkyl, phenyl, heterocyclyl, or heteroaryl (each optionally substituted).

[0114] In some embodiments, L 3A , L 3B , and L 3Cis present and is phenyl or heteroaryl (each optionally substituted).

[0115] In some embodiments, L 3A and L 3B is present and is cycloalkyl, phenyl, heterocyclyl, or heteroaryl (each optionally substituted).

[0116] In some embodiments, L 3A and L 3B is present and is phenyl or heteroaryl (each optionally substituted).

[0117] In some embodiments, L 3A is present and is cycloalkyl, phenyl, heterocyclyl, or heteroaryl (each optionally substituted).

[0118] In some embodiments, L 3A is present and is phenyl or heteroaryl (each optionally substituted).

[0119] In some embodiments, R 4 -L 1A -L 2A -L 3A is a group, wherein L 2A does not exist, and L 3A is cycloalkyl, phenyl, heterocyclyl, or heteroaryl (each optionally substituted); and R 6 is hydrogen or C 1~6 It is alkyl.

[0120] In some embodiments, R 4 -L 1A -L 2A -L 3A is a group, wherein L 2A does not exist, and L3A is phenyl or heteroaryl (each optionally substituted); and R 6 is hydrogen or C 1~6 It is alkyl.

[0121] In some embodiments, R 4 -L 1A -L 2A -L 3A is a group, wherein L 2A does not exist, and L 3A is cycloalkyl, phenyl, heterocyclyl, or heteroaryl (each optionally substituted); R 5 is hydrogen or -L 1B -L 2B -L 3B is a group, wherein L 2B does not exist; and R 6 is hydrogen or C 1~6 It is alkyl.

[0122] In some embodiments, R 4 -L 1A -L 2A -L 3A is a group, wherein L 2A does not exist, and L 3A is phenyl or heteroaryl (each optionally substituted); R 5 is hydrogen or -L 1B -L 2B -L 3B is a group, wherein L 2B does not exist; and R 6 is hydrogen or C 1~6 It is alkyl.

[0123] In some embodiments, L 2A , L 2B , and L 2C does not exist.

[0124] In some embodiments, R 4 -L 1A -L 2A -L3A is a group, wherein L 3A is cycloalkyl, phenyl, heterocyclyl, or heteroaryl (each optionally substituted); R 5 is hydrogen or -L 1B -L 2B -L 3B is a group, wherein L 3B is cycloalkyl, phenyl, heterocyclyl, or heteroaryl (each optionally substituted), or -L 1B -L 2B -L 3B The group is C 1~6 alkyl; and R 6 is hydrogen or C 1~6 It is alkyl.

[0125] In some embodiments, R 4 -L 1A -L 2A -L 3A is a group, wherein L 3A is phenyl or heteroaryl (each optionally substituted); R 5 is hydrogen or -L 1B -L 2B -L 3B is a group, wherein L 3B is phenyl or heteroaryl (each optionally substituted), or -L 1B -L 2B -L 3B The group is C 1~6 alkyl; and R 6 is hydrogen or C 1~6 It is alkyl.

[0126] In some embodiments, R 4 -L 1A -L 2A -L 3A is a group; R 5 is hydrogen or C 1~6 alkyl; and R 6 is hydrogen or C 1~6 It is alkyl.

[0127] In some embodiments, R 4 -L 1A -L 2A -L 3A is a group, wherein L 2A does not exist, and L 3A is cycloalkyl, phenyl, heterocyclyl, or heteroaryl (each optionally substituted); R 5 is hydrogen or C 1~6 alkyl; and R 6 is hydrogen or C 1~6 It is alkyl. In some embodiments, R 4 -L 1A -L 2A -L 3A is a group, wherein L 2A does not exist, and L 3A is phenyl or heteroaryl (each optionally substituted); R 5 is hydrogen or C 1~6 alkyl; and R 6 is hydrogen or C 1~6 It is alkyl.

[0128] In some embodiments, R 4 -L 1A -L 2A -L 3A It is a base; L 1A is C 1~3 is alkylene; L 2A does not exist; L 3A is phenyl or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring atoms, wherein L 3A is optionally selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, C 1~4 Alkyl, -N(R c1 )R d1 , -OR c1, -C(O)R c1 , -C(O)OR c1 , -OC(O)R c1 , -C(O)N(R d1 )R c1 , -N(R d1 )C(O)R c1 , -S(O) y R c1 , -S(O)2N(R d1 )R c1 , -N(R d1 )S(O)2R c1 , and (CH2) z N(R d1 )R c1 substituted with 1, 2, or 3 substituents independently selected from R c1 is hydrogen or C 1~4 is alkyl; R d1 is hydrogen or C 1~4 is alkyl; y is 0, 1, or 2; z is 1, 2, or 3; R 5 is hydrogen or -L 1B -L 2B -L 3B It is a base; L 1B is C 1~3 is alkylene; L 2B does not exist; L 3B is phenyl or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms, wherein L 3B is optionally selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, C 1~4 Alkyl, -N(R c2 )R d2 , -OR c2 , -C(O)R c2 , -C(O)OR c2 , -OC(O)R c2 , -C(O)N(Rd2 )R c2 , -N(R d2 )C(O)R c2 , -S(O) y’ R c2 , -S(O)2N(R d2 )R c2 , -N(R d2 )S(O)2R c2 , and (CH2) z’ N(R d2 )R c2 substituted with 1, 2, or 3 substituents independently selected from R c2 is hydrogen or C 1~4 is alkyl; R d2 is hydrogen or C 1~4 is alkyl; y' is 0, 1, or 2; and z' is 1, 2, or 3; or -L 1B -L 2B -L 3B The group is C 1~6 is alkyl; and R 6 is hydrogen or -L 1C -L 2C -L 3C is a group, where -L 1C -L 2C -L 3C is C 1~6 It is alkyl.

[0129] In some embodiments, R 4 -L 1A -L 2A -L 3A It is a base; L 1A is C 1~3 is alkylene; L 2A does not exist; L 3Ais phenyl or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring atoms, wherein L 3A is optionally selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, C 1~4 Alkyl, -N(R c1 )R d1 , -OR c1 , -C(O)R c1 , -C(O)OR c1 , -OC(O)R c1 , -C(O)N(R d1 )R c1 , -N(R d1 )C(O)R c1 , -S(O) y R c1 , -S(O)2N(R d1 )R c1 , -N(R d1 )S(O)2R c1 , and (CH2) z N(R d1 )R c1 substituted with 1, 2, or 3 substituents independently selected from R c1 is hydrogen or C 1~4 is alkyl; R d1 is hydrogen or C 1~4 is alkyl; y is 0, 1, or 2; z is 1, 2, or 3; R 5 is hydrogen or C 1~6 is alkyl; and R 6 is hydrogen or C 1~6 It is alkyl.

[0130] In some embodiments, R 4 -L 1A -L 2A -L 3A It is a base; L 1A is C1~3 is alkylene; L 2A does not exist; L 3A is phenyl or a 5- to 6-membered heteroaryl containing, as ring atoms, 1 or 2 heteroatoms independently selected from N, S, and O, where at least one heteroatom is N, wherein L 3A is optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methyl, and trifluoromethyl; R 5 is hydrogen or -L 1B -L 2B -L 3B It is a base; L 1B is C 1~3 is alkylene; L 2B does not exist; and L 3B is phenyl or a 5- to 6-membered heteroaryl containing, as ring atoms, 1 or 2 heteroatoms independently selected from N, S, and O, where at least one heteroatom is N, wherein L 3B is optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methyl, and trifluoromethyl; or -L 1B -L 2B -L 3B is C 1~6 is alkyl; and R 6 is hydrogen.

[0131] In some embodiments, R 4 -L 1A -L 2A -L 3A It is a base; L 1A is C 1~3 is alkylene; L 2A does not exist; L 3A is phenyl or a 5- to 6-membered heteroaryl containing, as ring atoms, 1 or 2 heteroatoms independently selected from N, S, and O, where at least one heteroatom is N, wherein L 3A is optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methyl, and trifluoromethyl; R 5 is hydrogen or C 1~6 is alkyl; and R 6 is hydrogen.

[0132] In some embodiments (Embodiment A), the compound is a compound of Formula (I): During the ceremony, R 1 is cyano, C 1~2 alkyl, or ethynyl; R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl or oxetanyl; X 1 is CR 7 and; X 2 is CR 8 and; X 3 is CR 9 and; R 7 and R 8 is hydrogen; R 9 is hydrogen, halogen, cyano, -N(R m )R n , C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 2~4 Alkynyl, C 3~6Cycloalkyl, phenyl, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, S, and O as ring atoms, and 5- to 7-membered monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, S, and O as ring atoms, wherein the cycloalkyl, phenyl, heteroaryl, and heterocyclyl are optionally selected from R a , R b , and / or R c Is it replaced by; or R 9 is spiroheterocyclyl, where X 3 is a 5- to 7-membered monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, S, and O as ring atoms, and a second ring is connected to the first ring by a common carbon atom, the second ring being a 3- to 6-membered monocyclic cycloalkyl or a 3- to 6-membered monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, S, and O as ring atoms, or a spiroheterocyclyl, wherein the spiroheterocyclyl is optionally selected from R a , R b , and / or R c is replaced by; R a is hydrogen, -N(R m )R n , C 1~6 Alkyl, oxo, -C(O)R d , -C(O)N(R f )R g , or C 1~6 Alkyl-N(R j )R k and; R b is hydrogen, -amino, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, C 1~4 Alkyl, C1~4 Alkyl-NH2, C 1~4 Alkyl-NH(C 1~4 alkyl), C 1~4 Alkyl-N(C 1~4 alkyl)2; R c is hydrogen; R d is hydrogen, C 1~4 Alkyl, C 3~6 cycloalkyl, or a 4- to 7-membered monocyclic heterocyclyl containing, as ring atoms, 1, 2, or 3 heteroatoms independently selected from N, S, and O, wherein the cycloalkyl and heterocyclyl are optionally selected from C 1~4 Alkyl, amino, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, C 1~6 Alkyl-NH2, C 1~6 Alkyl-NH(C 1~4 alkyl), C 1~6 Alkyl-N(C 1~4 alkyl)2, and C 1~4 substituted with 1 or 2 substituents independently selected from haloalkyl; R f is hydrogen or C 1~4 is alkyl; R g is hydrogen or C 1~4 is alkyl; R j is hydrogen or C 1~4 is alkyl; R k is hydrogen or C 1~4 is alkyl; Each R m are independently hydrogen or C 1~4 is alkyl; Each R n are independently hydrogen or C 1~4 is alkyl; R 4 -L 1A -L 2A -L 3A It is a base; L1A is C 1~3 is alkylene; L 2A does not exist; L 3A is phenyl or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, S, and O as ring atoms, wherein L 3A is optionally selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, C 1~4 Alkyl, -N(R c1 )R d1 , -OR c1 , -C(O)R c1 , -C(O)OR c1 , -OC(O)R c1 , -C(O)N(R d1 )R c1 , -N(R d1 )C(O)R c1 , -S(O) y R c1 , -S(O)2N(R d1 )R c1 , -N(R d1 )S(O)2R c1 , and (CH2) z N(R d1 )R c1 or substituted with 1, 2, or 3 substituents independently selected from: or -L 1A -L 2A -L 3A The group is C 1~6 is alkyl; R c1 is hydrogen or C 1~4 is alkyl; R d1 is hydrogen or C 1~4 is alkyl; y is 0, 1, or 2; z is 1, 2, or 3; R 5 is hydrogen or -L 1B -L 2B -L 3BIt is a base; L 1B is C 1~3 is alkylene; L 2B does not exist; L 3B is phenyl or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring atoms, wherein L 3B is optionally selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, C 1~4 Alkyl, -N(R c2 )R d2 , -OR c2 , -C(O)R c2 , -C(O)OR c2 , -OC(O)R c2 , -C(O)N(R d2 )R c2 , -N(R d2 )C(O)R c2 , -S(O) y’ R c2 , -S(O)2N(R d2 )R c2 , -N(R d2 )S(O)2R c2 , and (CH2) z’ N(R d2 )R c2 substituted with 1, 2, or 3 substituents independently selected from R c2 is hydrogen or C 1~4 is alkyl; R d2 is hydrogen or C 1~4 is alkyl; y' is 0, 1, or 2; z' is 1, 2, or 3; or -L 1B -L 2B -L 3B The group is C 1~6 is alkyl; R 6 is hydrogen or -L 1C-L 2C -L 3C is a group, where -L 1C -L 2C -L 3C The group is C 1~6 It is alkyl.

[0133] In some embodiments (Embodiment B), the compound is a compound of Formula (I): During the ceremony, R 1 is cyano or C 1~2 is alkyl; R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl or oxetanyl; X 1 is CR 7 and; X 2 is CR 8 and; X 3 is CR 9 and; R 7 and R 8 is hydrogen; R 9 is hydrogen, halogen, cyano, phenyl, 5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from N as ring atoms, wherein phenyl and 6 membered heteroaryl are optionally joined by R a and optionally substituted with R b and the 5-membered heteroaryl is optionally substituted with R at the 3-position distal to its attachment to the rest of the molecule. a and optionally substituted with R b or R 9 is (R 9a ) part or (R 9b )portion: [ka] and During the ceremony, Z 1 is N or CH, and Z 2 is N(R a ), O, S, CH(R a ), or C(R x )(R y ) where R x and R y together form a 4- to 6-membered monocyclic heterocyclyl containing one heteroatom selected from N, O, and S; optionally, Z 1 and Z 2 At least one of the groups is N or N(R a ) and; R a is hydrogen, -N(R m )R n , C 1~6 Alkyl, oxo, -C(O)R d , -C(O)N(R f )R g , or C 1~6 Alkyl-N(R j )R k and; R b is hydrogen or C 1~4 is alkyl; R c is hydrogen; R d is hydrogen, C 1~4 Alkyl, or C 3~6 cycloalkyl, where cycloalkyl is optionally selected from C 1~4 Alkyl, amino, -NH(C 1~4 alkyl), -N(C 1~4 alkyl)2, and C 1~4 substituted with 1 or 2 substituents independently selected from haloalkyl; R f is hydrogen or C 1~4 is alkyl; R g is hydrogen or C 1~4 is alkyl; R j is hydrogen or C 1~4is alkyl; R k is hydrogen or C 1~4 is alkyl; R m is hydrogen or C 1~4 is alkyl; R n is hydrogen or C 1~4 is alkyl; R 4 -L 1A -L 2A -L 3A It is a base; L 1A is C 1~3 is alkylene; L 2A does not exist; L 3A is phenyl or a 5- to 6-membered heteroaryl containing, as ring atoms, 1 or 2 heteroatoms independently selected from N, S, and O, where at least one heteroatom is N, wherein L 3A is optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methyl, and trifluoromethyl; R 5 is hydrogen or -L 1B -L 2B -L 3B It is a base; L 1B is C 1~3 is alkylene; L 2B does not exist; L 3B is phenyl or a 5- to 6-membered heteroaryl containing, as ring atoms, 1 or 2 heteroatoms independently selected from N, S, and O, where at least one heteroatom is N, wherein L 3B is optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, methyl, and trifluoromethyl; or -L 1B -L 2B -L3B The group is C 1~6 is alkyl; R 6 is hydrogen or -L 1C -L 2C -L 3C is a group, where -L 1C -L 2C -L 3C The group is C 1~6 It is alkyl.

[0134] In some embodiments (embodiment C), the compound is a compound of formula (I): During the ceremony, R 1 is cyano or -CH3; R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl or oxetanyl; X 1 is CR 7 and; X 2 is CR 8 and; X 3 is CR 9 and; R 7 and R 8 is hydrogen; R 9 is hydrogen, chloro, phenyl, piperidinyl (e.g., piperidin-1yl, piperidin-4-yl), piperazinyl (e.g., piperazin-1-yl), or imidazolyl (e.g., imidazol-5-yl), where phenyl, piperidinyl, piperazinyl, and imidazole are optionally selected from R a , R b , and / or R c is replaced by; R a is hydrogen, —CH3, —C(O)—CH3, —C(O)—C(CH2—CH2)—CH3, —C(O)—C(CH2—CH2)—NH2, —C(O)—NH2, —C(O)—N(CH3)2, or —CH2—NH2; R b is hydrogen or -CH3; R c is hydrogen or -CH3; R 4 is —CH2-(methylpyrazol-4-yl) (e.g., —CH2-(1-methylpyrazol-4-yl), —CH2-(trifluoromethylpyrazol-4-yl) (e.g., —CH2-(1-trifluoromethylpyrazol-4-yl)), or —CH2-(methylthiazol-5-yl) (e.g., —CH2-(2-methylthiazol-5-yl)); R 5 is —CH, —CHCH, —CH(CH)(CH), or —CH-(dimethylthiazol-5-yl) (e.g., —CH-(2,4-dimethylthiazol-5-yl)); and R 6 is hydrogen.

[0135] In further embodiments, the present invention provides the following compounds and pharmaceutically acceptable salts thereof: 2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(2-methylthiazol-5-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide; 2-Methoxyimino-N-(3-methyloxetan-3-yl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide; 2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide; 8-chloro-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide; 4-[2-Methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]-N,N-dimethyl-benzamide; 2-Methoxyimino-N-(1-methylcyclopropyl)-4-oxo-3-[[1-(trifluoromethyl)pyrazol-4-yl]methyl]-1H-quinazoline-6-sulfonamide; 2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-3-methylpiperazin-1-yl]-1H-quinazoline-6-sulfonamide; 2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-3-methyl-4-(1-methylcyclopropanecarbonyl)piperazin-1-yl]-1H-quinazoline-6-sulfonamide; N-(1-cyanocyclopropyl)-2-methoxyimino-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide; 2-Ethoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide; 2-Isopropoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide; (2E)-2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-4-acetyl-3-methyl-piperazin-1-yl]-1H-quinazoline-6-sulfonamide; (R,E)-2-(methoxyimino)-8-(6-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide / (R,E)-2-(methoxyimino)-8-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (E)-4-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-N,N,2-trimethylbenzamide; (E)-4-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)benzamide; (E)-8-(4-acetylphenyl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (E)-8-(4-(aminomethyl)phenyl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-8-(4-(1-methylcyclopropane-1-carbonyl)phenyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (E)-5-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-N,N-dimethylpicolinamide; (E)-6-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-N,N-dimethylnicotinamide; (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-3,4-dimethylpiperazin-1-yl]-1H-quinazoline-6-sulfonamide; (E)-8-(4-(1-hydroxy-2-oxocyclobutyl)phenyl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (E)-5-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-N,N-dimethyl-1H-imidazole-2-carboxamide; (2E)-2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-4-piperidyl]-1H-quinazoline-6-sulfonamide; (2E)-2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-1,2-dimethyl-4-piperidyl]-1H-quinazoline-6-sulfonamide; (2E)-2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-1-acetyl-2-methyl-4-piperidyl]-1H-quinazoline-6-sulfonamide; (2E)-2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-1-(1-methylcyclopropanecarbonyl)-4-piperidyl]-1H-quinazoline-6-sulfonamide; (2E)-2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-1,2-dimethyl-3,6-dihydro-2H-pyridin-4-yl]-1H-quinazoline-6-sulfonamide / (2E)-2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(6R)-1,6-dimethyl-3,6-dihydro-2H-pyridin-4-yl]-1H-quinazoline-6-sulfonamide; (2E)-2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-1-acetyl-2-methyl-3,6-dihydro-2H-pyridin-4-yl]-1H-quinazoline-6-sulfonamide / (2E)-2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(6R)-1-acetyl-6-methyl-3,6-dihydro-2H-pyridin-4-yl]-1H-quinazoline-6-sulfonamide; (2E)-2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-1-(1-methylcyclopropanecarbonyl)-3,6-dihydro-2H-pyridin-4-yl]-1H-quinazoline-6-sulfonamide / (2E)-2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(6R)-6-methyl-1-(1-methylcyclopropanecarbonyl)-3,6-dihydro-2H-pyridin-4-yl]-1H-quinazoline-6-sulfonamide; (R,E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-8-(3-methyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (R,E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-8-(3-methyl-4-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperazin-1-yl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (R,E)-8-(4-(1-cyanocyclopropane-1-carbonyl)-3-methylpiperazin-1-yl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (R,E)-8-(4-(1-(dimethylamino)cyclopropane-1-carbonyl)-3-methylpiperazin-1-yl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (R,E)-8-(4-isobutyryl-3-methylpiperazin-1-yl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (R,E)-8-(4-(3,3-difluoropyrrolidine-1-carbonyl)-3-methylpiperazin-1-yl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (R,E)-4-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-N,2-dimethyl-N-(2,2,2-trifluoroethyl)piperazine-1-carboxamide; (R,E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-8-(3-methyl-4-(1-methylcyclobutane-1-carbonyl)piperazin-1-yl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (R,E)-8-(4-(cyclopentanecarbonyl)-3-methylpiperazin-1-yl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (R,E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-8-(3-methyl-4-(pyrrolidine-1-carbonyl)piperazin-1-yl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (R,E)-4-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-N,N,2-trimethylpiperazine-1-carboxamide; (R,E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-8-(3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; rel-(R,E)-8-(4-(2,2-difluoro-2-(1-hydroxycyclobutyl)acetyl)-3-methylpiperazin-1-yl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; and rel-(R,E)-N-cyclopropyl-4-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-N,2-dimethylpiperazine-1-carboxamide.

