Substituted bicyclic heteroaryl sulfonamide derivatives for treatment of cancer

Abstract

The present invention provides compounds of Formula (I) and pharmaceutically acceptable salts thereof; wherein X1 is CR7 or N, X2 is CR8 or N, X3 is CR9 or N, and wherein R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as defined in the claims, and methods of using these compounds in the treatment of neoplastic diseases such as cancer.

Description

Technical Field

[0001] The present invention relates to a compound for inhibiting poly ADP-ribose glycogen hydrolase (PARG) and its application in treating tumor diseases such as cancer. Background Art

[0002] Genomic instability and replicative immortality are the main characteristics of cancer (Hanahan D, Cancer Discovery 2022). However, the continuous, uncontrolled proliferation driven by the loss of oncogenes and tumor suppressor genes can also put pressure on the metabolism of cancer cells. For example, the continuous activation of oncogenic pathways forces cells to pass through the cell cycle, leading to DNA replication stress (Gaillard H et al, Nature Reviews Cancer 2015). In order to cope with the latter and avoid harmful DNA damage, cells trigger various complementary DNA damage response and repair (DDR) pathways to resolve stalled replication forks and repair single-strand and / or double-strand DNA breaks (Brown JS et al, Cancer Discovery 2017).

[0003] Many components of different DDR pathways may be compromised in tumor suppressor gene functions lost in cancer, including in hereditary cancer syndromes. On the one hand, defects in certain DDR mechanisms can be compensated and buffered to a certain 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 pathways. Therefore, gaps in the repair machinery may create vulnerabilities that can be exploited for cancer therapy. This concept is also often referred to as synthetic lethality, whereby dysfunction of a biological process can remain compatible with cell viability, while genetic deletion or pharmacological inhibition of a parallel and / or compensatory process will lead to cell lethality (Hartwell and Friend, Science 1997).

[0004] The discovery and subsequent clinical translation of synthetic lethality in the setting of defective homologous recombination repair (HR) in cancer following inhibition of poly (ADP ribose) polymerases 1 and 2 (PARP1 / 2) has been a scientific and therapeutic breakthrough (Farmer H et al, Nature 2005; Bryant HE et al, Nature 2005). HR is the most accurate DNA repair pathway, but loss of the BRCA1 (breast CAncer gene 1) or BRCA2 (breast cancer gene 2) tumor suppressor genes in this pathway impairs its function, and affected cells instead rely on other less reliable DDR mechanisms to repair damaged DNA. PARP1 and PARP2 are DNA damage sensors that participate in the alternative non-homologous end joining (alt-NHEJ) and DNA single-strand break (SSB) repair / base excision repair (BER) pathways. In cancers lacking BRCA1 or BRCA2 or exhibiting so-called "BRCAness" (Turner N et al, Nature Reviews Cancer 2004), pharmacological inhibition of the PARP1 / 2 enzymes causes stalled DNA replication forks to collapse and DNA lesions to persist, leading to cancer cell death.

[0005] PARP1 / 2 enzymes belong to a family of 17 members (Hottiger MO et al, Trends Biochem. Sci. 2010). After sensing DNA damage, they use the coenzyme nicotinamide adenine dinucleotide (NAD+) as a substrate to rapidly post-translationally modify themselves and other target proteins with ADP ribose (ADPr). On the receptor protein, PARP1 / 2 usually forms ADPr polymers, called poly ADP-ribose (PAR) or PARylation, with different lengths and degrees of branching, which are thought to help recruit additional DNA repair enzymes at the site of DNA damage (Leung AKL, Trends in Cell Biology 2020). However, in order to complete DNA damage repair, the PAR chain needs to be removed from the receptor protein again. Poly (ADP-ribose) glycohydrolase (PARG) balances PARP1 / 2 by degrading the PAR chain. PARG mainly exhibits exogenous glycohydrolase activity, which can degrade PAR chains into monomeric ADPr (Barkauskaite E et al, Nature Communications 2013), but it has also been described to have endogenous glycohydrolase activity that leads to the release of protein-free PAR chains (Pourfarjam Y et al, BBRC2020).

[0006] Preclinical evidence suggests that increased removal of PAR 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 reduces tumor initiation, growth, and metastasis (Marques M et al, Oncogene 2019). Pharmacological inhibition of PARG was achieved using cell-permeable tool compounds. Importantly, these studies in cell-based cancer models suggest that PARG inhibitors have the potential to complement PARP inhibitors (Pillay N et al, Cancer Cell 2019) and may also work in the setting of acquired PARP inhibitor resistance (Coulson-Gilmer C et al, Journal of Experimental & Clinical Cancer Research 2021). It has been reported that sensitivity to PARG inhibition is associated with DNA replication fragility and DNA replication stress markers, and PARG inhibition leads to severe loss of mitotic potential in sensitive cancer cell lines (Pillay N et al, Cancer Cell 2019; Coulson-Gilmer C et al, Journal of Experimental & Clinical Cancer Research 2021). In addition, sustained PARylation is highly toxic to cells (Prokhorova E et al, Molecular Cell, 2021), and PARG inhibition prolongs PARylation at DNA lesions, thereby hindering DNA repair factors and inhibiting DNA repair (Chen SH & Yu X, Science Advances 2019). Therefore, PARG inhibition sensitizes to a range of 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 summary, PARG inhibitors are expected to be used as monotherapy or in combination with other therapies for cancer treatment.

[0007] WO2021 / 055744, WO2016 / 097749 and WO2016 / 092326 describe PARG inhibitors. Summary of the invention

[0008] In a first aspect, the present invention provides a compound of formula (I) and a pharmaceutically acceptable salt thereof,

[0009]

[0010] in

[0011] R 1 It is hydrogen, cyano, formyl, -CONH 2 、-CH 2 OH, -CH 2 OC 1-2 Alkyl, C 1-2 Alkyl, C 1-2 a haloalkyl or ethynyl group;

[0012] R 2 and R 3 Independently C 1-2 alkyl;

[0013] or R 2 and R 3 Together with the carbon atoms to which they are attached they form a cyclopropyl or oxetanyl group;

[0014] X 1 Yes CR 7 or N;

[0015] R 7 is hydrogen or fluorine;

[0016] X 2 Yes CR 8 or N;

[0017] R 8 is hydrogen or fluorine;

[0018] X 3 Yes CR 9 or N;

[0019] 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 Halogenated alkoxy, C 2-4 Alkynyl, C 3-6 Cycloalkyl, phenyl, heteroaryl, heterocyclyl, fused heterocyclyl, spiro heterocyclyl or bridged heterocyclyl, wherein the cycloalkyl, phenyl, heteroaryl, heterocyclyl, fused heterocyclyl, spiro heterocyclyl and bridged heterocyclyl are optionally substituted by R a , R band / or R c replace;

[0020] R a is hydrogen, -N(R m )R n , C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogen, cyano, oxo, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl 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) 2 N(R h )R i or C 1-6 Alkyl-N(R j )R k ;

[0021] R b and R c are independently hydrogen, -N(R m )R n , C 1-6 Alkyl, C 1-4 Alkyl-N(R m )R n , hydroxyl, C 1-6 Alkoxy, halogen, cyano, C 1-6 Haloalkyl or C 1-6 Haloalkoxy;

[0022] R d It is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, heteroaryl or heterocyclyl;

[0023] R e is hydrogen or C 1-6 alkyl;

[0024] R f , R g , R h , R i , R j , R k , R m and R n are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6Cycloalkyl, amino C 1-6 Alkyl or hydroxyl C 1-6 Alkyl; or

[0025] 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, they form a heterocyclic group;

[0026] in

[0027] (i)R a Cycloalkyl, heteroaryl and heterocyclyl;

[0028] (ii) R d alkyl, haloalkyl, cycloalkyl, phenyl, heteroaryl and heterocyclic groups;

[0029] (iii) By R f and R g and R h and R i or R j and R k combined with the nitrogen to which they are attached to form a heterocyclic group;

[0030] Each ((i), (ii), (iii)) is optionally replaced by 1, 2, 3 or 4 independently selected from 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 , hydroxyl, 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 Substitution of haloalkoxy substituents;

[0031] R 4 is hydrogen or a group -L 1A -L 2A -L 3A ;

[0032] L 1A Not present or optionally replaced by C 1-2 Alkyl or oxo-substituted C 1-3 Alkylene;

[0033] L 2A Does not exist 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) 2 N(R a1 )-or-N(R a1 )S(O) 2 -;

[0034] R a1 and R b1 are independently hydrogen or C 1-2 alkyl;

[0035] L 3A It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, heterocyclyl or heteroaryl, wherein L 3A Optionally independently selected from halogen, cyano, hydroxy, carboxyl, carbamoyl, sulphamoyl, 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) 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;

[0036] R c1 and Rd1 are independently hydrogen or C 1-4 alkyl;

[0037] y is 0, 1, or 2;

[0038] z is 1, 2, or 3;

[0039] R 5 is hydrogen or a group -L 1B -L 2B -L 3B ;

[0040] L 1B Not present or optionally replaced by C 1-2 Alkyl or oxo-substituted C 1-3 Alkylene;

[0041] L 2B Does not exist 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) 2 N(R a2 )-or-N(R a2 )S(O) 2 -;

[0042] R a2 and R b2 are independently hydrogen or C 1-2 alkyl;

[0043] L 3B It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, heterocyclyl or heteroaryl, wherein L 3B Optionally independently selected from halogen, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, 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(Rd2 )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;

[0044] R c2 and R d2 are independently hydrogen or C 1-4 alkyl;

[0045] y' is 0, 1, or 2;

[0046] z' is 1, 2, or 3;

[0047] R 6 is hydrogen or a group -L 1C -L 2C -L 3C ;

[0048] L 1C Not present or optionally replaced by C 1-2 Alkyl or oxo-substituted C 1-3 Alkylene;

[0049] L 2C Does not exist 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) 2 N(R a3 )-or-N(R a3 )S(O) 2 -;

[0050] R a3 and R b3 are independently hydrogen or C 1-2 alkyl;

[0051] L 3C It is hydrogen, C 1-6 Alkyl, C3-6 Cycloalkyl, phenyl, heterocyclyl or heteroaryl, wherein L 3C Optionally independently selected from halogen, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, 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) 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;

[0052] R c3 and R d3 are independently hydrogen or C 1-4 alkyl;

[0053] y" is 0, 1, or 2;

[0054] z” is 1, 2, or 3;

[0055] The conditions are:

[0056] Group-L 1A -L 2A -L 3A , -L 1B -L 2B -L 3B and -L 1C -L 2C -L 3C does not contain -OO-, -SO-, -OS- or -SS- units as linking units within the group;

[0057] Group-L 1A -L 2A -L 3A Do not place -ON- or -SN- units with R4 The connected ring nitrogen atoms are adjacent,

[0058] Group-L 1B -L 2B -L 3B Do not place N, O, or S atoms next to R 5 The attached oxime oxygen atoms are adjacent, and

[0059] Group-L 1C -L 2C -L 3C Do not place -ON- or -SN- units with R 6 The linked ring nitrogen atoms are adjacent.

[0060] In another aspect, the present invention provides a compound of formula (I) and a pharmaceutically acceptable salt thereof for use in treating a tumor disease, such as cancer, in a subject selected from a mammal, particularly a human.

[0061] In another aspect, the present invention provides the use of a compound of formula (I) and a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a tumor disease, such as cancer, in a subject selected from mammals, particularly humans.

[0062] In another aspect, the present invention provides a method for treating a tumor disease, such as cancer, in a subject selected from a mammal, particularly a human, comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof, for example in a therapeutically effective amount.

[0063] In another 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.

[0064] When the compound of formula (I) contains one or two or more chiral centers (for example, when R 1 , R 2 and R 3 When the compounds are different parts), such compounds can be provided as pure enantiomers or pure diastereomers and mixtures thereof in any ratio, all of which are included within the scope of the compounds of formula (I). The two geometric isomers produced due to the orientation of the bond between the oxime nitrogen atom and the oxygen atom, namely compounds (Ia) and (Ib) shown below, and mixtures thereof in any ratio are included within the scope of the present invention.

[0065]

[0066] The compounds of the present invention also include all isomers of the compounds of formula (I) and their intermediates. For example, as shown below, when R 4 is a hydrogen atom and / or R 6When it is a hydrogen atom, -N(R 4 )-C(=NOR 5 )-N(R 6 )-partially produced isomers.

[0067]

[0068] Isotope-labeled compounds including deuterium substitution and carbon-13 and / or carbon-14 labeling are also included in the scope of the compound of formula (I). The compound of formula (I) can also be solvated, particularly hydrated, and such solvated and hydrated forms of the compound of formula (I) are also included in the scope of the compound of formula (I). Solvation and hydration may occur during the preparation process.

[0069] Mentioning the compounds of the present invention includes pharmaceutically acceptable salts of the compounds. Such salts may also exist in the form of hydrates and solvates. Examples of pharmacologically acceptable salts of compounds of formula (I) are physiologically acceptable mineral acid salts, such as hydrochloric acid, sulfuric acid and phosphoric acid, or organic acid salts, such as methanesulfonic acid, p-toluenesulfonic acid, lactic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid. Other examples of pharmacologically acceptable salts of compounds of formula (I) are alkali metal salts and alkaline earth metal salts, such as sodium salts, potassium salts, lithium salts, calcium salts or magnesium salts, ammonium salts or organic base salts, such as methylamine salts, dimethylamine salts, triethylamine salts, piperidine salts, ethylenediamine salts, lysine salts, choline hydroxide salts, meglumine salts, morpholine salts or arginine salts.

[0070] "Alkylene" alone or as part of another substituent refers to a group having the specified number of carbon atoms (i.e., C 1-6 refers to a divalent saturated straight or branched hydrocarbon of 1 to 6 carbon atoms). Examples of alkylene include -CH 2 -、-CH 2 -CH 2 -、-CH(CH 3 )-、-CH 2 -CH 2 -CH 2 -、-CH(CH 3 )-CH 2 -、-CH(CH 2 CH 3 )- and -CH 2 CH(CH 3 )CH 2 -.

[0071] "Alkoxy" and "haloalkoxy" refer to an alkyl and haloalkyl group, respectively, attached to the rest of the molecule through an oxygen atom.

[0072] "Alkyl" alone or as part of another substituent refers to a group having the specified number of carbon atoms (i.e., C 1-6 The term "alkyl" refers to a saturated straight or branched hydrocarbon radical of 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl.

[0073] "Aminoalkyl" refers to an alkyl group substituted with N(R)R', wherein R and R' are independently hydrogen, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl or -C(O)C 1-6 Alkyl. For example, "amino C 1-6 "Alkyl" includes NH 2 1-4, 1-6, 1-dimethylaminomethyl, 1-diethylaminoethyl, 1-dimethylaminoethyl, 1-acetylaminomethyl, and 1-acetylaminoethyl. In some embodiments, N(R)R' is attached to a carbon atom of the alkyl group distal to the point of attachment to the rest of the molecule.

[0074] Unless otherwise indicated, a "bridged heterocyclic group" refers to a heterocyclic group having a n A saturated 5-7 membered monocyclic heterocyclic ring having two non-adjacent ring atoms connected by a radical, wherein n is 1, 2 or 3, and each X1 is CRR', NR, S, SO, SO 2 or O, where no more than one X1 is NR, SO, SO 2 or O, and R and R' are independently H or methyl. The 5-7 membered heterocyclic ring has 1, 2 or 3 heteroatoms independently selected from N, O, S as ring atoms, wherein the sulfur atom and the nitrogen atom are optionally oxidized, and the remaining ring atoms are carbon atoms. O and S are not bridgehead atoms, and such rings do not contain adjacent oxygen atoms, adjacent sulfur atoms, or adjacent oxygen atoms 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.

[0075] "Cycloalkyl" refers to a saturated hydrocarbon ring having the specified number of carbon atoms (e.g., C 3-6 Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0076] Unless otherwise indicated, "fused heterocyclyl" refers to 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, wherein the sulfur and nitrogen atoms are optionally oxidized, and the remaining ring atoms are carbon atoms, wherein the heterocyclyl ring is fused to phenyl, 5- or 6-membered heteroaryl, C 3-6Two adjacent ring members of a cycloalkyl or heterocyclyl are fused, each group being as defined herein. A fused heterocyclyl may be attached to the rest of the molecule via any ring atom. The number of ring atoms in a saturated or partially saturated monocyclic ring includes 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.

[0077] "Halogen" by itself or as part of another substituent refers to a fluorine, chlorine, bromine, or iodine atom.

[0078] "Haloalkyl" refers to an alkyl group substituted with 1 to 5 halogen atoms, including monohaloalkyl and polyhaloalkyl. 1-4 "Haloalkyl" includes trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl and 3-bromopropyl. Similarly, fluoromethyl also includes -CH 2 F, -CHF 2 and -CF 3 .

[0079] Unless otherwise indicated, "heteroaryl" refers to a 5- to 10-membered aromatic ring containing 1 to 5 heteroatoms independently selected from N, S and O as ring atoms, wherein the nitrogen and sulfur atoms are optionally oxidized. The heteroaryl group can be attached to the rest of the molecule via 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, quinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuranyl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridinyl, benzothiazolyl, benzofuranyl, benzothiophenyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furanyl, and thienyl.

[0080] Unless otherwise indicated, "heterocyclyl" refers to a saturated or partially unsaturated 4- to 10-membered monocyclic or bicyclic ring having 1 to 4 heteroatoms independently selected from N, S and O as ring atoms, wherein the sulfur atoms and nitrogen atoms are optionally oxidized, and the remaining ring atoms are carbon atoms. Such rings do not contain 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-dioxane, morpholinyl, thiomorpholinyl, thiomorpholinyl-S-oxide, 1,1-dioxothiomorpholinyl, piperazinyl, pyranyl, pyridonyl, 3-pyrrolidinyl, thiopyranyl, pyronyl, tetrahydrofuranyl, and tetrahydrothiophenyl. The heterocyclyl group may be attached to the rest of the molecule via a ring carbon atom or a heteroatom.

[0081] "Hydroxyalkyl" refers to an alkyl group as defined above substituted with 1 or 2 hydroxy moieties. For example, "hydroxyC 1-4 "Alkyl" includes hydroxymethyl, 1- or 2-hydroxyethyl, 1,2-dihydroxyethyl, and hydroxypropyl. In some embodiments, one hydroxyl moiety is attached to a carbon atom of the alkyl group distal to the point of attachment to the rest of the molecule.

[0082] Oxo is a =0 group. When a moiety is referred to as being "substituted with oxo," it is counted as being substituted with one substituent.

[0083] "Spiroheterocyclyl" refers to a saturated or partially unsaturated bicyclic ring of 5 to 12 ring atoms, wherein 1, 2 or 3 ring atoms are heteroatoms independently selected from N, S and O, wherein the sulfur atoms and nitrogen atoms are optionally oxidized, and the remaining ring atoms are carbon atoms, wherein the two rings are linked together by a 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]octane, 2-oxa-6-azaspiro[3.4]octane-6-yl, 4-oxaspiro[2.4]heptane, spiro[3.5]non-6-enyl, and 2,7-diazaspiro[4.4]nonane.

[0084] When a substituent is referred to as being "optionally substituted", the substituent may be unsubstituted or substituted with the substituents specified, for example, with 1, 2 or 3 of the substituents specified.

[0085] The following examples and embodiments of substituent definitions may be combined arbitrarily.

[0086] R 1It is hydrogen, cyano, formyl, -CONH 2 、-CH 2 OH, -CH 2 OC 1-2 Alkyl, C 1-2 Alkyl, C 1-2 A haloalkyl group or an ethynyl group.

[0087] Preferably, R 1 It is cyano, C 1-2 Alkyl or ethynyl.

[0088] In some embodiments, R 1 Is cyano or C 1-2 alkyl.

