PARG inhibitors

Abstract

Provided herein are PARG inhibitors, pharmaceutical compositions comprising inhibitory compounds, and methods of treating disease using PARG inhibitory compounds.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Patent Application No. 63 / 343,005, filed on May 17, 2022, which is hereby incorporated by reference in its entirety. Background Art

[0003] Poly(ADP-ribose)glycosyl hydrolase (PARG) is an enzyme involved in DNA replication and repair, and cells depleted or inhibited by PARG show increased sensitivity to DNA damaging agents.PARG inhibitors are expected to have utility as cancer treatments both as single agents and in combination with therapeutic agents and radiation therapy. Summary of the invention

[0004] Provided herein are PARG inhibitors, pharmaceutical compositions comprising the inhibitory compounds, and methods of using the inhibitory compounds for treating disease.

[0005] One embodiment provides a compound or a pharmaceutically acceptable salt or solvate thereof having the structure of formula (I):

[0006]

[0007] in,

[0008] A is selected from hydrogen, halo, -OH, -CN, optionally substituted C1-C6 alkoxy, -N(R 9 ) 2 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted (carbocyclyl)alkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aryl;

[0009] n is 1, 2 or 3;

[0010] X is O or NR 6 ;

[0011] Y is N, CH or CF;

[0012] Z is -N(H)- or -CH(R 8 )-;

[0013] G is a bond, optionally substituted cycloalkylene, or optionally substituted heterocycloalkylene;

[0014] R 1is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkylalkyl, optionally substituted aralkyl, optionally substituted heterocyclylalkyl, and optionally substituted heteroaralkyl;

[0015] R 2 and R 3 R is independently selected from hydrogen, halo, -OH, -CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted (cycloalkyl)alkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aryl; optionally, R 2 and R 3 are combined to form an optionally substituted carbocyclic or heterocyclic ring;

[0016] R 4 and R 5 R is independently selected from hydrogen, halo, -OH, -CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted (cycloalkyl)alkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aryl; optionally, R 4 and R 5 to form an optionally substituted carbocyclic or heterocyclic ring, or R 3 and R 4 are combined to form an optionally substituted carbocyclic or heterocyclic ring;

[0017] R 6 is selected from hydrogen, OH or optionally substituted C1-C5 alkyl;

[0018] R 7 is optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted 1,1'-bis(cyclopropyl)-1-yl;

[0019] R 8 is hydrogen, halo or optionally substituted alkyl; and

[0020] Each R 9 and R is independently hydrogen or optionally substituted C1-C6 alkyl.

[0021] One embodiment provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable excipient.

[0022] One embodiment provides a method of treating a disease or condition in a patient in need thereof, comprising administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides the method wherein the disease or condition is cancer.

[0023] Incorporation by reference

[0024] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference for the specific purpose identified herein. DETAILED DESCRIPTION

[0025] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, reference to "the cell" includes reference to one or more cells (or reference to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties (such as molecular weight) or chemical properties (such as chemical formulae), all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. When referring to numbers or numerical ranges, the term "about" means that the referenced numbers or numerical ranges are approximate within experimental variability (or within statistical experimental error), and thus, in some cases, the numbers or numerical ranges will vary between 1% and 15% of the stated numbers or numerical ranges. The term "comprising" (and related terms such as "including" or "having" or "containing") is not intended to exclude "consisting of" or "consisting essentially of" the features in certain other embodiments (e.g., embodiments of any composition of matter, composition, method, process, etc. described herein).

[0026] definition

[0027] As used in the specification and the appended claims, the following terms have the following indicated meanings unless indicated to the contrary.

[0028] "Amino" refers to -NH 2 Group.

[0029] "Cyano" refers to a -CN group.

[0030] "Nitro" refers to -NO 2 Group.

[0031] "Oxa" refers to an -O- group.

[0032] "Oxo" refers to a =0 group.

[0033] "Thio" refers to a =S group.

[0034] "Imino" refers to a =NH group.

[0035] "Oximo" refers to a =N-OH group.

[0036] "Hydrazino" refers to =N-NH 2 Group.

[0037] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C 1 -C 15 In certain embodiments, an alkyl group contains from one to thirteen carbon atoms (e.g., C 1 -C 13 In certain embodiments, an alkyl group contains from one to eight carbon atoms (e.g., C 1 -C 8 In other embodiments, the alkyl group contains from one to five carbon atoms (e.g., C 1 -C 5 In other embodiments, the alkyl group contains from one to four carbon atoms (e.g., C 1 -C 4 In other embodiments, the alkyl group contains from one to three carbon atoms (e.g., C 1 -C 3 In other embodiments, the alkyl group contains one to two carbon atoms (e.g., C 1 -C 2 In other embodiments, the alkyl group contains one carbon atom (e.g., C 1 In other embodiments, the alkyl group contains five to fifteen carbon atoms (e.g., C 5 -C 15 In other embodiments, the alkyl group contains five to eight carbon atoms (e.g., C 5 -C 8 In other embodiments, the alkyl group contains two to five carbon atoms (e.g., C 2 -C 5 In other embodiments, the alkyl group contains three to five carbon atoms (e.g., C 3 -C 5 Alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl group is connected to the rest of the molecule by a single bond. Unless otherwise specifically stated in the specification, the alkyl group is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a )2 、-C(O)R a 、-C(O)OR a 、-C(O)N(R a ) 2 、-N(R a )C(O)OR a 、-OC(O)-N(R a ) 2 、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a ) 2 (where t is 1 or 2), where each R a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl). In certain embodiments, the optionally substituted alkyl is haloalkyl. In other embodiments, the optionally substituted alkyl is fluoroalkyl. In other embodiments, the optionally substituted alkyl is -CF 3 Group.

[0038] "Alkoxy" refers to a group of the formula -O-alkyl bonded through an oxygen atom, wherein alkyl is an alkyl chain as defined above.