[0136] Some intermediates useful in the preparation of compounds of formula (I) are novel and form a further aspect of the invention. Thus, in a further aspect, the present invention provides compounds of formula (Int-I) [ka] or a salt thereof, During the ceremony, R 10 is hydrogen, halogen (e.g., chloro, bromo, iodo), —B(OH), —B(—OC(CH)—C(CH)—O—) (i.e., pinacol boronate), —S(O)OH, —S(O)Cl, or —S—CH-phenyl; and X 1 , X 2 , X 3 , R 4 , R 5 , and R 6 is as defined for compounds of formula (I), including preferred definitions and embodiments thereof; wherein the compound (Int-I) is not: 2-(hydroxyamino)-6-iodo-3-phenyl-4(3H)-quinazolinone (CAS RN: 221657-59-6); 6-iodo-2-(propoxyamino)-3-propyl-4(3H)-quinazolinone (CAS RN: 1101794-34-6); 6-Bromo-2-(propoxyamino)-3-propyl-4(3H)-quinazolinone (CAS RN: 1101796-68-2); 6-iodo-2-[(2-methylpropoxy)amino]-3-propyl-4(3H)-quinazolinone (CAS RN: 1101796-45-5); 6-bromo-2-[(2-methylpropoxy)amino]-3-propyl-4(3H)-quinazolinone (CAS RN: 1101794-11-9); 2-[[(3,4-dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)amino]oxy]acetic acid (CAS RN: 221657-88-1); (3,4-Dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)azanyl acetate (CAS RN: 221658-07-7); 2,4(1H,3H)-Quinazolinedione, 6-iodo-3-phenyl-, 2-[O-(ethoxycarbonyl)oxime] (CAS RN: 221657-74-5); (3,4-Dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)azanyl 2-chloroacetate (CAS RN: 221657-64-3); Ethyl 2-[[(3,4-dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)amino]oxy]acetate (CAS RN: 221657-82-5); (3,4-Dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)azanyl benzoate (CAS RN: 221658-09-9); (3,4-Dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)azanyl benzeneacetate (CAS RN: 221658-10-2); 1-[(3,4-dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)azanyl] 2-ethyl ethanedioate (CAS RN: 221657-99-4); 2-(hydroxyamino)-3-phenyl-4(3H)-quinazoline (CAS RN: 858236-63-2).

[0137] Regarding the excluded compounds listed above, see WO 1994 / 26722 and Abdel-Hamide et al. Acta Pharmaceutica (Zagreb) 1998, 48(4):249-258.

[0138] In some embodiments of compounds of Formula (Int-I), R 10 is hydrogen. In some embodiments of compounds of Formula (Int-I), R 10 is halogen (e.g., chloro, bromo, iodo). In some embodiments of compounds of Formula (Int-I), R 10 is -B(OH) or -B(-OC(CH)-C(CH)-O-). In some embodiments of compounds of Formula (Int-I), R 10 is —S(O)2Cl. In some embodiments of compounds of Formula (Int-I), R 10 is -S-CH2-phenyl. In some embodiments of compounds of Formula (Int-I), X 1 , X 2 , X 3 , R 4 , R 5 , and R 6 is as defined in embodiment A. In some embodiments of compounds of formula (Int-I), X 1 , X2 , X 3 , R 4 , R 5 , and R 6 is as defined in embodiment B. In some embodiments of compounds of formula (Int-I), X 1 , X 2 , X 3 , R 4 , R 5 , and R 6 is as defined in embodiment C.

[0139] In a further aspect, the present invention provides a compound of formula (Int-II) [ka] or a salt thereof, During the ceremony, R 11 is hydrogen or C 1~8 is alkyl; and X 1 , X 2 , X 3 , R 4 , R 5 , and R 6 is as defined for compounds of formula (I), including preferred definitions and embodiments thereof; The present invention provides a compound of formula (Int-II) or a salt thereof:

[0140] In some embodiments of the compound of Formula (Int-II), X 1 , X 2 , X 3 , R 4 , R 5 , and R 6 is as defined in embodiment A.

[0141] In some embodiments of the compound of Formula (Int-II), X 1 , X 2 , X 3 , R 4 , R 5 , and R 6 is as defined in embodiment B.

[0142] In some embodiments of the compound of Formula (Int-II), X 1 , X 2 , X 3 , R 4 , R 5 , and R 6 is as defined in embodiment C.

[0143] The present invention also relates to pharmaceutical compositions comprising, as an active ingredient, a compound of formula (I) or a pharmaceutically acceptable salt thereof, which may be particularly used in the treatment of neoplastic diseases (particularly cancer) as described herein.

[0144] The compounds of the present invention can be formulated as pharmaceutical compositions for parenteral administration (e.g., nasal, buccal, rectal, pulmonary, vaginal, sublingual, topical, transdermal, ocular, aural), or can be formulated for oral administration, particularly in the form of oral solid dosage forms such as, for example, granules, pellets, powders, tablets, films or dragees, effervescent tablets, hard and soft gelatin or HPMC capsules (optionally coated), orally disintegrating tablets, oral solutions, lipid emulsions or suspensions, or can be formulated for parenteral administration (e.g., intravenous, intramuscular, or subcutaneous, intrathecal, intradermal, or epidural administration) to mammals (particularly humans), for example, in the form of a solution containing microparticles or nanoparticles, lipid emulsion, or suspension. The compositions can contain the active ingredient alone, or, preferably, together with a pharmaceutically acceptable excipient.

[0145] The pharmaceutical composition may be processed with pharmaceutically inert inorganic or organic excipients for the preparation of oral solid dosage forms such as granules, pellets, powders, tablets, films or sugar-coated tablets, effervescent tablets, hard gelatin or HPMC capsules, or orally disintegrating tablets. Fillers (e.g., lactose, cellulose, mannitol, sorbitol, calcium phosphate, starch, or derivatives thereof), binders (e.g., cellulose, starch, polyvinylpyrrolidone, or derivatives thereof), glidants (e.g., talc, stearic acid, or a salt thereof), and flow agents (e.g., fumed silica) may be used as excipients for the formulation and preparation of oral solid dosage forms such as granules, pellets, powders, tablets, films or sugar-coated tablets, effervescent tablets, hard gelatin or HPMC capsules, or orally disintegrating tablets. Suitable excipients for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semisolid polyols, and liquid polyols.

[0146] Suitable excipients for the preparation of oral solutions, lipid emulsions, or suspensions are, for example, water, alcohols, polyols, sucrose, invert sugar, glucose, etc. Suitable excipients for parenteral preparations are, for example, water, alcohols, polyols, glycerol, vegetable oils, lecithin, surfactants, etc. Furthermore, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for changing osmotic pressure, buffers, masking agents, or antioxidants. The pharmaceutical compositions may also contain other therapeutically valuable substances.

[0147] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor® EL, or phosphate-buffered saline (PBS). The carrier may be, for example, a solvent or dispersion medium containing water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and the like), and suitable mixtures thereof. For intravenous injection of strongly lipophilic molecules, it may be advantageous to include solubilizing agents, such as surfactants, polymeric surfactants, polymers, complexing agents, and / or cosolvents, in the formulation, which can greatly increase the aqueous solubility of the compound. Examples of solubilizing agents include polyethylene glycol, propylene glycol, ethanol, glycerol, and cyclodextrins.

[0148] Sterile injectable solution can be prepared by incorporating the required amount of active compound into suitable solvent with one or combination of the above-listed ingredients as needed, followed by sterilization filtration.Generally, dispersion is prepared by incorporating active compound into a sterile vehicle that contains dispersion medium and other necessary ingredients as listed above.For the preparation of sterile powder for sterile injectable solution, preparation method is vacuum drying and freeze-drying, thereby obtaining powder of active ingredient and any additional desired ingredients from the solution that has been previously sterilized and filtered.

[0149] In addition, the pharmaceutical compositions used in the present invention may optionally include: buffers such as phosphate, citrate, or other organic acids; antioxidants such as butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone, amino acids such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, or other carbohydrates such as glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or non-ionic surfactants such as TWEEN®, PLURONICS®, or PEG.

[0150] Optionally, the pharmaceutical composition includes a pharmaceutically acceptable preservative. In some embodiments, the concentration of the preservative ranges from 0.1 to 2.0 percent (typically v / v). Suitable preservatives include those known in the pharmaceutical art, such as benzyl alcohol, phenol, m-cresol, methylparaben, and propylparaben.

[0151] The dosage can vary within wide limits and can, of course, be adjusted to the individual requirements in each particular case. Generally, in the case of oral administration, a daily dosage of about 1 to 1000 mg per person of the compound of general formula (I) should be appropriate, although it is possible to exceed the above upper or lower limits if necessary.

[0152] The compounds of formula (I) according to the present invention, as described above, or pharmaceutically acceptable salts thereof, when administered in a therapeutically effective amount, are particularly useful for treating neoplastic diseases, such as cancer. Examples of neoplastic diseases include, but are not limited to, epithelial tumors, squamous cell tumors, basal cell tumors, transitional cell papillomas and carcinomas, adenomas and adenocarcinomas, adnexal and skin appendage tumors, mucoepidermoid tumors, cystic tumors, mucinous and serous tumors, ducal, lobular, and medullary tumors, acinar cell tumors, mixed epithelial tumors, specialized gonadal tumors, paragangliomas and glomus tumors, nevi and melanomas, soft tissue tumors and sarcomas, fibromatous tumors, myxomatous tumors, lipomatous tumors, fibroid tumors, complex mixed and stromal tumors, fibroepithelial tumors, synovial tumors, and fibroblastic tumors. tumors, mesothelial tumors, germ cell tumors, trophoblastic tumors, mesonephromas, vascular tumors, lymphatic tumors, bone and cartilaginous tumors, giant cell tumors, mixed bone tumors, odontogenic tumors, gliomas, neuroepithelioma and neuroendocrine tumors, meningiomas, nerve sheath tumors, granular cell tumors and alveolar soft part sarcomas, Hodgkin's lymphoma and non-Hodgkin's lymphoma, B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma, Burkitt's lymphoma and other lymphoreticular tumors, plasma cell neoplasms, mast cell tumors, immunoproliferative disorders, leukemias, mixed myeloproliferative disorders, lymphoproliferative disorders, and myelodysplastic syndromes.

[0153] Examples of cancers involving affected organs and body parts include, but are not limited to, breast, cervix, ovary, colon, rectum (including colon and rectum, i.e., colorectal cancer), lung (including small cell lung cancer, non-small cell lung cancer, large cell lung cancer, and mesothelioma), endocrine system, bone, adrenal gland, thymus, liver, stomach (gastric cancer), intestine, pancreas, bone marrow, hematological malignancies (e.g., lymphoma, leukemia, myeloma, or lymphatic malignancies), bladder, urinary tract, kidney, skin, thyroid, brain, head, neck, prostate, and testicles. Preferably, the cancer is selected from the group consisting of breast cancer, prostate cancer, cervical cancer, ovarian cancer, stomach cancer, colorectal cancer, pancreatic cancer, liver cancer, brain cancer, neuroendocrine cancer, lung cancer, kidney cancer, bladder cancer, mesothelioma, hematological malignancies, melanoma, and sarcoma.

[0154] The cancer may be a primary tumor and / or a metastatic cancer. The cancer may originate from a solid tumor or a liquid tumor (e.g., a blood or peritoneal tumor). In some embodiments, the neoplastic disease (e.g., cancer) to be treated is a tumor, e.g., a solid tumor.

[0155] In some embodiments, the cancer treated by the compounds of the present invention is mediated by modulation of PARG. In some embodiments, the compounds of the present invention can treat cancer by modulating PARG (e.g., by inhibiting PARG). Such cancer can be, for example, ovarian cancer, lung cancer, or breast cancer.

[0156] "Pharmaceutically acceptable," as used herein, refers to items such as compounds and salts thereof, materials, compositions, and / or dosage forms that are suitable, within the scope of sound medical judgment, to be in contact with the tissues of warm-blooded animals (e.g., mammals or humans) without undue toxicity or other complications commensurate with a reasonable benefit / risk ratio.

[0157] A "pharmaceutical composition" is defined herein to refer to a solid or liquid formulation containing at least one therapeutic agent, together with one or more pharmaceutically acceptable excipients, administered to a subject (e.g., a mammal, particularly a human) to prevent or treat a particular disease or condition affecting the mammal.

[0158] "Prevent," "preventing," or "prevention," as used herein, includes the prevention of at least one symptom associated with or caused by the condition, disease, or disorder being prevented.

[0159] A "therapeutically effective amount," as used herein, relates to the amount of a compound, or material, composition, or dosage form containing a compound, that is effective to produce some desired therapeutic effect, when administered in accordance with a desired treatment regimen, commensurate with a reasonable benefit / risk ratio.

[0160] "Treatment" or "treating," as used herein in the context of treating a disease or disorder, generally refers to treatments and therapies, whether in humans or animals (e.g., veterinary applications), in which some desired therapeutic effect (e.g., inhibition of progression of the disease or disorder) is achieved, including slowing the rate of progression, halting the rate of progression, alleviating symptoms of the disease or disorder, ameliorating the disease or disorder, and curing the disease or disorder. Treatment as a preventative measure (i.e., prophylaxis) is also included. For example, use with patients who have not yet developed the disease or disorder but are at risk of developing the disease or disorder is encompassed by the term "treatment." For example, treatment includes preventing cancer, reducing the incidence of cancer, slightly alleviating cancer, etc.

[0161] The term "subject" refers to a mammal, preferably a human, and the term "patient" refers to a human submitting themselves to therapeutic treatment.

[0162] Compounds of formula (I) may be synthesized by the methods shown below or by methods similar thereto, for example, as shown in Scheme I. The schemes described herein are not intended to represent an exhaustive list of methods for preparing compounds of formula (I); rather, additional techniques recognized by the skilled chemist may be used in the synthesis of the compounds.

[0163] Those skilled in the art of organic synthesis will understand that optimal reaction conditions may vary depending on the particular reaction or solvent used, but such conditions can be determined by routine optimization procedures. In some cases, the following reaction schemes and / or the order of carrying out the reaction steps may be modified to facilitate the reaction or avoid the formation of undesired by-products. In addition, the functional groups present at various positions on the molecule must be compatible with the proposed reagents and reactions. Such restrictions on the substituents compatible with the reaction conditions will be readily apparent to those skilled in the art, and alternative methods must then be used. Furthermore, in some of the reactions mentioned herein, it may be necessary or desirable to protect any sensitive groups in the compounds, and it is envisioned that such protecting groups (PG) will be placed as necessary. Conventional protecting groups may be used in accordance with standard practices known in the art (see Wuts PGM, Greene's Protective Groups in Organic Synthesis, 5th Edition, Publisher: John Wiley & Sons, 2014 for an explanation). The protecting groups may be removed at any convenient stage in the synthesis or may be removed during a later reaction step or work-up using conventional techniques known in the art. In the general sequence of reactions outlined in Scheme 1 below, the abbreviation X 1 , X 2 , X 3 , as well as the general group R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is as defined for formula (I) unless otherwise specified. The general group E1 is generally a hydrogen atom, -OH, a methoxy group, a halogen atom, a sulfonic acid, a sulfonyl chloride, a boronic acid, a boronic ester, or -O-L1, where -O-L1 is a leaving group, and L1 is selected from perfluoroalkylsulfonyl, such as triflyl (trifluoromethanesulfonyl), and sulfonyl, such as tosyl (p-toluenesulfonyl) or mesyl (methanesulfonyl). The compounds of the present invention, their pharmaceutically acceptable salts, solvates, and hydrates may be prepared according to the general sequence of reactions outlined in Scheme 1 below, and, where appropriate, as follows: manipulation of substituents to give novel final products, which may include, but are not limited to, reduction, oxidation, alkylation, acylation, substitution, coupling, including transition metal catalyzed coupling, and hydrolysis reactions known to those skilled in the art; - removing any protecting groups; - form pharmaceutically acceptable salts; or - Form pharmaceutically acceptable solvates or hydrates.

[0164] Scheme 1 [ka]

[0165] The starting materials required for the synthetic methods described herein, if not commercially available, can be prepared by procedures described in the scientific literature or can be prepared from commercially available compounds by adapting processes reported in the scientific literature. For general guidance on reaction conditions and reagents, see, for example, March J., Smith M., Advanced Organic Chemistry, 7th Edition, Publisher: John Wiley & Sons, 2013.

[0166] The compounds of formulas (A) to (F) in which E1 is an -O-L1 group can be prepared by reacting the corresponding alcohols (A) to (F) in which E1 is -OH, respectively, with methanesulfonyl chloride or methanesulfonic anhydride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride or trifluoromethanesulfonic anhydride in a dry aprotic solvent such as pyridine, acetonitrile, tetrahydrofuran, or dichloromethane in the presence of a base such as triethylamine at -30 to 80°C.

[0167] Compounds of Formulas (A)-(F) where E1 is a halogen atom can be prepared from compounds of Formulas (A)-(F) where E1 is an -O-L1 group by a transition metal catalyzed coupling reaction. Typical catalysts include palladium(II) acetate, tris(dibenzylideneacetone)dipalladium(0), and the like. The reaction is typically carried out at temperatures between 0°C and 150°C, more often between 80°C and 120°C. This reaction is typically carried out in a wide variety of inert solvents or mixtures of solvents, such as toluene, tetrahydrofuran, dioxane, 1,2-dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, water, and acetonitrile, more frequently in dioxane, in the presence of a ligand such as di-tert-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane, di-tert-butyl-[2,3,4,5-tetramethyl-6-(2,4,6-triisopropylphenyl)phenyl]phosphane, 2-(dicyclohexylphosphino)biphenyl, or 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and a base such as sodium tert-butyrate, cesium carbonate, or potassium carbonate, more frequently cesium carbonate. Numerous protocols have been identified for transition metal-catalyzed coupling reactions, due to the numerous components involved, including the specific palladium catalyst, ligand, additive, solvent, and temperature. Those skilled in the art will be able to identify satisfactory protocols without undue experimentation.

[0168] Alternatively, compounds of Formulas (A)-(F) in which E1 is a halogen atom can be prepared from compounds of Formulas (A)-(F) in which E1 is a boronic acid or boronic ester by a halogenodeboronation reaction, which is typically carried out in the presence of copper(II) halide in methanol at temperatures ranging from 0°C to 100°C, more often at 90°C.

[0169] Compounds of formulas (C)-(F) in which E1 is a sulfonic acid can be prepared from compounds of formulas (C)-(F) in which E1 is a hydrogen atom by a sulfonation reaction, which is typically carried out in the presence of concentrated sulfuric acid, oleum, sulfur trioxide, or chlorosulfonic acid.

[0170] Compounds of formula (C)-(F) where E1 is a sulfonyl chloride can be prepared from compounds of formula (C)-(F) where E1 is a sulfonic acid using chlorosulfonic acid or a sulfonyl chloride.

[0171] Alternatively, compounds of formulae (C)-(F) in which E1 is a sulfonyl chloride can be prepared from compounds of formulae (C)-(F) in which E1 is a hydrogen atom by halosulfonation using chlorosulfonic acid.