[0089] R 1 Specific examples include cyano and -CH 3 .

[0090] R 2 and R 3 Independently C 1-2 Alkyl, or R 2 and R 3 Together with the carbon atom to which they are attached they form a cyclopropyl or oxetanyl group.

[0091] Preferably, R 2 and R 3 Together with the carbon atom to which they are attached they form a cyclopropyl or oxetanyl group (eg, an oxetanyl group wherein the oxygen atom is distal to the quaternary carbon atom).

[0092] Specific examples include cyclopropyl and oxetanyl (eg, oxetanyl wherein the oxygen atom is distal to the quaternary carbon atom).

[0093] X 1 Yes CR 7 or N, and R 7 It is hydrogen or fluorine.

[0094] In some embodiments, X 1 Yes CR 7 .

[0095] In some embodiments, X 1 Yes CR 7 , and R 7 It's H.

[0096] X 2 Yes CR 8 or N, and R 8 It is hydrogen or fluorine.

[0097] In some embodiments, X2 is CR 8 .

[0098] In some embodiments, X 2 Yes CR 8 , and R 8 It's H.

[0099] X 3 Yes CR 9 or N.

[0100] In some embodiments, X3 is CR 9 .

[0101] In some embodiments, X 1 , X 2 and X 3 No more than two of them are N;

[0102] In some embodiments, X 1 Yes CR 7 ;X 2 Yes CR 8 ; and X 3 Yes CR 9 .

[0103] In some embodiments, X 1 Yes CR 7 ;X 2 Yes CR 8 ;X 3 Yes CR 9 ; and R 7 and R 8 It's hydrogen.

[0104] 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 Halogenated alkoxy, C 2-4 Alkynyl, C 3-6 Cycloalkyl, phenyl, heteroaryl, heterocyclyl, fused heterocyclyl, spiro heterocyclyl or bridged heterocyclyl, wherein the cycloalkyl, phenyl, heteroaryl, heterocyclyl, fused heterocyclyl, spiro heterocyclyl and bridged heterocyclyl are optionally substituted by R a , R b and / or R c replace;

[0105] Preferably R 9 is hydrogen, halogen, cyano, -N(R m )R n , C 1-4 Alkyl, C 1-4 Haloalkyl, C1-4 Alkoxy, C 1-4 Halogenated alkoxy, 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, 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 replaced by R a , R b and / or R c replace; or

[0106] R 9 is a spiro heterocyclic group, wherein X 3 The first ring connected 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 the second ring is connected to the first ring through a common carbon atom and is 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, wherein the spiro heterocyclyl is optionally replaced by R a , R b and / or R c replace.

[0107] 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 replaced by R a , R b and / or R c replace; or

[0108] R 9 is a spirocyclic system, in which 3 The first ring connected is a 4- to 6-membered monocyclic heterocyclyl containing 1 to 2 heteroatoms selected from N as ring atoms, and the second ring is connected to the first ring through a common carbon atom, and the second ring is a 4- to 6-membered heterocyclyl containing 1 heteroatom independently selected from N, O and S (especially selected from O) as a ring atom, wherein the first ring of the spiroheterocyclyl is optionally replaced by R b and / or R c replace.

[0109] 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, wherein phenyl and 6-membered heteroaryl are optionally replaced by R in the para position to the rest of the molecule a substituted, and optionally further substituted by Rb substituted, and the 5-membered heteroaryl is optionally substituted at the 3-position distal to the rest of the molecule by R a substituted, and optionally further substituted by R b Replacement; or R 9 It is part (R 9a ) or part of ( R9b ):

[0110]

[0111] Where Z 1 N or CH, 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 as a ring atom; and wherein optionally Z 1 and Z 2 At least one of them is N or N(R a ). As with the definition of the heterocyclyl moiety, R 9a and R 9b The S and N ring atoms in are optionally oxidized. For clarity, in the section (R 9a ) and (R 9b ), the substituent R b occupies one of the two carbon atoms on the left side of the part shown in the figure, and R c Occupies one of the two carbon atoms on the right side of the portion shown.

[0112] Describe the possible stereoisomers (R 9a ) part is as follows (R c are the hydrogens in the lower right two structures):

[0113]

[0114] When Z 1 or Z 2 CH or CH(R a ), additional stereoisomers are possible.

[0115] Describe the possible stereoisomers (R 9b ) part is as follows (R c are the hydrogens in the lower right two structures):

[0116]

[0117] When Z 2CH or CH(R a ), additional stereoisomers are possible.

[0118] Can be R a , R b and / or R c Optionally substituted R 9 Specific examples include hydrogen, chlorine, phenyl, piperidinyl (eg, piperidin-1-yl, piperidin-4-yl), piperazinyl (eg, piperazin-1-yl), and imidazolyl (eg, imidazol-5-yl), where possible.

[0119] By R a , R b and / or R c When replaced 9 Specific examples include the following groups:

[0120]

[0121] R a is hydrogen, -N(R m )R n , C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogen, cyano, oxo, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl 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) 2 N(R h )R i or C 1-6 Alkyl-N(R j )R k wherein the cycloalkyl, heteroaryl and heterocyclyl are optionally substituted by 1, 2, 3 or 4 independently selected 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 , hydroxyl, oxo, C 1-6 Alkoxy, halogen, cyano, amino, -NH(C 1-4 Alkyl), -N(C 1-4 alkyl) 2 , C 1-6Haloalkyl and C 1-6 The substituents of the haloalkoxy group are substituted.

[0122] 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 .

[0123] For example, R a is hydrogen, -NH 2 、-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 Halogenated alkyl-C 3-6 Cycloalkyl, -C(O)-C 3-6 Cycloalkyl, -C(O)-C 3-6 Cycloalkyl-NH 2 、-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-NH 2 、-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)NH 2 、-C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 、-C(O)N(C 1-4 Alkyl)(C 3-6Cycloalkyl), 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 、-C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Alkyl-NH 2 、-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-NH 2 、-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-NH 2 、-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) 2 , 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, such as pyrrolidinyl or morpholinyl; and wherein the heterocyclyl is optionally attached to the carbonyl portion via a nitrogen atom, and wherein alkyl, haloalkyl, cycloalkyl, heteroaryl and heterocyclyl are optionally replaced by 1, 2, 3 or 4 heteroatoms independently selected from 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 , hydroxyl, 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 The substituents of the haloalkoxy group are substituted.

[0124] For example, R a It is hydrogen, C 1-4 Alkyl, -C(O)-C 1-4 Alkyl-C 3-6 Cycloalkyl, -C(O)-C 1-4 Halogenated alkyl-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-NH 2 、-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)NH 2 、-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-NH 2 , C 1-4 Alkyl-NH(C 1-4 Alkyl) or C 1-4 Alkyl-N(C 1-4 alkyl) 2 .

[0125] R a Specific examples include hydrogen, -CH 3 、-C(O)-CH 3 、-C(O)-C(CH 2 -CH 2 )-CH 3 、-C(O)-C(CH 2 -CH 2 )-NH 2 、-C(O)-NH 2 、-C(O)-N(CH 3 ) 2 and -CH 2 -NH 2 .

[0126] Part -C(O)-C(CH 2 -CH 2 )-CH 3 and -C(O)-C(CH 2 -CH2 )-NH 2 Respectively

[0127] shown.

[0128] R b is hydrogen, -N(R m )R n , C 1-6 Alkyl, C 1-4 Alkyl-N(R m )R n , hydroxyl, C 1-6 Alkoxy, halogen, cyano, C 1-6 Haloalkyl or C 1-6 Halogenated alkoxy.

[0129] 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-NH 2 , C 1-4 Alkyl-NH(C 1-4 Alkyl), C 1-4 Alkyl-N(C 1-4 alkyl) 2 .

[0130] In some embodiments, R b is hydrogen or C 1-4 alkyl.

[0131] R b Specific examples include hydrogen and -CH 3 .

[0132] R c is hydrogen, -N(R m )R n , C 1-6 Alkyl, C 1-4 Alkyl-N(R m )R n , hydroxyl, C 1-6 Alkoxy, halogen, cyano, C 1-6 Haloalkyl or C 1-6 Halogenated alkoxy.

[0133] Preferably, R c is hydrogen or C 1-4 alkyl;

[0134] R c Specific examples include hydrogen and -CH 3 .

[0135] R d It is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 wherein the alkyl, haloalkyl, cycloalkyl, phenyl, heteroaryl and heterocyclyl are optionally substituted by 1, 2, 3 or 4 groups independently selected from 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 , hydroxyl, 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 The substituents of the haloalkoxy group are substituted.

[0136] Preferably, R d It 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, and wherein said alkyl, haloalkyl, cycloalkyl and heterocyclyl are optionally substituted by 1 or 2 independently 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-NH 2 , C 1-6 Alkyl-NH(C 1-4 Alkyl), C 1-6 Alkyl-N(C 1-4 alkyl) 2 and C 1-4 The substituents of the haloalkyl group are substituted.

[0137] For example, R d It is hydrogen, C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein the cycloalkyl is optionally substituted by 1 or 2 independently selected C 1-4 Alkyl, amino, -NH(C 1-4 Alkyl), -N(C1-4 alkyl) 2 and C 1-4 The substituents of the haloalkyl group are substituted.

[0138] For example, R d It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl-C 3-6 Cycloalkyl, C 3-6 Cycloalkyl-NH 2 , 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-NH 2 , 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 , heterocyclic group, heterocyclic group-NH 2 、Heterocyclyl-NH(C 1-4 alkyl), heterocyclyl-N(C 1-4 alkyl) 2 , heterocyclyl-C 1-4 Alkyl, heterocyclic-C 1-4 Alkyl-NH 2 , heterocyclyl-C 1-4 Alkyl-NH(C 1-4 alkyl), heterocyclyl-C 1-4 Alkyl-N(C 1-4 alkyl) 2 , 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, for example pyrrolidinyl or morpholinyl.

[0139] R d Specific examples include hydrogen, -CH 3 、-C(CH 2 -CH 2 )-NH 2 and -C(CH 2 -CH 2 )-CH3 .

[0140] R e is hydrogen or C 1-6 alkyl.

[0141] R f It is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, amino C 1-6 Alkyl or hydroxyl C 1-6 alkyl.

[0142] Preferably, R f is hydrogen or C 1-4 alkyl.

[0143] R f Specific examples of include hydrogen.

[0144] R g It is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, amino C 1-6 Alkyl or hydroxyl C 1-6 alkyl.

[0145] Preferably, R g is hydrogen or C 1-4 alkyl.

[0146] R g Specific examples of include hydrogen.

[0147] Optionally, R f and R g Together with the nitrogen atom to which they are attached, they form a heterocyclic group, wherein the heterocyclic group is optionally substituted by 1, 2 or 3 independently selected 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 , hydroxyl, 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 The substituents of the haloalkoxy group are substituted.

[0148] R h It is hydrogen, C 1-6 Alkyl, C1-6 Haloalkyl, amino C 1-6 Alkyl or hydroxyl C 1-6 alkyl.

[0149] R i It is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, amino C 1-6 Alkyl or hydroxyl C 1-6 alkyl.

[0150] Optionally, R h and R i Together with the nitrogen atom to which they are attached, they form a heterocyclic group, wherein the heterocyclic group is optionally substituted by 1, 2 or 3 independently selected 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 , hydroxyl, 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 The substituents of the haloalkoxy group are substituted.

[0151] R j It is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, amino C 1-6 Alkyl or hydroxyl C 1-6 alkyl.

[0152] Preferably, R j is hydrogen or C 1-4 alkyl.

[0153] R j Specific examples of include hydrogen.

[0154] R k It is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, amino C 1-6 Alkyl or hydroxyl C 1-6 alkyl.

[0155] Preferably, R k is hydrogen or C 1-4 alkyl.

[0156] R k Specific examples of include hydrogen.

[0157] Optionally, R j and R k Together with the nitrogen atom to which they are attached, they form a heterocyclic group, wherein the heterocyclic group is optionally substituted by 1, 2 or 3 independently selected 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 , hydroxyl, 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 The substituents of the haloalkoxy group are substituted.

[0158] Each R m Independence is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, amino C 1-6 Alkyl or hydroxyl C 1-6 alkyl.

[0159] Preferably, each R m Independently hydrogen or C 1-4 alkyl.

[0160] Each R n Independence is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, amino C 1-6 Alkyl or hydroxyl C 1-6 alkyl.

[0161] Preferably, each R n Independently hydrogen or C 1-4 alkyl.

[0162] R 4 is hydrogen or a group -L 1A -L 2A -L 3A .

[0163] In some embodiments, R 4 It is a group-L 1A -L 2A -L 3A .

[0164] R 4 Specific examples include -CH 2-(methylpyrazol-4-yl) (e.g. -CH 2 -(1-methylpyrazol-4-yl), -CH 2 -(trifluoromethylpyrazol-4-yl) (e.g. -CH 2 -(1-trifluoromethylpyrazol-4-yl)) and -CH 2 -(methylthiazol-5-yl) (e.g. -CH 2 -(2-methylthiazol-5-yl)).

[0165] L 1A Does not exist or is C 1-2 Alkyl or oxo optionally substituted C 1-3 Alkylene.

[0166] In some embodiments, L 1A It is C 1-3 Alkylene.

[0167] In some embodiments, L 1A Does not exist.

[0168] L 1A Specific examples include -CH 2 -.

[0169] L 2A Does not exist 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) 2 N(R a1 )-or-N(R a1 )S(O) 2 -.

[0170] In some embodiments, L 2A Does not exist.

[0171] R a1 is hydrogen or C 1-2 alkyl.

[0172] R b1 is hydrogen or C 1-2 alkyl.

[0173] L 3A It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, heterocyclyl or heteroaryl, wherein L3A Optionally independently selected from halogen, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, 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) 2 N(R d1 )R c1 、-N(R d1 )S(O) 2 R c1 and -(CH 2 ) z N(R d1 )R c1 The invention is substituted with one or more (e.g., 1, 2 or 3) substituents.

[0174] In some embodiments, L 3A It 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 3A Optionally independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, 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 )Rc1 、-N(R d1 )S(O) 2 R c1 and -(CH 2 ) z N(R d1 )R c1 substituted with 1, 2 or 3 substituents.

[0175] In some embodiments, L 3A is phenyl or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, S and O as ring atoms, wherein L 3A Optionally independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, 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 1, 2 or 3 substituents.

[0176] In some embodiments, L 3A is phenyl or a 5- to 6-membered heteroaryl group containing 1 or 2 heteroatoms independently selected from N, S and O as ring atoms, wherein at least one heteroatom is N, wherein L 3A Optionally substituted with one or two substituents independently selected from halogen, cyano, methyl and trifluoromethyl.

[0177] 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 -(2-methylthiazol-5-yl)).

[0178] R c1 is hydrogen or C 1-4 alkyl.

[0179] R d1 is hydrogen or C 1-4 alkyl.

[0180] y is 0, 1, or 2.

[0181] z is 1, 2, or 3.

[0182] In some embodiments,

[0183] L 1A It is C 1-3 Alkylene;

[0184] L 2A Does not exist.

[0185] L 3A is phenyl or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S as ring atoms, wherein L 3A Optionally independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, 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 1, 2 or 3 substituents;

[0186] R c1 is hydrogen or C 1-4 alkyl;

[0187] R d1 is hydrogen or C 1-4 alkyl;

[0188] y is 0, 1, or 2; and

[0189] z is 1, 2, or 3.

[0190] In some embodiments,

[0191] L 1A It is C 1-3 Alkylene;

[0192] L 2A does not exist; and

[0193] L 3A is phenyl or a 5- to 6-membered heteroaryl group containing 1 or 2 heteroatoms independently selected from N, S and O as ring atoms, wherein at least one heteroatom is N, wherein L 3A Optionally substituted with one or two substituents independently selected from halogen, cyano, methyl and trifluoromethyl.

[0194] R 5 is hydrogen or a group -L 1B -L 2B -L 3B .

[0195] In some embodiments, R 5 It is a group-L 1B -L 2B -L 3B .

[0196] In some embodiments, R 5 is hydrogen or a group -L 1B -L 2B -L 3B , where the group -L 1B -L 2B -L 3B It is C 1-6 alkyl.

[0197] R 5 Specific examples include -CH 3 、-CH 2 CH 3 、-CH(CH 3 )(CH 3 ) and -CH 2 -(dimethylthiazol-5-yl) (e.g., -CH 2 -(2,4-dimethylthiazol-5-yl)).

[0198] L 1B Does not exist or is C 1-2 Alkyl or oxo optionally substituted C 1-3 Alkylene.

[0199] In some embodiments, L 1B It is C 1-3 Alkylene.

[0200] In some embodiments, L 1B Does not exist.

[0201] L 1B Specific examples include -CH 2 -.

[0202] L 2B Does not exist 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) 2 N(R a2 )-or-N(R a2 )S(O) 2 -.

[0203] In some embodiments, L 2B Does not exist.

[0204] R a2 is hydrogen or C 1-2 alkyl.

[0205] R b2 is hydrogen or C 1-2 alkyl.

[0206] L 3B It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, heterocyclyl or heteroaryl, wherein L 3B Optionally independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, 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)Rc2 、-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 The invention is substituted with one or more (e.g., 1, 2 or 3) substituents.

[0207] In some embodiments, L 3B It 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 Optionally independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, 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 1, 2 or 3 substituents.

[0208] In some embodiments, L 3B is phenyl or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, S and O as ring atoms, wherein L 3BOptionally independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, 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 1, 2 or 3 substituents.

[0209] In some embodiments, L 3B is phenyl or a 5- to 6-membered heteroaryl group containing 1 or 2 heteroatoms independently selected from N, S and O as ring atoms, wherein at least one heteroatom is N, wherein L 3B Optionally substituted with one or two substituents independently selected from halogen, cyano, methyl and trifluoromethyl.

[0210] L 3B Specific examples include -CH 3 、-CH 2 CH 3 、-CH(CH 3 )(CH 3 ) and dimethylthiazol-5-yl (eg, 2,4-dimethylthiazol-5-yl).

[0211] R c2 is hydrogen or C 1-4 alkyl.

[0212] R d2 is hydrogen or C 1-4 alkyl.

[0213] y' is 0, 1, or 2.

[0214] z' is 1, 2, or 3.

[0215] In some embodiments,

[0216] L 1B It is C 1-3 Alkylene;

[0217] L 2B does not exist;

[0218] L 3B is phenyl or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S as ring atoms, wherein L 3B Optionally independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, 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 1, 2 or 3 substituents;

[0219] R c2 is hydrogen or C 1-4 alkyl;

[0220] R d2 is hydrogen or C 1-4 alkyl;

[0221] y' is 0, 1, or 2; and

[0222] z' is 1, 2, or 3.

[0223] In some embodiments,

[0224] L 1B It is C 1-3 Alkylene;

[0225] L 2B does not exist; and

[0226] L3B is phenyl or a 5- to 6-membered heteroaryl group containing 1 or 2 heteroatoms independently selected from N, S and O as ring atoms, wherein at least one heteroatom is N, wherein L 3B Optionally substituted with one or two substituents independently selected from halogen, cyano, methyl and trifluoromethyl.

[0227] In some embodiments, -L 1B -L 2B -L 3B It is C 1-6 alkyl.

[0228] R 6 is hydrogen or a group -L 1C -L 2C -L 3C .

[0229] In some embodiments, R 6 is hydrogen or a group -L 1C -L 2C -L 3C , where the group -L 1C -L 2C -L 3C It is C 1-6 alkyl.

[0230] R 6 Specific examples of include hydrogen.

[0231] L 1C Does not exist or is C 1-2 Alkyl or oxo optionally substituted C 1-3 Alkylene.

[0232] In some embodiments, L 1C It is C 1-3 Alkylene.

[0233] In some embodiments, L 1C Does not exist.