[0039] "Alkenyl" refers to a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond and having two to twelve carbon atoms. In certain embodiments, alkenyl comprises two to eight carbon atoms. In other embodiments, alkenyl comprises two to four carbon atoms. Alkenyl is connected to the rest of the molecule by a single bond, such as ethenyl (i.e., vinyl (vinyl)), prop-1-enyl (i.e., allyl), but-1-enyl, penta-1-enyl, penta-1,4-dienyl, etc. Unless otherwise specifically stated in the specification, alkenyl groups are optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a ) 2 、-C(O)R a 、-C(O)OR a 、-C(O)N(R a ) 2 、-N(R a )C(O)OR a 、-OC(O)-N(R a ) 2 、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a ) 2 (where t is 1 or 2), where each R a and R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl).

[0040] "Alkynyl" refers to a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond and having two to twelve carbon atoms. In certain embodiments, the alkynyl group comprises two to eight carbon atoms. In other embodiments, the alkynyl group comprises two to six carbon atoms. In other embodiments, the alkynyl group comprises two to four carbon atoms. The alkynyl group is connected to the rest of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless otherwise specifically stated in the specification, the alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a ) 2 、-C(O)R a 、-C(O)OR a 、-C(O)N(R a ) 2 、-N(R a )C(O)OR a 、-OC(O)-N(R a ) 2 、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a ) 2 (where t is 1 or 2), where each R a and R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl).

[0041] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain consisting only of carbon and hydrogen that connects the rest of the molecule to a radical, contains no unsaturation, and has one to twelve carbon atoms, such as methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is connected to the rest of the molecule by a single bond and to the radical by a single bond. The point of attachment of the alkylene chain to the rest of the molecule and to the radical is through one carbon in the alkylene chain or through any two carbons in the chain. In certain embodiments, an alkylene group contains one to eight carbon atoms (e.g., C 1 -C 8 In other embodiments, the alkylene group contains one to five carbon atoms (e.g., C 1 -C 5 In other embodiments, the alkylene group contains one to four carbon atoms (e.g., C 1 -C 4 In other embodiments, the alkylene group contains one to three carbon atoms (e.g., C 1 -C 3 In other embodiments, the alkylene group contains one to two carbon atoms (e.g., C 1 -C 2 In other embodiments, the alkylene group contains one carbon atom (e.g., C 1 In other embodiments, the alkylene group contains five to eight carbon atoms (e.g., C 5 -C 8 In other embodiments, the alkylene group contains two to five carbon atoms (e.g., C 2 -C 5 In other embodiments, the alkylene group contains three to five carbon atoms (e.g., C 3 -C 5 Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a ) 2 、-C(O)R a 、-C(O)OR a 、-C(O)N(R a ) 2 、-N(R a )C(O)OR a 、-OC(O)-N(R a ) 2 、-N(R a)C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a ) 2 (where t is 1 or 2), where each R a and R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl).

[0042] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain consisting only of carbon and hydrogen that connects the rest of the molecule to a radical, contains at least one carbon-carbon double bond, and has from one to twelve carbon atoms. The alkenylene chain is connected to the rest of the molecule by a single bond and to the radical by a single bond. In certain embodiments, an alkenylene group comprises two to eight carbon atoms (e.g., C 2 -C 8 In other embodiments, the alkenylene group contains two to five carbon atoms (e.g., C 2 -C 5 In other embodiments, the alkenylene group contains two to four carbon atoms (e.g., C 2 -C 4 In other embodiments, the alkenylene group contains two to three carbon atoms (e.g., C 2 -C 3 In other embodiments, the alkenylene group contains two carbon atoms (e.g., C 2 In other embodiments, the alkenylene group contains five to eight carbon atoms (e.g., C 5 -C 8 In other embodiments, the alkenylene group contains three to five carbon atoms (e.g., C 3 -C5 Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a ) 2 、-C(O)R a 、-C(O)OR a 、-C(O)N(R a ) 2 、-N(R a )C(O)OR a 、-OC(O)-N(R a ) 2 、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a ) 2 (where t is 1 or 2), where each R a and R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl).

[0043] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen that connects the rest of the molecule to a radical, contains at least one carbon-carbon triple bond, and has from one to twelve carbon atoms. The alkynylene chain is connected to the rest of the molecule by a single bond and to the radical by a single bond. In certain embodiments, an alkynylene group comprises two to eight carbon atoms (e.g., C 2 -C8 In other embodiments, the alkynylene group contains two to five carbon atoms (e.g., C 2 -C 5 In other embodiments, the alkynylene group contains two to four carbon atoms (e.g., C 2 -C 4 In other embodiments, the alkynylene group contains two to three carbon atoms (e.g., C 2 -C 3 In other embodiments, the alkynylene group contains two carbon atoms (e.g., C 2 In other embodiments, the alkynylene group contains five to eight carbon atoms (e.g., C 5 -C 8 In other embodiments, the alkynylene group contains three to five carbon atoms (e.g., C 3 -C 5 Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a ) 2 、-C(O)R a 、-C(O)OR a 、-C(O)N(R a ) 2 、-N(R a )C(O)OR a 、-OC(O)-N(R a ) 2 、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a ) 2 (where t is 1 or 2), where each R aand R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl).

[0044] "Aryl" refers to a group derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing hydrogen atoms from ring carbon atoms. An aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbons of five to eighteen carbon atoms, wherein at least one ring in the ring system is fully unsaturated, i.e., according to Hückel theory, it contains a cyclic, delocalized (4n+2)π-electron system. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless otherwise specifically stated in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is intended to include aryl groups optionally substituted by one or more substituents independently selected from the following: optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, cyano, nitro, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a ) 2 , -R b -N(R a ) 2 , -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a ) 2 , -R b -OR c -C(O)N(R a ) 2 , -R b -N(R a )C(O)OR a , -Rb -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a ) 2 (where t is 1 or 2), where each R a R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and wherein unless otherwise specified, R a , R b or R c Each of the substituents is unsubstituted.