[0172] In addition, X 3 is CR 9 and R 9 C 3~6 The compound of formula (I) is a cycloalkyl group, a phenyl group, or a heteroaryl group, and X 3 is CR 9 and R 9The Suzuki reaction can be prepared from a compound of formula (I) where is a halogen atom, and this compound is reacted with a boronic acid or boronate ester. This Suzuki reaction is a palladium-catalyzed cross-coupling between an organoboronic acid and an aryl or vinyl halide or triflate. Typical catalysts include palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). This reaction can be carried out in a variety of organic solvents (e.g., toluene, tetrahydrofuran, dioxane, 1,2-dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, and acetonitrile), aqueous solvents, and under biphasic conditions. The reaction is typically carried out at room temperature to 150°C. This coupling is frequently promoted by additives such as cesium fluoride, potassium fluoride, potassium hydroxide, and sodium ethylate. Instead of boronic acid, potassium trifluoroborate and an organoborane or boronic acid ester can be used. The Suzuki reaction involves a number of components, including specific palladium catalysts, ligands, additives, solvents, and temperatures, and many protocols have been specified. Those skilled in the art will be able to identify satisfactory protocols without undue experimentation.

[0173] X 3 is CR 9 and R 9 Compounds of formula (I) wherein X is a heterocyclyl system 3 is CR 9 and R 9 These compounds can be prepared from compounds of formula (I) in which is a halogen atom, which is reacted with a heterocyclyl group by a transition metal catalyzed coupling reaction using conditions previously described.

[0174] Step 1: Compounds of formula (B) can be prepared from compounds of formula (A) and amines by a coupling reaction in the presence of an activating agent such as N,N'-dicyclohexylcarbodiimide or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, optionally with the addition of 1-hydroxybenzotriazole. Other suitable coupling agents, such as O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, carbonyldiimidazole, or diethylphosphoryl cyanide, can be used. Optionally, a base, such as triethylamine, N,N-diisopropylethylamine, or pyridine, can be added to carry out the coupling. The amide coupling is carried out in an inert solvent, preferably a dry aprotic solvent such as dichloromethane, acetonitrile, N,N-dimethylformamide, and chloroform, at temperatures between -20°C and 100°C. Step 2: Compounds of formula (D) can be prepared from compounds of formula (B) by cyclization using thiophosgene in 1,4-dioxane under reflux conditions (Pave G., Org. Lett., 2015, 17, 4930-4932). Step 3: Alternatively, compounds of formula (D) can be prepared from compounds of formula (C) and a halide, mesylate, tosylate, or triflate by a substitution reaction. The substitution reaction is generally carried out in the presence or absence of an inorganic base such as potassium carbonate or cesium carbonate, or an organic base such as trimethylamine, pyridine, or N,N-diisopropylethylamine, in a dry aprotic solvent such as dichloromethane, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, or tetrahydrofuran, at temperatures between −20° C. and 100° C. Step 4: Compounds of formula (E) can be prepared from compounds of formula (D) and O-substituted hydroxylamines by a condensation reaction, which is carried out in the presence or absence of an organic base such as sodium acetate, triethylamine, pyridine, etc., in a solvent such as N,N-dimethylformamide or N,N-dimethylacetamide, at temperatures between room temperature and 150°C. Step 5: Compounds of formula (F) may be prepared from compounds of formula (E) and a halide, mesylate, tosylate, or triflate by a substitution reaction using the conditions previously described. Step 6: Compounds of formula (G) can be prepared from compounds of formula (F) where E1 is a halogen atom or E1 is an -O-L1 group by a transition metal catalyzed coupling reaction using benzyl mercaptan and the conditions previously described. Step 7: Compounds of formula (I) may be prepared from compounds of formula (G) by oxidative chlorination using NCS or DCDMH under acidic conditions, followed by displacement of the resulting sulfonyl chloride with an amine using conditions previously described. Alternatively, compounds of formula (I) may be prepared directly from compounds of formula (F) where E1 is a sulfonyl chloride by displacement with an amine using conditions already described.

[0175] The oximes of the compounds of formulae (I), (E), (F), and (G) may be formed as a mixture of two isomers (E and Z) or may form only one isomer. If two isomers are formed, they can be separated at any convenient stage.

[0176] Certain embodiments of the present invention are described in the following examples, which serve to more fully illustrate the invention and should not be construed as limiting the invention in any way. [Brief explanation of the drawings]

[0177] [Figure 1A]Figure 1 shows the increase in cellular protein-bound PAR levels after treatment with a PARG inhibitor. Figure 1A: Kuramochi HGSOC cells were treated with either the compound solvent DMSO or increasing concentrations of Examples 1, 5, 7, or 8 for 8 hours, followed by cell extraction and Western blotting to detect cellular PAR levels. α-Tubulin was blotted as a loading control. [Figure 1B] FIG. 1B: NCI-H1650 NSCLC cells were treated with either compound solvent DMSO or increasing concentrations of Examples 1, 5, 7, or 8 for 8 hours, followed by Western blotting as described above. DETAILED DESCRIPTION OF THE INVENTION

[0178] Example All reagents and solvents are generally used as received from commercial sources. Unless otherwise specified, reactions are always carried out under an argon or nitrogen atmosphere in thoroughly dried glassware with anhydrous solvents. Evaporation is carried out by rotary evaporation under reduced pressure, and workup procedures are carried out after removal of residual solids by filtration. All temperatures are given in degrees Celsius (°C) and are approximate; unless otherwise specified, operations are carried out at room temperature (rt), i.e., typically in the range of 18°C to 25°C. Column chromatography (via flash procedure) is used to purify compounds. Conventional flash chromatography is often replaced by an automated system. This does not change the separation process itself. Those skilled in the art can replace conventional flash chromatography processes with automated processes, and vice versa. Typical automated systems, such as those provided by Büchi, Biotage, or Isco (combiflash), can be used. Reaction mixtures, unless otherwise specified, can often be separated by preparative HPLC, for example, using water and acetonitrile as the eluent system. Those skilled in the art will find suitable conditions for each separation; the compounds are isolated as the parent compounds after purification, or in the form of the corresponding trifluoroacetic acid (TFA) salt or respective formate salt. Reactions requiring higher temperatures are usually carried out using conventional heating equipment, but may be carried out using a microwave apparatus (CEM Explorer) with a power of 250 W unless otherwise specified. Hydrogenation or hydrogenolysis reactions may be carried out using hydrogen gas in a balloon or using a Parr apparatus system or other suitable hydrogenation apparatus. Solutions are concentrated and solids are dried under reduced pressure unless otherwise specified. Reaction progress is generally monitored by TLC, HPLC, or LC / MS, and reaction times are given for illustrative purposes only; yields are given for illustrative purposes only and are not necessarily the maximum achievable value. The structure and purity of the final products of the present invention are generally confirmed by NMR spectroscopy, HPLC, and mass spectrometry techniques.

[0179] Proton NMR spectra were recorded on a Brucker 400 MHz spectrometer. Chemical shifts (δ) are reported in ppm relative to Me4Si or the solvent peak as internal standard, and NMR coupling constants (J values) are reported in Hertz (Hz). Peaks are designated as broad singlet (br), singlet (s), doublet (d), triplet (t), quartet (q), doublet of doublet (dd), triplet of doublet (td), or multiplet (m). HPLC of the final product was performed (Method A) on a Dionex Ultimate 3000™ instrument equipped with a Dionex MSQ ESI mode and the following conditions: Mobile phase A: Water and 0.1% formic acid Mobile phase B: acetonitrile and 0.1% formic acid Column: YMC triart C18 5μm 100mm×4.6mm Column temperature: 25°C Detection: UV 250 nm Injection: 2 μL of 10 mM sample in DMSO Flow rate: 1.6mL / min Gradient Time (min) Mobile phase B % 0 5 8 95 10 95 10.1 5 Equilibrium 13 5 equilibrium or (Method B) using a Waters Acquity Ultra Performance Liquid Chromatography (UPLC) equipped with an SQ 3100 mass detector spectrometer. Mobile phase A: Water and 0.05% formic acid Mobile phase B: acetonitrile and 0.05% formic acid Column: Acquity BEH C18 1.7μm, 2.1×50mm Flow rate: 0.6mL / min Gradient Time (min) Mobile phase B % 0 3 0.4 3 2.5 98 3.5 98 3.6 3 4 3

[0180] The gradients described can be varied depending on the physicochemical properties of the compounds being analyzed and are in no way limiting. Mass spectra were generated using a q-Tof Ultima™ (Waters AG or Thermo Scientific MSQ Plus) mass spectrometer in positive or negative ESI mode. The system was equipped with a standard Lockspray interface. Each intermediate is purified to the standards required for the next step and characterized in sufficient detail to confirm the correctness of the assigned structure. Analytical and preparative HJPLC on non-chiral phases is performed using RP-C18 based columns. The following abbreviations may be used (for a comprehensive list of standard abbreviations and acronyms, the Journal of Organic Chemistry Guidelines for Authors may also be consulted): AcOH acetic acid ACN Acetonitrile Bn Benzyl BnSH benzyl mercaptan Compounds with CAS Chemical Abstracts Services Registry Numbers Cbz N-carboxybenzyl CDCl3 deuterated chloroform DCDMH 1,3-dichloro-5,5-dimethylhydantoin DCM dichloromethane Diox 1,4-dioxane DIPEA N,N-Diisopropylethylamine DMA N,N-dimethylacetamide DME Dimethoxyethane DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DMSO-d6 Deuterated Dimethyl Sulfoxide EA Ethyl acetate EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ELSD Evaporative Light Scattering Detection ESI electrospray ionization EtOH ethanol Example: Example HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HOBt N-hydroxybenzotriazole HPLC High Performance Liquid Chromatography LC / MS Liquid chromatography coupled with mass spectrometry MeOH Methanol Me4Si Tetramethylsilane MS mass spectrometry MW Microwave NCS N-chlorosuccinimide NMR nuclear magnetic resonance Pd / C Palladium-activated carbon Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2 [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(PPh3)4 tetrakis(triphenylphosphine)-palladium(0) PE Petroleum Ether rt room temperature TEA Triethylamine TFA trifluoroacetic acid THF tetrahydrofuran Xant-Phos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0181] The following examples refer to compounds of formula (I) as shown in Table 1. The examples listed in the table below can be prepared using the procedures described above, and detailed synthetic methods are described in detail below. The example numbers used in the left-most column are used to identify each compound in the text of this application.

[0182] Table 1. Exemplary compounds JPEG2025526453000013.jpg201129 JPEG2025526453000014.jpg213129 JPEG2025526453000015.jpg212129 JPEG2025526453000016.jpg206129 JPEG2025526453000017.jpg213130 JPEG2025526453000018.jpg206129 JPEG2025526453000019.jpg213129 JPEG2025526453000020.jpg212129 JPEG2025526453000021.jpg213129 JPEG2025526453000022.jpg174129 JPEG2025526453000023.jpg213129 JPEG2025526453000024.jpg213129 JPEG2025526453000025.jpg213129 JPEG2025526453000026.jpg212130 JPEG2025526453000027.jpg213128 JPEG2025526453000028.jpg201130 A hyphen in the third column indicates that the synthetic procedure is described below.

[0183] Example 1: Preparation of 2-methoxyimino-N-(1-methylcyclopropyl)-3-[(2-methylthiazol-5-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide [ka]

[0184] Step 1: Preparation of 2-chloro 3-[(2-methylthiazol-5-yl)methyl]quinazolin-4-one: To a stirred solution of 5-(chloromethyl)-2-methyl-thiazole (2.70 g, 17.4 mmol) in DME (50 mL) and DMF (10 mL) at 0 °C was added NaH (0.76 g, 19.1 mmol, 60% dispersion in mineral oil), followed by LiBr (3.05 g, 34.7 mmol) and 2-chloro-3H-quinazolin-4-one (3.3 g, 17.4 mmol). After stirring at 60 °C for 16 h, the reaction mixture was extracted with EA and HO. The combined organic layers were dried over NaSO, filtered, concentrated, and purified by column chromatography (silica gel; PE:DA; 7:3; v:v) to give 2-chloro-3-[(2-methylthiazol-5-yl)methyl]quinazolin-4-one as an off-white solid (3.8 g, 71% yield). MS m / z(+ESI): 292.1, 294.1 [M+H] + .

[0185] Step 2: Preparation of 2-methoxyimino-3-[(2-methylthiazol-5-yl)methyl]-1H-quinazolin-4-one: To a stirred solution of 2-chloro-3-[(2-methylthiazol-5-yl)methyl]quinazolin-4-one (0.5 g, 1.63 mmol) in DMF (5 mL) was added methoxyamine hydrochloride (0.7 g, 8.14 mmol), followed by TEA (1.0 g, 9.77 mmol). After stirring at 100 °C for 2 h, the reaction mixture was poured into HO (50 mL) and the resulting precipitate was collected by filtration to give 2-methoxyimino-3-[(2-methylthiazol-5-yl)methyl]-1H-quinazolin-4-one as a white solid (0.4 g, 77% yield). MS m / z (+ESI): 303.1 [M+H] + .

[0186] Step 3: Preparation of 2-methoxyimino-3-[(2-methylthiazol-5-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonic acid: A solution of 2-methoxyimino-3-[(2-methylthiazol-5-yl)methyl]-1H-quinazolin-4-one (0.35 g, 1.10 mmol) in chlorosulfonic acid (1 mL) was stirred at 60° C. for 1 h. The reaction mixture was then poured onto ice and purified by Biotage combiflash to give 2-methoxyimino-3-[(2-methylthiazol-5-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonic acid as a pale yellow solid (0.42 g, 90% yield). MS m / z (+ESI): 333.1 [M+H] + .

[0187] Step 4: Preparation of 2-methoxyimino-3-[(2-methylthiazol-5-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonyl chloride: A solution of 2-methoxyimino-3-[(2-methylthiazol-5-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonic acid (0.42 g, 0.99 mmol) in SOCl (4 mL) was stirred at 75° C. for 2 h. The reaction mixture was then concentrated and purified by preparative HPLC to give 2-methoxyimino-3-[(2-methylthiazol-5-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonyl chloride as a pale yellow solid (0.21 g, 48% yield). MS m / z (+ESI): 401.0, 403.0 [M+H] + .

[0188] Step 5: Preparation of 2-methoxyimino-N-(1-methylcyclopropyl)-3-[(2-methylthiazol-5-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide: To a stirred solution of 2-methoxyimino-3-[(2-methylthiazol-5-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonyl chloride (0.2 g, 0.45 mmol) in DCM (10 mL) was added 1-methylcycloproanamine hydrochloride (0.5 g, 4.49 mmol), followed by TEA (1.92 mL, 13.5 mmol). After stirring for 1 h, the reaction mixture was concentrated and purified by preparative HPLC to give 2-methoxyimino-N-(1-methylcyclopropyl)-3-[(2-methylthiazol-5-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide as a white solid (35 mg, 17% yield). 1 H NMR(400MHz,DMSO-d6+D2O)δ ppm:8.19(d,J=2.0Hz,1H),7.86(dd,J=2.0,8.8Hz,1H),7.65(s,1H),7.49(d,J=8.8H z,1H),5.11(s,2H),3.83(s,3H),2.57(s,3H),1.03(s,3H),0.57(m,2H),0.35(m,2H). MS m / z(+ESI):436.5[M+H] + .

[0189] Example 3: Preparation of 2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide [ka]

[0190] Step 1: Preparation of 2-[(2,4-dimethylthiazol-5-yl)methoxy]isoindoline-1,3-dione: To a stirred solution of 5-(chloromethyl)-2,4-dimethyl-thiazole (100 mg, 0.56 mmol) in ACN (5 mL) was added N-hydroxyphthalimide (93 mg, 0.56 mmol), followed by DIPEA (202 μL, 1.11 mmol). After stirring for 16 h, the reaction mixture was concentrated and purified by column chromatography (silica gel; PE:DA; 2:1; v:v) to give 2-[(2,4-dimethylthiazol-5-yl)methoxy]isoindoline-1,3-dione as a white solid (140 mg, 83% yield). MS m / z (+ESI): 289.1 [M+H] + .

[0191] Step 2: Preparation of O-[(2,4-dimethylthiazol-5-yl)methyl]hydroxylamine: To a stirred solution of 2-[(2,4-dimethylthiazol-5-yl)methoxy]isoindoline-1,3-dione (3.7 g, 12.2 mmol) in DCM (100 mL) was added hydrazine hydrate (0.93 g, 18.3 mmol). After stirring for 4 h, the reaction mixture was filtered, and the filtrate was concentrated to give O-[(2,4-dimethylthiazol-5-yl)methyl]hydroxylamine as a yellow oil (1.9 g, 89% yield), which was used in the next step without further purification. MS m / z (+ESI): 159.1 [M+H] + .

[0192] Step 3: Preparation of 6-bromo-2-chloro-3-[(1-methylpyrazol-4-yl)methyl]quinazolin-4-one: To a stirred solution of 6-bromo-2-chloro-3H-quinazolin-4-one (4.3 g, 12.4 mmol) in DMF (40 mL) was added 4-(chloromethyl)-1-methyl-pyrazole (3.42 g, 23.6 mmol), followed by KCO (5.25 g, 37.3 mmol). After stirring for 16 h, the reaction mixture was diluted with HO (150 mL), and the resulting suspension was filtered. The cake was washed with HO and dried under high vacuum to give a yellow solid, which was suspended in PE:EA (60 mL, 2:1, v:v). The resulting suspension was sonicated for 30 min and filtered. The cake was dried under high vacuum to give 6-bromo-2-chloro-3-[(1-methylpyrazol-4-yl)methyl]quinazolin-4-one as a yellow solid (2.5 g, 51% yield). 1 H NMR(400MHz,DMSO-d6)δ ppm:8.21(d,J=2.4Hz,1H),8.01(dd,J=2.4,8.4Hz,1H),7.76(s,1H),7.58(d,J=8.4Hz,1H),7.48(s,1H),5.21(s,2H),3.77(s,3H).MS m / z(+ESI):353.0,355.0 [M+H] + .

[0193] Step 4: Preparation of 6-bromo-2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-3-[(1-methylpyrazol-4-yl)methyl]-1H-quinazolin-4-one: To a stirred solution of 6-bromo-2-chloro-3-[(1-methylpyrazol-4-yl)methyl]quinazolin-4-one (200 mg, 0.51 mmol) in DMA (5 mL) was added O-[(2,4-dimethylthiazol-5-yl)methyl]hydroxylamine (180 mg, 1.02 mmol), followed by TEA (290 μL, 2.04 mmol). After stirring at 100° C. for 3 hours, the reaction mixture was diluted with HO (50 mL) and the resulting suspension was filtered. The cake was washed with HO and dried under high vacuum to give 6-bromo-2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-3-[(1-methylpyrazol-4-yl)methyl]-1H-quinazolin-4-one as a yellow solid (220 mg, 82% yield), which was used in the next step without further purification. MS m / z(+ESI): 475.0, 477.0 [M+H] + .

[0194] Step 5: Preparation of 6-benzylsulfanyl-2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-3-[(1-methylpyrazol-4-yl)methyl]-1H-quinazolin-4-one: To a stirred solution of 6-bromo-2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-3-[(1-methylpyrazol-4-yl)methyl]-1H-quinazolin-4-one (650 mg, 1.23 mmol) in Diox (30 mL) was added benzyl mercaptan (221 μL, 1.84 mmol), followed by Xant-Phos (145 mg, 0.24 mmol), Pd(dba) (115 mg, 0.12 mmol), and DIPEA (415 μL, 2.46 mmol). After stirring at 100°C for 2 hours, the reaction mixture was concentrated and purified by column chromatography (silica gel; PE:EA; 1:1; v:v) to give 6-benzylsulfanyl-2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-3-[(1-methylpyrazol-4-yl)methyl]-1H-quinazolin-4-one as a yellow solid (530 mg, 75% yield). 1H NMR(400MHz,DMSO-d6)δ ppm:10.35(s,1H),7.70(d,J=2.0Hz,1H),7.48(dd,J=2.0,8.4Hz,1H),7.45(s,1H),7.30(m,2H),7.25 (m,4H),7.21(m,1H),5.11(s,2H),4.78(s,2H),4.15(s,2H),3.72(s,3H),2.56(s,3H),2.35(s,3H).MS m / z(+ESI):519.2 [M+H] + .