[0234] L 2C Does not exist 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) 2 N(R a3 )-or-N(R a3 )S(O)2 -.

[0235] In some embodiments, L 2C Does not exist.

[0236] R a3 is hydrogen or C 1-2 alkyl.

[0237] R b3 is hydrogen or C 1-2 alkyl.

[0238] L 3C It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, heterocyclyl or heteroaryl, wherein L 3C Optionally independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, 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) 2 N(R d3 )R c3 、-N(R d3 )S(O) 2 R c3 and -(CH 2 ) z” N(R d3 )R c3 is substituted with one or more substituents.

[0239] In some embodiments, L 3C It 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 3COptionally independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, 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 1, 2 or 3 substituents.

[0240] In some embodiments, L 3C is phenyl or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, S and O as ring atoms, wherein L 3C Optionally independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, 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 c1substituted with 1, 2 or 3 substituents.

[0241] In some embodiments, L 3C is phenyl or a 5- to 6-membered heteroaryl group containing 1 or 2 heteroatoms independently selected from N, S and O as ring atoms, wherein at least one heteroatom is N, wherein L 3C Optionally substituted with one or two substituents independently selected from halogen, cyano, methyl and trifluoromethyl.

[0242] R c3 is hydrogen or C 1-4 alkyl.

[0243] R d3 is hydrogen or C 1-4 alkyl.

[0244] y" is 0, 1, or 2.

[0245] z” is 1, 2, or 3.

[0246] In the compounds of formula (I), the group -L 1A -L 2A -L 3A , -L 1B -L 2B -L 3B and -L 1C -L 2C -L 3C does not contain -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, such as -S(O)-, -S(O) 2- .

[0247] In the compounds of formula (I), the group -L 1A -L 2A -L 3A Do not place -ON- or -SN- units with R 4 The attached ring nitrogen atoms are adjacent; the group -L 1B -L 2B -L 3B Do not place N, O, or S with R 5 The oxime oxygen atoms are adjacent, and the group -L 1C -L 2C -L 3C Do not place -ON- or -SN- units with R 6 The linked ring nitrogen atoms are adjacent.

[0248] In some embodiments, the compound of formula (I) is a compound of formula (la).

[0249] In some embodiments, the compound of formula (I) is a compound of formula (Ib).

[0250] In some embodiments,

[0251] R 1 is methyl or cyano; and

[0252] R 2 and R 3 Together with the carbon atom to which they are attached they form a cyclopropyl or oxetanyl group.

[0253] In some embodiments, R 9 It is C 3-6 Cycloalkyl, phenyl, heteroaryl (especially 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, S and O as ring atoms), heterocyclyl (especially 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 replaced by R a , R b and / or R c replace;

[0254] or R 9 is a spiro heterocyclic group (especially a spiro ring system, wherein X 3 The first ring connected is a 5- to 7-membered monocyclic heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, S and O as ring atoms (especially 1 to 2 heteroatoms selected from N as ring atoms), and the second ring is connected to the first ring through 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 (especially 1 heteroatom selected from O and S as ring atoms), wherein the spiroheterocyclyl is optionally replaced by R a , R b and / or R c replace.

[0255] In some embodiments, R 9 is 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 replaced by R a , R b and / or R c replace; or

[0256] R 9 is a spirocyclic system, in which 3The first ring connected is a 4- to 6-membered monocyclic heterocyclyl containing 1 to 2 heteroatoms selected from N as ring atoms, and the second ring is connected to the first ring via 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 (especially selected from O) as a ring atom, wherein the first ring of the spiroheterocyclyl is optionally replaced by R b and / or R c replace.

[0257] In some embodiments, R 9 is phenyl, 5- to 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N as ring atoms, wherein the phenyl and 6-membered heteroaryl are optionally replaced by R in the para position to the rest of the molecule a and optionally further substituted by R b substituted, and the 5-membered heteroaryl is optionally substituted at the 3-position distal to the rest of the molecule by R a and optionally further substituted by R b replace; or

[0258] R 9 is the part as described above (R 9a ) or (R 9b ), where Z 1 N or CH, 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 heterocyclic ring containing one heteroatom selected from N, O and S; and wherein optionally Z 1 and Z 2 At least one of them is N or N(R a );

[0259] and among them, R a Can be 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 , and optionally

[0260] R d Can be C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein the cycloalkyl is optionally substituted by 1 or 2 independently selected C 1-4 Alkyl, amino, -NH(C1-4 Alkyl), -N(C 1-4 alkyl) 2 and C 1-4 The substituents of the haloalkyl group are substituted.

[0261] In some embodiments,

[0262] 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 ;

[0263] 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

[0264] C 1-4 Alkyl-N(C 1-4 alkyl) 2 ;

[0265] R c is hydrogen or C 1-4 alkyl;

[0266] R d It is hydrogen, C 1-4 Alkyl, 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, and wherein the cycloalkyl and heterocyclyl are optionally substituted by 1 or 2 heteroatoms independently selected from C 1-4 Alkyl, amino, -NH(C 1-4 alkyl),

[0267] -N(C 1-4 alkyl) 2 , 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 and C1-4 Substitution of haloalkyl groups;

[0268] R f is hydrogen or C 1-4 alkyl;

[0269] R g is hydrogen or C 1-4 alkyl;

[0270] R j is hydrogen or C 1-4 alkyl;

[0271] R k is hydrogen or C 1-4 alkyl;

[0272] R m is hydrogen or C 1-4 Alkyl; and

[0273] R n is hydrogen or C 1-4 alkyl.

[0274] In some embodiments, when R 9 When L is an optionally substituted cycloalkyl, phenyl, heteroaryl, heterocyclyl, fused heterocyclyl, spiroheterocyclyl or bridged heterocyclyl, 3C is not cycloalkyl, phenyl, heterocyclyl or heteroaryl, each of which is optionally substituted.

[0275] In some embodiments, L 3A , L 3B and L 3C No more than two of the groups are cycloalkyl, phenyl, heterocyclyl or heteroaryl, each of which is optionally substituted.

[0276] In some embodiments, L 3A , L 3B and L 3C wherein no more than two of the groups are cycloalkyl, phenyl, heterocyclyl or heteroaryl, each of which is optionally substituted; and when R 9 When L is an optionally substituted cycloalkyl, phenyl, heteroaryl, heterocyclyl, fused heterocyclyl, spiroheterocyclyl or bridged heterocyclyl, 3C is not cycloalkyl, phenyl, heterocyclyl or heteroaryl, each of which is optionally substituted.

[0277] In some embodiments, L 3A , L 3B and L 3C At least one of them exists and each is an optionally substituted cycloalkyl, phenyl, heterocyclyl or heteroaryl.

[0278] In some embodiments, L 3A , L3B and L 3C At least one of them exists and each is optionally substituted phenyl or heteroaryl.

[0279] In some embodiments, L 3A and L 3B At least one of them exists and each is an optionally substituted cycloalkyl, phenyl, heterocyclyl or heteroaryl.

[0280] In some embodiments, L 3A and L 3B At least one of them exists and each is optionally substituted phenyl or heteroaryl.

[0281] In some embodiments, L 3A is present and is each optionally substituted cycloalkyl, phenyl, heterocyclyl or heteroaryl.

[0282] In some embodiments, L 3A is present and is each optionally substituted phenyl or heteroaryl.

[0283] In some embodiments, R 4 It is a group-L 1A -L 2A -L 3A , where 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 alkyl.

[0284] In some embodiments, R 4 It is a group-L 1A -L 2A -L 3A , where L 2A does not exist, and L 3A is phenyl or heteroaryl, each optionally substituted; and R 6 is hydrogen or C 1-6 alkyl.

[0285] In some embodiments, R 4 It is a group-L 1A -L 2A -L 3A , where L 2A does not exist, and L 3A is cycloalkyl, phenyl, heterocyclyl or heteroaryl, each optionally substituted; R 5 is hydrogen or a group -L 1B -L 2B -L 3B , where L2B does not exist; and R 6 is hydrogen or C 1-6 alkyl.

[0286] In some embodiments, R 4 It is a group-L 1A -L 2A -L 3A , where L 2A does not exist, and L 3A is phenyl or heteroaryl, each optionally substituted; R 5 is hydrogen or a group -L 1B -L 2B -L 3B , where L 2B does not exist; and R 6 is hydrogen or C 1-6 alkyl.

[0287] In some embodiments, L 2A , L 2B and L 2C Does not exist.

[0288] In some embodiments, R 4 It is a group-L 1A -L 2A -L 3A , where L 3A is cycloalkyl, phenyl, heterocyclyl or heteroaryl, each optionally substituted; R 5 is hydrogen or a group -L 1B -L 2B -L 3B , where L 3B is cycloalkyl, phenyl, heterocyclyl or heteroaryl, each optionally substituted, or a group -L 1B -L 2B -L 3B It is C 1-6 Alkyl; and R 6 is hydrogen or C 1-6 alkyl.

[0289] In some embodiments, R 4 It is a group-L 1A -L 2A -L 3A , where L 3A is phenyl or heteroaryl, each optionally substituted; R 5 is hydrogen or a group -L 1B -L 2B -L 3B , where L 3B is phenyl or heteroaryl, each optionally substituted, or a group -L 1B -L2B -L 3B It is C 1-6 Alkyl; and R 6 is hydrogen or C 1-6 alkyl.

[0290] In some embodiments, R 4 It is a group-L 1A -L 2A -L 3A ; R 5 is hydrogen or C 1-6 Alkyl; and R 6 is hydrogen or C 1-6 alkyl.

[0291] In some embodiments, R 4 It is a group-L 1A -L 2A -L 3A , where 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 alkyl.

[0292] In some embodiments, R 4 It is a group-L 1A -L 2A -L 3A , where 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 alkyl.

[0293] In some embodiments,

[0294] R 4 It is a group-L 1A -L 2A -L 3A ;

[0295] L 1A It is C 1-3 Alkylene;

[0296] L 2A does not exist;

[0297] L 3Ais phenyl or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S as ring atoms, wherein L 3A Optionally independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, 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 1, 2 or 3 substituents;

[0298] R c1 is hydrogen or C 1-4 alkyl;

[0299] R d1 is hydrogen or C 1-4 alkyl;

[0300] y is 0, 1, or 2;

[0301] z is 1, 2 or 3;

[0302] R 5 is hydrogen or a group -L 1B -L 2B -L 3B ;

[0303] L 1B It is C 1-3 Alkylene;

[0304] L 2B does not exist;

[0305] L 3B is phenyl or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S as ring atoms, wherein L 3BOptionally independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, 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 1, 2 or 3 substituents;

[0306] R c2 is hydrogen or C 1-4 alkyl;

[0307] R d2 is hydrogen or C 1-4 alkyl;

[0308] y' is 0, 1, or 2; and

[0309] z' is 1, 2 or 3;

[0310] or group-L 1B -L 2B -L 3B It is C 1-6 Alkyl; and

[0311] R 6 is hydrogen or a group -L 1C -L 2C -L 3C , where -L 1C -L 2C -L 3C It is C 1-6 alkyl.

[0312] In some embodiments,

[0313] R 4 It is a group-L 1A -L 2A-L 3A ;

[0314] L 1A It is C 1-3 Alkylene;

[0315] L 2A does not exist;

[0316] L 3A is phenyl or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S as ring atoms, wherein L 3A Optionally independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, 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 1, 2 or 3 substituents;

[0317] R c1 is hydrogen or C 1-4 alkyl;

[0318] R d1 is hydrogen or C 1-4 alkyl;

[0319] y is 0, 1, or 2;

[0320] z is 1, 2, or 3;

[0321] R 5 is hydrogen or C 1-6 Alkyl; and

[0322] R 6 is hydrogen or C1-6 alkyl.

[0323] In some embodiments,

[0324] R 4 It is a group-L 1A -L 2A -L 3A ;

[0325] L 1A It is C 1-3 Alkylene;

[0326] L 2A does not exist;

[0327] L 3A is phenyl or a 5- to 6-membered heteroaryl group containing 1 or 2 heteroatoms independently selected from N, S and O as ring atoms, wherein at least one heteroatom is N, wherein L 3A optionally substituted with one or two substituents independently selected from halogen, cyano, methyl and trifluoromethyl;

[0328] R 5 is hydrogen or a group -L 1B -L 2B -L 3B ;

[0329] L 1B It is C 1-3 Alkylene;

[0330] L 2B does not exist; and

[0331] L 3B is phenyl or a 5- to 6-membered heteroaryl group containing 1 or 2 heteroatoms independently selected from N, S and O as ring atoms, wherein at least one heteroatom is N, wherein L 3B optionally substituted with one or two substituents independently selected from halogen, cyano, methyl and trifluoromethyl;

[0332] or -L 1B -L 2B -L 3B It is C 1-6 Alkyl; and

[0333] R 6 It's hydrogen.

[0334] In some embodiments,

[0335] R 4 It is a group-L 1A -L 2A -L 3A ;

[0336] L 1A It is C 1-3Alkylene;

[0337] L 2A does not exist;

[0338] L 3A is phenyl or a 5- to 6-membered heteroaryl group containing 1 or 2 heteroatoms independently selected from N, S and O as ring atoms, wherein at least one heteroatom is N, wherein L 3A optionally substituted with one or two substituents independently selected from halogen, cyano, methyl and trifluoromethyl;

[0339] R 5 is hydrogen or C 1-6 Alkyl; and

[0340] R 6 It's hydrogen.

[0341] In some embodiments (embodiment A), the compound is a compound of formula (I), wherein

[0342] R 1 It is cyano, C 1-2 Alkyl or ethynyl;

[0343] R 2 and R 3 Together with the carbon atoms to which they are attached they form a cyclopropyl or oxetanyl group;

[0344] X 1 Yes CR 7 ;

[0345] X 2 Yes CR 8 ;

[0346] X 3 Yes CR 9 ;

[0347] R 7 and R 8 It is hydrogen;

[0348] 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 Halogenated alkoxy, 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, 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 replaced by R a , R b and / or R c replace;

[0349] or R 9 is a spiro heterocyclic group, wherein X 3 The first ring connected is a 5- to 7-membered monocyclic heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, S and O as ring atoms, and the second ring is connected to the first ring through a common carbon atom and is a 3- to 6-membered monocyclic cycloalkyl or a 3- to 6-membered monocyclic heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, S and O as ring atoms, wherein the spiro heterocyclic group is optionally replaced by R a , R b and / or R c replace;

[0350] 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 ;

[0351] 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 ;

[0352] R c For hydrogen:

[0353] R d It is hydrogen, C 1-4 Alkyl, C 3-6Cycloalkyl or a 4- to 7-membered monocyclic heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, S and O as ring atoms, and wherein the cycloalkyl and heterocyclyl are optionally substituted by 1 or 2 heteroatoms independently selected from C 1-4 Alkyl, amino, -NH(C 1-4 Alkyl), -N(C 1-4 alkyl) 2 , 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 and C 1-4 Substitution of haloalkyl groups;

[0354] R f is hydrogen or C 1-4 alkyl;

[0355] R g is hydrogen or C 1-4 alkyl;

[0356] R j is hydrogen or C 1-4 alkyl;

[0357] R k is hydrogen or C 1-4 alkyl;

[0358] Each R m is independently hydrogen or C1-4 alkyl;

[0359] Each R n Independently hydrogen or C 1-4 alkyl;

[0360] R 4 It is a group-L 1A -L 2A -L 3A ;

[0361] L 1A It is C 1-3 Alkylene;

[0362] L 2A does not exist;

[0363] L 3A is phenyl or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, S and O as ring atoms, wherein L 3A Optionally independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, 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) 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 1, 2 or 3 substituents;

[0364] or group-L 1A -L 2A -L 3A It is C 1-6 alkyl;

[0365] R c1 is hydrogen or C 1-4 alkyl;

[0366] R d1 is hydrogen or C 1-4 alkyl;

[0367] y is 0, 1, or 2;

[0368] z is 1, 2, or 3;

[0369] R 5 is hydrogen or a group -L 1B -L 2B -L 3B ;

[0370] L 1B It is C 1-3 Alkylene;

[0371] L 2B does not exist;

[0372] L 3B is phenyl or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S as ring atoms, wherein L 3BOptionally independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, 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 1, 2 or 3 substituents;

[0373] R c2 is hydrogen or C 1-4 alkyl;

[0374] R d2 is hydrogen or C 1-4 alkyl;

[0375] y' is 0, 1, or 2;

[0376] z' is 1, 2, or 3;

[0377] or group-L 1B -L 2B -L 3B It is C 1-6 alkyl;

[0378] R 6 is hydrogen or a group -L 1C -L 2C -L 3C , where the group -L 1C -L 2C -L 3C It is C 1-6 alkyl.

[0379] In some embodiments (embodiment B), the compound is of formula (I), wherein

[0380] R 1 Is cyano or C1-2 alkyl;

[0381] R 2 and R 3 Together with the carbon atoms to which they are attached they form a cyclopropyl or oxetanyl group;

[0382] X 1 Yes CR 7 ;

[0383] X 2 Yes CR 8 ;

[0384] X 3 Yes CR 9 ;

[0385] R 7 and R 8 It is hydrogen;

[0386] R 9 is hydrogen, halogen, cyano, phenyl, 5- to 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N as ring atoms, wherein phenyl and 6-membered heteroaryl are optionally replaced by R in the para position to the rest of the molecule a substituted, and optionally further substituted by R b substituted, and the 5-membered heteroaryl is optionally substituted at the 3-position distal to the attachment to the rest of the molecule by R a substituted, and optionally further substituted by R b Replacement; or R 9 It is part (R 9a ) or part (R 9b ):

[0387]

[0388] Where Z 1 N or CH, 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 heterocyclic group containing one heteroatom selected from N, O and S; and wherein optionally Z 1 and Z 2 At least one of them is N or N(R a );

[0389] R a is hydrogen, -N(R m )R n , C 1-6 Alkyl, Oxo, -C(O)Rd 、-C(O)N(R f )R g or C 1-6 Alkyl-N(R j )R k ;

[0390] R b is hydrogen or C 1-4 alkyl;

[0391] R c is hydrogen;

[0392] R d It is hydrogen, C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein the cycloalkyl is optionally substituted by 1 or 2 independently selected C 1-4 Alkyl, amino, -NH(C 1-4 Alkyl), -N(C 1-4 alkyl) 2 and C 1-4 Substitution of haloalkyl groups;

[0393] R f is hydrogen or C 1-4 alkyl;

[0394] R g is hydrogen or C 1-4 alkyl;

[0395] R j is hydrogen or C 1-4 alkyl;

[0396] R k is hydrogen or C 1-4 alkyl;

[0397] R m is hydrogen or C 1-4 alkyl;

[0398] R n is hydrogen or C 1-4 alkyl;

[0399] R 4 It is a group-L 1A -L 2A -L 3A ;

[0400] L 1A It is C 1-3 Alkylene;

[0401] L 2A does not exist;

[0402] L 3Ais phenyl or a 5- to 6-membered heteroaryl group containing 1 or 2 heteroatoms independently selected from N, S and O as ring atoms, wherein at least one heteroatom is N, wherein L 3A optionally substituted with one or two substituents independently selected from halogen, cyano, methyl and trifluoromethyl;

[0403] R 5 is hydrogen or a group -L 1B -L 2B -L 3B ;

[0404] L 1B It is C 1-3 Alkylene;

[0405] L 2B does not exist;

[0406] L 3B is phenyl or a 5- to 6-membered heteroaryl group containing 1 or 2 heteroatoms independently selected from N, S and O as ring atoms, wherein at least one heteroatom is N, wherein L 3B optionally substituted with one or two substituents independently selected from halogen, cyano, methyl and trifluoromethyl;

[0407] or group-L 1B -L 2B -L 3B It is C 1-6 alkyl;

[0408] R 6 is hydrogen or a group -L 1C -L 2C -L 3C , where the group -L 1C -L 2C -L 3C It is C 1-6 alkyl.