[0045] "Arylalkyl" refers to a group of the formula -R c -aryl radical, wherein R c is an alkylene chain as defined above, for example methylene, ethylene, etc. The alkylene chain part of the aralkyl group is optionally substituted as described above for alkylene chains. The aryl part of the aralkyl group is optionally substituted as described above for aryl groups.

[0046] "Aralkenyl" refers to a group of the formula -R d -aryl radical, wherein R dis an alkenylene chain as defined above. The aryl part of the aralkenyl group is optionally substituted as described above for aryl groups. The alkenylene chain part of the aralkenyl group is optionally substituted as defined above for alkenylene groups.

[0047] "Arylalkynyl" refers to a group of the formula -R e -aryl radical, wherein R e is an alkynylene chain as defined above. The aryl part of the aralkynyl group is optionally substituted as described above for aryl groups. The alkynylene chain part of the aralkynyl group is optionally substituted as defined above for alkynylene chains.

[0048] "Aralkyloxy" refers to a radical of the formula -OR c -aryl radical, wherein R c is an alkylene chain as defined above, for example methylene, ethylene, etc. The alkylene chain part of the aralkyl group is optionally substituted as described above for alkylene chains. The aryl part of the aralkyl group is optionally substituted as described above for aryl groups.

[0049] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, including condensed rings or bridged ring systems, with three to fifteen carbon atoms. In certain embodiments, the carbocyclyl comprises three to ten carbon atoms. In other embodiments, the carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is connected to the rest of the molecule by a single bond. The carbocyclyl is saturated (i.e., only containing a single C-C bond) or unsaturated (i.e., containing one or more double bonds or triple bonds). Fully saturated carbocyclyl groups are also referred to as "cycloalkyl". Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Unsaturated carbocyclyls are also referred to as "cycloalkenyl". Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Polycyclic carbocyclyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Unless otherwise specifically stated in the specification, the term "carbocyclyl" is intended to include carbocyclyl groups optionally substituted by one or more substituents independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, oxo, thio, cyano, nitro, -R ... b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a ) 2 , -R b-N(R a ) 2 , -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a ) 2 , -R b -OR c -C(O)N(R a ) 2 , -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a ) 2 (where t is 1 or 2), where each R a R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and wherein unless otherwise specified, R a , R b or R c Each of the substituents is unsubstituted.

[0050] "Carbocyclylalkyl" refers to a group of the formula -R c -Carbocyclic group, where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl group are optionally substituted as defined above.

[0051] "Carbocyclylalkynyl" refers to a group of the formula -R c -Carbocyclic group, where R c is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl group are optionally substituted as defined above.

[0052] "Carbocyclylalkoxy" refers to a radical of the formula -OR bonded through an oxygen atom. c -Carbocyclic group, where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl group are optionally substituted as defined above.

[0053] "Halo" or "halogen" refers to a bromo, chloro, fluoro, or iodo substituent.

[0054] "Fluoroalkyl" refers to an alkyl group as defined above substituted with one or more fluoro groups as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl group is optionally substituted as defined above for an alkyl group.

[0055] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring group containing two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise specifically stated in the specification, the heterocyclyl group is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes a spirocyclic, condensed or bridged ring system. The heteroatoms in the heterocyclyl group are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl group is partially or completely saturated. The heterocyclyl group is connected to the rest of the molecule through any atom of one or more rings. Examples of such heterocyclyl groups include, but are not limited to, dioxolanyl, thienyl [1,3] dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. In some embodiments, heterocyclyl groups include 2-oxa-7-azaspiro [3.5] nonanyl. Unless otherwise specifically stated in the specification, the term "heterocyclyl" is intended to include heterocyclyl groups as defined above, which are optionally substituted by one or more substituents selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a ) 2 , -R b -N(R a ) 2 , -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a ) 2 , -R b -OR c -C(O)N(R a ) 2 , -R b -N(R a )C(O)OR a , -R b -N(R a)C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a ) 2 (where t is 1 or 2), where each R a R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and wherein unless otherwise specified, R a , R b or R c Each of the substituents is unsubstituted.

[0056] "N-heterocyclyl" or "N-attached heterocyclyl" refers to a heterocyclyl group as defined above containing at least one nitrogen, and wherein the point of attachment of the heterocyclyl group to the rest of the molecule is through the nitrogen atom in the heterocyclyl group. N-heterocyclyl groups are optionally substituted as described above for heterocyclyl groups. Examples of such N-heterocyclyl groups include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, and imidazolidinyl.

[0057] "C-heterocyclyl" or "C-attached heterocyclyl" refers to a heterocyclyl as defined above containing at least one heteroatom and wherein the point of attachment of the heterocyclyl group to the rest of the molecule is through a carbon atom in the heterocyclyl group. C-heterocyclyl groups are optionally substituted as described above for heterocyclyl groups. Examples of such C-heterocyclyl groups include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0058] "Heterocyclylalkyl" refers to a group of the formula -R c -heterocyclic group, wherein R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally connected to the alkyl group at the nitrogen atom. The alkylene chain of the heterocyclylalkyl group is optionally substituted as defined above for the alkylene chain. The heterocyclyl moiety of the heterocyclylalkyl group is optionally substituted as defined above for the heterocyclyl group.

[0059] "Heterocyclylalkoxy" refers to a radical of the formula -OR bonded through an oxygen atom. c -heterocyclic group, wherein R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally connected to the alkyl group at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy group is optionally substituted as defined above for the alkylene chain. The heterocyclyl moiety of the heterocyclylalkoxy group is optionally substituted as defined above for the heterocyclyl group.