[0195] Step 6: Preparation of 2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonyl chloride: To a stirred solution of 6-benzylsulfanyl-2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-3-[(1-methylpyrazol-4-yl)methyl]-1H-quinazolin-4-one (300 mg, 0.52 mmol) in AcOH (3 mL) and HO (1 mL) was added NCS (293 mg, 2.08 mmol). After stirring for 2 h, the reaction mixture was diluted with EA (20 mL), dried over NaSO, filtered, and concentrated to give 2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonyl chloride as a yellow oil (260 mg, 40% yield), which was used in the next step without further purification. MS m / z(+ESI): 495.1, 497.1 [M+H] + .

[0196] Step 7: Preparation of 2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide: The title compound was prepared as a white solid (17 mg, 14% yield) according to Scheme 1 and analogously to Example 1 (Step 5) using 2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonyl chloride (260 mg, 0.21 mmol) as starting material. 1 H NMR(400MHz,DMSO-d6+D2O)δ ppm:8.18(d,J=2.4Hz,1H),7.84(dd,J=2.4,8.8Hz,1H),7.47(m,2H),7.32(s,1H),5.13(s,2H) ,4.80(s,2H),3.72(s,3H),2.56(s,3H),2.35(s,3H),1.02(s,3H),0.56(m,2H),0.35(m,2H).MS m / z(+ESI):530.4 [M+H] + .

[0197] Example 5: Preparation of 4-[2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]-N,N-dimethyl-benzamide [ka] To a stirred solution of 8-chloro-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide (120 mg, 0.25 mmol) in Diox (1.5 mL) and HO (0.3 mL) was added [4-(dimethylcarbamoyl)phenyl]boronic acid (60 mg, 0.30 mmol), followed by KPO (163 mg, 0.76 mmol), Pd(PPh) (45 mg, 0.04 mmol), and PdCl(dppf) (28 mg, 0.04 mmol). After stirring at 95 °C for 4 h, the reaction mixture was filtered. The filtrate was concentrated and purified by preparative HPLC to give 4-[2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]-N,N-dimethyl-benzamide as a white solid (38 mg, 26% yield). 1 H NMR(400MHz,DMSO-d6+D2O)δ ppm:8.28(d,J=2.0Hz,1H),7.83(d,J=2.0Hz,1H),7.69(s,1H),7.62(m,4H),7.43(s,1H),4.82(s, 2H),3.75(s,3H),3.69(s,3H),3.01(s,3H),2.94(s,3H),1.08(s,3H),0.62(m,2H),0.40(m,2H).MS m / z(+ESI):566.4 [M+H] + .

[0198] Examples 7 and 8: Preparation of 2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-3-methylpiperazin-1-yl]-1H-quinazoline-6-sulfonamide, and 2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-3-methyl-4-(1-methylcyclopropanecarbonyl)piperazin-1-yl]-1H-quinazoline-6-sulfonamide: [ka]

[0199] Step 1: Preparation of 5-bromo-3-fluoro-2-nitro-benzoic acid: To a stirred solution of 2-amino-5-bromo-3-fluoro-benzoic acid in TFA (10 mL) was added 30% aqueous HO (5.9 mL, 58.0 mmol). After stirring at 60 °C for 2 h, the reaction mixture was quenched by the addition of aqueous NaHSO at 0 °C, concentrated, and purified by Biotage combiflash to give 5-bromo-3-fluoro-2-nitro-benzoic acid as a yellow solid (1.52 g, 63% yield). 1 H NMR(400MHz,DMSO-d6)δ ppm:8.31(dd,J=9.2Hz,2.0Hz,1H),7.98(t,J=1.6Hz,1H).MS m / z(+ESI):263.9,265.9 [M+H] + .

[0200] Step 2: Preparation of 3-[(3R)-4-benzyloxycarbonyl-3-methyl-piperazin-1-yl]-5-bromo-2-nitro-benzoic acid: To a stirred solution of 5-bromo-3-fluoro-2-nitro-benzoic acid (100 mg, 0.34 mmol) in EtOH (1 mL) was added benzyl (2R)-2-methylpiperazine-1-carboxylate (416 mg, 1.70 mmol). After stirring at 115° C. for 2 h, the reaction mixture was concentrated and purified by Biotage combiflash to give 3-[(3R)-4-benzyloxycarbonyl-3-methyl-piperazin-1-yl]-5-bromo-2-nitro-benzoic acid as a yellow solid (160 mg, 88% yield). 1 H NMR(400MHz,DMSO-d6)δ ppm:14.28(br,1H),7.98(d,J=2.0Hz,1H),7.87(d,J=2.0Hz,1H),7.36(m,5H),5.10( m,2H),4.25(m,1H),3.86(m,1H),3.08(m,1H),2.93(m,4H),1.14(d,J=6.8Hz,3H).MS m / z(+ESI):476.4,478.4 [M+H]+ .

[0201] Step 3: Preparation of 2-amino-3-[(3R)-4-benzyloxycarbonyl-3-methyl-piperazin-1-yl]-5-bromo-benzoic acid: To a stirred solution of 3-[(3R)-4-benzyloxycarbonyl-3-methyl-piperazin-1-yl]-5-bromo-2-nitro-benzoic acid (150 mg, 0.28 mmol) in THF (2 mL) and AcOH (1 mL) was added Zn (186 mg, 2.82 mmol). After stirring for 16 h, the reaction mixture was diluted with THF and filtered. The filtrate was concentrated and purified by Biotage combiflash to give 2-amino-3-[(3R)-4-benzyloxycarbonyl-3-methyl-piperazin-1-yl]-5-bromo-benzoic acid as a yellow solid (110 mg, 78% yield). 1 H NMR(400MHz,DMSO-d6)δ ppm:7.61(d,J=2.0Hz,1H),7.38(m,4H),7.33(m,1H),7.17(d,J=2.0Hz,1H),5.11(m,2H),4.30(m ,1H),3.85(m,1H),3.38(m,1H),2.83(m,1H),2.83(m,2H),2.46(m,1H),1.32(d,J=6.8Hz,3H).MS m / z(+ESI):448.2,450.2 [M+H] + .

[0202] Step 4: Preparation of benzyl (2R)-4-[2-amino-5-bromo-3-[(1-methylpyrazol-4-yl)methylcarbamoyl]phenyl]-2-methyl-piperazine-1-carboxylate: To a stirred solution of 2-amino-3-[(3R)-4-benzyloxycarbonyl-3-methyl-piperazin-1-yl]-5-bromo-benzoic acid (1.25 g, 2.51 mmol) in DMF (8 mL) was added (1-methylpyrazol-4-yl)methanamine (563 mg, 5.02 mmol), followed by HATU (1.28 g, 3.26 mmol) and DIPEA (1.3 mL, 7.53 mmol). After stirring for 4 h, the reaction mixture was concentrated and purified by Biotage combiflash to give benzyl (2R)-4-[2-amino-5-bromo-3-[(1-methylpyrazol-4-yl)methylcarbamoyl]phenyl]-2-methyl-piperazine-1-carboxylate as a white solid (1.18 g, 78% yield). 1 H NMR(400MHz,DMSO-d6)δ ppm:8.72(t,J=5.6Hz,1H),7.58(s,1H),7.48(d,J=2.0Hz,1H),7.35(m,6H),7.09(d,J=2.0Hz,1H),6.28(s,2H),5.10(m,2H),4.29(m MS m / z(+ESI):541.2,543.2 [M+H] + .

[0203] Step 5: Preparation of benzyl (2R)-4-[6-bromo-2-chloro-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-quinazolin-8-yl]-2-methyl-piperazine-1-carboxylate: To a stirred solution of benzyl (2R)-4-[2-amino-5-bromo-3-[(1-methylpyrazol-4-yl)methylcarbamoyl]phenyl]-2-methyl-piperazine-1-carboxylate (105 mg, 0.17 mmol) in Diox (4 mL) was added thiophosgene (81 mg, 0.70 mmol). After stirring for 1 h at rt and 1 h at 105 °C, the reaction mixture was concentrated and purified by Biotage combiflash to give benzyl (2R)-4-[6-bromo-2-chloro-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-quinazolin-8-yl]-2-methyl-piperazine-1-carboxylate as a yellow solid (87 mg, 76% yield). 1 H NMR(400MHz,DMSO-d6)δ ppm:7.75(m,2H),7.47(s,1H),7.35(m,6H),5.19(s,2H),5.11(m,2H),4.29(m,1H),3.92(m,1) H),3.78(m,1H),3.77(s,3H),3.48(m,1H),3.27(m,1H),2.82(m,2H),1.37(d,J=6.8Hz,3H).MS m / z(+ESI):584.9,586.8 [M+H] + .

[0204] Steps 6-9: Preparation of benzyl (2R)-4-[2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]piperazine-1-carboxylate: The title compound was prepared as a pale yellow solid according to Scheme 1 and analogously to Example 3 (steps 4-7) using benzyl (2R)-4-[6-bromo-2-chloro-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-quinazolin-8-yl]-2-methyl-piperazine-1-carboxylate, benzyl mercaptan, methoxyamine hydrochloride, and 1-methylcyclopropanamine hydrochloride as starting materials. 1H NMR(400MHz,DMSO-d6)δ ppm:8.59(s,1H),8.03(d,J=2.0Hz,1H),8.01(s,1H),7.73(d,J=2.0Hz,1H ),7.69(s,1H),7.43(s,1H),7.36(m,5H),5.12(m,2H),4.82(m,2H),4.35( m,1H),4.00(m,1H),3.82(s,3H),3.76(s,3H),3.28(m,1H),2.94(m,3H),2 .73(m,1H),1.40(d,J=6.8Hz,3H),1.03(s,3H),0.58(m,2H),0.37(m,2H). MS m / z(+ESI):651.0 [M+H] + .

[0205] Step 10: Preparation of 2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-3-methylpiperazin-1-yl]-1H-quinazoline-6-sulfonamide: To a stirred solution of benzyl (2R)-4-[2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]piperazine-1-carboxylate (350 mg, 0.48 mmol) in EtOH (5 mL) and EA (5 mL) was added 10% Pd / C (200 mg, 0.19 mmol), followed by 37% aqueous HCl (1.4 mL, 16.8 mmol). After stirring under a hydrogen stream for 24 h, the reaction mixture was diluted with MeOH / DCM (10 / 1, v / v) and filtered. The filtrate was concentrated and purified by preparative HPLC to give 2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-3-methylpiperazin-1-yl]-1H-quinazoline-6-sulfonamide as a pale yellow solid (124 mg, 45% yield). 1H NMR(400MHz,DMSO-d6+D2O)δ ppm:8.01(d,J=2.0Hz,1H),7.69(d,J=2.0Hz,1H),7.67(s,1H),7.42(s,1H),4.81(s,2H),3.83(s,3H),3.74(s,3H) ,3.19(m,2H),3.01(m,3H),2.81(m,1H),2.62(m,1H),1.16(d,J=6.4Hz,3H),1.01(s,3H),0.57(m,2H),0.37(m,2H). MS m / z(+ESI):517.4 [M+H] + .

[0206] Step 11: Preparation of 2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-3-methyl-4-(1-methylcyclopropanecarbonyl)piperazin-1-yl]-1H-quinazoline-6-sulfonamide: To a stirred solution of 2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-3-methylpiperazin-1-yl]-1H-quinazoline-6-sulfonamide (90 mg, 0.16 mmol) in DMF (5 mL) was added 1-methylcyclopropanecarboxylic acid (32 mg, 0.31 mmol), followed by EDCI (62 mg, 0.31 mmol) and HOBt (44 mg, 0.31 mmol). After stirring for 3 h, the reaction mixture was concentrated and purified by preparative HPLC to give 2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-3-methyl-4-(1-methylcyclopropanecarbonyl)piperazin-1-yl]-1H-quinazoline-6-sulfonamide as a white solid (28 mg, 29% yield). 1H NMR(400MHz,DMSO-d6+D2O)δ ppm:8.03(d,J=2.0Hz,1H),7.76(d,J=2.0Hz,1H),7.69(s,1H),7.43(s,1H),4.82(s,2H),4.61(m,1H),4.26(m,1H),3.82(s, 3H),3.76(s,3H),2.96(m,3H),2.67(m,2H),1.41(br,3H),1.25(s,3H),1.01(s,3H),0.83(m,2H),0.57(m,4H),0.37(m,2H). MS m / z(+ESI):599.5 [M+H] + .

[0207] Example 12: Preparation of (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-4-acetyl-3-methyl-piperazin-1-yl]-1H-quinazoline-6-sulfonamide [ka] To a solution of (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-3-methylpiperazin-1-yl]-1H-quinazoline-6-sulfonamide (74 mg, 0.13 mmol) in THF (2 mL) was added acetic anhydride (66 mg, 0.64 mmol). The reaction solution was stirred at 30° C. for 1 hour. The reaction solution was directly purified by preparative HPLC (ACN / HO-0.1% HCOOH) to give the desired product as a white solid (32 mg, 44% yield). 1H NMR(400MHz,DMSO-d6+ D2O)δ ppm:8.04(d,J=2.0Hz,1H),7.71(d,J=2.0Hz,1H),7.70(s,1H),7.44(s,1H),4.83(s,2H),4.68 and 4.20(2m,1H),4.39 and 2.61(2m,1H),3.82(s,3H) ,3.77(s,3H),3.46(m,1H),2.96(m,3H),2.77(m,1H),2.06 and 2.04(2s,3H ), 1.46 and 1.34 (2d, J=6.8Hz, 3H), 1.03 (s, 3H), 0.58 (m, 2H), 0.37 (m, 2H). MS m / z(+ESI):559.3 [M+H] + .

[0208] Example 13: Preparation of (R,E)-2-(methoxyimino)-8-(6-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide / (R,E)-2-(methoxyimino)-8-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide [ka]

[0209] Step 1: tert-butyl (R)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate / tert-butyl (R)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate: Under an argon atmosphere, NaHMDS (2.8 mL, 5.6 mmol, 2 M solution in THF) was added dropwise to a stirred solution of 1,1-dimethylethyl (2R)-2-methyl-4-oxo-1-piperidinecarboxylate (600 mg, 2.76 mmol) in dry THF (20 mL) at −78° C. The solution was stirred at −78° C. for 30 minutes and then treated with a solution of 1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide (2.0 g, 5.5 mmol) in dry THF (10 mL). The reaction solution was allowed to warm slowly to room temperature and stirred for an additional 2 hours. The reaction was quenched with aqueous NH4Cl solution and then extracted twice with EA. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under vacuum. The residue was purified by Biotage Combiflash (0-10% EA in PE, recovery: 5% EA in PE) to give the title compound as a colorless oil (840 mg, 88% yield, mixture of isomers). 1 H NMR(400MHz,CDCl3)δ ppm:5.75(m,1H),4.68(m,1H),4.43(m,0.6H),4.25(m,0.4H),3.65(m,0.6H),3.00(m,0.4H),2.81(m,0. 6H), 2.59 (m, 0.4H), 2.22 (m, 0.4H), 2.08 (m, 0.6H), 1.49 and 1.48 (2s, 9H), 1.25 and 1.19 (2d, J=6.8Hz, 3H).

[0210] Step 2: tert-butyl (R)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate / tert-butyl (R)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate: To a solution of a mixture of tert-butyl (R)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate and tert-butyl (R)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (0.84 g, 2.43 mmol) in 1,4-dioxane (10 mL) was added potassium acetate (386 mg, 3.89 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (756 mg, 2.92 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride (72 mg, 0.10 mmol). The suspension was degassed and filled with N gas, then stirred at 100° C. for 2 h. The reaction suspension was concentrated in vacuo. The residue was directly purified by Biotage Combiflash (ACN / HO and 0.1% HCOOH; recovery: 80% ACN in HO) to give the desired product as a brown oil (455 mg, 58% yield, mixture of isomers). 1 H NMR(400MHz,CDCl3)δ ppm:6.43(m,1H),4.46(m,1H),4.21(m,0.55H),4.06(m,0.45H),3.61(m,0.55H),2.75(m,0.55H),2.43 (m,0.45H),2.15(m,1H),2.05(m,0.45H),1.46(s,9H),1.26(s,12H),1.18 and 1.06(2d,J=6.8Hz,3H).MS m / z(+ESI):324.2[M+H] + ;268.1[M+H- t Bu] + .

[0211] Step 3: tert-butyl (2R)-2-methyl-4-[(2E)-2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylate / tert-butyl (6R)-4-[(2E)-2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]-6-methyl-3,6-dihydro-2H-pyridine-1-carboxylate: To a solution of (2E)-8-bromo-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide (300 mg, 0.54 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added tert-butyl (2R)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate and tert-butyl A mixture of (6R)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (421 mg, 1.30 mmol), potassium phosphate tripotassium (351 mg, 1.63 mmol), 2-(dicyclohexylphosphino)-2',4',6'-tri-i-propyl-1,1'-biphenyl (53 mg, 0.11 mmol), and dipalladium-tris(dibenzylideneacetone) chloroform complex (57 mg, 0.05 mmol) was added. The resulting solution was degassed and backfilled with N gas, then stirred at 75 °C for 3.5 hours. The suspension was concentrated to dryness under vacuum. The residue was purified by Biotage Combiflash (10-80% EA in PE, recovery: 60% EA in PE) to give the desired product as a yellow solid (150 mg, 45% yield, mixture of isomers). 1 H NMR(400MHz,DMSO-d6)δ ppm:8.58(s,0.6H,N H,isomer2),8.34(s,0.4H,N H ,isomer 1),8.18(d,J=2.0Hz,0.4H,isomer 1),8.17(d,J=2.0Hz,0.6H,isomer 2),8.06(s,0.4H,SO2N H , Isomer 1), 8.03(s, 0.6H, SO2N H ,isomer 2),7.76(d,J=2.0Hz,0.6H,isomer 2),7.70(m,1.4H),7.43(s,1H),6.06(m,0.6H,isomer 2),6.03(m,0.4H,isomer 1),4 .82(s,2H),4.53(m,1H),4.28(m,0.4H,isomer 1),4.09(m,0.6H,isomer 2),3.81(s,1.8H,isomer 2),3.80(s,1.2H,isomer 1),3. 77(s,3H),3.70(m,0.6H,isomer 2),3.04(m,0.4H,isomer 1),2.71(m,0.4H,isomer 1),2.54(m,0.6H,isomer 2),2.09(m,1H),1.4 5(s,9H),1.25(d,J=6.8Hz,1.8H,isomer 2),1.25(d,J=6.8Hz,1.2H,isomer 1),1.06(s,3H),0.60(m,2H),0.39(m,2H).MS m / z(+ESI):614.3 [M+H] + .

[0212] Step 4: (2E)-2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-quinazoline-6-sulfonamide / (2E)-2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(6R)-6-methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-quinazoline-6-sulfonamide: tert-Butyl (2R)-2-methyl-4-[(2E)-2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylate in DCM (9 mL) To a solution of a mixture of (6R)-6-methyl-4-[(2E)-2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (117 mg, 0.19 mmol) was added trifluoroacetic acid (9 mL, 115 mmol), and the reaction was then stirred for 1 hour at 25° C. The volatiles were removed in vacuo to give the crude product, which was purified by preparative HPLC (ACN / HO and 0.1% HCOOH) to give the product as a white solid (42 mg, 43.0% yield, mixture of isomers). 1 H NMR(400MHz,DMSO-d6+D2O)δ ppm:8.26(s,0.8H,HCOOH),8.18(d,J=2.0Hz,1H),7.77(d,J=2.0Hz,0.64H),7.73(d,J=2.0Hz,0.36H),7.70(s,1H ),7.44(s,1H),6.07(m,0.36H),5.97(m,0.64H),4.82(s,2H),3.82(s,1.1H),3.81(s,1.9H),3.77(s,3H),3.65(m, 0.64H),3.55(m,1H),3.22(m,0.64H),3.08(m,0.36H),2.97(m,0.64H),2.32(m,1H),2.8(m,0.36H),2.14(m,0.36H) ),1.24(d,J=6.8Hz,1.9H),1.19(d,J=6.8Hz,1.1H),1.06(s,3H),0.60(m,2H),0.39(m,2H);Mixture of two isomers (approximately 36:64). MS m / z(+ESI):514.5 [M+H] + .