[0409] In one embodiment (Embodiment C), the compound is a compound of formula (I), wherein

[0410] R 1 is cyano or -CH 3 ;

[0411] R 2 and R 3 Together with the carbon atoms to which they are attached they form a cyclopropyl or oxetanyl group;

[0412] X 1 Yes CR 7 ;

[0413] X 2 Yes CR 8 ;

[0414] X 3 Yes CR 9 ;

[0415] R 7 and R 8 It is hydrogen;

[0416] R 9 is hydrogen, chlorine, phenyl, piperidinyl (e.g., piperidin-1-yl, piperidin-4-yl), piperazinyl (e.g., piperazin-1-yl) or imidazolyl (e.g., imidazolyl), wherein phenyl, piperidinyl, piperazinyl and imidazolyl are optionally replaced by R a , R b and / or R c replace;

[0417] R a is hydrogen, -CH 3 、-C(O)-CH 3 、-C(O)-C(CH 2 -CH 2 )-CH 3 、-C(O)-C(CH 2 -CH 2 )-NH 2 、-C(O)-NH 2 、-C(O)-N(CH 3 ) 2 or -CH 2 -NH 2 ;

[0418] R b is hydrogen or -CH 3 ;

[0419] R c is hydrogen or -CH 3 ;

[0420] R 4 Yes-CH 2 -(methylpyrazol-4-yl) (e.g. -CH 2 -(1-methylpyrazol-4-yl), -CH 2 -(trifluoromethylpyrazol-4-yl) (e.g. -CH 2 -(1-trifluoromethylpyrazol-4-yl)) or -CH 2 -(methylthiazol-5-yl) (e.g. -CH 2 -(2-methylthiazol-5-yl));

[0421] R 5 Yes-CH 3 、-CH 2 CH 3、-CH(CH 3 )(CH 3 ) or -CH 2 -(dimethylthiazol-5-yl) (e.g. -CH 2 -(2,4-dimethylthiazol-5-yl)); and

[0422] R 6 It's hydrogen.

[0423] In a further embodiment, the present invention provides the following compounds and pharmaceutically acceptable salts thereof:

[0424] 2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(2-methylthiazol-5-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide;

[0425] 2-Methoxyimino-N-(3-methyloxetan-3-yl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide;

[0426] 2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide;

[0427] 8-Chloro-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide;

[0428] 4-[2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]-N,N-dimethylbenzamide;

[0429] 2-Methoxyimino-N-(1-methylcyclopropyl)-4-oxo-3-[[1-(trifluoromethyl)pyrazol-4-yl]methyl]-1H-quinazoline-6-sulfonamide;

[0430] 2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-3-methylpiperazin-1-yl]-1H-quinazoline-6-sulfonamide;

[0431] 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;

[0432] N-(1-cyanocyclopropyl)-2-methoxyimino-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide;

[0433] 2-Ethoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide;

[0434] 2-Isopropoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide;

[0435] (2E)-2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-4-acetyl-3-methylpiperazin-1-yl]-1H-quinazoline-6-sulfonamide;

[0436] (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;

[0437] (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;

[0438] (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;

[0439] (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;

[0440] (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;

[0441] (E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-8-(4-(1-methylcyclopropane-1-carboxyl)phenyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide;

[0442] (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;

[0443] (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;

[0444] (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;

[0445] (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;

[0446] (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;

[0447] (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-4-piperidinyl]-1H-quinazoline-6-sulfonamide;

[0448] (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-1,2-dimethyl-4-piperidinyl]-1H-quinazoline-6-sulfonamide;

[0449] (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-1-acetyl-2-methyl-4-piperidinyl]-1H-quinazoline-6-sulfonamide;

[0450] (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-1-(1-methylcyclopropanecarbonyl)-4-piperidinyl]-1H-quinazoline-6-sulfonamide;

[0451] (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;

[0452] (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;

[0453] (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;

[0454] (R,E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-8-(3-methyl-4-(3,3,3-trifluoropropionyl)piperazin-1-yl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide;

[0455] (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;

[0456] (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;

[0457] (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;

[0458] (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;

[0459] (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;

[0460] (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;

[0461] (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;

[0462] (R,E)-8-(4-(cyclopentylcarbonyl)-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;

[0463] (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;

[0464] (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;

[0465] (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;

[0466] 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

[0467] 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.

[0468] Some of the intermediates used to prepare the compounds of formula (I) are novel and constitute other aspects of the present invention. Therefore, another aspect of the present invention is to provide a compound of formula (Int-I) or a salt thereof,

[0469]

[0470] in

[0471] R 10 It is hydrogen, halogen (such as chlorine, bromine, iodine), -B(OH) 2 、-B(-OC(CH 3 ) 2 -C(CH 3 ) 2 -O-) (i.e., pinacol borate), -S(O) 2 OH, -S(O) 2 Cl or -S-CH 2 -phenyl; and

[0472] X 1 , X 2 , X 3 , R 4 , R 5 and R 6 Same as the definition of the compound of formula (I), including its preferred definitions and embodiments;

[0473] The compound (Int-I) is not

[0474] 2-(Hydroxyamino)-6-iodo-3-phenyl-4(3H)-quinazolinone (CAS RN: 221657-59-6);

[0475] 6-iodo-2-(propoxyamino)-3-propyl-4(3H)-quinazolinone (CAS RN: 1101794-34-6);

[0476] 6-Bromo-2-(propoxyamino)-3-propyl-4(3H)-quinazolinone (CAS RN: 1101796-68-2);

[0477] 6-iodo-2-[(2-methylpropoxy)amino]-3-propyl-4(3H)-quinazolinone (CAS RN: 1101796-45-5);

[0478] 6-Bromo-2-[(2-methylpropoxy)amino]-3-propyl-4(3H)-quinazolinone (CAS RN: 1101794-11-9);

[0479] 2-[[(3,4-dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)amino]oxy]acetic acid (CAS RN: 221657-88-1);

[0480] (3,4-dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)azanyl acetate (CAS RN: RN: 221658-07-7);

[0481] 2,4(1H,3H)-quinazolinedione,6-iodo-3-phenyl-,2-[O-(ethoxycarbonyl)oxime](CAS RN:221657-74-5);

[0482] (3,4-Dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)azanyl 2-chloroacetate (CAS RN: 221657-64-3);

[0483] Ethyl 2-[[(3,4-dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)amino]oxy]acetate (CASRN: 221657-82-5);

[0484] (3,4-Dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)azanyl benzoate (CAS RN: 221658-09-9);

[0485] (3,4-Dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)azanylphenylacetate (CAS RN: 221658-10-2);

[0486] 1-[(3,4-dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)azanyl]2-ethyloxalate (CASRN: 221657-99-4)

[0487] 2-(Hydroxyamino)-3-phenyl-4(3H)-quinazoline (CAS RN: 858236-63-2).

[0488] For compounds other than the above, see WO 1994 / 26722 and Abdel-Hamide et al. Acta Pharmaceutica (Zagreb) 1998, 48(4): 249-258.

[0489] In some embodiments of the compound of Formula (Int-I), R 10 It's hydrogen.

[0490] In some embodiments of the compound of Formula (Int-I), R 10 It is a halogen (such as chlorine, bromine, iodine).

[0491] In some embodiments of the compound of Formula (Int-I), R 10 Yes -B(OH) 2 or -B(-OC(CH 3 ) 2 -C(CH 3 ) 2 -O-).

[0492] In some embodiments of the compound of Formula (Int-I), R 10 Yes-S(O) 2 Cl.

[0493] In some embodiments of the compound of Formula (Int-I), R 10 Yes-S-CH 2 -phenyl.

[0494] In some embodiments of the compound of Formula (Int-I), X 1 , X 2 , X 3 , R 4 , R 5 and R 6 As defined in embodiment A.

[0495] In some embodiments of the compound of Formula (Int-I), X 1 , X 2 , X 3 , R 4 , R 5 and R 6 As defined in embodiment B.

[0496] In some embodiments of the compound of Formula (Int-I), X 1 , X 2 , X 3 , R 4 , R 5 and R 6As defined in embodiment C.

[0497] Another aspect of the present invention provides a compound of formula (Int-II) or a salt thereof,

[0498]

[0499] in

[0500] R 11 is hydrogen or C 1-8 Alkyl; and

[0501] X 1 , X 2 , X 3 , R 4 , R 5 and R 6 The same as the definitions of the compounds of formula (I), including their preferred definitions and embodiments.

[0502] In some embodiments of the compound of formula (Int-II), X 1 , X 2 , X 3 , R 4 , R 5 and R 6 As defined in embodiment A.

[0503] In some embodiments of the compound of formula (Int-II), X 1 , X 2 , X 3 , R 4 , R 5 and R 6 As defined in embodiment B.

[0504] In some embodiments of the compound of formula (Int-II), X 1 , X 2 , X 3 , R 4 , R 5 and R 6 As defined in embodiment C.

[0505] The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. As described herein, these pharmaceutical compositions are particularly useful for treating neoplastic diseases, especially cancer.

[0506] The compounds of the present invention can be formulated into pharmaceutical compositions for parenteral administration, such as nasal, oral, rectal, pulmonary, vaginal, sublingual, topical, transdermal, ophthalmic, otic or in particular oral administration, such as in the form of oral solid dosage forms, such as granules, pills, powders, tablets, film or sugar-coated tablets, effervescent tablets, hard and soft gelatin or HPMC capsules, orally disintegrating tablets coated as required, oral solutions, lipid emulsions or suspensions, or for parenteral administration to mammals, in particular humans, such as intravenous, intramuscular or subcutaneous, intrathecal, intradermal or epidural injections, such as in the form of solutions, lipid emulsions or suspensions containing microparticles or nanoparticles. The composition can contain the active ingredient alone or preferably together with a pharmaceutically acceptable excipient.

[0507] The pharmaceutical composition can be processed with pharmaceutically inert, inorganic or organic excipients for the production of oral solid dosage forms such as granules, pills, powders, tablets, film or sugar-coated tablets, effervescent tablets, hard gelatin or HPMC capsules or orally disintegrating tablets. Fillers such as lactose, cellulose, mannitol, sorbitol, calcium phosphate, starch or its derivatives, binders such as cellulose, starch, polyvinyl pyrrolidone or its derivatives, glidants such as talc, stearic acid or its salts, and flow agents such as fumed silica can be used as excipients for the preparation and manufacture of oral solid dosage forms such as granules, pills, powders, tablets, film or sugar-coated tablets, effervescent tablets, hard gelatin or HPMC capsules or orally disintegrating tablets. Excipients suitable for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc.

[0508] Excipients suitable for the manufacture of oral solutions, lipid emulsions or suspensions are, for example, water, alcohols, polyols, sugars, invert sugar, glucose, etc. Excipients suitable for parenteral formulations are, for example, water, alcohols, polyols, glycerol, vegetable oils, lecithin, surfactants, etc. In addition, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for changing the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances.

[0509] Pharmaceutical compositions suitable for injection include sterile aqueous solutions (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, In some embodiments, the present invention provides a kind of lipophilic molecule.In some embodiments, the lipophilic molecule is lipophilic ...

[0510] Sterile injection solutions can be prepared by adding the required amount of active compound to an appropriate solvent together with one or more of the above-mentioned ingredients as needed, and then filtering and sterilizing. Generally speaking, dispersions are prepared by adding the active compound to a sterile solvent, which contains a dispersion medium and other ingredients required among the above-mentioned ingredients. For sterile powders for preparing sterile injection solutions, the preparation method is vacuum drying and freeze drying to obtain a powder of the active ingredient and any other desired ingredients from a solution thereof that has previously been sterile filtered.

[0511] In addition, the pharmaceutical compositions used in the present invention optionally include buffers such as phosphate, citric acid or other organic acids; antioxidants including butylated hydroxytoluene (BHT), butylated hydroxyanisole (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 including glucose, mannose or dextrin; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEEN®. TM 、PLURONICS TM or PEG.

[0512] Optionally, the pharmaceutical composition contains a pharmaceutically acceptable preservative. In some embodiments, the concentration of the preservative ranges from 0.1% to 2.0%, typically v / v. Suitable preservatives include those known in the pharmaceutical art, such as benzyl alcohol, phenol, m-cresol, methyl benzoate, and propyl benzoate.

[0513] Dosage can vary over a wide range and is of course determined according to the different requirements of each specific case. In general, in the case of oral administration, a daily dose of about 1 to 1000 mg per person of a compound of formula (I) should be suitable, but the above lower or upper limits may be exceeded if necessary.

[0514] The compounds of formula (I) or their pharmaceutically acceptable salts according to the present invention described above are particularly suitable for treating neoplastic diseases, such as cancer, for example when administered in a therapeutically effective amount. Examples of neoplastic diseases include, but are not limited to, epithelial tumors, squamous cell tumors, basal cell tumors, transitional cell papilloma and carcinoma, adenomas and adenocarcinomas, adnexal and skin appendage tumors, mucoepidermoid tumors, cystic tumors, mucinous and serous tumors, ductal tumors (ducal-), lobular tumors and medullary tumors, acinar cell tumors, complex epithelial tumors, specific gonadal tumors, paragangliomas and glomus tumors, nevi and melanomas, soft tissue tumors and sarcomas, fibromatous tumors, myxomatous tumors, lipomatous tumors, myomatous tumors, complex mixed and stromal tumors, fibroepithelial tumors, synovial tumors, mesothelioma Tumors, germ cell tumors, trophoblastic tumors, mesonephrosomas, hemangiomas, lymphangiogenic tumors, bone and cartilage tumors, giant cell tumors, mixed bone tumors, odontogenic tumors, gliomas, neuroepitheliomatous and neuroendocrine tumors, meningiomas, nerve sheath tumors, granular cell tumors and alveolar soft tissue sarcomas, Hodgkin and non-Hodgkin lymphomas, B-cell lymphomas, T-cell lymphomas, hairy cell lymphomas, Burkitt lymphoma and other lymphoreticular cell tumors, plasma cell tumors, mast cell tumors, immunoproliferative disorders, leukemias, mixed myeloproliferative disorders, lymphoproliferative disorders, and myelodysplastic syndromes.

[0515] In terms of affected organs and body parts, examples of cancer include, but are not limited to, breast cancer, cervical cancer, ovarian cancer, colon cancer, rectal cancer (including colon and rectum, i.e., colorectal cancer), lung cancer (including small cell lung cancer, non-small cell lung cancer, large cell lung cancer and mesothelioma), endocrine system cancer, bone cancer, adrenal cancer, thymic cancer, liver cancer, abdominal cancer (gastric cancer), intestinal cancer, pancreatic cancer, bone marrow cancer, hematological malignancies (such as lymphoma, leukemia, myeloma or lymphoid malignancies), bladder cancer, urinary tract cancer, kidney cancer, skin cancer, thyroid cancer, brain cancer, head cancer, neck cancer, prostate cancer and testicular cancer. Preferably, the cancer is selected from the group consisting of breast cancer, prostate cancer, cervical cancer, ovarian cancer, gastric cancer, colorectal cancer, pancreatic cancer, liver cancer, brain cancer, neuroendocrine cancer, lung cancer, kidney cancer, bladder cancer, mesothelioma, hematological malignancies, melanoma and sarcoma.

[0516] Cancer can be a primary tumor and / or a metastatic tumor. Cancer may originate from a solid tumor or a liquid tumor (such as a blood tumor or an intraperitoneal tumor). In some embodiments, the neoplastic disease (such as cancer) to be treated is a tumor, such as a solid tumor.

[0517] In some embodiments, the cancer treated by the compounds of the present invention is mediated by regulating PARG. In some embodiments, the compounds of the present invention can treat cancer by regulating PARG (such as inhibiting PARG). Such cancers can be, for example, ovarian cancer, lung cancer, or breast cancer.

[0518] As used herein, "pharmaceutically acceptable" refers to compounds and their salts, materials, compositions and / or dosage forms that are, within the scope of reasonable medical judgment, suitable for contact with the tissues of warm-blooded animals (such as mammals or humans) without causing excessive toxicity or other complications, and are commensurate with a reasonable benefit / risk ratio.

[0519] A "pharmaceutical composition" as defined herein refers to a solid or liquid formulation containing at least one therapeutic agent together with one or more pharmaceutically acceptable excipients for administration to a subject, such as a mammal, particularly a human, to prevent or treat a particular disease or condition affecting the mammal.

[0520] As used herein, "preventing" and other forms of the word include preventing at least one symptom associated with or caused by the condition, disease or disorder being prevented.

[0521] As used herein, "therapeutically effective amount" refers to an amount of a compound or a material, composition or dosage form containing a compound that, when administered according to an intended treatment regimen, is effective in producing a desired therapeutic effect and is commensurate with a reasonable benefit / risk ratio.

[0522] As used herein, "treatment" and other forms of the term when treating a disease or disorder generally refer to treatment and therapy, whether for humans or animals (such as in veterinary applications), to achieve some desired therapeutic effect, such as inhibiting the progression of the disease or disorder, including reducing the rate of progression, stopping the rate of progression, alleviating the symptoms of the disease or disorder, ameliorating the disease or disorder, and curing the disease or disorder. Treatment as a preventative measure (i.e., prevention) is also included. For example, the term "treatment" covers the use of patients who have not yet developed a disease or disorder but are at risk of developing a disease or disorder. For example, treatment includes preventing cancer, reducing the incidence of cancer, alleviating the symptoms of cancer, etc.

[0523] The term "subject" refers to a mammal, preferably a human, and the term "patient" refers to a human who comes to receive treatment.

[0524] Compounds of formula (I) can be synthesized by the methods given below or analogous methods, as shown in Scheme I. The schemes described herein are not intended to be an exhaustive list of methods for preparing compounds of formula (I); rather, other techniques known to the skilled chemist may also be used to synthesize the compounds.

[0525] It is understood by those skilled in the art of organic synthesis that the optimal reaction conditions may vary depending on the specific reactant or solvent used, but these conditions may be determined by conventional optimization procedures. In some cases, the following reaction scheme and / or the order of execution of the reaction steps may be changed to promote the reaction or avoid forming unwanted by-products. In addition, the functionality of each position of the molecule must be compatible with the proposed reagent and reaction. This restriction on substituents compatible with the reaction conditions is obvious to those skilled in the art, and therefore alternative methods must be used. In addition, in some reactions mentioned herein, it may be necessary or desirable to protect any sensitive group in the compound, so it is assumed that such a protecting group (PG) already exists as required in the appropriate position. Conventional protecting groups can be used according to standard practices well known in the art (see Wuts P. GM, Greene's Protective Groups in Organic Synthesis, 5th Edition, Publisher: John Wiley & Sons, 2014). Protecting groups can be removed using conventional techniques well known in the art at any convenient stage during the synthesis, or can be removed in a later reaction step or processing.

[0526] In the general reaction sequence outlined in Scheme 1 below, the abbreviation X is used unless otherwise indicated. 1 , X 2 , X 3 and the general group R 1 , R 2 , R 3 , R 4 , R 5 and R 6 Same as the definition of formula (I). Common group E1 is usually a hydrogen atom, -OH, methoxy, halogen atom, sulfonic acid, sulfonyl chloride, boric acid, boric ester or -O-L1, and -O-L1 is a leaving group, wherein L1 is selected from perfluoroalkylsulfonyl, such as triflyl (trifluoromethanesulfonyl) and sulfonyl (sulfonyl), such as tosyl (tosyl) (p-toluenesulfonyl (p-toluenesulfonyl)) or mesyl (mesyl) (methanesulfonyl).