[0060] "Heteroaryl" refers to a group derived from a 3- to 18-membered aromatic ring group containing two to seventeen carbon atoms and one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, a heteroaryl group is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one ring in the ring system is fully unsaturated, i.e., according to Hückel theory, it contains a cyclic, delocalized (4n+2)π-electron system. Heteroaryl includes fused rings or bridged ring systems. One or more heteroatoms in the heteroaryl group are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl group is connected to the rest of the molecule through any atom of one or more rings. Examples of heteroaryl groups include, but are not limited to, aza- azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl yl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl / benzothiophenyl, benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cycloheptatrienol[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanone, furano[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraenol[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraenol[d]pyridazinyl, 5 ,6,7,8,9,10-hexahydrocyclooctatetraen[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolyl, isoindolyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinone, oxadiazolyl, 2-oxoazepine yl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolyl, isoquinolyl, tetrahydroquinoline , 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cycloheptatrienol[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thienyl. In some embodiments, heteroaryl includes 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl and 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl. Unless otherwise specifically stated in the specification, the term "heteroaryl" is intended to include heteroaryl groups as defined above, which are optionally substituted by one or more substituents selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, optionally substituted fluoroalkyl, optionally substituted haloalkenyl, optionally substituted haloalkynyl, oxo, thioxo, cyano, nitro, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a ) 2 , -R b -N(R a ) 2 , -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a ) 2 , -R b -OR c -C(O)N(R a ) 2 , -R b -N(R a)C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a ) 2 (where t is 1 or 2), where each R a R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and wherein unless otherwise specified, R a , R b or R c Each of the substituents is unsubstituted.

[0061] "N-heteroaryl" refers to a heteroaryl group as defined above containing at least one nitrogen, wherein the point of attachment of the heteroaryl group to the rest of the molecule is through the nitrogen atom in the heteroaryl group. N-heteroaryl groups are optionally substituted as described above for heteroaryl groups.

[0062] "C-heteroaryl" refers to a heteroaryl group as defined above, wherein the point of attachment of the heteroaryl group to the rest of the molecule is through a carbon atom in the heteroaryl group. A C-heteroaryl group is optionally substituted as described above for a heteroaryl group.

[0063] "Heteroarylalkyl" refers to a group of the formula -Rc -heteroaryl radical, wherein R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally connected to the alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkyl group is optionally substituted as defined above for the alkylene chain. The heteroaryl moiety of the heteroarylalkyl group is optionally substituted as defined above for the heteroaryl group.

[0064] "Heteroarylalkoxy" refers to a radical of the formula -OR c -heteroaryl radical, wherein R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally connected to the alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkoxy group is optionally substituted as defined above for the alkylene chain. The heteroaryl moiety of the heteroarylalkoxy group is optionally substituted as defined above for the heteroaryl group.

[0065] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers, thus producing enantiomers, diastereomers and other stereoisomeric forms, which are defined as (R)- or (S)- according to absolute stereochemistry. Unless otherwise indicated, the disclosure is intended to consider all stereoisomeric forms of the compounds disclosed herein. When the compounds described herein contain olefin double bonds, and unless otherwise indicated, the disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers and their racemic and optically pure forms and all tautomeric forms are also intended to be included. The term "geometric isomer" refers to E or Z geometric isomers (e.g., cis or trans) of olefin double bonds. The term "positional isomer" refers to structural isomers around a central ring, such as ortho, meta and para isomers around a benzene ring.

[0066] As used herein, "carboxylic acid bioisostere" refers to a functional group or moiety that exhibits physical, biological, and / or chemical properties similar to a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to:

[0067]

[0068] wait.

[0069] "Tautomers" refers to molecules in which a proton can move from one atom of a molecule to another atom of the same molecule. In certain embodiments, the compounds described herein exist as tautomers. Where tautomerization is possible, a chemical equilibrium of tautomers will exist. The exact ratio of tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0070]

[0071] In some embodiments, the compounds disclosed herein are used in different isotopically enriched forms, such as 2 H. 3 H. 11 C. 13 C and / or 14 C content. In a specific embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Pat. Nos. 5,846,514 and 6,334,997. As described in U.S. Pat. Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy, thereby increasing the duration of drug action.

[0072] Unless otherwise stated, structures depicted herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, except for the replacement of hydrogen by deuterium or tritium or the replacement of carbon by 13 C- or 14 Compounds having the present structures other than C-enriched carbon substitutions are within the scope of this disclosure.

[0073] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C) Use 2 H. 11 C. 13 C. 14 C. 15 C. 12 N. 13 N. 15 N. 16 N. 16 O. 17 O. 14 F. 15 F. 16 F. 17 F. 18 F. 33 S. 34 S. 35 S. 36 S. 35 Cl, 37 Cl, 79 Br, 81 Br, 125Isotopic substitutions of I are contemplated. In some embodiments, 18 Isotopic substitution of F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0074] In certain embodiments, some or all of the compounds disclosed herein 1 H atoms are 2 H atom substitution. Methods for the synthesis of deuterium containing compounds are known in the art and include the following synthetic methods by way of non-limiting example only.

[0075] Deuterium substituted compounds are synthesized using various methods, such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, p. 110; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0076] Deuterated starting materials are readily available and are subject to the synthetic methods described herein to provide the synthesis of deuterated compounds. A large number of deuterated reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0077] Deuterium transfer reagents suitable for nucleophilic substitution reactions such as iodomethane-d 3 (CD 3 I) is readily available and can be used to transfer deuterium-substituted carbon atoms to reaction substrates under nucleophilic substitution reaction conditions. 3 The use of I is illustrated in the following reaction schemes by way of example only.

[0078]

[0079] Deuterium transfer reagents such as lithium aluminum deuteride (LiAlD 4) is used to transfer deuterium to the reaction substrate under reducing conditions. LiAlD 4 The use of is illustrated in the following reaction schemes by way of example only.

[0080]

[0081] Deuterium gas and palladium catalysts are used to reduce unsaturated carbon-carbon bonds and to effect reductive substitution of aromatic carbon-halogen bonds as illustrated by way of example only in the following reaction schemes.

[0082]

[0083] In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compounds disclosed herein are completely substituted with deuterium atoms and do not contain non-exchangeable 1 H hydrogen atom. In one embodiment, the deuterium incorporation level is determined by a synthesis method in which deuterated synthetic building blocks are used as starting materials.

[0084] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. Pharmaceutically acceptable salts of any of the PARG inhibitory compounds described herein are intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0085] "Pharmaceutically acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like, and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Also contemplated are salts of amino acids such as arginates, gluconates, and galacturonates (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)). In some embodiments, the acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt according to methods and techniques familiar to those skilled in the art.