[0213] Example 14: Preparation of (E)-4-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-N,N,2-trimethylbenzamide [ka] (2E)-8-chloro-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide (100 mg, 0.21 mmol), tripotassium phosphate (226 mg, 1.05 mmol), 2-dicyclohexylphosphino-2',4', To a stirred solution of 6'-triisopropylbiphenyl (21 mg, 0.04 mmol) and dipalladium-tris(dibenzylideneacetone) chloroform complex (22 mg, 0.02 mmol) at 25 °C was added N,N,2-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide ester (303 mg, 1.05 mmol). The reaction solution was degassed and backfilled with N gas and then stirred at 85 °C for 2 h. The reaction was cooled to room temperature and then filtered. The filtrate was subjected to preparative HPLC purification to give the desired product as a white solid (39 mg, 32% yield). 1 H NMR(400MHz,DMSO-d6+ D2O)δ ppm:8.28(d,J=2.0Hz,1H),7.84(d,J=2.0Hz,1H),7.70(s,1H),7.47(s,1H),7.44(s,1H),7.40(m,2H),4.82(s ,2H),3.77(s,3H),3.71(s,3H),3.04(s,3H),2.79(s,3H),2.28(s,3H),1.09(s,3H),0.63(m,2H),0.41(m,2H). MS m / z(+ESI):580.5 [M+H] + .

[0214] Example 20: Preparation of (E)-6-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-N,N-dimethylnicotinamide Step 1: (2E)-N,N-dimethyl-6-(tributylstannyl)nicotinamide: [ka] To a solution of 6-bromo-N,N-dimethyl-pyridine-3-carboxamide (1.30 g, 4.82 mmol) in 1,4-dioxane (6 mL) was added lithium chloride (1.24 g, 28.9 mmol), tricyclohexylphosphine (418 mg, 1.45 mmol), tris(dibenzylideneacetone)dipalladium-chloroform adduct (451 mg, 0.48 mmol), and hexabutyldistannane (2.98 mL, 5.79 mmol). The suspension was stirred at 125 °C for 2 h. This reaction suspension was combined with another batch and purified by Biotage Combiflash (elution with 0–100% EA in PE, recovery: 60% EA in PE) to give the desired product as a yellow oil (900 mg, 27.6% yield). 1 H NMR(400MHz,DMSO-d6)δ ppm:8.70(dd,J=2.0Hz,0.8Hz,1H),7.64(dd,J=7.6Hz,2.0Hz,1H),7.53(dd,J=7.6Hz,0.8Hz,1 H),2.99(s,3H),2.92(s,3H),1.53(m,6H),1.28(m,6H),1.08(m,6H),0.84(t,J=7.2Hz,9H).MS m / z(+ESI):441.1 [M+H] + .

[0215] Step 2: (E)-6-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-N,N-dimethylnicotinamide: A sealed tube was charged with (2E)-8-chloro-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide (100 mg, 0.21 mmol), N,N-dimethyl-6-tributylstannyl-pyridine-3-carboxamide (205 mg, 0.42 mmol), palladium(0) tetrakis(triphenylphosphine) (25 mg, 0.02 mmol), and THF (2 mL). The reaction solution was heated to 100 °C and stirred under a N atmosphere for 16 h. The reaction solution was directly purified by preparative HPLC eluting with MeOH / HO (0.1% HCOOH) to give the desired product as a yellow solid (21 mg, 17.4% yield). 1 H NMR(400MHz,DMSO-d6+ D2O)δ ppm:8.79(d,J=2.0Hz,1H),8.59(d,J=2.0Hz,1H),8.34(d,J=2.0Hz,1H),8.23(d,J=8.4Hz,1H),8.15(dd,J=8.4Hz,2.0Hz,1H),7.7 1(s,1H),7.45(s,1H),4.86(s,2H),3.90(s,3H),3.76(s,3H),3.04(s,3H),2.99(s,3H),1.06(s,3H),0.64(m,2H),0.40(m,2H).MS m / z(+ESI):567.4 [M+H] + .

[0216] Example 21: Preparation of (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-3,4-dimethylpiperazin-1-yl]-1H-quinazoline-6-sulfonamide [ka] To a solution of (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-3-methylpiperazin-1-yl]-1H-quinazoline-6-sulfonamide (120 mg, 0.21 mmol) in methanol (2 mL) was added sodium cyanoborohydride (69 mg, 1.05 mmol) and formaldehyde (85 mg, 1.05 mmol, 37% aqueous solution). The reaction solution was stirred at 25° C. for 1 hour. The reaction solution was directly purified by preparative HPLC (ACN / HO-0.1% HCOOH) to give the desired product as a white solid (44 mg, 38% yield). 1 H NMR(400MHz,DMSO-d6+ D2O)δ ppm:8.01(d,J=2.0Hz,1H),7.71(m,2H),7.44(s,1H),4.82(s,2H),3.85(s,3H),3.77(s,3H),2.89(m,4H) ,2.54(m,1H),2.35(m,2H),2.29(s,3H),1.06(d,J=6.4Hz,3H),1.02(s,3H),0.58(m,2H),0.37(m,2H).MS m / z(+ESI):531.4 [M+H] + .

[0217] Example 22: Preparation of (E)-8-(4-(1-hydroxy-2-oxocyclobutyl)phenyl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide [ka]

[0218] Step 1: tert-butyl N-[1-[4-[(2E)-2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]benzoyl]cyclopropyl]carbamate: To a solution of tert-butyl N-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]cyclopropyl]carbamate (654 mg, 1.01 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added (2E)-8-bromo-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide (140 mg, 0.25 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride (19 mg, 0.025 mmol), and potassium carbonate (78 mg, 0.56 mmol). The reaction solution was stirred at 75° C. under a N atmosphere for 2 hours. The solution was concentrated in vacuo, and the residue was diluted with 0 to 60% EA in PE (EA / PE=1 / 1, R f Purification by Biotage Combiflash eluting with 200 MPa (=0.5) gave the desired product as a brown solid (160 mg, 83.9% yield, 90%). 1 H NMR(400MHz,CDCl3)δ ppm:8.56(d,J=1.6Hz,1H),8.23(s,1H),7.92(m,2H),7.88(d,J=1.6Hz,1H),7.69(s,1H),7.58(s,1H),7.49(m,2H),5.30(br s,1H,BocN H ),4.96(s,2H),3.89(s,3H),3.80(s,3H),1.80(m,2H),1.27(m,11H),1.24(s,3H),0.80(m,2H),0.51(m,2H).MS m / z(+ESI):678.1 [M+H] + .

[0219] Step 2: (2E)-8-[4-(1-hydroxy-2-oxo-cyclobutyl)phenyl]-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide: To a solution of tert-butyl N-[1-[4-[(2E)-2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]benzoyl]cyclopropyl]carbamate (160 mg, 0.21 mmol) in DCM (1 mL) was added trifluoroacetic acid (1.49 g, 13.1 mmol) at 25 °C. The solution was stirred at 25 °C for 0.5 h. The reaction solution was concentrated in vacuo, and the residue was purified by preparative HPLC eluting with ACN / HO (0.1% HCOOH). The collected fractions were allowed to stand at room temperature for 24 h and then lyophilized to give product 22 (22 mg, 17.2% yield). 1 H NMR(400MHz,DMSO-d6+ D2O)δ ppm:8.27(d,J=2.0Hz,1H),7.79(d,J=2.0Hz,1H),7.68(m,3H),7.57(d,J=8.4Hz,2H),7.44(s,1H),4.82(s,2H),3. 76(s,3H),3.70(s,3H),3.11(m,1H),3.01(m,1H),2.66(m,1H),2.32(m,1H),1.08(s,3H),0.62(m,2H),0.39(m,2H). MS m / z(+ESI):579.3 [M+H] + .

[0220] Example 23: Preparation of (E)-5-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-N,N-dimethyl-1H-imidazole-2-carboxamide [ka]

[0221] Step 1: Ethyl (E)-4-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate: To a solution of (2E)-8-bromo-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide (400 mg, 0.72 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was added [2-ethoxycarbonyl-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]boronic acid (1.82 g, 2.90 mmol), potassium phosphate tripotassium (800 mg, 3.62 mmol), dipalladium-tris(dibenzylideneacetone) chloroform complex (76 mg, 0.07 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (71 mg, 0.15 mmol). The resulting solution was degassed and backfilled with N2 gas, then stirred for 1.5 h at 90° C. The reaction solution was directly purified by Biotage Combiflash eluting with ACN / HO (0.1% HCOOH) to give the desired product as a yellow solid (380 mg, 68.8% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm:12.54(s,1H),8.55(s,1H),8.32(d,J=2.0Hz,1H),8.20(d,J=2.0Hz,1H), 8.05(s,1H),7.72(s,1H),7.46(s,1H),5.81(s,2H),4.87(s,2H),4.43(q,J=7. 2Hz,2H),3.88(s,3H),3.77(s,3H),3.61(t,J=7.6Hz,2H),1.37(t,J=7.2Hz,3H ),1.08(s,3H),0.87(t,J=7.6Hz,2H),0.63(m,2H),0.38(m,2H),-0.06(s,9H). M.S. m / z(+ESI):687.5 [M+H] + .

[0222] Step 2: 4-[(2E)-2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxylic acid: To a solution of ethyl 4-[(2E)-2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxylate (200 mg, 0.26 mmol) in methanol (2 mL) and water (2 mL) was added sodium hydroxide (32 mg, 0.79 mmol). The solution was stirred for 16 hours at 25° C. The reaction solution was acidified with 1N HCl to pH=5 and then purified by Biotage Combiflash eluting with ACN / HO (0.1% HCOOH) to give the desired product as a yellow solid (160 mg, 74.1% yield). 1 H NMR(400MHz,DMSO-d6)δ ppm:13.06(s,1H),8.45(s,1H),8.32(d,J=2.0Hz,1H),8.17(d,J=1.6Hz,1H),8.03(s,1H),7.71(s,1H),7.45(s,1H),5.83(s,2H),4.8 6(s,2H),3.83(s,3H),3.77(s,3H),3.60(t,J=8.0Hz,2H),1.08(s,3H),0.87(t,J=8.0Hz,2H),0.63(m,2H),0.38(m,2H),-0.06(s,9H). MS m / z(+ESI):659.4 [M+H] + .

[0223] Step 3: (E)-4-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-N,N-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxamide: To a solution of 4-[(2E)-2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxylic acid (150 mg, 0.18 mmol) in DCM (1 mL) was added 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (107 mg, 0.27 mmol), Hunig's base (71 mg, 0.55 mmol), and dimethylamine (0.46 mL, 0.91 mmol, 2 M THF solution) at 25° C. The reaction solution was stirred for 2 hours at 25° C. The reaction solution was concentrated in vacuo and the residue was purified by Biotage Combiflash eluting with ACN / H2O (0.1% HCOOH) to give the desired product as a yellow solid (80 mg, 57.5% yield). 1 H NMR(400MHz,DMSO-d6)δ ppm:12.51(s,1H),8.37(s,1H),8.32(d,J=2.0Hz,1H),8.18(s,1H),8. 05(s,1H),7.71(s,1H),7.45(s,1H),5.60(s,2H),4.86(s,2H),3.86(s, 3H),3.77(s,3H),3.54(t,J=8.0Hz,2H),3.21(s,3H),3.09(s,3H),1.08 (s,3H),0.85(t,J=8.0Hz,2H),0.63(m,2H),0.39(m,2H),-0.06(s,9H). MS m / z(+ESI):686.1 [M+H] + .

[0224] Step 4: (E)-5-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-N,N-dimethyl-1H-imidazole-2-carboxamide: To a solution of 4-[(2E)-2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]-N,N-dimethyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (50 mg, 0.06 mmol) in DCM (1 mL) was added trifluoroacetic acid (0.83 mL, 10.9 mmol). The solution was stirred at 25° C. for 2 hours. The solution was concentrated in vacuo, and the residue was treated with methanol (2 mL) and 25% ammonium hydroxide (0.2 mL). The resulting solution was stirred at 25° C. for an additional 1 hour. The volatiles were removed in vacuo, and the residue was combined with another batch and purified by preparative HPLC eluting with ACN / H2O (0.1% HCOOH) to give the desired compound as a white solid (27 mg, 28.5% yield). 1 H NMR(400MHz,DMSO-d6+ D2O)δ ppm:8.34(d,J=2.0Hz,1H),8.17(d,J=2.0Hz,1H),8.09(s,1H),7.71(s,1H),7.46(s,1H),4.86(s, 2H),3.85(s,3H),3.76(s,3H),3.51(s,3H),3.08(s,3H),1.06(s,3H),0.63(m,2H),0.39(m,2H).MS m / z(+ESI):556.4 [M+H] + .

[0225] Example 24: Preparation of (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-4-piperidyl]-1H-quinazoline-6-sulfonamide [ka] To a solution of a mixture of (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-quinazoline-6-sulfonamide and (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(6R)-6-methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-quinazoline-6-sulfonamide (130 mg, 0.26 mmol) in ethyl acetate (3 mL) and ethanol (9 mL) was added platinum(IV) oxide (293 mg, 1.27 mmol). The suspension was stirred under a hydrogen balloon atmosphere for 24 h at 25 °C. The catalyst was removed by filtration. The filtrate was purified by preparative HPLC (ACN-HO and 0.1% TFA) and (ACN-HO and 0.1% HCOOH) to give the desired product as a white solid (46 mg, 34% yield). 1 H NMR (400MHz, DMSO-d + D2O) δ ppm:8.38(s,1H,HCOOH),8.16(d,J=2.0Hz,1H),7.78 and 7.74(2d,J=2.0Hz,1H , epimer), 7.69(s,1H),7.44(s,1H),4.84(s,2H),3.84 and 3.83(2s,3H,epimer),3. 76(s,3H),3.24(m,2H),3.11(m,1H),2.94(m,1H),1.86(m,2H),1.59(m,1H), 1.39(m,1H),1.17(d,J=6.4Hz,3H),1.02(s,3H),0.57(m,2H),0.36(m,2H).MS m / z(+ESI):516.4 [M+H] + .

[0226] Example 25: Preparation of (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-1,2-dimethyl-4-piperidyl]-1H-quinazoline-6-sulfonamide [ka] To a solution of (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-4-piperidyl]-1H-quinazoline-6-sulfonamide (120 mg, 0.17 mmol) in methanol (3 mL) was added formaldehyde (76 mg, 0.93 mmol, 37% aqueous solution) and sodium cyanoborohydride (37 mg, 0.56 mmol). The reaction solution was stirred at 25° C. for 1 hour. The reaction solution was directly purified by preparative HPLC (ACN / HO and 0.1% HCOOH) to give the desired product as a white solid (36 mg, 36% yield). 1 H NMR (400MHz, DMSO-d + D2O) δ ppm:8.22(s,1H,HCOOH),8.15(d,J=2.0Hz,1H),7.80(d,J=2.0Hz,1H),7.69(s,1H) ,7.43(s,1H),4.83(s,2H),3.84 and 3.83(2s,3H,epimer),3.76(s,3H),2.98(m,2H),2 .69(m,1H),2.32(m,1H),2.29(s,3H),1.78(m,2H),1.64(m,1H),1.37(m,1H),1.14 and 1.08(2d,J=6.8Hz,3H),1.01 and 1.00(2s,3H,epimer),0.57(m,2H),0.36(m,2H).MS m / z(+ESI):530.5 [M+H] + .

[0227] Example 26: Preparation of (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-1-acetyl-2-methyl-4-piperidyl]-1H-quinazoline-6-sulfonamide [ka] To a solution of (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-4-piperidyl]-1H-quinazoline-6-sulfonamide (125 mg, 0.19 mmol) in THF (3 mL) was added acetic anhydride (100 mg, 0.97 mmol). The reaction solution was stirred at 25° C. for 2 hours. The reaction solution was directly purified by preparative HPLC eluting with MeOH / HO (0.1% HCOOH) to give the desired product as a white solid (29 mg, 26% yield). 1 H NMR(400MHz,DMSO-d6+D2O)δ ppm:8.15(d,J=2.0Hz,1H),7.83(d,J=2.0Hz,1H),7.69(s,1H),7.43(s,1H),4.83(s,2H),4.17(m,1H),3.84(s,3H),3.76(s,3H),3.28(m,1H) ,3.12(m,2H),2.22(m,1H),2.04(s,3H),1.87(m,1H),1.73(m,1H),1.4 4(m,1H),1.14(d,J=6.4Hz,3H),1.01(s,3H),0.58(m,2H),0.37(m,2H). MS m / z(+ESI):558.5 [M+H] + .

[0228] Example 27: Preparation of (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-1-(1-methylcyclopropanecarbonyl)-4-piperidyl]-1H-quinazoline-6-sulfonamide [ka] To a solution of (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-4-piperidyl]-1H-quinazoline-6-sulfonamide (150 mg, 0.23 mmol) in DMF (6 mL) was added 1-methylcyclopropanecarboxylic acid (37 mg, 0.35 mmol), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (137 mg, 0.35 mmol), and Hunig's base (91 mg, 0.70 mmol). The solution was stirred at 25° C. for 2 hours. The reaction solution was directly purified by preparative HPLC (ACN-H2O and 0.1% HCOOH) to give the desired product as a white solid (65 mg, 46% yield). 1 H NMR (400 MHz, DMSO-d6 + DO) δ ppm: 8.14 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.69 and 7.68 (2s, 1H, epimer), 7.44 and 7.43 (2s, 1H, epimer), 4.83 and 4.82 (2s, 2H, epimer), 4.74 and 4.32 (m, 1H, epimer), 4.21 (m, 1H), 4.05 (m, 1H), 3.84 and 3.81 (2s, 3H, epimer), 3.76 and and 3.75 (2s, 3H, epimer), 3.10 (m, 1H), 2.32 (m, 1H), 1.91 (m, 1H), 1.76 (m, 1H), 1.38 (m, 1H), 1.27 and 1.23 (2s, 3H, epimer), 1.12 (d, J = 6.4 Hz, 3H), 1.01 and 0.98 (2s, 3H, epimer), 0.88 (m, 1H), 0.75 (m, 1H), 0.57 (m, 4H), 0.36 (m, 2H). MS m / z (+ESI): 598.6 [M+H] + .

[0229] Example 28: Preparation of (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-1,2-dimethyl-3,6-dihydro-2H-pyridin-4-yl]-1H-quinazoline-6-sulfonamide / (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(6R)-1,6-dimethyl-3,6-dihydro-2H-pyridin-4-yl]-1H-quinazoline-6-sulfonamide [ka] (2E)-2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-quinazoline-6-sulfonamide and (2E)-2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-quinazoline-6-sulfonamide in methanol (5 mL). To a solution of a mixture of [(6R)-6-methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-quinazoline-6-sulfonamide (50 mg, 0.097 mmol), formaldehyde (20 mg, 0.24 mmol, 37% aqueous solution) and sodium cyanoborohydride (6 mg, 0.097 mmol) were added. The reaction was stirred for 1 hour at 25° C. The reaction solution was purified by preparative HPLC (ACN / HO and 0.1% HCOOH) to give the desired product as a white solid (22 mg, 43% yield). 1H NMR(400MHz,DMSO-d6+D2O)δ ppm:8.18(m,1H),8.16(s,0.7H,HCOOH),7.78(d,J=2.0Hz,0.57H),7.73(d,J=2.0Hz,0.43H),7.70(s,1H),7. 44(s,1H),6.00(m,0.43H),5.90(m,0.57H),4.82(s,2H),3.82(s,1.3H),2.81(s,1.7H),3.77(s,3H),3.36(m ,0.6H),3.15(m,0.4H),2.99(m,1H),2.82(m,0.4H),2.58(m,0.6H),2.47-2.30(m,1.6H),2.16(m,0.4H),1.2 2(d,J=6.8Hz,1.7H),1.12(d,J=6.8Hz,1.3H),1.06(s,3H),0.60(m,2H),0.39(m,2H);Mixture of two isomers (approximately 40:60). MS m / z(+ESI):528.3 [M+H] + .