[0527] The compounds according to the present invention, their pharmaceutically acceptable salts, solvates and hydrates can be prepared according to the general reaction sequence outlined in Scheme 1 below, followed by the following steps if necessary:

[0528] - Manipulation of substituents to obtain new end products. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, substitution, coupling (including transition metal catalyst coupling and hydrolysis reactions), which are reactions generally known to those skilled in the art;

[0529] - removal of any protecting groups;

[0530] - forming a pharmaceutically acceptable salt; or

[0531] - forming a pharmaceutically acceptable solvate or hydrate.

[0532] Solution 1

[0533]

[0534] 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 by modifying methods reported in the scientific literature and prepared from commercially available compounds. For general guidance on reaction conditions and reagents, the reader can refer to, for example, March J., Smith M., Advanced Organic Chemistry, 7th Edition, Publisher: John Wiley & Sons, 2013.

[0535] Compounds of formula (A) to (F) wherein E1 is an -O-L1 group can be prepared by reacting the corresponding alcohols (A) to (F) (wherein E1 is -OH) with methanesulfonyl chloride or methanesulfonic anhydride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride or trifluoromethanesulfonic anhydride in the presence of a base (such as triethylamine, etc.) in a dry aprotic solvent (such as pyridine, acetonitrile, tetrahydrofuran or dichloromethane) at a temperature between -30°C and 80°C.

[0536] Compounds of formula (A) to (F) wherein E1 is a halogen atom can be prepared from compounds of formula (A) to (F) wherein E1 is a -O-L1 group via a transition metal catalyst coupling reaction. Typical catalysts include palladium (II) acetate, tris (dibenzylideneacetone) dipalladium (0), and the like. The reaction is usually carried out at a temperature of 0°C to 150°C, more typically at a temperature of 80°C to 120°C. The reaction is usually carried out in the presence of a ligand such as di-tert-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphine, di-tert-butyl-[2,3,4,5-tetramethyl-6-(2,4,6-triisopropylphenyl)phenyl]phosphine, 2-(dicyclohexylphosphino)biphenyl, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, etc. and a base such as sodium tert-butyrate, cesium carbonate, potassium carbonate, more commonly cesium carbonate, in a variety of inert solvents such as toluene, tetrahydrofuran, dioxane, 1,2-dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, water and acetonitrile, or a mixture of solvents, more commonly dioxane. Since transition metal catalyst coupling reactions have many components, such as specific palladium catalysts, ligands, additives, solvents, temperatures, etc., many protocols have been established. Those skilled in the art will be able to find satisfactory solutions without undue experimentation.

[0537] Alternatively, compounds of formula (A) to (F) wherein E1 is a halogen atom can be prepared from compounds of formula (A) to (F) wherein E1 is a boronic acid or a boronic ester via a halodeboronation reaction. The reaction is typically carried out in methanol in the presence of a copper (II) halide at a temperature ranging from 0°C to 100°C, more typically at 90°C.

[0538] The compounds of formula (C) to (F) wherein E1 is a sulfonic acid can be prepared from the compounds of formula (C) to (F) wherein E1 is a hydrogen atom via a sulfonation reaction. The reaction is usually carried out in the presence of concentrated sulfuric acid, oleum, sulfur trioxide or chlorosulfonic acid.

[0539] Compounds of formula (C) to (F) wherein E1 is a sulfonyl chloride can be prepared from compounds of formula (C) to (F) wherein E1 is a sulfonic acid using chlorosulfonic acid or sulfonyl chloride.

[0540] Alternatively, compounds of formula (C) to (F) wherein E1 is a sulfonyl chloride can be prepared from compounds of formula (C) to (F) wherein E1 is a hydrogen atom via halogenation sulfonation using chlorosulfonic acid.

[0541] Additionally, where X 3 CR 9 (R 9 C 3-6The compound of formula (I) containing a cycloalkyl, phenyl or heteroaryl group) can be prepared by Suzuki reaction from a boronic acid or boronic acid ester wherein X 3 CR 9 (R 9 is a halogen atom). The Suzuki reaction is a palladium-catalyzed cross-coupling reaction between an organic boronic acid and an aryl or vinyl halide or triflate. Typical catalysts include palladium acetate (II), tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium dichloride (II) and [1,1'bis (diphenylphosphino) ferrocene] dichloropalladium (II). The reaction can be carried out in a variety of organic solvents, including toluene, tetrahydrofuran, dioxane, 1,2-dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide and acetonitrile, and can also be carried out in aqueous solvents and under biphasic conditions. The reaction is usually carried out between room temperature and 150 ° C. Additives such as cesium fluoride, potassium fluoride, potassium hydroxide or sodium ethoxide often accelerate the coupling reaction. Potassium trifluoroborate and organic boranes or boric esters can be used instead of boric acid. Although there are many components of the Suzuki reaction, such as specific palladium catalysts, ligands, additives, solvents, temperatures, etc., many protocols have been determined. Those skilled in the art will be able to find satisfactory solutions without undue experimentation.

[0542] Where X 3 CR 9 (R 9 The compound of formula (I) wherein X is a heterocyclic system) can be prepared by a transition metal catalyst coupling reaction using the aforementioned conditions from a heterocyclic group reacting with a 3 CR 9 (R 9 is a halogen atom).

[0543] Step 1:

[0544] The compound of formula (B) can be prepared by coupling reaction of the compound of formula (A) and an amine in the presence of an activating agent such as N,N'-dicyclohexylcarbodiimide or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, and optionally 1-hydroxybenzotriazole can be added. 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 also be used. Optionally, a base such as triethylamine, N,N-diisopropylethylamine or pyridine can be added for coupling. The amide coupling is carried out at a temperature between -20°C and 100°C in an inert solvent (preferably a dry aprotic solvent such as dichloromethane, acetonitrile, N,N-dimethylformamide and chloroform).

[0545] Step 2:

[0546] The compound of formula (D) can be prepared from the compound of formula (B) by cyclization in 1,4-dioxane using thiophosgene under reflux conditions (Pavé G., Org. Lett., 2015, 17, 4930-4932).

[0547] Step 3:

[0548] Alternatively, the compound of formula (D) can be prepared by a substitution reaction of a compound of formula (C) and a halide, a methanesulfonate, a toluenesulfonate or a trifluoromethanesulfonate. The substitution reaction is generally carried out at a temperature between -20°C and 100°C in a dry aprotic solvent (such as dichloromethane, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide or tetrahydrofuran) without or with an inorganic base (such as potassium carbonate or cesium carbonate) or an organic base (such as trimethylamine, pyridine or N,N-diisopropylethylamine).

[0549] Step 4:

[0550] The compound of formula (E) can be prepared by condensation reaction of the compound of formula (D) and O-substituted hydroxylamine. The reaction is carried out at a temperature between room temperature and 150°C in a solvent such as N,N-dimethylformamide or N,N-dimethylacetamide, with or without the use of an organic base such as sodium acetate, triethylamine, pyridine, etc.

[0551] Step 5:

[0552] The compound of formula (F) can be prepared from the compound of formula (E) and a halide, a methanesulfonate, a toluenesulfonate or a trifluoromethanesulfonate by substitution reaction, and the preparation conditions are as described above.

[0553] Step 6:

[0554] The compound of formula (G) can be prepared from the compound of formula (F) wherein E1 is a halogen atom or wherein E1 is a -O-L1 group by a transition metal catalyst coupling reaction using benzyl mercaptan, and the preparation conditions are as described above.

[0555] Step 7:

[0556] The compound of formula (I) can be prepared from the compound of formula (G) by oxidative chlorination using NCS or DCDMH under acidic conditions and then replacing the generated sulfonyl chloride with an amine. The preparation conditions are as described above.

[0557] Alternatively, the compound of formula (I) can also be directly prepared from the compound of formula (F) wherein E1 is sulfonyl chloride by substitution with an amine, and the preparation conditions are as described above.

[0558] The oximes of the compounds of formula (I), (E), (F) and (G) may form a mixture of two isomeric forms (E and Z) or may form only one isomer. If two isomers are formed, they may be separated at any convenient stage.

[0559] Specific embodiments of the present invention are described in the following examples, which are used to illustrate the present invention in more detail and should not be construed as limiting the present invention in any way. BRIEF DESCRIPTION OF THE DRAWINGS

[0560] Figure 1 shows the increase in cellular protein-bound PAR levels after PARG inhibitor treatment. Figure 1A Kuramochi HGSOC cells were treated with compound vehicle DMSO or increasing concentrations of Examples 1, 5, 7 or 8 for 8 hours, then cells were extracted and cellular PAR levels were measured by Western blotting. α-Tubulin was used as a loading control for blotting. Figure 1B NCI-H1650 NSCLC cells were treated with compound vehicle DMSO or increasing concentrations of Examples 1, 5, 7 or 8 for 8 hours and then subjected to Western blot detection as described above. DETAILED DESCRIPTION

[0561] Example

[0562] All reagents and solvents were generally used as received from commercial suppliers.

[0563] Unless otherwise stated, reactions were generally performed under argon or nitrogen atmosphere in well-dried glassware with anhydrous solvents.

[0564] Evaporation was performed by rotary evaporation under reduced pressure and the work-up procedure was followed by removal of residual solids by filtration.

[0565] All temperatures are in degrees Celsius (°C) and are approximate; unless otherwise stated, operations are performed at room temperature (rt), typically 18°C-25°C.

[0566] Column chromatography (flash procedure) was used to purify the compounds.

[0567] Classical flash chromatography is often replaced by automated systems. This does not change the separation process itself. One skilled in the art can replace classical flash chromatography with automated flash chromatography and vice versa. Typical automated systems can be used, such as those provided by Büchi, Biotage or Isco (combiflash).

[0568] Unless otherwise indicated, the reaction mixture can usually be separated by preparative HPLC, for example using water and acetonitrile as an eluent system. The person skilled in the art will find suitable conditions for each separation; the compounds are isolated after purification as the parent compound or the corresponding trifluoroacetic acid (TFA) salt or the corresponding formate salt.

[0569] Reactions requiring higher temperatures were generally performed using a classical heating apparatus, but a microwave apparatus (CEM Explorer) with a power of 250 W was also used unless otherwise stated.

[0570] The hydrogenation or hydrogenolysis reaction can be carried out using hydrogen in a balloon or a Parr-apparatus system or other suitable hydrogenation equipment.

[0571] Unless otherwise stated, concentration of solutions and drying of solids were carried out under reduced pressure.

[0572] Generally, the reaction process is tracked by TLC, HPLC or LC / MS, and the reaction time is for reference only; the yield is for reference only and is not necessarily the highest achievable yield.

[0573] The structure and purity of the final products of the present invention are generally confirmed by NMR spectroscopy, HPLC and mass spectrometry techniques.

[0574] Proton NMR spectra were recorded on a Brucker 400 MHz spectrometer. Chemical shifts (δ) are expressed relative to Me 4 The Si or internal standard solvent peak is reported in ppm, and the NMR coupling constant (J value) is in Hertz (Hz). Each peak is represented as a broad singlet (br), singlet (s), doublet (d), triplet (t), quartet (q), doublet of a doublet (dd), triplet of a triplet (td), or multiplet (m).

[0575] Dionex Ultimate 3000 coupled to Dionex MSQ ESI using (Method A) TM The final product was analyzed by HPLC using the following instruments and conditions:

[0576]

[0577]

[0578] Or using (Method B) Waters Acquity ultra-performance liquid chromatography (UPLC) equipped with a SQ 3100 mass detector spectrometer.

[0579]

[0580] The gradients described may vary depending on the physicochemical properties of the compounds analyzed and are not intended to be limiting.

[0581] Mass spectrometry using q-Tof Ultima TM (Waters AG or Thermo Scientific MSQ Plus) mass spectrometer in positive or negative ESI mode. The system is equipped with a standard Lockspray interface.

[0582] Each intermediate was purified to the standards required for subsequent stages and characterized in sufficient detail to confirm that the assigned structure was correct.

[0583] Analytical and preparative HPLC on achiral phases were performed using RP-C18 based columns.

[0584] The following abbreviations may be used (see also the Journal of Organic Chemistry Author's Guide for a complete list of standard abbreviations and acronyms):

[0585] AcOH Acetic acid

[0586] CAN Acetonitrile

[0587] Bn Benzyl

[0588] BnSH Benzyl mercaptan

[0589] CAS Compounds with Chemical Abstracts Service Registry Numbers

[0590] Cbz N-Carboxybenzyl

[0591] CDCl 3 Tritiated chloroform

[0592] DCDMH 1,3-Dichloro-5,5-dimethylhydantoin

[0593] DCM Dichloromethane

[0594] Diox 1,4-Dioxane

[0595] DIPEA N,N-Diisopropylethylamine

[0596] DMA N,N-Dimethylacetamide

[0597] DME Dimethoxyethane

[0598] DMF N,N-Dimethylformamide

[0599] DMSO Dimethyl sulfoxide

[0600] DMSO-d 6 Tritiated dimethyl sulfoxide

[0601] EA Ethyl acetate

[0602] EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0603] ELSD Evaporative Light Scattering Detection

[0604] ESI Electrospray ionization

[0605] EtOH

[0606] Ex. Example

[0607] HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0608] HOBt N-Hydroxybenzotriazole

[0609] HPLC High Performance Liquid Chromatography

[0610] LC / MS Liquid chromatography-mass spectrometry

[0611] MeOH Methanol

[0612] Me 4 Si Tetramethylsilane

[0613] MS Mass Spectrometer

[0614] MW Microwave

[0615] NCS N-chlorosuccinimide

[0616] NMR Nuclear Magnetic Resonance

[0617] Pd / C activated carbon supported palladium

[0618] Pd 2 (dba) 3 Tris(dibenzylideneacetone)dipalladium(0)

[0619] Pd(dppf)Cl 2 [1,1-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[0620] Pd(PPh 3 ) 4 Tetrakis(triphenylphosphine)palladium(0)

[0621] PE Petroleum Ether

[0622] rt room temperature

[0623] TEA Triethylamine

[0624] TFA Trifluoroacetic acid

[0625] THF Tetrahydrofuran

[0626] Xant-Phos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0627] The following examples relate to compounds of formula (I) shown in Table 1.

[0628] The examples listed in the table below can be prepared by the above procedures, and the detailed synthesis methods are described below. The example numbers used in the leftmost column are used to identify the corresponding compounds in the application text.

[0629] Table 1. Example compounds

[0630]

[0631]

[0632]

[0633]

[0634]

[0635]

[0636]

[0637]

[0638]

[0639]

[0640]

[0641]

[0642] A hyphen in the third column indicates that a synthesis process is described below.

[0643] Preparation Example 1: 2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(2-methylthiazol-5-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide:

[0644]

[0645] Step 1: Preparation of 2-chloro-3-[(2-methylthiazol-5-yl)methyl]quinazolin-4-one:

[0646] To a stirred solution of 5-(chloromethyl)-2-methylthiazole (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 mixture was heated to 40°C with EA and H 2 The reaction mixture was extracted with O. The combined organic layers were purified by 2 SO 4 Dried on ice, filtered, concentrated, and purified by column chromatography (silica gel; PE:EA; 7:3; v:v) to give 2-chloro-3-[(2-methylthiazol-5-yl)methyl]quinazolin-4-one (3.8 g, 71% yield) as an off-white solid.

[0647] MS m / z(+ESI):292.1,294.1[M+H] + .

[0648] Step 2: Preparation of 2-methoxyimino-3-[(2-methylthiazol-5-yl)methyl]-1H-quinazolin-4-one:

[0649] 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 H 2 O (50 mL), and the resulting precipitate was collected by filtration to give 2-methoxyimino-3-[(2-methylthiazol-5-yl)methyl]-1H-quinazolin-4-one (0.4 g, 77% yield) as a white solid.

[0650] MS m / z(+ESI): 303.1[M+H] + .

[0651] Step 3: Preparation of 2-methoxyimino-3-[(2-methylthiazol-5-yl)methyl]-4-oxo-1H-quinazoline- 6-Sulfonic acid:

[0652] 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 for 1 hour at 60° C. The reaction mixture was then poured into ice and purified by Biotage Combiflash to give 2-methoxyimino-3-[(2-methylthiazol-5-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonic acid (0.42 g, 90% yield) as a light yellow solid.

[0653] MS m / z(+ESI): 333.1[M+H] + .

[0654] Step 4: Preparation of 2-methoxyimino-3-[(2-methylthiazol-5-yl)methyl]-4-oxo-1H-quinazoline- 6-Sulfonyl chloride:

[0655] 2-Methoxyimino-3-[(2-methylthiazol-5-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonic acid (0.42 g, 0.99 mmol) was stirred in SOCl at 75 °C. 2 (4 mL) 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 (0.21 g, 48% yield) as a light yellow solid.

[0656] MS m / z(+ESI):401.0,403.0[M+H] + .

[0657] Step 5: Preparation of 2-methoxyimino-N-(1-methylcyclopropyl)-3-[(2-methylthiazol-5-yl)methyl]- 4-Oxo-1H-quinazoline-6-sulfonamide:

[0658] 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-methylcyclopropylamine hydrochloride (0.5 g, 4.49 mmol) followed by TEA (1.92 mL, 13.5 mmol). After stirring for 1 hour, 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 (35 mg, 17% yield) as a white solid.

[0659] 1 H NMR (400 MHz, DMSO-d 6 +D 2 O)δppm:8.19(d,J=2.0Hz,1H),7.86(dd,J=2.0,8.8Hz,1H),7.65(s,1H),7.49(d,J=8.8 Hz,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).

[0660] MS m / z(+ESI):436.5[M+H] + .

[0661] Preparation Example 3: 2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide:

[0662]

[0663] Step 1: Preparation of 2-[(2,4-dimethylthiazol-5-yl)methoxy]isoindoline-1,3-dione:

[0664] To a stirred solution of 5-(chloromethyl)-2,4-dimethylthiazole (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:EA; 2:1; v:v) to give 2-[(2,4-dimethylthiazol-5-yl)methoxy]isoindoline-1,3-dione (140 mg, 83% yield) as a white solid.

[0665] MS m / z(+ESI): 289.1[M+H] + .

[0666] Step 2: Preparation of O-[(2,4-dimethylthiazol-5-yl)methyl]hydroxylamine:

[0667] 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 hours, the reaction mixture was filtered and the filtrate was concentrated to give O-[(2,4-dimethylthiazol-5-yl)methyl]hydroxylamine (1.9 g, 89% yield) as a yellow oil, which was used in the next step without further purification.

[0668] MS m / z(+ESI):159.1[M+H] + .

[0669] Step 3: Preparation of 6-bromo-2-chloro-3-[(1-methylpyrazol-4-yl)methyl]quinazolin-4-one:

[0670] 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-methylpyrazole (3.42 g, 23.6 mmol) followed by K 2 CO 3 (5.25 g, 37.3 mmol). After stirring for 16 hours, the mixture was added with H2 The reaction mixture was diluted with H2O (150 mL) and the resulting suspension was filtered. 2 The filter cake was washed with 0 and dried under high vacuum to obtain a yellow solid, which was suspended in PE:EA solution (60 mL, 2:1, v:v). The resulting suspension was sonicated for 30 minutes and filtered. After the filter cake was dried under high vacuum, a yellow solid 6-bromo-2-chloro-3-[(1-methylpyrazol-4-yl)methyl]quinazolin-4-one (2.5 g, 51% yield) was obtained.

[0671] 1 H NMR (400 MHz, DMSO-d 6 )δppm: 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).

[0672] MS m / z(+ESI):353.0,355.0[M+H] + .

[0673] Step 4: Preparation of 6-bromo-2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-3-[(1-methylpyrazole- 4-yl)methyl]-1H-quinazolin-4-one:

[0674] 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 h, the mixture was heated with H 2 The reaction mixture was diluted with H2O (50 mL) and the resulting suspension was filtered. 2 O 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 (220 mg, 82% yield) as a yellow solid, which was used in the next step without further purification.

[0675] MS m / z(+ESI):475.0,477.0[M+H] + .