[0086] "Pharmaceutically acceptable base addition salts" refer to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared by adding inorganic or organic bases to the free acids. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hepamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0087] "Pharmaceutically acceptable solvate" refers to a composition of matter in the form of a solvent addition. In some embodiments, the solvate contains a stoichiometric or non-stoichiometric amount of a solvent and is formed during preparation with a pharmaceutically acceptable solvent such as water, ethanol, etc. Hydrates are formed when the solvent is water or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed in the processes described herein. The compounds provided herein exist in unsolvated or solvated forms.

[0088] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates such as chimpanzees and other apes and monkeys; farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; experimental animals including rodents such as rats, mice and guinea pigs, etc. In one aspect, the mammal is a human.

[0089] As used herein, "treatment" or "treating" or "alleviate" or "mitigate" are used interchangeably. These terms refer to methods of obtaining beneficial or desired results, including but not limited to therapeutic benefit and / or preventive benefit. "Therapeutic benefit" refers to the eradication or alleviation of the underlying condition being treated. In addition, therapeutic benefit is achieved by eradication or alleviation of one or more physiological symptoms associated with the underlying condition, such that an improvement is observed in the patient, although the patient still suffers from the underlying condition. In some embodiments, for preventive benefit, the composition is administered to a patient at risk of developing a particular disease, or to a patient reporting one or more physiological symptoms of a disease, even if a diagnosis of the disease has not yet been made.

[0090] Poly(ADP-ribose)glycosyl hydrolase

[0091] DNA single-strand breaks (SSBs) are the most common type of damage that occurs in cells, and poly(ADP-ribose) glycosyl hydrolase (PARG) is involved in SSB repair and another repair mechanism called base excision repair together with poly(ADP-ribose) polymerase (PARP) and many other proteins. PARG, as well as PARP, are involved in DNA replication and repair, and cells in which PARG is depleted or inhibited show increased sensitivity to DNA damaging agents. PARG can reverse the action of the PARP enzyme by hydrolyzing the ribose bonds present in poly(ADP-ribose) (PAR). PARG is the main hydrolase involved in the degradation of PAR, has endoglycosyl hydrolase and exoglycosyl hydrolase activities, and is responsible for the rapid removal of ADP-ribose moieties from modified proteins to convert NAD + One of the hydrolases that is recycled back into the cellular system.

[0092] PARG inhibition may provide a therapeutic advantage in PARP inhibitor resistant cells. Furthermore, it has been reported that in breast cancer cells, depletion of PARG results in a gene expression pattern that is significantly different from PARP depletion. Although current models show that PARG depletion results in PARP-dependent effects on DNA repair, recent studies have shown a mechanistic divergence from the PARP mechanism. In contrast to PARP depletion, genotoxic stimuli of PARG followed by depletion result in a decrease in NAD levels. This results in lung cancer cell death, possibly due to energy failure.

[0093] PARG exists as a single gene, and its isoform resides in the nucleus, mitochondria and cytosol. The only other known protein with glycosyl hydrolase activity is ARH3 located in mitochondria. Although mainly known for its direct role in DNA repair, PARG affects PAR signal transduction in splicing, transcription and epigenetic pathways. PARG can play a role in preventing the accumulation of cytoplasmic PAR, and can also play a role in parthanatos (cell death of PAR-mediated types). In some cases, the accumulation of disturbed replication intermediates can lead to synthetic lethality. PARG inhibitors can have uses as a single agent and in combination with therapeutic agents and radiotherapy as cancer treatment.

[0094] Cancer cells can exploit specific DNA repair pathways and thrive when other mechanisms of DNA repair are non-functional. Tumors carrying mutations in proteins involved in double-strand break repair are often more sensitive to PARP inhibitors of SSB repair. There is already some evidence that PARG depletion inhibits SSB repair and reduces survival of BRCA2-deficient cells. However, other tumor mutations can cause defects in double-strand DNA repair machinery (so-called "BRCA-ness"), thereby sensitizing tumor cells to PARG inhibition.

[0095] PARG depletion has been studied in many mouse and human model systems. Mouse cells in which PARG is null or depleted show increased sensitivity to experimental and clinical DNA damaging agents. However, since the lack of PARG does not sensitize all agents (e.g., gemcitabine, camptothecin), this suggests that PARG function is specific to certain DNA damage repair pathways as well as chemotherapy and radiotherapy. In humans, PARG depletion sensitizes lung, cervical, and pancreatic cancer cells to gamma radiation or experimental DNA damaging agents (e.g., hydrogen peroxide, methyl methanesulfonate).

[0096] In humans, the PARG gene is located on a single chromosome at locus 10q11.23-21, but can undergo alternative splicing, resulting in different PARG isoforms, such as PARG 111 , PARG 102 , PARG 99 , PARG 60 , PARG 55 Different PARG isoforms can be localized in different subcellular locations. 111 It is the largest isoform that can be localized in the nucleus and translocated to the cytoplasm. 111 It has four domains, namely the PARG catalytic domain, the macrodomain, the intrinsic disordered regulatory region and the hinge domain. 102 and PARG 99(which lacks part of the N-terminal domain) can be localized in the cytoplasm and has a perinuclear distribution that can translocate to the nucleus. 102 and PARG 99 Has a greater degree of whole-cell activity. 60 and PARG 55 Can be localized in mitochondria and lack catalytic activity.

[0097] PARG can be used together with PARP for DNA repair. The PARP enzyme family has at least 17 members, of which PARP1-3 are localized in the nucleus and are involved in many cellular processes. Nuclear PARP enzymes are part of DNA repair, as well as transcription, chromatin modification, and cell death pathways. PARP1-3 contain DNA binding domains to facilitate interaction with DNA and are activated by DNA damage. One of the ways PARP1-3 works is by adding a large number of post-translational modifications to other proteins and themselves, which can be reversed by PARG. By inhibiting PARG, it can change the kinetics of dePARylation, which causes the protein to be inappropriately modified.