[0230] Example 29: Preparation of (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-1-acetyl-2-methyl-3,6-dihydro-2H-pyridin-4-yl]-1H-quinazoline-6-sulfonamide / (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(6R)-1-acetyl-6-methyl-3,6-dihydro-2H-pyridin-4-yl]-1H-quinazoline-6-sulfonamide [ka] To a solution of a mixture of (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-quinazoline-6-sulfonamide and (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(6R)-6-methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-quinazoline-6-sulfonamide (50 mg, 0.097 mmol) in THF (5 mL) was added acetic anhydride (15 mg, 0.14 mmol), and the reaction was then stirred for 1 h at 25° C. The reaction solution was purified by preparative HPLC (ACN / H2O and 0.1% HCOOH) to give the desired product as a white solid (22 mg, 41% yield). 1 H NMR(400MHz,DMSO-d6+D2O)δ ppm:8.18(d,J=2.0Hz,0.4H,isomer 1),8.16(d,J=2.0Hz,0.6H,isomer 2),7.74(m,0.6H,isomer 2),7.69(m,1.4H),7.43(s,1) H),6.06(m,0.6H,isomer 2),6.03(m,0.4H,isomer 1),4.91(m,0.4H,isomer 1),4.82(s,2H),4.57(m,0.6H,isomer 2),4.33(m,0.4 H, isomer 1), 3.92 (m, 0.6H, isomer 2), 3.80 (m, 3H), 3.76 (s, 3H), 3.55-3.30 (m, 1H, overlaps with the top of H2O), 2.83 (m, 0.4H), 2.67 (m, 0. 6H),2.07(m,4H),1.35-1.15(4d,J=6.8Hz,3H,isomer),1.05(s,3H),0.59(m,2H),0.38(m,2H);Mixture of two isomers (approximately 40:60). MS m / z(+ESI):556.3 [M+H] + .

[0231] Example 30: Preparation of (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-1-(1-methylcyclopropanecarbonyl)-3,6-dihydro-2H-pyridin-4-yl]-1H-quinazoline-6-sulfonamide / (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(6R)-6-methyl-1-(1-methylcyclopropanecarbonyl)-3,6-dihydro-2H-pyridin-4-yl]-1H-quinazoline-6-sulfonamide [ka] (2E)-2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-quinazoline-6-sulfonamide and (2E)-2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(6R)-6-methyl-1,2,3,6 To a solution of a mixture of [-tetrahydropyridin-4-yl]-1H-quinazoline-6-sulfonamide (70 mg, 0.14 mmol), 1-methylcyclopropanecarboxylic acid (14 mg, 0.14 mmol), N-hydroxybenzotriazole (HOBt) (28 mg, 0.20 mmol), Hunig's base (36 mg, 0.27 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (40 mg, 0.20 mmol) were added. The reaction was then stirred for 1 hour at 25° C. The reaction solution was directly purified by preparative HPLC (ACN / HO and 0.1% HCOOH) to give the desired product as a white solid (37 mg, 44% yield). 1H NMR(400MHz,DMSO-d6+D2O)δ ppm:8.19(d,J=2.0Hz,0.42H,isomer 1),8.18(d,J=2.0Hz,0.58H,isomer 2),7.80(d,J=2.0Hz,0.58H,isomer 2),7.73(d,J=2.0Hz,0.42 H, isomer 1), 7.70(s,1H),7.44(s,1H),6.09(m,0.58H,isomer 2),6.05(m,0.42H,isomer 1),4.86(m,1H),4.82(s,2H),4.63(m,0.42H,isomer 1), isomer 1), 4.36 (m, 0.58H, isomer 2), 3.81 (s, 1.7H, isomer 2), 3.80 (s, 1.3H, isomer 1), 3.77 (s, 3H), 3.38 (m, 1.42H, overlaps with the top of H2O), 2.75 (m, 0.5 8H, isomer 2), 2.10(m,1H), 1.28(m,6H), 1.06(s,3H), 0.93(m,1H), 0.78(m,1H), 0.60(m,4H), 0.39(m,2H); mixture of two isomers (approximately 40:60). MS m / z(+ESI):596.4 [M+H] + .

[0232] Example 32: Preparation of (R,E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-8-(3-methyl-4-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperazin-1-yl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide [ka] To a stirred solution of 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (28.5 mg, 0.186 mmol) in DMF (3 mL) was added HATU (88 mg, 0.232 mmol) followed by DIPEA (59 mg, 0.464 mmol) at 0° C. The resulting reaction mixture was stirred at 0° C. for 5 minutes, after which (R,E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-8-(3-methylpiperazin-1-yl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (80 mg, 0.155 mmol) was added. The resulting reaction mixture was allowed to warm to room temperature and stirred for 6 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with cold water (2 x 5 mL), dried over anhydrous NaSO, filtered, and the filtrate was evaporated under reduced pressure to give the crude product, which was purified by preparative HPLC (10 mM NHHCO / ACN in HO) to give the desired product as an off-white solid (13.8 mg, 14% yield). 1 H NMR(400MHz,DMSO-d6)δ ppm:8.63(s,1H),8.04(d,J=1.6Hz,1H),8.01(s,1H),7.77(d,J=1.6Hz,1H),7.70(s ,1H),7.44(s,1H),4.87-4.79(m,2H),4.64(bs,1H),4.30-4.23(m,1H),3.83(s,3H), 3.77(s,3H),3.52-3.50(m,1H),2.99-2.96(m,3H),2.67-2.66(m,1H),1 .42-1.23(m,7H),1.03(s,3H),0.60-0.57(m,2H),0.38-0.36(m,2H).MS m / z(+ESI):651.3 [M+H] + .

[0233] Example 36: Preparation of (R,E)-8-(4-(3,3-difluoropyrrolidine-1-carbonyl)-3-methylpiperazin-1-yl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide [ka] To a stirred solution of (R,E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-8-(3-methylpiperazin-1-yl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (90 mg, 0.174 mmol) in DCM (2.5 mL) was added EtN (73 mg, 0.52 mmol) and triphosgene (64 mg, 0.203 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 5 minutes, followed by the addition of compound 3,3-difluoropyrrolidine (24 mg, 0.174 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 6 hours. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3×20 mL). The combined organic layers were washed with cold water (2 x 5 mL), dried over anhydrous NaSO, filtered, and the filtrate was evaporated under reduced pressure to give the crude product, which was purified by preparative HPLC (10 mM NHHCO / ACN in HO) to give the desired product as an off-white solid (9.0 mg, 8% yield). 1H NMR(400MHz,DMSO-d6)δ ppm:8.60(s,1H),8.03(d,J=1.6Hz,1H),8.00(s,1H),7.75(d,J=2.0Hz,1H),7.70(s ,1H),7.44(s,1H),4.82(s,2H),4.02-4.01(m,1H),3.83(s,3H),3.77-3.70(m,5H), 3.60-3.57(m,3H),3.36-3.26(m,1H),2.99-2.88(m,3H),2.76-2.72(m,1H),2.45-2 .32(m,2H),1.44-1.42(m,3H),1.03(s,3H),0.60-0.58(m,2H),0.38-0.36(m,2H).MS m / z(+ESI):650.5 [M+H] + .

[0234] Example 42: Preparation of (R,E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-8-(3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide [ka] To a stirred solution of (R,E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-8-(3-methylpiperazin-1-yl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (0.200 g, 0.368 mmol) and ethyl 2,2,2-trifluoroacetate (1.3 g, 9.67 mmol) in THF (4 mL) was added 1.0 M LiHMDS in THF (6.0 mL, 5.834 mmol) dropwise at −10° C. The reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with saturated brine solution (10 mL), dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (10 mM NHHCO / ACN in HO) to give the desired product as an off-white solid (10 mg, 4% yield). 1 H NMR(400MHz,DMSO-d6)δ ppm:8.60(brs,1H),8.04-8.00(m,2H),7.78(brs,1H),7.69(s,1H),7.43(s,1H),4.86-4.78(m,2H),4.65-4.26(m, 2H),3.82-3.68(m,7H),3.06-2.81(m,4H),1.60-1.48(m,3H),1.03(s,3H),0.60-0.59(m,2H),0.36-0.35(m,2H).MS m / z(+ESI):613.3 [M+H] + .

[0235] Intermediate used in the preparation of Examples 13 and 22: Preparation of (E)-8-bromo-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide: [ka]

[0236] Step 1: Preparation of 8-bromo-2-chloroquinazolin-4(3H)-one: To a stirred solution of 8-bromo-2,4-dichloroquinazoline (2.5 g, 8.7 mmol) in THF (15 mL) was added a solution of sodium hydroxide (0.87 g, 21.8 mmol) in water (20 mL) at 25 °C. The reaction suspension turned into a clear solution after 10 minutes. Stirring was continued for an additional 3 hours at 25 °C. The reaction solution was acidified with AcOH to pH = 5, and the resulting suspension was filtered off. The filter cake was rinsed with HO and dried under vacuum to give the target product as a pale yellow solid (2.04 g, 81.1% yield). MS m / z (+ESI): 259.0, 261.0 [M+H] + .

[0237] Step 2: Preparation of 8-bromo-2-chloro-3-((1-methyl-1H-pyrazol-4-yl)methyl)quinazolin-4(3H)-one: To a solution of 8-bromo-2-chloro-3H-quinazolin-4-one (6.4 g, 22.2 mmol) in NMP (100 mL) was added 4-(chloromethyl)-1-methyl-pyrazole (7.2 g, 44.4 mmol), potassium carbonate (9.4 g, 66.6 mmol), and Hunig's base (8.8 g, 66.6 mmol). The reaction solution was stirred at 25° C. for 16 hours. The reaction was diluted with EA and water. The organic phase was separated and evaporated under vacuum to give the crude product, which was purified by column chromatography eluting with PA / EA=1:1 to give the desired product as a white solid (6.0 g, 68% yield). 1 H NMR(400MHz,CDCl3)δ ppm:8.21(dd,J = 8.0Hz,1.2Hz,1H),8.02(dd,J=8.0Hz,1.2Hz,1H),7.64(s,1H),7.57(s,1H),7.35(t,J=8.0Hz,1H),5.54(s,2H),3.87(s,3H).MS m / z(+ESI):352.9 & 354.9 [M+H] + .

[0238] Step 3: (2E)-8-Bromo-2-methoxyimino-3-[(1-methylpyrazol-4-yl)methyl]-1H-quinazolin-4-one To a solution of 8-bromo-2-chloro-3-[(1-methylpyrazol-4-yl)methyl]quinazolin-4-one (6.0 g, 15.3 mmol) in DMA (100 mL) was added methoxyamine hydrochloride (3.3 g, 38.2 mmol) and triethylamine (6.3 g, 61.1 mmol). The reaction was heated to 100° C. for 3 hours. The reaction was poured into 500 mL of vigorously stirred water. The precipitated solid was collected by filtration, rinsed with water, and dried under vacuum to give the desired product as a white solid (6.0 g, 97.1% yield). 1 H NMR(400MHz,CDCl3)δ ppm:8.29(s,1H),8.01(dd,J = 8.0Hz,1.2Hz,1H),7.68(m,2H),7.57(s,1H),6.95(t,J=8.0Hz,1H),4.97(s,2H),3.95(s,3H),3.87(s,3H).MS m / z(+ESI):364.0,366.0 [M+H] + .

[0239] Step 4: (2E)-8-bromo-2-methoxyimino-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonyl chloride: In a sealed tube, a solution of (2E)-8-bromo-2-methoxyimino-3-[(1-methylpyrazol-4-yl)methyl]-1H-quinazolin-4-one (500 mg, 1.24 mmol) in chlorosulfonic acid (2.01 mL, 30.9 mmol) was stirred at 80° C. for 20 hours. The reaction solution was poured onto ice and then extracted with DCM. The organic layer was dried over anhydrous NaSO and used directly in the next step without further purification. MS m / z (+ESI): 461.8, 463.8 [M+H] + .

[0240] Step 5: (2E)-8-bromo-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide: To a suspension of 1-methylcyclopropylamine hydrochloride (489 mg, 4.46 mmol) in DCM (10 mL) was added triethylamine (1.26 mL, 8.92 mmol). After stirring for 10 min at 25° C., a solution of (2E)-8-bromo-2-methoxyimino-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonyl chloride (550 mg, 0.89 mmol) in DCM was added dropwise at 25° C. The reaction mixture was stirred for 1 h at 25° C. The crude product, combined with another batch, was diluted with 0-70% EA in PE (EA / PE=1 / 2, R f Purification by Biotage Combiflash eluting with 200 sachets (=0.2) gave the desired product as a yellow solid (600 mg, 81.3% yield). 1 H NMR(400MHz,DMSO-d6)δ ppm:8.41(s,1H,N H ),8.22(d,J = 1.6Hz,1H),8.19(s,1H,SO2N H ),8.15(d,J=1.6Hz,1H),7.70(s,1H),7.44(s,1H),4.83(s,2H),3.88(s,3H),3.77(s,3H),1.08(s,3H),0.60(m,2H),0.41(m,2H).MS m / z(+ESI):496.9,498.9 [M+H] + .

[0241] Intermediate used in the preparation of Example 22: Preparation of tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)cyclopropyl)carbamate: [ka] To a solution of tert-butyl N-[1-(4-chlorobenzoyl)cyclopropyl]carbamate (450 mg, 1.37 mmol) in 1,4-dioxane (5 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (710 mg, 2.74 mmol), potassium acetate (407 mg, 4.11 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (135 mg, 0.27 mmol), and dipalladium-tris(dibenzylideneacetone) chloroform complex (145 mg, 0.14 mmol). The suspension was degassed and backfilled with N gas and then stirred at 110 °C for 2 h. The suspension was concentrated under vacuum and the residue was diluted with 0-40% EA in PE (EA / PE=1 / 4, R f Purification by Biotage Combiflash eluting with 200 sachets (=0.5) gave the desired product as a brown oil (650 mg, 98.1% yield). 1 H NMR(400MHz,CDCl3)δ ppm:7.83(d,J=8.0Hz,2H),7.67(m,2H),5.24(br s,1H,N H ),1.72(m,2H),1.35(s,12H),1.26(m,11H).MS m / z(+ESI):288.2 [M+H-Boc] + & 332.1 [M+H- t Bu] + .

[0242] Preparation of Intermediate III used in the preparation of Example 18: (1-methylcyclopropyl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone: [ka] Under an argon atmosphere, bis(pinacolato)diboron (683 mg, 2.63 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride (98 mg, 0.13 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (129 mg, 0.26 mmol), and potassium acetate (392 mg, 3.95 mmol) were added to a suspension of (4-bromophenyl)-(1-methylcyclopropyl)methanone (350 mg, 1.32 mmol) in dioxane (5 mL). The suspension was stirred at 90°C for 2 hours under an argon atmosphere. The reaction suspension was used directly in the next step without any workup or purification. MS m / z (+ESI): 287.1 [M+H] + .

[0243] Biological Examples PARG enzyme assay Inhibition of PARG enzyme activity by compounds was determined as follows: Recombinant His-tagged human PARG protein expressed in Sf21 insect cells (Adipogen AG, #40T-0022) was aliquoted and stored at -80°C until use. The artificial enzyme substrate, 4-(trifluoromethyl)umbelliferone (TFMU)-ADPr, was prepared essentially as described (Drown BS et al., Cell Chemical Biology 2018) and stored at -20°C as a 10 mM stock solution in DMSO (dimethyl sulfoxide) until use. Typical final concentrations of enzyme and TFMU-ADPr for reactions were 1 nM and 200 μM, respectively. Reactions were performed in black 384-well low-volume round-bottom assay plates (Corning, #4514) in a final volume of 10 μL. For this purpose, PARG was diluted to 1.67 nM in reaction buffer (50 mM KHPO, 50 mM KCl, 10 mM β-mercaptoethanol, pH 7.4) and 6 μL was dispensed per assay well using a multichannel pipette. Compounds were then dispensed into each well using an Echo dispenser (Beckman Coulter) to obtain pre-specified final concentrations across the concentration range to be tested (typically eight consecutive concentrations ranging from 0.01 to 10 μM, 0.001 to 1 μM, or 0.0001 to 0.1 μM), volume-corrected with 100% DMSO (0.5% final DMSO concentration in the reaction mixture). The plate was mixed, and after 15 min, 4 μL of TFMU-ADPr was added to each well using a multichannel pipette, followed by gentle mixing. Fluorescence intensity signals were then measured after 30 minutes on an EnVision microplate reader (PerkinElmer) using 380 / 10 nm and 535 / 25 nm filters (gain: 150) for excitation and emission, respectively. The assay window was set using a DMSO control (top) and a control without PARG enzyme (bottom). Delta values were plotted as concentration-response curves fitted to a sigmoidal four-parameter logistic model to determine IC. 50 Values were calculated (Scigilian Analyze).

[0244] PARG NanoBRET-based cellular target binding assay PARG Nano-Luciferase Construct: The PARG-NanoLuc® fusion vector was generated by Promega by inserting the full-length human PARG cDNA sequence encoding a 976 amino acid protein (Gene ID: 8505, UniProt: Q86W56) into the pNLF1-C[CMV / Hygro] vector (C-terminal fusion with the NanoLuc® enzyme). PARG target-binding tracer synthesis: NanoBRET tracers for PARG were prepared according to a general tracer synthesis procedure previously reported. PARG probe displacement assay using NanoBRET: HEK293T (DSMZ#ACC 635) cells transiently transfected with PARG-NanoLuc fusion constructs were cultured in phenol red-free OptiMEM (Gibco#11058-021) at 2.4 × 10 5 The cells were resuspended to a concentration of 10 cells / mL, and 9 μL per well was then added to a white 384-well low volume microplate (Greiner #784080) and incubated under standard growth conditions for 24 hours. Compounds were then dispensed into each well using an Echo dispenser (BeckmanCoulter) to obtain pre-specified final concentrations in the concentration range to be tested (typically 8 consecutive concentrations ranging from either 0.01 to 10 μM, or 0.001 to 1 μM, or 0.0001 to 0.1 μM), volume-corrected with 100% DMSO (0.5% final DMSO concentration in the reaction mixture). After mixing and incubation at room temperature for 15 minutes, 1 μl of NanoBRET probe (final concentration 0.89 μM) was added to the microplate using a multichannel pipette. The plate was mixed and incubated for 2 hours at 37°C in a 5% CO2 environment. Then, 5 μL / well of a solution consisting of a 1:31.25 dilution of Nano-Glo substrate (Promega) and a 1:500 dilution of NanoLuc extracellular inhibitor (Promega) in phenol red-free OptiMEM was added to each well, followed by further mixing. Filtered luminescence was measured using an EnVision plate reader (PerkinElmer) equipped with a 460 nm filter (donor) and a 645 nm filter (acceptor). BRET ratios were plotted as concentration-response curves fitted to a sigmoidal four-parameter logistic model to determine IC 50 The values were calculated (Scigillian Analyze) and the results are shown in Table 2 below.

[0245] Detection of cellular PAR levels by Western blotting Kuramochi high-grade serous ovarian carcinoma (HGSOC) (JCRB, #JCRB0098) cells or NCI-H1650 non-small cell lung carcinoma (NSCLC) (ATCC, #CRL-5883) cells were cultured in RPMI (BioConcept, #1-41F03-I) containing 10% FCS (Sigma, #F9665) and 1% penicillin-streptomycin (BioConcept, #4-01F00-H). When cells reached 70% confluency in 6-well plates (TPP, #92006), they were treated with either the test compound solvent DMSO or the test compound at the indicated final concentration for 4, 6, or 8 hours. The culture medium was then removed, and cells were harvested by scraping in lysis buffer (20 mM Tris HCl pH 7.5, 150 mM NaCl, 1 mM EGTA, 1 mM EDTA, 1% Triton, and 1% NP-40) containing protease and phosphatase inhibitors (Halt™ Protease & Phosphatase Inhibitor Cocktail 100x ThermoScientific, #1861281) and 1 mM PMSF (Fluka, #93482). The cleared lysates were stored in Eppendorf Tubes™ at -80°C until use, and the protein concentration in the lysates was determined using Pierce 660 nm Protein Assay Reagent (ThermoScientific, #22660). 20 μg of protein was diluted in 4× Laemmli buffer (Biorad, #161-0747) containing 10% β-mercaptoethanol, separated by SDS-PAGE using a 10% gel, and then transferred to a PVDF membrane (Trans Blot Turbo Transfer Pack BioRad, #1704156) using the Trans-Blot® Turbo™ System semi-dry blotting methodology (BioRad). Primary antibodies were incubated overnight at 4°C in TBS-0.1% Tween-20 buffer containing 3% bovine serum albumin (Millipore, #81-053-3).The following primary antibodies were used: anti-PAR (Ab-1) mouse monoclonal antibody (10H) (Millipore, #AM80-100UG), poly / mono-ADP-ribose (PAR / MAR) (E6F6A) rabbit monoclonal antibody (Cell Signaling, #83732), and rabbit anti-GAPDH clone 14C10 (Cell Signaling, #2118S) diluted 1:2000 to control for equal protein loading, or mouse α-tubulin (Sigma, #T5168) diluted 1:5000. Secondary antibodies conjugated with horseradish peroxidase (HRP) were incubated at 1:5000 in TBS-0.1% Tween-20 buffer containing 5% nonfat dry milk (Sigma, #M7409) for 1 hour at room temperature. The following secondary antibodies were used: goat anti-mouse HRP (Jackson, #115-035-146) and goat anti-rabbit HRP (Jackson, #111-035-144). The membranes were incubated with enhanced chemiluminescence (ECL) Prime Western Blot Detection Reagent (Amersham, #RPN2236), and specific signals were detected using a Fusion SOLO S imaging system (Vilber Lourmat). The results are shown in Figure 1.