[0676] Step 5: Preparation of 6-benzylthiol-2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-3-[(1-methyl [4-(2-(2-pyrazol-4-yl)methyl)-1H-quinazolin-4-one]:

[0677] 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 2 (dba) 3 (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 a yellow solid 6-benzylthiol-2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-3-[(1-methylpyrazol-4-yl)methyl]-1H-quinazolin-4-one (530 mg, 75% yield).

[0678] 1 H NMR (400 MHz, DMSO-d 6 )δppm: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).

[0679] MS m / z(+ESI):519.2[M+H] + .

[0680] Step 6: Preparation of 2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-3-[(1-methylpyrazol-4-yl) [methyl]-4-oxo-1H-quinazoline-6-sulfonyl chloride:

[0681] To 6-benzylthiol-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 H 2 NCS (293 mg, 2.08 mmol) was added to the stirred solution in O (1 mL). After stirring for 2 hours, the reaction mixture was diluted with EA (20 mL) and washed with Na 2 SO 4Drying, filtration and concentration gave 2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonyl chloride (260 mg, 40% yield) as a yellow oil which was used in the next step without further purification.

[0682] MS m / z(+ESI): 495.1,497.1[M+H] + .

[0683] 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:

[0684] Starting from 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), the title compound was prepared as a white solid (17 mg, 14% yield) according to Scheme 1 and analogously to Example 1 (Step 5).

[0685] 1 H NMR (400 MHz, DMSO-d 6 +D 2 O)δppm: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,2 H),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).

[0686] MS m / z(+ESI):530.4[M+H] + .

[0687] Preparation Example 5: 4-[2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]-N,N-dimethylbenzamide:

[0688]

[0689] To 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 H 2To the stirred solution in 2% CO (0.3 mL) was added [4-(dimethylcarbamoyl)phenyl]boronic acid (60 mg, 0.30 mmol), followed by K 3 PO 4 (163 mg, 0.76 mmol), Pd(PPh 3 ) 4 (45 mg, 0.04 mmol) and PdCl 2 (dppf) 2 (28 mg, 0.04 mmol). After stirring at 95 °C for 4 hours, the reaction mixture was filtered. The filtrate was concentrated and purified by preparative HPLC to give a white solid 4-[2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]-N,N-dimethylbenzamide (38 mg, 26% yield).

[0690] 1 H NMR (400 MHz, DMSO-d 6 +D 2 O)δppm: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).

[0691] MS m / z(+ESI):566.4[M+H] + .

[0692] Preparation Examples 7 and 8: 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:

[0693]

[0694] Step 1: Preparation of 5-bromo-3-fluoro-2-nitrobenzoic acid:

[0695] To a stirred solution of 2-amino-5-bromo-3-fluorobenzoic acid in TFA (10 mL) was added 30% H2 O 2 Aqueous solution (5.9 mL, 58.0 mmol). After stirring at 60 °C for 2 hours, NaHSO was added at 0 °C. 3 The reaction mixture was quenched with aqueous solution, concentrated and purified by Biotage Combiflash to give 5-bromo-3-fluoro-2-nitrobenzoic acid (1.52 g, 63% yield) as a yellow solid.

[0696] 1 H NMR (400 MHz, DMSO-d 6 ) δppm: 8.31 (dd, J = 9.2Hz, 2.0Hz, 1H), 7.98 (t, J = 1.6Hz, 1H).

[0697] MS m / z(+ESI):263.9,265.9[M+H] + .

[0698] Step 2: Preparation of 3-[(3R)-4-benzyloxycarbonyl-3-methyl-piperazin-1-yl]-5-bromo-2-nitrobenzoic acid:

[0699] To a stirred solution of 5-bromo-3-fluoro-2-nitrobenzoic acid (100 mg, 0.34 mmol) in EtOH (1 mL) was added (2R)-2-methylpiperazine-1-carboxylic acid benzyl ester (416 mg, 1.70 mmol). After stirring at 115 °C for 2 hours, the reaction mixture was concentrated and purified by Biotage Combiflash to give 3-[(3R)-4-benzyloxycarbonyl-3-methyl-piperazin-1-yl]-5-bromo-2-nitrobenzoic acid (160 mg, 88% yield) as a yellow solid.

[0700] 1 H NMR (400 MHz, DMSO-d 6 )δppm:14.28(br,1H),7.98(d,J=2.0Hz,1H),7.87(d,J=2.0Hz,1H),7.36(m,5H),5.1 0(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).

[0701] MS m / z(+ESI):476.4,478.4[M+H] + .

[0702] Step 3: Preparation of 2-amino-3-[(3R)-4-benzyloxycarbonyl-3-methyl-piperazin-1-yl]-5-bromobenzoic acid:

[0703] To a stirred solution of 3-[(3R)-4-benzyloxycarbonyl-3-methyl-piperazin-1-yl]-5-bromo-2-nitrobenzoic 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-bromobenzoic acid (110 mg, 78% yield) as a yellow solid.

[0704] 1 H NMR (400 MHz, DMSO-d 6 )δppm: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).

[0705] MS m / z(+ESI): 448.2,450.2[M+H] + .

[0706] Step 4: Preparation of (2R)-4-[2-amino-5-bromo-3-[(1-methylpyrazol-4-yl)methylcarbamoyl]benzene Benzyl]-2-methyl-piperazine-1-carboxylate:

[0707] To a stirred solution of 2-amino-3-[(3R)-4-benzyloxycarbonyl-3-methyl-piperazin-1-yl]-5-bromobenzoic 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 hours, the reaction mixture was concentrated and purified using a Biotage Combiflash to give (2R)-4-[2-amino-5-bromo-3-[(1-methylpyrazol-4-yl)methylcarbamoyl]phenyl]-2-methyl-piperazine-1-carboxylic acid benzyl ester (1.18 g, 78% yield) as a white solid.

[0708] 1 H NMR (400 MHz, DMSO-d 6)δppm: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,1H),4.21(d,J=5.6Hz,2H),3.85(m,1H),3.77(s,3H),3.37(m,1H),2.99(m,1H),2.80(m,2H),2.46(m,1H),1.31(d,J=6.8Hz,3H).

[0709] MS m / z(+ESI):541.2,543.2[M+H] + .

[0710] Step 5: Preparation of (2R)-4-[6-bromo-2-chloro-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-quinazoline- 8-yl]-2-methyl-piperazine-1-carboxylic acid benzyl ester:

[0711] To a stirred solution of (2R)-4-[2-amino-5-bromo-3-[(1-methylpyrazol-4-yl)methylcarbamoyl]phenyl]-2-methyl-piperazine-1-carboxylic acid benzyl ester (105 mg, 0.17 mmol) in Diox (4 mL) was added thiophosgene (81 mg, 0.70 mmol). Stirring was carried out at room temperature for 1 hour and then at 105 °C for 1 hour. The reaction mixture was concentrated and purified with Biotage Combiflash to give (2R)-4-[6-bromo-2-chloro-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-quinazolin-8-yl]-2-methyl-piperazine-1-carboxylic acid benzyl ester (87 mg, 76% yield) as a yellow solid.

[0712] 1 H NMR (400 MHz, DMSO-d 6 )δppm: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 ,1H),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).

[0713] MS m / z(+ESI):584.9,586.8[M+H] + .

[0714] Step 6-9: Preparation of (2R)-4-[2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1- [methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]piperazine-1-carboxylic acid benzyl ester:

[0715] Starting from (2R)-4-[6-bromo-2-chloro-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-quinazolin-8-yl]-2-methyl-piperazine-1-carboxylic acid benzyl ester, benzyl mercaptan, methoxyamine hydrochloride and 1-methylcyclopropylamine hydrochloride, the title compound was prepared as a light yellow solid according to Scheme 1 and analogously to Example 3 (steps 4-7).

[0716] 1 H NMR (400 MHz, DMSO-d 6 )δppm: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).

[0717] MS m / z(+ESI): 651.0[M+H] + .

[0718] 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:

[0719] To a stirred solution of (2R)-4-[2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]piperazine-1-carboxylic acid benzyl ester (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 for 24 h under a stream of hydrogen, 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 (124 mg, 45% yield) as a light yellow solid.

[0720] 1 H NMR (400 MHz, DMSO-d 6 +D2 O)δppm: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).

[0721] MS m / z(+ESI):517.4[M+H] + .

[0722] Step 11: Preparation of 2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]- 4-Oxo-8-[(3R)-3-methyl-4-(1-methylcyclopropylcarbonyl)piperazin-1-yl]-1H-quinazoline-6-sulfonamide:

[0723] 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 hours, 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-methylcyclopropylcarbonyl)piperazin-1-yl]-1H-quinazoline-6-sulfonamide (28 mg, 29% yield) as a white solid.

[0724] 1 H NMR (400 MHz, DMSO-d 6 +D 2 O)δppm: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).

[0725] MS m / z(+ESI):599.5[M+H] + .

[0726] Preparation Example 12: (2E)-2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-4-acetyl-3-methylpiperazin-1-yl]-1H-quinazoline-6-sulfonamide:

[0727]

[0728] 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 product was directly purified by preparative HPLC (ACN / H 2 The reaction solution was purified by precipitating with 0.2% 2-0.1% HCOOH) to obtain the desired product (32 mg, 44% yield) as a white solid.

[0729] 1 H NMR (400 MHz, DMSO-d 6 +D 2 O)δppm: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),4.68and 4.20(2m,1H),4.39and 2.61(2m,1H),3.82(s,3H),3.77(s,3H),3.46(m,1H),2.96(m,3H),2.77(m,1H),2.06and 2.04(2s,3H),1.46and 1.34(2d,J=6.8Hz,3H),1.03(s,3H),0.58(m,2H),0.37(m,2H).

[0730] MS m / z(+ESI): 559.3[M+H] + .

[0731] Preparation Example 13: (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:

[0732]

[0733] Step 1: (R)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid tert- Butyl Ester / (R)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester:

[0734] 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) was added dropwise NaHMDS (2.8 mL, 5.6 mmol, 2 M solution in THF) at -78°C under argon atmosphere. 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 slowly warm to room temperature and stirred for another 2 hours. The mixture was heated to room temperature with NH 4 The reaction was quenched with aqueous Cl solution and then extracted twice with EA. The combined organic layers were washed with water and brine and purified by anhydrous Na 2 SO 4 Dry, filter, and concentrate to dryness in vacuo. The residue was purified by Biotage Combiflash (0-10% EA in PE, collection: 5% EA in PE) to give the title compound as a colorless oil. (840 mg, 88% yield, mixture of isomers).

[0735] 1 H NMR (400 MHz, CDCl 3 )δppm: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),1.49and 1.48(2s,9H),1.25and 1.19(2d,J=6.8Hz,3H).

[0736] Step 2: (R)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dioxaborolan-2-yl Hydropyridine-1(2H)-carboxylic acid tert-butyl ester / (R)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- tert-Butyl)-3,6-dihydropyridine-1(2H)-carboxylate:

[0737] To a solution of a mixture of (R)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester and (R)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (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'-bis-1,3,2-dioxaborolane (756 mg, 2.92 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (72 mg, 0.10 mmol). The suspension was evacuated and backfilled with N 2 The reaction mixture was concentrated in vacuo. The residue was directly purified by Biotage Combiflash (ACN / H 2 O contains 0.1% HCOOH; collect: H 2 Purification by 80% ACN in 0.5% ethanol (455 mg, 58% yield, mixture of isomers) afforded the desired product as a brown oil.

[0738] 1 H NMR (400 MHz, CDCl 3 )δppm: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),1.18and 1.06(2d,J=6.8Hz,3H).

[0739] MS m / z(+ESI): 324.2[M+H] + ; 268.1[M+H- t Bu] + .

[0740] Step 3: (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-carboxylic acid tert-butyl Esters / (6R)-4-[(2E)-2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazole-4- [(4-(2-(2-((2-(((((((((((((((((((((- ...

[0741] 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) were added (2R)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester and (6R) -6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (421 mg, 1.30 mmol), tripotassium phosphate (351 mg, 1.63 mmol), 2-(dicyclohexylphosphino)-2',4',6'-tri-isopropyl-1,1'-biphenyl (53 mg, 0.11 mmol) and dipalladium-tris(dibenzylideneacetone) chloroform complex (57 mg, 0.05 mmol). The resulting solution was evacuated and backfilled with N 2 The mixture was stirred at 75°C for 3.5 hours. The suspension was concentrated to dryness under vacuum. The residue was purified by Biotage Combiflash (10-10% EA in PE, collection: 5% EA in PE) to give the desired product as a medium yellow solid. (150 mg, 45% yield, mixture of isomers).

[0742] 1 H NMR (400 MHz, DMSO-d 6 )δppm:8.58(s,0.6H,N H , isomer 2), 8.34(s, 0.4H, N H , isomer 1), 8.18 (d, J = 2.0 Hz, 0.4 H, isomer 1), 8.17 (d, J = 2.0 Hz, 0.6 H, isomer 2), 8.06 (s, 0.4 H, SO 2 N H , isomer 1), 8.03(s, 0.6H, SO 2 N H, isomer 2), 7.76 (d, J = 2.0 Hz, 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), 1.45 (s, 9H), 1.25 (d, J = 6.8 Hz, 1.8H, Isomer 2), 1.25 (d, J = 6.8 Hz, 1.2H, Isomer 1), 1.06 (s, 3H), 0.60 (m, 2H), 0.39 (m, 2H).

[0743] MS m / z(+ESI): 614.3[M+H] + .

[0744] 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-methoxy Imino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8- [( 6R ) - 6-甲基-1,2,3,6-四氢吡啶-4-基 ] - 1H-喹唑啉-6-磺酰胺 ：

[0745] To a solution of a mixture of (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-carboxylic acid tert-butyl ester and (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-carboxylic acid tert-butyl ester (117 mg, 0.19 mmol) in DCM (9 mL) was added trifluoroacetic acid (9 mL, 115 mmol), and the reaction was stirred at 25° C. for 1 hour. The volatiles were removed under vacuum to give the crude product, which was purified by preparative HPLC (ACN / H 2 The product was purified by HPLC (containing 0.1% HCOOH) to obtain a white solid product (42 mg, 43.0% yield, mixture of isomers).

[0746] 1 H NMR (400 MHz, DMSO-d 6 +D 2O)δppm:8.26(s,0.8H, H COOH),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 (~36:64).

[0747] MS m / z(+ESI):514.5[M+H] + .

[0748] Preparation Example 14: (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:

[0749]

[0750] To a stirred solution of (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',6'-triisopropylbiphenyl (21 mg, 0.04 mmol) and dipalladium-tris(dibenzylideneacetone) chloroform complex (22 mg, 0.02 mmol) in 1,4-dioxane (8 mL) and water (1 mL) was added N,N,2-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (303 mg, 1.05 mmol) at 25 °C. The reaction solution was evacuated and backfilled with N 2gas, and then stirred at 85°C for 2 hours. The reactant was cooled to room temperature and then filtered. The filtrate was purified by preparative high performance liquid chromatography to obtain the desired product as a white solid (39 mg, 32% yield).

[0751] 1 H NMR (400 MHz, DMSO-d 6 +D 2 O)δppm: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).

[0752] MS m / z(+ESI):580.5[M+H] + .

[0753] Preparation Example 20: (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:

[0754] Step 1: 2E )- N,N- Dimethyl-6-(tributyltin) nicotinamide:

[0755]

[0756] To a solution of 6-bromo-N,N-dimethylpyridine-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 hours. The reaction suspension was combined with another batch of reaction suspension and purified by Biotage Combiflash, eluting with 0-100% EA in PE, collecting: 60% EA in PE) to give the desired product (900 mg, 27.6% yield) as a yellow oil.

[0757] 1H NMR (400 MHz, DMSO-d 6 )δppm: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 ,1H),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).

[0758] MS m / z(+ESI):441.1[M+H] + .

[0759] 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:

[0760] 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-tributyltin-pyridine-3-carboxamide (205 mg, 0.42 mmol), tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.02 mmol) and THF (2 mL). The reaction solution was heated to 100° C. and heated under N 2 The reaction solution was directly purified by preparative HPLC with MeOH / H 2 O (0.1% HCOOH) was used as the eluent to give the desired product (21 mg, 17.4% yield) as a yellow solid.

[0761] 1 H NMR (400 MHz, DMSO-d 6 +D 2 O)δppm: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), 7.71(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).

[0762] MS m / z(+ESI):567.4[M+H] + .

[0763] Preparation Example 21: (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:

[0764]

[0765] 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 product was directly purified by preparative HPLC (ACN / H 2 The reaction solution was purified by precipitating with 0.2% 2-0.1% HCOOH) to obtain the desired product as a white solid (44 mg, 38% yield).

[0766] 1 H NMR (400 MHz, DMSO-d 6 +D 2 O)δppm: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).

[0767] MS m / z(+ESI):531.4[M+H] + .

[0768] Preparation Example 22: (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:

[0769]

[0770] Step 1: N-[1-[4-[(2E)-2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1- [methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]benzoyl]cyclopropyl]carbamic acid tert-butyl ester:

[0771] 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)ferrocenepalladium(II) chloride (19 mg, 0.025 mmol) and potassium carbonate (78 mg, 0.56 mmol). The reaction solution was heated at 75°C under N 2 The solution was concentrated in vacuo and the residue was purified by Biotage Combiflash using 0-60% EA in PE (EA / PE = 1 / 1, R f =0.5) to give the desired product as a brown solid (160 mg, 83.9% yield, 90%).

[0772] 1 H NMR (400 MHz, CDCl 3 )δppm: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).

[0773] MS m / z(+ESI): 678.1[M+H ]+ .

[0774] Step 2: (2E)-8-[4-(1-hydroxy-2-oxo-cyclobutyl)phenyl]-2-methoxyimino-N-(1-methyl Cyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide:

[0775] 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) at 25°C was added trifluoroacetic acid (1.49 g, 13.1 mmol). The solution was stirred at 25°C for 0.5 h. The reaction solution was concentrated under vacuum and the residue was purified by preparative HPLC with ACN / H 2 The collected fractions were allowed to stand at room temperature for 24 hours and then freeze-dried to obtain the product 22 (22 mg, 17.2% yield).

[0776] 1 H NMR (400 MHz, DMSO-d 6 +D 2 O)δppm: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).

[0777] MS m / z(+ESI):579.3[M+H] + .

[0778] Preparation Example 23: (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:

[0779]

[0780] Step 1: (E)-4-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1- ((2-(trimethylsilyl)ethoxy)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-1-(((2-(trimethylsilyl)ethoxy)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)- (2-(4-( ...methyl-1-yl)methyl)-1H-imidazole-2-carboxylic acid ethyl ester):

[0781] 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), tripotassium phosphate (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 evacuated and backfilled with N 2 The reaction solution was directly treated with ACN / H2O using Biotage Combiflash. 2 The resulting mixture was purified by eluting with O (0.1% HCOOH) to afford the desired product (380 mg, 68.8% yield) as a yellow solid.

[0782] 1 H NMR (400 MHz, DMSO-d 6 )δppm: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,3 H), 1.08 (s, 3H), 0.87 (t, J = 7.6Hz, 2H), 0.63 (m, 2H), 0.38 (m, 2H), -0.06 (s, 9H).

[0783] MS m / z(+ESI): 687.5[M+H] + .

[0784] Step 2: 4-[(2E)-2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrrolidone [(2-trimethylsilylethoxymethyl)imidazole-2-carboxylic acid]-4-oxo-1H-quinazolin-8-yl)methyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxylic acid:

[0785] 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 at 25° C. for 16 hours. The reaction solution was acidified to pH=5 with 1N HCl and then heated to 40° C. with ACN / H2O using a Biotage Combiflash. 2 The resulting mixture was purified by eluting with O (0.1% HCOOH) to afford the desired product (160 mg, 74.1% yield) as a yellow solid.