[0098] PARG enzyme function

[0099] PARG and PARP can work together to promote downstream cellular processes. The exoglycosyl hydrolase activity of PARG involves binding to the two most terminal ADP-ribose residues within the PARG chain, generating free PAR and a mono-ADP-ribose moiety. Mono-ADP-ribose is metabolized by ADP-ribose pyrophosphohydrolase to AMP and ribose 5' phosphate. AMP is then used in cell signaling pathways, while ribose can be used for other biomolecules, such as, but not limited to, DNA and RNA. The endoglycosyl hydrolase activity of PARG can occur through hyper-PARP activity, which results in the generation of free PAR chains. Free PAR chains may be associated with apoptosis and act to signal cell death.

[0100] PARG also functions to maintain a stable level of PAR to protect cells from parthanatos triggered by the release of apoptosis-inducing factor (AIF) from mitochondria to the nucleus. In the nuclear chromatin environment, AIF can lead to massive DNA fragmentation and chromatin condensation, leading to cell death. PARG depletion prevents the release of AIF from mitochondria to prevent oxidative stress-induced parthanatos. PARG can also play a useful role in telomere maintenance by negatively regulating access to telomeric DNA by reversing ADP-ribosylation of the telomere-specific protein TRF1. This results in PARG contributing to the regulation of telomere repair and replication.

[0101] PARP inhibitors have been studied for cancers with defects in the DNA damage response mechanism, because PARP enzymes can perform many DNA repair functions, such as but not limited to DNA single-strand breaks (Pilger et al., Genes Dev. 2021). The immune response of PARP is related to DNA repair, where DNA damage can activate anti-tumor immunity. (Pilger et al., Genes Dev. 2021). Studies have shown that PARP inhibitors can affect the innate and adaptive immune responses of cells through DNA damage and repair mechanisms, highlighting the significance of PARP inhibitors for the therapeutic use of immune checkpoint inhibitors or as biomarkers in DNA damage response.

[0102] PARP enzymes catalyze the addition of PAR subunits to receptor proteins and to themselves. PARP inhibitors have been studied for cancer therapy and have been successful in treating ovarian, breast, and prostate cancers. PARP inhibitors have been found to be useful in treating defects in the homologous recombination DNA repair pathway, particularly for tumors with BRCA1 and BRCA2 mutations (Ding et al., Cell Reports 2018; et al., Nature Comm. 2019). BRCA mutant cells may therefore be dependent on PARP-mediated DNA repair and survival and thus sensitive to PARP inhibition.

[0103] PARP inhibitors have also shown clinical efficacy in subjects with BRCA mutations. PARP inhibitors can elicit local and systemic anti-tumor immunity and can participate in the innate immune response through the stimulator of interferon genes (STING)-dependent pathway (Ding et al., Cell Reports 2018; et al., Nature Comm. 2019). The study found that STING-dependent type I interferon (IFN) signaling can mediate the therapeutic effect of PARP inhibition in BRCA1-deficient tumors. In addition, it was found that treatment with PARP inhibitors can stimulate upregulation of IFN signaling genes in vitro and in vivo and can accelerate upregulation of innate immune responses in BRCA1- or BRCA2-deficient tumors ( et al., Nature Comm. 2019).

[0104] PARP inhibitors exhibit synthetic lethality to BRCA loss of function and could be developed for the treatment of ovarian cancer as monotherapy for patients with germline or somatic BRCA1 and BRCA2 mutations, or as maintenance therapy following platinum chemotherapy in subjects with platinum-sensitive relapsed disease (Ding et al., Cell Reports 2018). Further studies have shown that the addition of PD-1 blockade can prolong the activity of PARP inhibitors by overcoming the increased PD-L1 expression on tumor cells that occurs when cells are treated with PARP inhibitors alone (Ding et al., Cell Reports 2018).

[0105] Prior Art PARG inhibitors

[0106] The study of PARG inhibitors has not reached the extent of PARP inhibitors. Clinical resistance to PARP inhibitors has been described, and there is therefore a need to discover alternative inhibitors that target the DNA damage repair pathway. Previously described PARG inhibitors include bicyclic aromatic and heteroaromatic compounds as described in WO 2016 / 092326, WO 2016 / 097749, WO 2021 / 055744, WO 2018 / 237296, WO 2020 / 023802 and WO 2020 / 205646. There is still a need to find alternative PARG inhibitors that have strong independent efficacy on the DNA break repair cycle and also synergize with PARP inhibitors.

[0107] PARG inhibitory compounds

[0108] In one aspect, provided herein is a PARG inhibitory compound.

[0109] One embodiment provides a compound or a pharmaceutically acceptable salt or solvate thereof having the structure of formula (I):

[0110]

[0111] in,

[0112] A is selected from hydrogen, halo, -OH, -CN, optionally substituted C1-C6 alkoxy, -N(R 9 ) 2 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted (carbocyclyl)alkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aryl;

[0113] n is 1, 2 or 3;

[0114] X is O or NR 6 ;

[0115] Y is N, CH or CF;

[0116] Z is -N(H)- or -CH(R 8 )-;

[0117] G is a bond, optionally substituted cycloalkylene, or optionally substituted heterocycloalkylene;

[0118] R 1 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkylalkyl, optionally substituted aralkyl, optionally substituted heterocyclylalkyl, and optionally substituted heteroaralkyl;

[0119] R 2 and R 3 R is independently selected from hydrogen, halo, -OH, -CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted (cycloalkyl)alkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aryl; optionally, R 2 and R 3 are combined to form an optionally substituted carbocyclic or heterocyclic ring;

[0120] R 4 and R 5 R is independently selected from hydrogen, halo, -OH, -CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted (cycloalkyl)alkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aryl; optionally, R 4 and R 5 to form an optionally substituted carbocyclic or heterocyclic ring, or R 3 and R 4 are combined to form an optionally substituted carbocyclic or heterocyclic ring;

[0121] R 6 is selected from hydrogen, OH or optionally substituted C1-C5 alkyl;

[0122] R 7 is optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted 1,1'-bis(cyclopropyl)-1-yl;

[0123] R 8 is hydrogen, halo or optionally substituted alkyl; and

[0124] Each R9 and R is independently hydrogen or optionally substituted C1-C6 alkyl.