[0246] Cell proliferation assay For Examples 1-11, RMUG-S mucinous cystadenocarcinoma (JCRB, #IFO50320) and TOV-112D endometrioid adenocarcinoma (ATCC, #CRL-11731) ovarian cancer cell lines were grown using standard cell culture techniques in DMEM / F-12 with glutamine (BioConcept, #1-26F09-I) and RPMI with glutamine (BioConcept, #1-41F03-I), respectively, both media containing 10% FBS (Sigma-Aldrich, #F9665) and supplemented with 1% penicillin-streptomycin (BioConcept, #4-01F00-H). The RMUG-S and TOV-112D ovarian cancer cell lines were selected as highly and weakly PARG-dependent, respectively, based on PARG shRNA (short hairpin ribonucleic acid) dropout profiles published in the Cancer Dependency Map (DepMap) data portal (Broad Institute DepMap Project; Cheung HW et al., Proceedings of the National Academy of Sciences 2011; Cowley GS et al., Scientific Data 2014; McDonald ER et al., Cell 2017). PARG dependence of these cell lines was independently validated and confirmed by genetic and pharmacological means using shRNA-mediated PARG depletion and the previously reported cell-permeable quinazolinedione PARG inhibitor tool compound PDD00017273 (Pillay N et al., Cancer Cell 2019). Therefore, growth inhibition of the RMUG-S cell line serves as a functional on-target inhibition readout, and the observation of potent growth inhibition of TOV-112D indicates off-target activity of the compound. Cells were seeded into clear-bottom 96-well plates (Huberlab, #7.655090) at a seeding density of 5000 cells per well in 100 μL of medium, and the plates were incubated overnight at 37°C with 5% CO2 before treatment with compounds. Experimental compounds were prepared in DMSO at a concentration of 10 mM.Compounds were diluted to the desired final concentration using a Tecan D300e Digital Dispenser (TECAN) and normalized to the maximum DMSO volume. Plates were incubated for 120 hours, and then cell numbers were measured using CellTiter-Glo® (Promega, #G9241) essentially as recommended by the manufacturer. Briefly, for CellTiter-Glo® proliferation readout, 50 μL of reconstituted CellTiter-Glo® 2.0 Reagent was added to 100 μL of medium containing cells. Plates were incubated at room temperature for 10 minutes to allow the luminescence signal to stabilize, and then the luminescence intensity signal was measured using a Synergy 4™ microplate reader (BioTek Instruments). Relative proliferation values were calculated by normalizing raw data using DMSO-treated cells (100% proliferation) and the signal obtained from cells evaluated upon compound addition (0% proliferation). Concentration-response data were fitted to a sigmoidal four-parameter logistic model with the maximum value constrained to 100%. GI. 50 Values were calculated from the curves as the compound concentration that reduced proliferation by 50%. The results are shown in Table 2 below. The cell proliferation assay protocol was modified and used for MUG-S in Examples 12-44 and subsequently used to test Examples 1-44 in the NCI-H1650 cell line. Modified cell proliferation assay NCI-H1650 (ATCC, #CRL-5883) or RMUG-S cells were seeded at 300 cells per well in 25 μL of RPMI1640 medium (Pan Biotech, #P04-22100) containing 10% FCS (Capricorn, #FBS-11A; lot CP22-5141) and 1% glutamine (Pan Biotech, #P04-80100) on day 1 in a 384-well plate (Greiner, #781080) to ensure assay linearity and optimal signal intensity. After 24 hours of incubation in a humidified chamber at 37°C / 5% CO2, compound / DMSO was dispensed at various concentrations using an Echo 520 (Beckman Coulter). Cells were further incubated at 37°C and 5% CO2 for 120 hours. Cells treated with the compound solvent DMSO were used as a negative control, and cells treated with 10 μM staurosporine (LC Laboratories, #S-9300) served as a positive control. On day 6, CellTiter Glo Reagent was prepared according to the kit's instructions (Promega Inc.), and the reagent was mixed 1:1 with cell culture medium. The mixture and assay plate were then equilibrated at room temperature for 20 minutes. An equal volume of the reagent-medium mixture was added to the amount of culture medium present in each well. The plate was mixed at approximately 200 rpm on an orbital shaker (Timix5, Edmund Buehler GmbH) for approximately 2 minutes. The microplate was then incubated at room temperature for 10 minutes to stabilize the luminescence signal. After incubation, luminescence was recorded using a Victor X5 microplate reader (Perkin Elmer) with an integration time of 200 ms. The data were then analyzed in Excel using the XLFIT Plugin (Dose Response Fit 205) to determine the concentration required for half-maximal inhibition (i.e., the inflection point of the fitted curve). As a quality control, a Z' factor was calculated from the 16 positive and negative control values. Only assay results showing a Z' factor of 0.5 or greater were used for further analysis.

[0247] Table 2: PARG biochemical enzyme inhibition, intracellular PARG target binding (TE), and growth inhibition of RMUG-S (high PARG dependent), NCI-H1650 (high PARG dependent), and TOV-112D (low PARG dependent) ovarian cancer cell lines. TIFF2025526453000053.tif238162 TIFF2025526453000054.tif157163 PARG IC 50 For (nM): +++ if <30, ++ if 30-99, + if 100-1000. PARG TE IC 50 For (nM): +++ if <30, ++ if 30-99, + if 100-1000. RMUG-S GI 50 For (nM): <500 = +++, 500-1999 = ++, 2000-8999 = +. The highest concentration tested is 9000 nM. ND: Not determined. NCI-H1650 GI 50 For (nM): <500 = +++, 500-1999 = ++, >2000 = +. The highest concentration tested is 30,000 nM. ND: Not determined. TOV-112D GI 50 For (nM): <500 = +++, 500-1999 = ++, 2000-8999 = ++, ≥9000 = -. The highest concentration tested is 9000 nM. ND: Not determined.

[0248] Literature References Ordered as citations appear in the text Hanahan D, Cancer Discovery 2022,12(1):31-46 Gaillardh et al,Nature Reviews Cancer 2015,15(5):276-89 Brown JS et al,Cancer Discovery 2017,7(1):20-37 Curtin NJ,Nature Reviews Cancer 2012,12(12):801-17 Hartwell LH et al,Science 1997,278(5340):1064-8 Farmerh et al,Nature 2005,434(7035):917-21 Bryanthe et al,Nature 2005,434(7035):913-7 Turner N et al,Nature Reviews Cancer 2004,4(10):814-9 Hottiger MO et al,Trends in Biochemical Sciences 2010,35(4):208-19 Leung AKL,Trends in Cell Biology 2020,30(5):370-383 Barkauskaite E at al,Nature Communications 2013,4:2164 Pourfarjam Y et al,Biochemical and Biophysical Research Communications 2020,527(3):818-823 Marques M et al,Oncogene 2019,38(12):2177-2191 Pillay N et al,Cancer Cell 2019,35(3):519-533 Coulson-Gilmer C et al,Journal of Experimental&Clinical Cancer Research 2021,40(1):323 Prokhorova E et al,Molecular Cell,2021,81(12):2640-2655 Chen S-H and Yu X,Science Advances 2019,5(4):eaav4340 Slade D,Genes&Development 2020,34(5-6):360-394 Houl JH et al,Nature Communications 2019,10(1):5654 Wuts P.G.M,Greene’s Protective Groups in Organic Synthesis,5 th Edition,Publisher:John Wiley&Sons,2014 Drown BS et al,Cell Chemical Biology 2018,25(12):1562-1570 CheunghW et al,Proceedings of the National Academy of Sciences USA 2011,108(30):12372-7 Cowley GS et al,Scientific Data 2014,1:140035 McDonald ER et al,Cell 2017,170(3):577-592

Claims

1. Equation (I) 【Chemistry 1】 A compound of or a pharmaceutically acceptable salt thereof During the ceremony, R １ It is hydrogen, cyano, formyl, -CONH ２ ien-CH ２ OH, -CH ２ OC １～２ Alkyl, C １～２ Alkyl, C １～２ It is a haloalkyl or ethynyl; R ２ and R ３ are each, independently, C １～２ alkyl; or R ２ and R ３ These, together with the carbon atoms to which they are attached, form cyclopropyl or oxetanyl; X １ CR ７ or N; R ７ is hydrogen or fluoro; X ２ CR ８ or N; R ８ is hydrogen or fluoro; X ３ CR ９ or N; R ９ is hydrogen, halogen, cyano, -N(R) ｍ ) R ｎ , C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ２～４ Alkinyl, C ３～６ Cycloalkyl, phenyl, heteroaryl, heterocyclil, condensed heterocyclil, spiroheterocyclil, or crosslinked heterocyclil, where the cycloalkyl, phenyl, heteroaryl, heterocyclil, condensed heterocyclil, spiroheterocyclil, and crosslinked heterocyclil are optionally R ａ , R ｂ , and / or R ｃ It has been replaced with; R ａ is hydrogen, -N(R ｍ ) R ｎ , C １～６ Alkyl, hydroxy, C １～６ Alkoxy, halogen, cyano, oxo, C １～６ Haloalkyl, C １～６ Haloalkoxy, HydroxyC １～６ Alkyl, C ３～６ Cycloalkyl, heteroaryl, heterocyclyl, -C(O)R ｄ , -C(O)OR ｅ , -C(O)N(R ｆ ) R ｇ , -S(O) ２ N(R) ｈ ) R ｉ , or C １～６ Alkyl-N(R) ｊ ) R ｋ And; R ｂ and R ｃ These are, independently, hydrogen, -N(R) ｍ ) R ｎ , C １～６ Alkyl, C １～４ Alkyl-N(R) ｍ ) R ｎ , hydroxy, C １～６ Alkoxy, halogen, cyano, C １～６ Haloalkyl, or C １～６ It is a haloalkoxy; R ｄ is hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ It is a cycloalkyl, phenyl, heteroaryl, or heterocyclyl; R ｅ is hydrogen or C １～６ It is alkyl; R ｆ , R ｇ , R ｈ , R ｉ , R ｊ , R ｋ , R ｍ , and R ｎ These are, independently, hydrogen and C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, amino C １～６ Alkyl or hydroxy C １～６ It is alkyl; or R ｆ and R ｇ , R ｈ and R ｉ , or R ｊ and R ｋ These, along with the nitrogen atoms to which they are attached, form heterocyclines; Here, (i) R ａ The cycloalkyl, heteroaryl, and heterocyclyl compounds; (ii) R ｄ The alkyl, haloalkyl, cycloalkyl, phenyl, heteroaryl, and heterocyclyl compounds; (iii) R ｆ and R ｇ , R ｈ and R ｉ , or R ｊ and R ｋ and the nitrogen to which they are attached, said heterocyclyl formed by the combination is each optionally ((i), (ii), (iii)) C １～６ alkyl, C ３～６ cycloalkyl, C １～６ alkyl-NH ２ -, C １～６ alkyl-NH(C １～４ alkyl), C １～６ alkyl-N(C １～４ alkyl) ２ -, hydroxy, oxo, C １～６ alkoxy, halogen, cyano, amino, -NH(C １～４ alkyl), -N(C １～４ alkyl) ２ -, C １～６ haloalkyl, and C １～６ [[ID= R ４ is hydrogen or -L １Ａ -L ２Ａ -L ３Ａ It is the basis; L １Ａ It does not exist, or C １～２ C is optionally substituted with alkyl or oxo. １～３ It is alkylene; L ２Ａ It does not exist, or -O-, -S-, -S(O)-, -S(O) ２ -, -N(R ａ１ )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R ａ１ )-,-N(R ａ１ )C(O)-,-N(R ａ１ ) C(O)N(R ｂ１ )-,-S(O) ２ N(R) ａ１ ) - or -N(R ａ１ ) S(O) ２ - and; R ａ１ and R ｂ１ Each of them independently consists of hydrogen or C １～２ It is alkyl; L ３Ａ is hydrogen, C １～６ Alkyl, C ３～６ It is a cycloalkyl, phenyl, heterocyclyl, or heteroaryl, where L ３Ａ The following can be optionally selected: halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, C １～４ Alkyl, -N(R) ｃ１ ) R ｄ１ , -OR ｃ１ , -C(O)R ｃ１ , -C(O)OR ｃ１ , -OC(O)R ｃ１ , -C(O)N(R ｄ１ ) R ｃ１ , -N(R ｄ１ ) C(O)R ｃ１ , -S(O) ｙ R ｃ１ , -S(O) ２ N(R) ｄ１ ) R ｃ１ , -N(R ｄ１ ) S(O) ２ R ｃ１ , and (CH ２ ) ｚ N(R) ｄ１ ) R ｃ１ Substituted with one or more substituents independently selected from; R ｃ１ and R ｄ１ Each of them independently consists of hydrogen or C １～４ It is alkyl; y is 0, 1, or 2; z is 1, 2, or 3; R ５ is hydrogen or -L １Ｂ -L ２Ｂ -L ３Ｂ It is the basis; L １Ｂ It does not exist, or C １～２ C is optionally substituted with alkyl or oxo. １～３ It is alkylene; L ２Ｂ It does not exist, or -O-, -S-, -S(O)-, -S(O) ２ -, -N(R ａ２ )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R ａ２ )-,-N(R ａ２ )C(O)-,-N(R ａ２ ) C(O)N(R ｂ２ )-,-S(O) ２ N(R) ａ２ ) - or -N(R ａ２ ) S(O) ２ - and; R ａ２ and R ｂ２ Each of them independently consists of hydrogen or C １～２ It is alkyl; L ３Ｂ is hydrogen, C １～６ Alkyl, C ３～６ It is a cycloalkyl, phenyl, heterocyclyl, or heteroaryl, where L ３Ｂ The following can be optionally selected: halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, C １～４ Alkyl, -N(R) ｃ２ ) R ｄ２ , -OR ｃ２ , -C(O)R ｃ２ , -C(O)OR ｃ２ , -OC(O)R ｃ２ , -C(O)N(R ｄ２ ) R ｃ２ , -N(R ｄ２ ) C(O)R ｃ２ , -S(O) ｙ’ R ｃ２ , -S(O) ２ N(R) ｄ２ ) R ｃ２ , -N(R ｄ２ ) S(O) ２ R ｃ２ , and (CH ２ ) ｚ’ N(R) ｄ２ ) R ｃ２ Substituted with one or more substituents independently selected from; R ｃ２ and R ｄ２ Each of them independently consists of hydrogen or C １～４ It is alkyl; y' is 0, 1, or 2; z' is 1, 2, or 3; R ６ is hydrogen or -L １Ｃ -L ２Ｃ -L ３Ｃ It is the basis; L １Ｃ It does not exist, or C １～２ C is optionally substituted with alkyl or oxo. １～３ It is alkylene; L ２Ｃ It does not exist, or -O-, -S-, -S(O)-, -S(O) ２ -, -N(R ａ３ )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R ａ３ )-,-N(R ａ３ )C(O)-,-N(R ａ３ ) C(O)N(R ｂ３ )-,-S(O) ２ N(R) ａ３ ) - or -N(R ａ３ ) S(O) ２ - and; R ａ３ and R ｂ３ Each of them independently consists of hydrogen or C １～２ It is alkyl; L ３Ｃ is hydrogen, C １～６ Alkyl, C ３～６ It is a cycloalkyl, phenyl, heterocyclyl, or heteroaryl, where L ３Ｃ The following can be optionally selected: halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carbonyl, carbamoyl, sulfamoyl, C １～４ Alkyl, -N(R) ｃ３ ) R ｄ３ , -OR ｃ３ , -C(O)R ｃ３ , -C(O)OR ｃ３ , -OC(O)R ｃ３ , -C(O)N(R ｄ３ ) R ｃ３ , -N(R ｄ３ ) C(O)R ｃ３ , -S(O) ｙ” R ｃ３ , -S(O) ２ N(R) ｄ３ ) R ｃ３ , -N(R ｄ３ ) S(O) ２ R ｃ３ , and (CH ２ ) ｚ” N(R) ｄ３ ) R ｃ３ Substituted with one or more substituents independently selected from; R ｃ３ and R ｄ３ Each of them independently consists of hydrogen or C １～４ It is alkyl; y'' is 0, 1, or 2; z'' is 1, 2, or 3; however, Said-L １Ａ -L ２Ａ -L ３Ａ Group, -L １Ｂ -L ２Ｂ -L ３Ｂ Base, and L １Ｃ -L ２Ｃ -L ３Ｃ The base does not include -O-O- units, -S-O- units, -O-S- units, or -S-S- units as linked units within the base; Said-L １Ａ -L ２Ａ -L ３Ａ The base is R ４ No -O-N- or -S-N- units are placed adjacent to the ring nitrogen atom connected to it; Said-L １Ｂ -L ２Ｂ -L ３Ｂ The base is R ５ No N, O, or S atoms are positioned adjacent to the oxime oxygen atom connected to it; and -L １Ｃ -L ２Ｃ -L ３Ｃ R ６ No -O-N- or -S-N- units are placed adjacent to the ring nitrogen atom connected to it. A compound of formula (I) or a pharmaceutically acceptable salt thereof.

2. X １ CR ７ X ２ CR ８ And, X ３ CR ９ The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R １ is cyano, C １～２ A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, which is alkyl or ethynyl.

4. R ２ and R ３ The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein these, together with the carbon atoms to which they are attached, form cyclopropyl or oxetanyl.

5. R ９ is hydrogen, halogen, cyano, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ２～４ Alkinyl, C ３～６ Cycloalkyl, phenyl, 5-6 membered heteroaryl, comprising a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, S, and O as ring atoms, and a 5-7 membered monocyclic heterocyclil, comprising a 5-7 membered monocyclic heterocyclil containing 1, 2, or 3 heteroatoms independently selected from N, S, and O as ring atoms, wherein the heteroalkyl, phenyl, heteroaryl, and heterocyclil are optionally R ａ , R ｂ , and / or R ｃ It is replaced by; or R ９ X is a spiroheterocycline, where X ３ The first ring connected to the first ring is a 5-7 member monocyclic heterocycline, comprising one, two, or three heteroatoms independently selected from N, S, and O as ring atoms, and a second ring connected to the first ring by a common carbon atom, the second ring being a spiroheterocycline, which is a 3-6 member monocyclic cycloalkyl or 3-6 member monocyclic heterocycline, comprising one, two, or three heteroatoms independently selected from N, S, and O as ring atoms, and where the spiroheterocycline is optionally R ａ , R ｂ , and / or R ｃ It is replaced by The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

6. R ９ This is a 5-6 membered heteroaryl comprising hydrogen, halogen, cyano, phenyl, and one or two heteroatoms selected from N as ring atoms, wherein the phenyl and the 6 membered heteroaryl are optionally connected at the para position with respect to the rest of the molecule. ａ It is replaced with R, and in addition, R is optionally replaced. ｂ The 5-membered heteroaryl is substituted, and optionally, at the 3-position distal to the rest of the molecule, R ａ It is replaced with R, and in addition, R is optionally replaced. ｂ It is replaced by the above (R9 ａ ) part or the aforementioned (R9 ｂ )portion: 【Chemistry 2】 And, During the ceremony, Z １ is N or CH, Z ２ N(R) ａ ), O, S, CH (R ａ ), or C (R ｘ ) (Caution ｙ ) and in the formula, R ｘ and R ｙ Both are 4-6 member monocyclic heterocyclines, forming a 4-6 member monocyclic heterocycline containing one heteroatom selected from N, O, and S. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in claim 5.