[0786] 1 H NMR (400 MHz, DMSO-d 6 )δppm: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. 86(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).

[0787] MS m / z(+ESI): 659.4[M+H] + .

[0788] 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-(trimethyl (silyl)ethoxy)methyl)-1H-imidazole-2-carboxamide:

[0789] 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) at 25°C 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, 2M THF solution). The reaction solution was stirred at 25°C for 2 hours. The reaction solution was concentrated under vacuum and the residue was purified by Biotage Combiflash with ACN / H 2 The resulting mixture was purified by eluting with O (0.1% HCOOH) to afford the desired product (80 mg, 57.5% yield) as a yellow solid.

[0790] 1 H NMR (400 MHz, DMSO-d 6 )δppm: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),1.0 8(s,3H),0.85(t,J=8.0Hz,2H),0.63(m,2H),0.39(m,2H),-0.06(s,9H).

[0791] MS m / z(+ESI): 686.1[M+H] + .

[0792] 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-carboxylic acid Amide;

[0793] 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 under vacuum 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 another hour. The volatiles were removed under vacuum and the residue was combined with another batch and purified by preparative HPLC with ACN / H 2 The resulting mixture was purified by eluting with O (0.1% HCOOH) to afford the desired compound (27 mg, 28.5% yield) as a white solid.

[0794] 1 H NMR (400 MHz, DMSO-d 6 +D 2 O)δppm: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).

[0795] MS m / z(+ESI): 556.4[M+H] + .

[0796] Preparation Example 24: (2E)-2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-4-piperidinyl]-1H-quinazoline-6-sulfonamide:

[0797]

[0798] 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 at 25° C. under a hydrogen balloon atmosphere for 24 hours. The catalyst was filtered off. The filtrate was purified by preparative HPLC (ACN-H 2 O) and (ACN-H containing 0.1% HCOOH 2 O) to obtain the desired product as a white solid (46 mg, 34% yield).

[0799] 1 H NMR (400 MHz, DMSO-d 6 +D 2 O)δppm:8.38(s,1H, H COOH),8.16(d,J=2.0Hz,1H),7.78and 7.74(2d,J=2.0Hz,1H,epimers),7.69(s,1H),7.44(s,1H),4.84(s,2H),3.84and3.83(2s,3H,epimers),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).

[0800] MS m / z(+ESI):516.4[M+H] + .

[0801] Preparation Example 25: (2E)-2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-1,2-dimethyl-4-piperidinyl]-1H-quinazoline-6-sulfonamide:

[0802]

[0803] To a solution of (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-4-piperidinyl]-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 analyzed by preparative HPLC (ACN / H containing 0.1% HCOOH) 2 O) to obtain the desired product as a white solid (36 mg, 36% yield).

[0804] 1 H NMR (400 MHz, DMSO-d 6 +D 2 O)δppm:8.22(s,1H, H COOH),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),3.84and 3.83(2s,3H,epimers),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),1.14and 1.08(2d,J=6.8Hz,3H),1.01and 1.00(2s,3H,epimers),0.57(m,2H),0.36(m,2H).

[0805] MS m / z(+ESI):530.5[M+H] + .

[0806] Preparation Example 26: (2E)-2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-1-acetyl-2-methyl-4-piperidinyl]-1H-quinazoline-6-sulfonamide:

[0807]

[0808] To a solution of (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-3-methyl-4-piperidinyl]-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 analyzed by preparative HPLC with MeOH / H 2 The product was purified by eluting with O (0.1% HCOOH) to obtain the desired product as a white solid (29 mg, 26% yield).

[0809] 1 H NMR (400 MHz, DMSO-d 6 +D 2 O)δppm: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).

[0810] MS m / z(+ESI):558.5[M+H] + .

[0811] Preparation Example 27: (2E)-2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-1-(1-methylcyclopropanecarbonyl)-4-piperidinyl]-1H-quinazoline-6-sulfonamide:

[0812]

[0813] To a solution of (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-4-piperidinyl]-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-H containing 0.1% HCOOH) 2 O) to obtain the desired product as a white solid (65 mg, 46% yield).

[0814] 1 H NMR (400 MHz, DMSO-d 6 +D 2 O)δppm:8.14(d,J=2.0Hz,1H),7.78(d,J=2.0Hz,1H),7.69and 7.68(2s,1H,epimers),7.44and 7.43(2s,1H,epimers),4.83and 4.82(2s,2H,epimers),4.74and 4.32(m,1H,epimers),4.21(m,1H),4.05(m,1H),3.84and 3.81(2s,3H,epimers),3.76and 3.75(2s,3H,epimers),3.10(m,1H),2.32(m,1H),1.91(m,1H),1.76(m,1H),1.38(m,1H),1.27and 1.23(2s,3H,epimers),1.12(d,J=6.4Hz,3H),1.01and0.98(2s,3H,epimers),0.88(m,1H),0.75(m,1H),0.57(m,4H),0.36(m,2H).

[0815] MS m / z(+ESI):598.6[M+H] + .

[0816] Preparation Example 28: (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:

[0817]

[0818] 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 methanol (5 mL) were added formaldehyde (20 mg, 0.24 mmol, 37% aqueous solution) and sodium cyanoborohydride (6 mg, 0.097 mmol). The reaction was stirred at 25°C for 1 hour. The reaction solution was purified by preparative HPLC (ACN / H 2 O) to afford the desired product (22 mg, 43% yield) as a white solid.

[0819] 1 H NMR (400 MHz, DMSO-d 6 +D 2 O)δppm: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,0.43 H),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),1.22(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 (~40:60).

[0820] MS m / z(+ESI): 528.3[M+H] + .

[0821] Preparation Example 29: (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:

[0822]

[0823] 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 then stirred at 25° C. for 1 hour. The reaction solution was purified by preparative HPLC (ACN / H containing 0.1% HCOOH). 2O) to afford the desired product (22 mg, 41% yield) as a white solid.

[0824] 1 H NMR (400 MHz, DMSO-d 6 +D 2 O) δ ppm: 8.18 (d, J = 2.0 Hz, 0.4H, isomer 1), 8.16 (d, J = 2.0 Hz, 0.6H, isomer 2), 7.74 (m, 0.6H, isomer 2), 7.69 (m, 1.4H), 7.43 (s, 1H), 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, 0.4H, isomer 1), 3.92 (m, 0.6H, isomer 2), 3.80 (m, 3H), 3.76 (s, 3H), 3.55-3.30 (m, 1H, overlapped with H 2 O peak), 2.83 (m, 0.4H), 2.67 (m, 0.6H), 2.07 (m, 4H), 1.35-1.15 (4d, J = 6.8 Hz, 3H, isomer s), 1.05 (s, 3H), 0.59 (m, 2H), 0.38 (m, 2H); mixture of two isomers (~40:60).

[0825] MS m / z(+ESI): 556.3[M+H] + .

[0826] Preparation Example 30: (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:

[0827]

[0828] To (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 mixture (70 mg, 0.14 mmol) in DMF (5 mL) was added 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). Then, the reaction was stirred at 25 ° C for 1 hour. The reaction solution was directly analyzed by preparative HPLC (ACN / H containing 0.1% HCOOH) 2 O) to afford the desired product (37 mg, 44% yield) as a white solid.

[0829] 1 H NMR (400 MHz, DMSO-d 6 +D 2 O) δppm: 8.19 (d, J = 2.0 Hz, 0.42H, isomer 1), 8.18 (d, J = 2.0 Hz, 0.58H, isomer 2), 7.80 (d, J = 2.0 Hz, 0.58H, isomer 2), 7.73 (d, J = 2.0 Hz, 0.42H, 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), 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, overlapped with H 2 O peak), 2.75 (m, 0.58H, 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 (~40:60).

[0830] MS m / z(+ESI):596.4[M+H] + .

[0831] Preparation Example 32: (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:

[0832]

[0833] To a stirred solution of 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (28.5 mg, 0.186 mmol) in DMF (3 mL) at 0°C was added HATU (88 mg, 0.232 mmol) followed by DIPEA (59 mg, 0.464 mmol). The resulting reaction mixture was stirred at 0°C for 5 min and then (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 reach room temperature and stirred for 6 h. 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 (2×5 mL) and purified by anhydrous Na 2 SO 4 Dry, filter, and evaporate the filtrate under reduced pressure to obtain a crude product. 2 O / 10 mM NH 4 HCO 3 ) to afford the desired product (13.8 mg, 14% yield) as an off-white solid.

[0834] 1 H NMR (400 MHz, DMSO-d 6)δppm: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).

[0835] MS m / z(+ESI): 651.3[M+H] + .

[0836] Preparation Example 36: (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:

[0837]

[0838] 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 Et 3 N (73 mg, 0.52 mmol) and triphosgene (64 mg, 0.203 mmol) were added and the resulting reaction mixture was stirred at 0°C for 5 minutes, and then compound 3,3-difluoropyrrolidine (24 mg, 0.174 mmol) was added. The resulting reaction mixture was allowed to reach 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 (2×5 mL) and dried over anhydrous Na 2 SO 4 Dry, filter, and evaporate the filtrate under reduced pressure to obtain a crude product. 2 O / 10 mM NH 4 HCO 3 ) to afford the desired product (9.0 mg, 8% yield) as an off-white solid.

[0839] 1 H NMR (400 MHz, DMSO-d 6 )δppm: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).

[0840] MS m / z(+ESI): 650.5[M+H] + .

[0841] Preparation Example 42: (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:

[0842]

[0843] 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 and the reaction mixture was allowed to warm to room temperature and stirred for 16 hours. 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) and purified by anhydrous Na 2 SO 4 Drying and concentrating under reduced pressure gave a crude product, which was purified by pre-HPLC (H 2 O / 10 mM NH 4 HCO 3) to afford the desired product (10 mg, 4% yield) as an off-white solid.

[0844] 1 H NMR (400 MHz, DMSO-d 6 )δppm: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).

[0845] MS m / z(+ESI): 613.3[M+H] + .

[0846] Preparation of the intermediate used to prepare Example 13 and Example 22: (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:

[0847]

[0848] Step 1: Preparation of 8-bromo-2-chloroquinazolin-4(3H)-one:

[0849] To a stirred suspension of 8-bromo-2,4-dichloroquinazoline (2.5 g, 8.7 mmol) in THF (15 mL) at 25°C was added a solution of sodium hydroxide (0.87 g, 21.8 mmol) in water (20 mL). After 10 minutes, the reaction suspension became a clear solution. Stirring was continued at 25°C for 3 hours. The reaction solution was acidified to pH = 5 with AcOH and the resulting suspension was filtered. The filter cake was washed with H 2 O, and dried in vacuo to obtain the desired product as a pale yellow solid (2.04 g, 81.1% yield).

[0850] MS m / z(+ESI):259.0,261.0[M+H] + .

[0851] Step 2: Preparation of 8-bromo-2-chloro-3-((1-methyl-1H-pyrazol-4-yl)methyl)quinazolin-4(3H)-one:

[0852] 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-methylpyrazole (7.2 g, 44.4 mmol), potassium carbonate (9.4 g, 66.6 mmol) and "Hunig base" (8.8 g, 66.6 mmol). The reaction solution was stirred at 25 ° C for 16 hours. The reactants were diluted with EA and water. The organic phase was separated and evaporated under vacuum to obtain a crude product, which was purified by column chromatography with PE / EA = 1:1 to obtain the desired product as a white solid. (6.0 g, 68% yield).

[0853] 1 H NMR (400 MHz, CDCl 3 )δppm: 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).

[0854] MS m / z(+ESI): 352.9&354.9[M+H] + .

[0855] Step 3: (2E)-8-Bromo-2-methoxyimino-3-[(1-methylpyrazol-4-yl)methyl]-1H-quinazoline-4-yl ketone:

[0856] 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. With vigorous stirring, the reactants were poured into 500 mL of 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).

[0857] 1 H NMR (400 MHz, CDCl 3 )δppm: 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).

[0858] MS m / z(+ESI):364.0,366.0[M+H] +.

[0859] Step 4: (2E)-8-Bromo-2-methoxyimino-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinoline Oxazoline-6-sulfonyl chloride:

[0860] 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 in a sealed tube. The reaction solution was poured into ice and then extracted with DCM. The organic layer was purified by anhydrous Na 2 SO 4 After drying, it was used directly in the next step without further purification.

[0861] MS m / z(+ESI): 461.8,463.8[M+H] + .

[0862] Step 5: (2E)-8-Bromo-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl) [methyl]-4-oxo-1H-quinazoline-6-sulfonamide:

[0863] 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 at 25°C for 10 minutes, 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 solution was stirred at 25°C for 1 hour. The crude product was combined with another batch of product and purified by Biotage Combiflash with 0-70% EA in PEEA / PE=1 / 2, R f = 0.2 to give the desired product as a yellow solid (600 mg, 81.3% yield).

[0864] 1 H NMR (400 MHz, DMSO-d 6 )δppm:8.41(s,1H,N H ),8.22(d,J=1.6Hz,1H),8.19(s,1H,SO 2 N 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).

[0865] MS m / z(+ESI): 496.9,498.9[M+H] + .

[0866] Preparation of the intermediate used to prepare Example 22: tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)cyclopropyl)carbamate:

[0867]

[0868] 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 evacuated and backfilled with N 2 The suspension was concentrated in vacuo and the residue was purified by Biotage Combiflash using 0-40% EA in PE (EA / PE=1 / 1, R f =0.5) to afford the desired product (650 mg, 98.1% yield) as a brown oil.

[0869] 1 H NMR (400 MHz, CDCl 3 )δppm: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).

[0870] MS m / z(+ESI): 288.2[M+H-Boc] + &332.1[M+H- t Bu] + .

[0871] Preparation of Intermediate-III for Example 18: (1-methylcyclopropyl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone:

[0872]

[0873] Under argon atmosphere, to a suspension of (4-bromophenyl)-(1-methylcyclopropyl)methanone (350 mg, 1.32 mmol) in dioxane (5 mL) were added bis(pinacol)diboron (683 mg, 2.63 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(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). The suspension was stirred at 90° C. under argon atmosphere for 2 hours. The reaction suspension was used directly in the next step without any workup and purification.

[0874] MS m / z(+ESI): 287.1[M+H] + .

[0875] Biological Examples

[0876] PARG enzymatic assay

[0877] The inhibition of PARG enzymatic activity by compounds was determined as follows: Recombinant His-tagged human PARG protein (Adipogen AG, #40T-0022) expressed in Sf21 insect cells was aliquoted and stored at -80°C until use. The artificial enzyme substrate 4-(trifluoromethyl)umbelliferyl (TFMU)-ADPr was prepared essentially as described (Drown BS ​​et al, Cell Chemical Biology 2018) and stored at -20°C as a stock solution in 10 mM DMSO (dimethyl sulfoxide) until use. For the reaction, the final concentration of the enzyme was typically 1 nM and the final concentration of TFMU-ADPr was typically 200 μM. The reaction was performed in a black 384-well low-volume round-bottom assay plate (Corning, #4514) in a final volume of 10 μL. To this end, PARG was diluted in reaction buffer (50 mM K 2 HPO 4, 50mM KCl, 10mM β-mercaptoethanol, pH 7.4) to 1.67nM and 6μL was dispensed into each assay well using a multichannel pipette. The compound was then dispensed into each well using an Echo dispenser (BeckmanCoulter) to obtain a preset final concentration of the concentration range to be tested (usually an 8-point serial concentration ranging from 0.01μM to 10μM, or from 0.001μM to 1μM, or from 0.0001μM to 0.1μM) and volume corrected with 100% DMSO (the final concentration of DMSO in the reaction mixture was 0.5%). The plate was mixed and 4μL of TFMU-ADPr was added to each well 15 minutes later using a multichannel pipette and mixed briefly. After 30 minutes, the fluorescence intensity signal was measured on an EnVision microplate reader (PerkinElmer) using 380 / 10 nm and 535 / 25 nm filters for excitation and emission, respectively (gain: 150). The detection window was set using a DMSO control group (upper panel) and a control group without PARG enzyme (lower panel). The Δ values ​​were plotted as concentration-response curves and fitted to a sigmoid four-parameter logistic model to calculate the IC 50 Value (Scigilian Analyze).

[0878] PARG NanoBRET-based Cellular Target Engagement Assay

[0879] PARG Nano-Luciferase Construct: The fusion vector was created by Promega by inserting the full-length human PARG cDNA sequence (gene ID: 8505, UniProt: Q86W56) encoding a 976-amino acid protein into the pNLF1-C[CMV / Hygro] vector (with the C-terminus Enzyme fusion) generated.

[0880] PARG target engagement tracer synthesis: NanoBRET tracer for PARG was prepared following the general tracer synthesis procedure reported previously.

[0881] PARG probe displacement assay using NanoBRET: HEK293T (DSMZ #ACC635) cells transiently transfected with PARG-NanoLuc fusion construct were resuspended in OptiMEM without phenol red (Gibco #11058-021) at a concentration of 2.4 × 10 5 9 μL per well was then added to a white 384-well low-volume microplate (Greiner #784080) and cultured under standard growth conditions for 24 hours.

[0882] Compounds were then dispensed into each well using an Echo dispenser (Beckman Coulter) to obtain a preset final concentration of the concentration range to be tested (usually an 8-point sequence ranging from 0.01 μM to 10 μM, or from 0.001 μM to 1 μM, or from 0.0001 μM to 0.1 μM) and corrected for volume with 100% DMSO (the final concentration of DMSO in the reaction mixture was 0.5%).

[0883] After mixing and incubation at room temperature for 15 min, 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 at 37 °C, 5% CO 2 After incubation for 2 h in the presence of 5 μL 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 OptiMEM without phenol red, 5 μL of the solution was added to each well, followed by a mixing step. Filtered fluorescence was measured on 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 and fitted to a sigmoid four-parameter logistic model to calculate IC 50 Value (Scigilian Analyze).

[0884] The results are shown in Table 2 below.

[0885] Detection of cellular PAR levels by Western blot

[0886] Kuramochi high grade serous ovarian cancer (HGSOC) (JCRB, #JCRB0098) or NCI-H1650 non-small cell lung cancer (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 the cells reached 70% density in a 6-well plate (TPP, #92006), the cells were treated with the test compound vehicle DMSO or with the test compound at the indicated final concentration for 4, 6 or 8 hours. Then, the medium was removed and the cells were incubated in a 6-well plate containing protease and phosphatase inhibitors (Halt, #92006). TMThe cells were collected by scraping in a 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 & Phosphatase inhibitor cocktail 100x ThermoScientific, #1861281) and 1 mM PMSF (Fluka, #93482). The lysate was stored in Eppendorf Tubes at -80°C. TM The protein concentration in the lysate was determined using the Pierce 660nm protein assay reagent (ThermoScientific, #22660) until use. 20 μg of protein was diluted in 4x Laemmli buffer (Biorad, #161-0747) containing 10% β-mercaptoethanol, separated by SDS-PAGE using a 10% gel, and then Turbo TMSystem semi-dry blotting (BioRad) was transferred to a PVDF membrane (Trans Blot Turbo Transfer Pack BioRad, #1704156). The 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 primary antibodies used were as follows: anti-PAR (Ab-1) mouse monoclonal antibody (10H) (Millipore, #AM80-100UG), poly / mono-ADP ribose (PAR / MAR) (E6F6A) rabbit monoclonal antibody (Cell Signaling, #83732), rabbit anti-GAPDH clone 14C10 (Cell Signaling, #2118S) diluted 1:2000 or mouse α-tubulin (Sigma, #T5168) diluted 1:5000 to control for equal protein loading. The secondary antibody conjugated to horseradish peroxidase (HRP) was incubated at room temperature for one hour at a dilution of 1:5000 in TBS-0.1% Tween-20 buffer (Sigma, #M7409) containing 5% skim milk. The secondary antibodies used were as follows: goat anti-mouse-HRP (Jackson, #115-035-146) and goat anti-rabbit-HRP (Jackson, #111-035-144). The membrane was incubated with enhanced chemiluminescence (ECL) Prime Western Blot detection reagent (Amersham, #RPN2236) and specific signals were detected using the FusionSOLOS imaging system (Vilber Lourmat). The results are shown in Figure 1.