[0125] Another embodiment provides the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein A is hydrogen.

[0126] Another embodiment provides the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein A is halo, -OH or -CN.

[0127] Another embodiment provides the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein A is an optionally substituted C1-C6 alkoxy group or -N(R 9 ) 2 .

[0128] Another embodiment provides the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein A is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl and optionally substituted carbocyclylalkyl.

[0129] Another embodiment provides the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein A is an optionally substituted heterocyclyl or an optionally substituted heterocyclylalkyl.

[0130] Another embodiment provides the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein A is selected from optionally substituted heteroaryl or optionally substituted aryl.

[0131] One embodiment provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, which has the structure of formula (Ia):

[0132]

[0133] in,

[0134] n is 1, 2 or 3;

[0135] X is O or NR 6 ;

[0136] Y is N, CH or CF;

[0137] Z is -N(H)- or -CH(R 8 )-;

[0138] G is a bond, optionally substituted cycloalkylene, or optionally substituted heterocycloalkylene;

[0139] R 1is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkylalkyl, optionally substituted aralkyl, optionally substituted heterocyclylalkyl, and optionally substituted heteroaralkyl;

[0140] R 2 and R 3 R is independently selected from hydrogen, halo, -OH, -CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted (cycloalkyl)alkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aryl; optionally, R 2 and R 3 are combined to form an optionally substituted carbocyclic or heterocyclic ring;

[0141] R 4 and R 5 R is independently selected from hydrogen, halo, -OH, -CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted (cycloalkyl)alkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aryl; optionally, R 4 and R 5 to form an optionally substituted carbocyclic or heterocyclic ring, or R 3 and R 4 are combined to form an optionally substituted carbocyclic or heterocyclic ring;

[0142] R 6 is selected from hydrogen, OH or optionally substituted C1-C5 alkyl;

[0143] R 7 is optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted 1,1'-bis(cyclopropyl)-1-yl; and

[0144] R 8 is hydrogen, halogenated or optionally substituted alkyl.

[0145] Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 or 3.

[0146] Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein X is O. Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein X is NR 6 .

[0147] Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is N. Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is CH. Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein Y is CF.

[0148] Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted C1-C4 alkyl group and is substituted by at least one selected from -CN, -OR 8 , halogenated, oxo-, -N(R 8 ) 2 or-CON(R 8 ) 2 substituted by a substituent; wherein each R 8 and R is independently hydrogen or optionally substituted C1-C4 alkyl.

[0149] Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted heteroaralkyl and the heteroaryl group is selected from a 5-membered or 6-membered heteroaryl group. Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1It is an optionally substituted heteroarylalkyl and the heteroaryl is selected from a 5-membered nitrogen-containing heteroaryl. Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 5-membered nitrogen-containing heteroaryl is selected from an optionally substituted thiazole, an optionally substituted oxazole, an optionally substituted imidazole, an optionally substituted pyrazole, an optionally substituted isoxazole, an optionally substituted pyrrole, an optionally substituted oxadiazole, an optionally substituted triazole, an optionally substituted thiadiazole or an optionally substituted isothiazole. Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 5-membered nitrogen-containing heteroaryl is an optionally substituted pyrazole. Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 5-membered nitrogen-containing heteroaryl is substituted by at least one optionally substituted C1-C5 alkyl. Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C5 alkyl is an optionally substituted C1 alkyl.

[0150] Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted heteroarylalkyl and the alkylene is an optionally substituted C1-C4 alkylene. Another embodiment provides a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C4 alkylene is -CH 2 -.

[0151] Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted aralkyl. Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted aralkyl comprises an optionally substituted phenyl. Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted aralkyl comprises an optionally substituted C1-C4 alkylene. Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C4 alkylene is -CH 2 -. Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein the heteroaryl group is a 6-membered nitrogen-containing heteroaryl group. Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein the 6-membered nitrogen-containing heteroaryl group is an optionally substituted pyridine or pyrazine.

[0152] Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted cycloalkylalkyl is an optionally substituted cyclopropylmethyl.

[0153] Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heterocyclylalkyl is an optionally substituted oxetanylmethyl or an optionally substituted pyrazolonylmethyl.

[0154] Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 For hydrogen.

[0155] Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 For hydrogen.

[0156] Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 For hydrogen.

[0157] Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C5 alkyl is an optionally substituted C1-C2 alkyl.

[0158] Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 and R 3 Each is an optionally substituted C1-C5 alkyl group.

[0159] Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 and R3 to form an optionally substituted carbocyclic or heterocyclic ring.

[0160] Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is an optionally substituted C1-C5 alkynyl group.

[0161] Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is an optionally substituted heterocyclic group.

[0162] Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted cycloalkyl is:

[0163]

[0164] Where R 8 Selected from hydrogen, -CH 3 、-CH 2 F, -CHF 2 , -CF 3 , -CN, cyclopropyl, -CH 2 CH 3 、-CH(CH 3 ) 2 and -C(CH 3 ) 3 .

[0165] Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein G is a bond. Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein G is an optionally substituted cycloalkylene. Another embodiment provides the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein G is an optionally substituted heterocycloalkylene.

[0166] Another embodiment provides the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -N(H)-.

[0167] One embodiment provides a PARG inhibitory compound or a pharmaceutically acceptable salt or solvate thereof having the structure shown in Table 1.

[0168] Table 1

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195] Another embodiment provides a PARG inhibitory compound or a pharmaceutically acceptable salt or solvate thereof having a structure shown in Tables 2A-2I.