7. R ａ is hydrogen, -N(R ｍ ) R ｎ , C １～６ Alkyl, oxo, -C(O)R ｄ , -C(O)N(R ｆ ) R ｇ , or C １～６ Alkyl-N(R) ｊ ) R ｋ And; R ｂ is hydrogen, amino, -NH(C) １～４ Alkyl), -N(C １～４ Alkyl) ２ , C １～４ Alkyl, C １～４ Alkyl-NH ２ , C １～４ Alkyl-NH(C) １～４ Alkyl), or C １～４ Alkyl-N(C) １～４ Alkyl) ２ And; R ｃ is hydrogen or C １～４ It is alkyl; R ｄ is hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ A cycloalkyl, phenyl, heteroaryl, or heterocyclyl, where the alkyl, haloalkyl, cycloalkyl, phenyl, heteroaryl, and heterocyclyl are optionally C １～６ Alkyl, C ３～６ Cycloalkyl, C １～６ Alkyl-NH ２ , C １～６ Alkyl-NH(C) １～４ Alkyl), C １～６ Alkyl-N(C) １～４ Alkyl) ２ hydroxy, oxo, C １～６ Alkoxy, halogen, cyano, amino, -NH(C) １～４ Alkyl), -N(C １～４ ) ２ , C １～６ Haloalkyl and C １～６ It is substituted with one, two, three, or four substituents independently selected from the haloalkoxy, R ｆ is hydrogen or C １～４ It is alkyl; R ｇ is hydrogen or C １～４ It is alkyl; R ｊ is hydrogen or C １～４ It is alkyl; R ｋ is hydrogen or C １～４ It is alkyl; R ｍ is hydrogen or C １～４ Alkyl; and R ｎ is hydrogen or C １～４ It is alkyl. A compound of formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

8. R ４ is the aforementioned -L １Ａ -L ２Ａ -L ３Ａ It is the basis; L ２Ａ , L ２Ｂ , and L ２Ｃ It does not exist; L ３Ａ is a cycloalkyl, phenyl, heterocyclyl, or heteroaryl compound, each optionally substituted; L ３Ａ , L ３Ｂ , and L ３Ｃ Two or fewer of these are cycloalkyl, phenyl, heterocyclyl, or heteroaryl, each optionally substituted; and R ９ However, if it is a cycloalkyl, phenyl, heteroaryl, heterocyclyl, condensed heterocyclyl, spiroheterocyclyl, or cross-linked heterocyclyl, L ３Ｃ It is not a cycloalkyl, phenyl, heterocyclyl, or heteroaryl compound. A compound of formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

9. R ４ is the aforementioned -L １Ａ -L ２Ａ -L ３Ａ It is a base, and in the formula, L ３Ａ R is a cycloalkyl, phenyl, heterocyclyl, or heteroaryl compound, each optionally substituted; ５ is hydrogen or the aforementioned -L １Ｂ -L ２Ｂ -L ３Ｂ It is a base, and in the formula, L ３Ｂ is a cycloalkyl, phenyl, heterocyclyl, or heteroaryl compound, each optionally substituted, or -L １Ｂ -L ２Ｂ -L ３Ｂ C １～６ Alkyl; and R ６ is hydrogen or C １～６ A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, which is alkyl.

10. R ４ is the aforementioned -L １Ａ -L ２Ａ -L ３Ａ It is the basis; L １Ａ C １～３ It is alkylene; L ２Ａ It does not exist; L ３Ａ L is a phenyl or 5-6 membered heteroaryl, which contains 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring atoms, where L ３Ａ The following can be optionally selected: halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, C １～４ Alkyl, -N(R) ｃ１ ) R ｄ１ , -OR ｃ１ , -C(O)R ｃ１ , -C(O)OR ｃ１ , -OC(O)R ｃ１ , -C(O)N(R ｄ１ ) R ｃ１ , -N(R ｄ１ ) C(O)R ｃ１ , -S(O) ｙ R ｃ１ , -S(O) ２ N(R) ｄ１ ) R ｃ１ , -N(R ｄ１ ) S(O) ２ R ｃ１ , and (CH ２ ) ｚ N(R) ｄ１ ) R ｃ１ Substituted with one, two, or three substituents independently selected from; R ｃ１ is hydrogen or C １～４ It is alkyl; R ｄ１ is hydrogen or C １～４ It is alkyl; y is 0, 1, or 2; z is 1, 2, or 3; R ５ is hydrogen or the aforementioned -L １Ｂ -L ２Ｂ -L ３Ｂ It is the basis; L １Ｂ C １～３ It is alkylene; L ２Ｂ It does not exist; L ３Ｂ L is a phenyl or 5-6 membered heteroaryl, which contains 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring atoms, where L ３Ｂ The following can be optionally selected: halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, C １～４ Alkyl, -N(R) ｃ２ ) R ｄ２ , -OR ｃ２ , -C(O)R ｃ２ , -C(O)OR ｃ２ , -OC(O)R ｃ２ , -C(O)N(R ｄ２ ) R ｃ２ , -N(R ｄ２ ) C(O)R ｃ２ , -S(O) ｙ’ R ｃ２ , -S(O) ２ N(R) ｄ２ ) R ｃ２ , -N(R ｄ２ ) S(O) ２ R ｃ２ , and (CH ２ ) ｚ’ N(R) ｄ２ ) R ｃ２ Substituted with one, two, or three substituents independently selected from; R ｃ２ is hydrogen or C １～４ It is alkyl; R ｄ２ is hydrogen or C １～４ It is alkyl; y' is 0, 1, or 2; z' is either 1, 2, or 3; or the above-L １Ｂ -L ２Ｂ -L ３Ｂ The base is C １～６ Alkyl; and R ６ is hydrogen or the aforementioned -L １Ｃ -L ２Ｃ -L ３Ｃ It is the base, and here, -L １Ｃ -L ２Ｃ -L ３Ｃ C １～６ It is alkyl. A compound of formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

11. R １ is cyano, C １～２ Alkyl or ethynyl; R ２ and R ３ These, together with the carbon atoms to which they are attached, form cyclopropyl or oxetanyl; X １ CR ７ And; X ２ CR ８ And; X ３ CR ９ And; R ７ and R ８ is hydrogen; R ９ is hydrogen, halogen, cyano, -N(R) ｍ ) R ｎ , C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ２～４ Alkinyl, C ３～６ A cycloalkyl, phenyl, 5-6 membered heteroaryl, comprising a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, S, and O as ring atoms, and a 5-6 membered monocyclic heterocyclil, comprising a 5-6 membered monocyclic heterocyclil containing 1, 2, or 3 heteroatoms independently selected from N, S, and O as ring atoms, wherein the cycloalkyl, phenyl, heteroaryl, and heterocyclil are optionally R ａ , R ｂ , and / or R ｃ Is it replaced by; or R ９ X is a spiroheterocycline, where X ３ The first ring connected to the first ring is a 5-7 member monocyclic heterocycline, comprising one, two, or three heteroatoms independently selected from N, S, and O as ring atoms, and a second ring connected to the first ring by a common carbon atom, the second ring being a spiroheterocycline, which is a 3-6 member monocyclic cycloalkyl or 3-6 member monocyclic heterocycline, comprising one, two, or three heteroatoms independently selected from N, S, and O as ring atoms, and where the spiroheterocycline is optionally R ａ , R ｂ , and / or R ｃ It has been replaced with; R ａ is hydrogen, -N(R ｍ ) R ｎ , C １～６ Alkyl, oxo, -C(O)R ｄ , -C(O)N(R ｆ ) R ｇ , or C １～６ Alkyl-N(R) ｊ ) R ｋ And; R ｂ is hydrogen, -amino, -NH(C) １～４ Alkyl), -N(C １～４ Alkyl) ２ , C １～４ Alkyl, C １～４ Alkyl-NH ２ , C １～４ Alkyl-NH(C) １～４ Alkyl), C １～４ Alkyl-N(C) １～４ Alkyl) ２ And; R ｃ is hydrogen; R ｄ is hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ A cycloalkyl, phenyl, heteroaryl, or heterocyclil, where the cycloalkyl, phenyl, heteroaryl, and heterocyclil are optionally C １～６ Alkyl, C １～６ Alkyl-NH ２ , C １～６ Alkyl-NH(C) １～４ Alkyl), C １～６ Alkyl-N(C) １～４ Alkyl) ２ , hydroxy, C １～６ Alkoxy, halogen, cyano, amino, -NH(C) １～４ Alkyl), -N(C １～４ Alkyl) ２ , C １～６ Haloalkyl and C １～６ It is substituted with one, two, or three substituents independently selected from the haloalkoxy; R ｆ is hydrogen or C １～４ It is alkyl; R ｇ is hydrogen or C １～４ It is alkyl; R ｊ is hydrogen or C １～４ It is alkyl; R ｋ is hydrogen or C １～４ It is alkyl; Each R ｍ These are, independently, hydrogen or C １～４ It is alkyl; Each R ｎ These are, independently, hydrogen or C １～４ It is alkyl; R ４ is, -L １Ａ -L ２Ａ -L ３Ａ It is the basis; L １Ａ C １～３ It is alkylene; L ２Ａ It does not exist; L ３Ａ L is a phenyl or 5-6 membered heteroaryl, which contains 1, 2, or 3 heteroatoms independently selected from N, S, and O as ring atoms, where L ３Ａ The following can be optionally selected: halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, C １～４ Alkyl, -N(R) ｃ１ ) R ｄ１ , -OR ｃ１ , -C(O)R ｃ１ , -C(O)OR ｃ１ , -OC(O)R ｃ１ , -C(O)N(R ｄ１ ) R ｃ１ , -N(R ｄ１ ) C(O)R ｃ１ , -S(O) ｙ R ｃ１ , -S(O) ２ N(R) ｄ１ ) R ｃ１ , -N(R ｄ１ ) S(O) ２ R ｃ１ , and (CH ２ ) ｚ N(R) ｄ１ ) R ｃ１ Substituting with one, two, or three substituents independently selected from; or the above-L １Ａ -L ２Ａ -L ３Ａ The base is C １～６ It is alkyl; R ｃ１ is hydrogen or C １～４ It is alkyl; R ｄ１ is hydrogen or C １～４ It is alkyl; y is 0, 1, or 2; z is 1, 2, or 3; R ５ is hydrogen or -L １Ｂ -L ２Ｂ -L ３Ｂ It is the basis; L １Ｂ C １～３ It is alkylene; L ２Ｂ It does not exist; L ３Ｂ L is a phenyl or 5-6 member heteroaryl, which contains 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring atoms, where L ３Ｂ The following can be optionally selected: halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, C １～４ Alkyl, -N(R) ｃ２ ) R ｄ２ , -OR ｃ２ , -C(O)R ｃ２ , -C(O)OR ｃ２ , -OC(O)R ｃ２ , -C(O)N(R ｄ２ ) R ｃ２ , -N(R ｄ２ ) C(O)R ｃ２ , -S(O) ｙ’ R ｃ２ , -S(O) ２ N(R) ｄ２ ) R ｃ２ , -N(R ｄ２ ) S(O) ２ R ｃ２ , and (CH ２ ) ｚ’ N(R) ｄ２ ) R ｃ２ It is substituted with one, two, or three substituents independently selected from; R ｃ２ is hydrogen or C １～４ It is alkyl; R ｄ２ is hydrogen or C １～４ It is alkyl; y' is 0, 1, or 2; Is z' 1, 2, or 3? or the above-L １Ｂ -L ２Ｂ -L ３Ｂ The base is C １～６ It is alkyl; R ６ is hydrogen or -L １Ｃ -L ２Ｃ -L ３Ｃ It is the base, and here, -L １Ｃ -L ２Ｃ -L ３Ｃ The base is C １～６ It is alkyl. A compound of formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

12. The aforementioned compound, 2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(2-methylthiazole-5-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide; 2-Methoxyimino-N-(3-methyloxetan-3-yl)-3-[(1-methylpyrazole-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide; 2-[(2,4-dimethylthiazole-5-yl)methoxyimino]-N-(1-methylcyclopropyl)-3-[(1-methylpyrazole-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide; 8-Chloro-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazole-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide; 4-[2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazole-4-yl)methyl]-4-oxo-1H-quinazoline-8-yl]-N,N-dimethylbenzamide; 2-Methoxyimino-N-(1-methylcyclopropyl)-4-oxo-3-[[1-(trifluoromethyl)pyrazole-4-yl]methyl]-1H-quinazoline-6-sulfonamide; 2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazole-4-yl)methyl]-4-oxo-8-[(3R)-3-methylpiperazine-1-yl]-1H-quinazoline-6-sulfonamide; 2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazole-4-yl)methyl]-4-oxo-8-[(3R)-3-methyl-4-(1-methylcyclopropanecarbonyl)piperazine-1-yl]-1H-quinazoline-6-sulfonamide; N-(1-cyanocyclopropyl)-2-methoxyimino-3-[(1-methylpyrazole-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide; 2-Ethoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazole-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide; 2-Isopropoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazole-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide; (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazole-4-yl)methyl]-4-oxo-8-[(3R)-4-acetyl-3-methylpiperazine-1-yl]-1H-quinazoline-6-sulfonamide; (R,E)-2-(methoxyimino)-8-(6-methyl-1,2,3,6-tetrahydropyridine-4-yl)-3-((1-methyl-1H-pyrazole-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide / (R,E)-2-(methoxyimino)-8-(2-methyl-1,2,3,6-tetrahydropyridine-4-yl)-3-((1-methyl-1H-pyrazole-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (E)-4-(2-(methoxyimino)-3-((1-methyl-1H-pyrazole-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-8-yl)-N,N,2-trimethylbenzamide; (E)-4-(2-(methoxyimino)-3-((1-methyl-1H-pyrazole-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-8-yl)benzamide; (E)-8-(4-acetylphenyl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazole-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (E)-8-(4-(aminomethyl)phenyl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazole-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (E)-5-(2-(methoxyimino)-3-((1-methyl-1H-pyrazole-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-8-yl)-N,N-dimethylpicolinamide; (E)-6-(2-(methoxyimino)-3-((1-methyl-1H-pyrazole-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-8-yl)-N,N-dimethylnicotinamide; (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazole-4-yl)methyl]-4-oxo-8-[(3R)-3,4-dimethylpiperazine-1-yl]-1H-quinazoline-6-sulfonamide; (E)-8-(4-(1-hydroxy-2-oxocyclobutyl)phenyl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazole-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (E)-5-(2-(methoxyimino)-3-((1-methyl-1H-pyrazole-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-8-yl)-N,N-dimethyl-1H-imidazole-2-carboxamide; (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazole-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-4-piperidyl]-1H-quinazoline-6-sulfonamide; (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazole-4-yl)methyl]-4-oxo-8-[(2R)-1,2-dimethyl-4-piperidyl]-1H-quinazoline-6-sulfonamide; (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazole-4-yl)methyl]-4-oxo-8-[(2R)-1-acetyl-2-methyl-4-piperidyl]-1H-quinazoline-6-sulfonamide; (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazole-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-1-(1-methylcyclopropanecarbonyl)-4-piperidyl]-1H-quinazoline-6-sulfonamide; (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazole-4-yl)methyl]-4-oxo-8-[(2R)-1,2-dimethyl-3,6-dihydro-2H-pyridine-4-yl]-1H-quinazoline-6-sulfonamide / (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazole-4-yl)methyl]-4-oxo-8-[(6R)-1,6-dimethyl-3,6-dihydro-2H-pyridine-4-yl]-1H-quinazoline-6-sulfonamide; (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazole-4-yl)methyl]-4-oxo-8-[(2R)-1-acetyl-2-methyl-3,6-dihydro-2H-pyridine-4-yl]-1H-quinazoline-6-sulfonamide / (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazole-4-yl)methyl]-4-oxo-8-[(6R)-1-acetyl-6-methyl-3,6-dihydro-2H-pyridine-4-yl]-1H-quinazoline-6-sulfonamide; (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazole-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-1-(1-methylcyclopropanecarbonyl)-3,6-dihydro-2H-pyridine-4-yl]-1H-quinazoline-6-sulfonamide / (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazole-4-yl)methyl]-4-oxo-8-[(6R)-6-methyl-1-(1-methylcyclopropanecarbonyl)-3,6-dihydro-2H-pyridine-4-yl]-1H-quinazoline-6-sulfonamide; (R,E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazole-4-yl)methyl)-8-(3-methyl-4-(3,3,3-trifluoropropanoyl)piperazine-1-yl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (R,E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazole-4-yl)methyl)-8-(3-methyl-4-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperazine-1-yl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (R,E)-8-(4-(1-cyanocyclopropane-1-carbonyl)-3-methylpiperazine-1-yl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazole-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (R,E)-8-(4-(1-(dimethylamino)cyclopropane-1-carbonyl)-3-methylpiperazine-1-yl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazole-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (R,E)-8-(4-isobutyryl-3-methylpiperazine-1-yl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazole-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (R,E)-8-(4-(3,3-difluoropyrrolidine-1-carbonyl)-3-methylpiperazine-1-yl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazole-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (R,E)-4-(2-(methoxyimino)-3-((1-methyl-1H-pyrazole-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-8-yl)-N,2-dimethyl-N-(2,2,2-trifluoroethyl)piperazine-1-carboxamide; (R,E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazole-4-yl)methyl)-8-(3-methyl-4-(1-methylcyclobutan-1-carbonyl)piperazine-1-yl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (R,E)-8-(4-(cyclopentanecarbonyl)-3-methylpiperazine-1-yl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazole-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (R,E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazole-4-yl)methyl)-8-(3-methyl-4-(pyrrolidine-1-carbonyl)piperazine-1-yl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (R,E)-4-(2-(methoxyimino)-3-((1-methyl-1H-pyrazole-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-8-yl)-N,N,2-trimethylpiperazine-1-carboxamide; (R,E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazole-4-yl)methyl)-8-(3-methyl-4-(2,2,2-trifluoroacetyl)piperazine-1-yl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; rel-(R,E)-8-(4-(2,2-difluoro-2-(1-hydroxycyclobutyl)acetyl)-3-methylpiperazine-1-yl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazole-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazole-4-yl)methyl)-8-(4-(1-methylcyclopropane-1-carbonyl)phenyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; and rel-(R,E)-N-cyclopropyl-4-(2-(methoxyimino)-3-((1-methyl-1H-pyrazole-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-8-yl)-N,2-dimethylpiperazine-1-carboxamide A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

13. A compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, used for the treatment of neoplastic diseases, preferably in humans, in subjects selected from mammals, preferably in humans, and preferably in cancer.

14. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.

15. Equation (Int - I) 【Transformation 3】 A compound or salt thereof, During the ceremony, R １０ is hydrogen, halogen (e.g., chloro, bromo, iodine), -B(OH) ２ , -B(-OC(CH ３ ) ２ -C(CH ３ ) ２ -O-), -S(O) ２ OH, -S(O) ２ Cl, or -S-CH ２ - is phenyl; and X １ , X ２ , X ３ , R ４ , R ５ , and R ６ This is as defined in claim 1 with respect to the compound of formula (I), Here, the compound (Int-I) is 2-(hydroxyamino)-6-iodo-3-phenyl-4(3H)-quinazolinone; 6-iodo-2-(propoxyamino)-3-propyl-4(3H)-quinazolinone; 6-bromo-2-(propoxyamino)-3-propyl-4(3H)-quinazolinone; 6-iodo-2-[(2-methylpropoxy)amino]-3-propyl-4(3H)-quinazolinone; 6-bromo-2-[(2-methylpropoxy)amino]-3-propyl-4(3H)-quinazolinone; 2-[[(3,4-dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)amino]oxy]; (3,4-dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)azanyl acetate; 2,4(1H,3H)-Quinazolinedione,6-iodo-3-phenyl-,2-[O-(ethoxycarbonyl)oxime]; (3,4-dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)azanil 2-chloroacetate; Ethyl 2-[[(3,4-dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)amino]oxy]acetate; (3,4-dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)azanil benzoate; (3,4-dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)azanyl benzene acetate; 1-[(3,4-dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)azanyl] 2-ethyl ethanediate 2-(hydroxyamino)-3-phenyl-4(3H)-quinazoline isn't it, Compounds of formula (Int-I) or salts thereof; or Formula (Int-II) 【Chemistry 4】 A compound or salt thereof, During the ceremony, R １１ is hydrogen or C １～８ Alkyl; and X １ , X ２ , X ３ , R ４ , R ５ , and R ６ This is as defined in claim 1 with respect to the compound of formula (I), A compound of formula (Int-II) or a salt thereof.

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