[0887] Cell proliferation assay

[0888] For Example 1-11, RMUG-S mucinous cystadenocarcinoma (JCRB, #IFO50320) and TOV-112D endometrioid adenocarcinoma (ATCC, #CRL-11731) ovarian cancer cell lines were grown in DMEM / F-12 containing glutamine (BioConcept, #1-26F09-I) and RPMI containing glutamine (BioConcept, #1-41F03-1) culture media, respectively, both of which contained 10% FBS (Sigma-Aldrich, #F9665) and 1% penicillin-streptomycin (BioConcept, #4-01F00-H), and standard cell culture techniques were used. Based on the PARG shRNA (short hairpin RNA) deletion maps 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), RMUG-S and TOV-112D ovarian cancer cell lines were selected as cell lines with high and low PARG dependence, respectively. The PARG dependence of these cell lines was independently verified 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 served as a functional on-target inhibition readout, while strong growth inhibition observed for TOV-112D indicated off-target activity of the compound. Cells were seeded in 96-well plates with clear bottoms (Huberlab, #7.655090) at a seeding density of 5000 cells per well in 100 μL of culture medium and the plates were incubated at 37°C, 5% CO prior to compound treatment. 2 The plates were incubated overnight in DMSO. Test compounds were prepared in DMSO at a concentration of 10 mM. Compounds were dispensed at the desired final concentration using a Tecan D300e digital dispenser (TECAN) and normalized to the highest DMSO volume. The plates were incubated for 120 hours and then used (Promega, #G9241) was used to measure cell number in essentially the same manner as recommended by the manufacturer. When measuring proliferation, 50 μL of the reconstituted 2.0 reagent was added to 100 μL of culture medium containing cells. The plate was incubated at room temperature for 10 minutes to stabilize the luminescent signal, and then the Synergy4 TM The luminescence intensity signal was measured by a microplate reader (BioTek Instruments). Relative proliferation values ​​were calculated by normalizing the raw data using the signal obtained from cells treated with DMSO (100% proliferation) and the cells evaluated when the compound was added (0% proliferation). The concentration-response data were fitted to a sigmoid 4-parameter logistic model with a maximum limit of 100%. The GI calculated from the curves 50 The value is the compound concentration that reduces proliferation by 50%. The results are shown in Table 2 below.

[0889] The cell proliferation assay protocol was modified to use RMUG-S for Examples 12-44 and subsequently used to test Examples 1-44 in the NCI-H1650 cell line.

[0890] Modified cell proliferation assay

[0891] NCI-H1650 (ATCC, #CRL-5883) or RMUG-S were seeded at 300 cells per well in 384-well plates (Greiner, #781080) on day 1, which ensured assay linearity and optimal signal intensity in 25 μL RPMI1640 medium (Pan Biotech, #P04-22100) containing 10% FCS (Capricorn, #FBS-11A; Lot: CP22-5141) and 1% glutamine (Pan Biotech, #P04-80100). The cells were incubated at 37°C / 5% CO 2 After incubation in a humidified chamber for 24 h, different concentrations of compound / DMSO were dispensed using an Echo 520 (Beckman Coulter). Cells were maintained at 37°C and 5% CO 2 The cells were further cultured for 120 hours. Cells treated with the compound vehicle DMSO served as a negative control, and cells treated with 10 μM Staurosporine (LC Laboratories, #S-9300) served as a positive control.

[0892] On day 6, CellTiter Glo reagent was prepared by mixing the reagent with the cell culture medium in a 1:1 ratio according to the instructions of the kit (Promega Inc.). The mixture and the assay plate were then equilibrated at room temperature for 20 minutes. An equal volume of the reagent-medium-mixture was added to the culture medium in each well. The plate was mixed at about 200 rpm on an orbital shaker (Timix5, Edmund Buehler GmbH) for 2 minutes. The microplate was then incubated at room temperature for 10 minutes to stabilize the luminescent signal. After incubation, luminescence was recorded using a 200 ms integration time on a Victor X5 microplate reader (Perkin Elmer). The data were then analyzed using the XLFIT plug-in in Excel (Dose Response Fit 205) to determine the concentration required for half-maximal inhibition (i.e., the inflection point of the fitted curve).

[0893] As a quality control, a Z' factor was calculated from 16 positive and negative control values. Only assay results showing a Z' factor ≥ 0.5 were used for further analysis.

[0894] Table 2: PARG bioenzymatic inhibition, intracellular PARG target engagement (TE), and growth inhibition of RMUG-S (high PARG dependence), NCI-H1650 (high PARG dependence), and TOV-112D (low PARG dependence) ovarian cancer cell lines.

[0895]

[0896] For PARG IC 50 (nM): +++ when <30, ++ when 30-99, + when 100-1000.

[0897] For PARG TE IC 50 (nM): +++ when <30, ++ when 30-99, + when 100-1000.

[0898] For RMUG-S GI 50 (nM): +++ for <500, ++ for 500-1999, + for 2000-8999. The highest concentration tested was 9000 nM. ND: Not determined.

[0899] For NCI-H1650 GI50 (nM): +++ for <500, ++ for 500-1999, + for >2000. The highest concentration tested was 30000 nM. ND: Not determined.

[0900] For TOV-112D GI 50(nM): +++ for <500, ++ for 500-1999, + for 2000-8999, - for ≥9000. The highest concentration tested was 9000 nM. ND: Not determined.

[0901] References

[0902] Citations are listed in the order in which they appear in the text

[0903] Hanahan D,Cancer Discovery 2022,12(1):31-46

[0904] Gaillard H et al,Nature Reviews Cancer 2015,15(5):276-89

[0905] Brown JS et al,Cancer Discovery 2017,7(1):20-37

[0906] Curtin NJ,Nature Reviews Cancer 2012,12(12):801-17

[0907] Hartwell LH et al,Science 1997,278(5340):1064-8

[0908] Farmer H et al,Nature 2005,434(7035):917-21

[0909] Bryant HE et al,Nature 2005,434(7035):913-7

[0910] Turner N et al,Nature Reviews Cancer 2004,4(10):814-9

[0911] Hottiger MO et al,Trends in Biochemical Sciences 2010,35(4):208-19

[0912] Leung AKL,Trends in Cell Biology 2020,30(5):370-383

[0913] Barkauskaite E at al,Nature Communications 2013,4:2164

[0914] Pourfarjam Y et al,Biochemical and Biophysical ResearchCommunications 2020,527(3):818-823

[0915] Marques M et al,Oncogene 2019,38(12):2177-2191

[0916] Pillay N et al,Cancer Cell 2019,35(3):519-533

[0917] Coulson-Gilmer C et al,Journal of Experimental&Clinical CancerResearch 2021,40(1):323

[0918] Prokhorova E et al,Molecular Cell,2021,81(12):2640-2655

[0919] Chen S-H and Yu X,Science Advances 2019,5(4):eaav4340

[0920] Slade D,Genes&Development 2020,34(5-6):360-394

[0921] Houl JH et al,Nature Communications 2019,10(1):5654

[0922] Wuts P.G.M,Greene’s Protective Groups in Organic Synthesis,5 th Edition,Publisher:John Wiley&Sons,2014

[0923] Drown BS et al,Cell Chemical Biology 2018,25(12):1562-1570

[0924] Cheung HW et al,Proceedings of the National Academy of Sciences USA2011,108(30):12372-7

[0925] Cowley GS et al, Scientific Data 2014,1:140035

[0926] McDonald ER et al, Cell 2017,170(3):577-592.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in R 1 It is hydrogen, cyano, formyl, -CONH2, -CH2OH, -CH2OC 1-2 Alkyl, C 1-2 Alkyl, C 1-2 a haloalkyl or ethynyl group; R 2 and R 3 Independently C 1-2 alkyl; or R 2 and R 3 Together with the carbon atoms to which they are attached they form a cyclopropyl or oxetanyl group; X 1 Yes CR 7 or N; R 7 is hydrogen or fluorine; X 2 Yes CR 8 or N; R 8 is hydrogen or fluorine; X 3 Yes 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, spiro heterocyclyl or bridged heterocyclyl, wherein the cycloalkyl, phenyl, heteroaryl, heterocyclyl, fused heterocyclyl, spiro heterocyclyl and bridged heterocyclyl are optionally substituted by R a , R b and / or R c replace; R a is hydrogen, -N(R m )R n , C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogen, cyano, oxo, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl 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 ; R b and R c are independently hydrogen, -N(R m )R n , C 1-6 Alkyl, C 1-4 Alkyl-N(R m )R n , hydroxyl, C 1-6 Alkoxy, halogen, cyano, C 1-6 Haloalkyl or C 1-6 Haloalkoxy; R d It 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 alkyl; R f , R g , R h , R i , R j , R k , R m and R n are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, amino C 1-6 Alkyl or hydroxyl C 1-6 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, they form a heterocyclic group; in (i)R a Cycloalkyl, heteroaryl and heterocyclyl; (ii) R d alkyl, haloalkyl, cycloalkyl, phenyl, heteroaryl and heterocyclic groups; (iii) By R f and R g , R h and R i or R j and R k combined with the nitrogen to which they are attached to form a heterocyclic group; Each ((i), (ii), (iii)) is optionally replaced by 1, 2, 3 or 4 independently selected from 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 Substitution of haloalkoxy substituents; R 4 is hydrogen or a group -L 1A -L 2A -L 3A ; L 1A Not present or optionally replaced by C 1-2 Alkyl or oxo-substituted C 1-3 Alkylene; L 2A Does not exist 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 independently hydrogen or C 1-2 alkyl; L 3A It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, heterocyclyl or heteroaryl, wherein L 3A Optionally independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, 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 one or more substituents; R c1 and R d1 are independently hydrogen or C 1-4 alkyl; y is 0, 1, or 2; z is 1, 2, or 3; R 5 is hydrogen or a group -L 1B -L 2B -L 3B ; L 1B Not present or optionally replaced by C 1-2 Alkyl or oxo-substituted C 1-3 Alkylene; L 2B Does not exist 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 independently hydrogen or C 1-2 alkyl; L 3B It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, heterocyclyl or heteroaryl, wherein L 3B Optionally independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, 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 one or more substituents; R c2 and R d2 are independently hydrogen or C 1-4 alkyl; y' is 0, 1, or 2; z' is 1, 2, or 3; R 6 is hydrogen or a group -L 1C -L 2C -L 3C ; L 1C Not present or optionally replaced by C 1-2 Alkyl or oxo-substituted C 1-3 Alkylene; L 2C Does not exist 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 independently hydrogen or C 1-2 alkyl; L 3C It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, heterocyclyl or heteroaryl, wherein L 3C Optionally independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, 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)2N(R d3 )R c3 、-N(R d3 )S(O)2R c3 and -(CH2) z” N(R d3 )R c3 substituted with one or more substituents; R c3 and R d3 are independently hydrogen or C 1-4 alkyl; y" is 0, 1, or 2; z” is 1, 2, or 3; The condition is Group-L 1A -L 2A -L 3A , -L 1B -L 2B -L 3B and -L 1C -L 2C -L 3C does not contain -OO-, -SO-, -OS- or -SS- units as linking units within the group; Group-L 1A -L 2A -L 3A Do not place -ON- or -SN- units with R 4 The connected ring nitrogen atoms are adjacent, Group-L 1B -L 2B -L 3B Do not place N, O, or S atoms next to R 5 The attached oxime oxygen atoms are adjacent, and -L 1C -L 2C -L 3C Do not place -ON- or -SN- units with R 6 The linked ring nitrogen atoms are adjacent.

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

3. A compound of formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 1 It is cyano, C 1-2 Alkyl or ethynyl.

4. A compound of formula (I) according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 Together with the carbon atom to which they are attached they form a cyclopropyl or oxetanyl group.

5. A compound of formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein 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 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, 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 replaced by R a , R b and / or R c replace; or R 9 is a spiro heterocyclic group, wherein X 3 The first ring connected 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 the second ring is connected to the first ring through a common carbon atom and is 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, wherein the spiro heterocyclyl is optionally replaced by R a , R b and / or R c replace.

6. A compound of formula (I) according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein R 9 is hydrogen, halogen, cyano, phenyl, 5- to 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N as ring atoms, wherein the phenyl and 6-membered heteroaryl are optionally replaced by R in the para position to the rest of the molecule a and optionally further substituted by R b substituted, and the 5-membered heteroaryl is optionally substituted at the 3-position distal to the rest of the molecule by R a and optionally further substituted by R b Replacement; or R 9 It is part (R 9a ) or part (R 9b ): Where Z 1 N or CH, Z 2 is N(R a )、O、S、CH(R a ) or C(R x )(R y ), where R x and R y Together they form a 4- to 6-membered monocyclic heterocyclic ring containing one heteroatom selected from N, O and S.

7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein 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 ; 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) or C 1-4 Alkyl-N(C 1-4 Alkyl)2; R c is hydrogen or C 1-4 alkyl; R d It is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 wherein the alkyl, haloalkyl, cycloalkyl, phenyl, heteroaryl and heterocyclyl are optionally substituted by 1, 2, 3 or 4 groups independently selected from 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 Substitution of haloalkoxy substituents; R f is hydrogen or C 1-4 alkyl; R g is hydrogen or C 1-4 alkyl; R j is hydrogen or C 1-4 alkyl; R k is hydrogen or C 1-4 alkyl; R m is hydrogen or C 1-4 Alkyl; and R n is hydrogen or C 1-4 alkyl.

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 4 It is a group-L 1A -L 2A -L 3A ; L 2A , L 2B and L 2C does not exist; L 3A is cycloalkyl, phenyl, heterocyclyl or heteroaryl, each optionally substituted; L 3A , L 3B and L 3C No more than two of them are cycloalkyl, phenyl, heterocyclyl or heteroaryl, each of which is optionally substituted; and When R 9 When L is a cycloalkyl group, a phenyl group, a heteroaryl group, a heterocyclic group, a fused heterocyclic group, a spiro heterocyclic group or a bridged heterocyclic group, 3C Not cycloalkyl, phenyl, heterocyclyl or heteroaryl.

9. A compound of formula (I) according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein R 4 It is a group-L 1A -L 2A -L 3A , where L 3A is cycloalkyl, phenyl, heterocyclyl or heteroaryl, each optionally substituted; R 5 is hydrogen or a group -L 1B -L 2B -L 3B , where L 3B is cycloalkyl, phenyl, heterocyclyl or heteroaryl, each optionally substituted, or -L 1B -L 2B -L 3B It is C 1-6 Alkyl; and R 6 is hydrogen or C 1-6 alkyl.

10. A compound of formula (I) according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein R 4 It is a group-L 1A -L 2A -L 3A ; L 1A It is C 1-3 Alkylene; L 2A does not exist; L 3A is phenyl or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S as ring atoms, wherein L 3A Optionally independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, 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; R c1 is hydrogen or C 1-4 alkyl; R d1 is hydrogen or C 1-4 alkyl; y is 0, 1, or 2; z is 1, 2, or 3; R 5 is hydrogen or a group -L 1B -L 2B -L 3B ; L 1B It is C 1-3 Alkylene; L 2B does not exist; L 3B is phenyl or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S as ring atoms, wherein L 3B Optionally independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, 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; R c2 is hydrogen or C 1-4 alkyl; R d2 is hydrogen or C 1-4 alkyl; y' is 0, 1, or 2; z' is 1, 2, or 3; or group-L 1B -L 2B -L 3B It is C 1-6 Alkyl; and R 6 is hydrogen or a group -L 1C -L 2C -L 3C , where -L 1C -L 2C -L 3C It is C 1-6 alkyl.

11. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It is cyano, C 1-2 Alkyl or ethynyl; R 2 and R 3 Together with the carbon atoms to which they are attached they form a cyclopropyl or oxetanyl group; X 1 Yes CR 7 ; X 2 Yes CR 8 ; X 3 Yes CR 9 ; R 7 and R 8 It 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 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, S and O as ring atoms, 5- to 6-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 replaced by R a , R b and / or R c replace; or R 9 is a spiro heterocyclic group, wherein X 3 The first ring connected 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 the second ring is connected to the first ring through a common carbon atom and is 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, wherein the spiro heterocyclyl is optionally replaced by R a , R b and / or R c replace; 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 ; 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) or C 1-4 Alkyl-N(C 1-4 Alkyl)2; R c For hydrogen: R d It is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, heteroaryl or heterocyclyl, wherein the cycloalkyl, phenyl, heteroaryl and heterocyclyl are optionally substituted by 1, 2 or 3 independently selected 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, hydroxyl, 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 Substitution of haloalkoxy substituents; R f is hydrogen or C 1-4 alkyl; R g is hydrogen or C 1-4 alkyl; R j is hydrogen or C 1-4 alkyl; R k is hydrogen or C 1-4 alkyl; Each R m is independently hydrogen or C1-4 alkyl; Each R n Independently hydrogen or C 1-4 alkyl; R 4 It is a group-L 1A -L 2A -L 3A ; L 1A It is C 1-3 Alkylene; L 1A does not exist; L 3A is phenyl or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, S and O as ring atoms, wherein L 3A Optionally independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, 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; or group-L 1A -L 2A -L 3A It is C 1-6 alkyl; R c1 is hydrogen or C 1-4 alkyl; R d1 is hydrogen or C 1-4 alkyl; y is 0, 1, or 2; z is 1, 2, or 3; R 5 is hydrogen or a group -L 1B -L 2B -L 3B ; L 1B It is C 1-3 Alkylene; L 2B does not exist; L 3B is phenyl or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S as ring atoms, wherein L 3B Optionally independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, 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; R c2 is hydrogen or C 1-4 alkyl; R d2 is hydrogen or C 1-4 alkyl; y' is 0, 1, or 2; z' is 1, 2, or 3; or group-L 1B -L 2B -L 3B It is C 1-6 alkyl; R 6 is hydrogen or a group -L 1C -L 2C -L 3C , where the group -L 1C -L 2C -L 3C It is C 1-6 alkyl.

12. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from: 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-dimethylbenzamide; 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-methylpiperazin-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)-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-piperidinyl]-1H-quinazoline-6-sulfonamide; (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-1,2-dimethyl-4-piperidinyl]-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-piperidinyl]-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-piperidinyl]-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-trifluoropropionyl)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-(cyclopentylcarbonyl)-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; (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; 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.

13. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 12 for use in treating a neoplastic disease, preferably cancer, in a subject selected from mammals, preferably humans.

14. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, and optionally one or more pharmaceutically acceptable excipients.

15. A compound of formula (Int-I) or a salt thereof, in R 10 is hydrogen, halogen (e.g., chlorine, bromine, iodine), -B(OH)2, -B(-OC(CH3)2-C(CH3)2-O-), -S(O)2OH, -S(O)2Cl or -S-CH2-phenyl; and X 1 , X 2 , X 3 , R 4 , R 5 and R 6 As defined for the compound of formula (I) according to any one of claims 1 to 12; The compound (Int-I) is not 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]acetic acid; (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)azanyl 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)azanyl benzoate; (3,4-dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)azanylphenylacetate; 1-[(3,4-dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)azanyl]2-ethyl oxalate; 2-(Hydroxyamino)-3-phenyl-4(3H)-quinazoline; or A compound of formula (Int-II) or a salt thereof, in R 11 is hydrogen or C 1-8 Alkyl; and X 1 , X 2 , X 3 , R 4 , R 5 and R 6 As defined for a compound of formula (I) as claimed in any one of claims 1 to 12.

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