[0196] Table 2A

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203] Table 2B

[0204]

[0205]

[0206] Table 2C

[0207]

[0208]

[0209] Table 2D

[0210]

[0211]

[0212] Table 2E

[0213]

[0214] Table 2F

[0215]

[0216] Table 2G

[0217]

[0218] Table 2H

[0219]

[0220]

[0221] Table 2I

[0222]

[0223]

[0224] Preparation of compounds

[0225] The compounds used in the synthetic chemistry reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or from compounds described in the chemical literature. “Commercially available chemicals” were obtained from standard commercial sources, including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0226] Suitable reference books and papers detailing the synthesis of reactants that can be used to prepare the compounds described herein, or providing references to articles describing such preparations, include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations," 2nd edition, Academic Press, New York, 1983; H O House, "Modern Synthetic Reactions," 2nd edition, WA Benjamin, Inc. Menlo Park, Calif. 1972; TL Gilchrist, "Heterocyclic Chemistry," 2nd edition, John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th edition, Wiley-Interscience, New York, 1992. Other suitable reference books and papers that detail the synthesis of reactants that can be used to prepare the compounds described herein or provide references to articles describing the preparations include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", 2nd Revised and Expanded Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J.(Editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, TWG "Organic Chemistry" 7th edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, JC, "Intermediate Organic Chemistry" 2nd edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia"(1999)John Wiley & Sons, ISBN: 3-527-29645-X, 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, more than 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, 73 volumes. .

[0227] Specific and similar reactants are optionally identified by an index of known chemicals produced by the Chemical Abstract Service of the American Chemical Society, which is available in most public and university libraries and through online databases (contact the American Chemical Society in Washington, D.C. for more details). Chemicals known in the catalog but not commercially available are optionally prepared by custom chemical synthesis agencies, many of which provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0228] General synthetic scheme

[0229] The PARG inhibitory compounds disclosed herein can be prepared by a variety of synthetic routes, including but not limited to the routes described in Schemes I or II below.

[0230] Scheme I

[0231]

[0232] Reaction of 2,4-quinazolinedione derivative 1.1 with chlorosulfonic acid affords chlorosulfonyl derivative 1.2. Reaction of compound 1.2 with substituted amines provides sulfonamide 1.3. Chlorination of compound 1.3 affords dichloroquinazoline derivative 1.4, which undergoes selective hydrolysis at the 4-position upon treatment with an aqueous base. Under basic conditions, 2-chloroquinazolinone 1.5 is substituted on the amide nitrogen by treatment with a suitable electrophile to afford compound 1.6. Annulation of the 5-membered imidazole ring begins with replacement of the chloro group by reaction with a suitable amino alcohol to afford 2-aminoquinazolinone derivative 1.7. Closing of the imidazole ring to obtain the target compound 1.8 is accomplished under Mitsunobu conditions (e.g., DEAD, PPh 3 ) or by activating the alcohol as a suitable leaving group, such as conversion to a mesylate or with SOCl 2 Chlorination followed by treatment with a base to effect cyclization. One skilled in the art will recognize that the use of 1,2-amino alcohols will provide the 5-membered imidazole compound 1.8, while the use of 1,3-amino alcohols will provide a similar 6-membered compound. Similarly, the use of 1,4-amino alcohols will provide a similar 7-membered compound. In the event that a single stereoisomer of the target compound is desired, chiral chromatography and supercritical fluid chromatography may be employed. Alternatively, non-racemic, chiral starting materials such as amino alcohols may be employed as appropriate.

[0233] Solution II

[0234]

[0235] Anthranilic acid derivative 2.1 can be condensed with an alkyl isothiocyanate to give 2-thioxo-2,3-dihydroquinazolin-4(1H)-one derivative 2.2. Chlorination provides compound 2.3, which is substituted with an amino alcohol to give quinazolinone derivative 2.4. Closing the imidazole ring to obtain compound 2.5 is a simple process under Mitsunobu conditions (e.g., DIAD, PPh 3 ) or, alternatively, by activating the alcohol as a suitable leaving group, by conversion to methanesulfonyl chloride (MeSO 2 Cl) or thionyl chloride (SOCl 2) to achieve the cyclization, followed by treatment with a base to achieve the cyclization. One skilled in the art will recognize that the use of a 1,2-amino alcohol will provide the 5-membered imidazole compound 2.5, while the use of a 1,3-amino alcohol will provide the analogous 6-membered compound. Likewise, the use of a 1,4-amino alcohol will provide the analogous 7-membered compound. Palladium-catalyzed thiolation of the imidazole compound 2.5 provides the sulfide 2.6, which is subjected to oxidative chlorination to provide the sulfonyl chloride 2.7. Reaction of the sulfonyl chloride with an appropriate amine provides the target compound 2.8.

[0236] Those skilled in the art of organic synthesis will recognize that due to the 1 -R 5 and R 7 The nature of the substituents in the group may require changes in Scheme I or II. Such modifications may include, for example, the use of protecting groups to change the reactivity of the substituents, or changing the time and temperature of the reaction. In addition, the compounds of formula 1.8 or 2.8 can be further modified to obtain the desired PARG inhibitory compounds. In the case where a single stereoisomer of the target compound is required, chiral chromatography and supercritical fluid chromatography can be used. Alternatively, non-racemic, chiral starting materials such as amino alcohols can be used as appropriate.

[0237] The PARG inhibitory compounds described herein as Formula (I) or (Ia) or in Table 1 or Tables 2A-2I can be synthesized using the methods described in Scheme I or II above using appropriate starting materials.

[0238] Pharmaceutical composition

[0239] In certain embodiments, the PARG inhibitory compounds described herein are administered as pure chemicals. In other embodiments, the PARG inhibitory compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier), which is selected based on the selected route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Edition Mack Pub. Co., Easton, PA (2005)).

[0240] Provided herein are pharmaceutical compositions comprising at least one PARG inhibitory compound described herein or a stereoisomer, pharmaceutically acceptable salt, hydrate or solvate thereof and one or more pharmaceutically acceptable carriers. One or more carriers (or one or more excipients) are acceptable or suitable if the carrier is compatible with the other ingredients of the composition and is not harmful to the recipient (i.e., subject or patient) of the composition.

[0241] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof.

[0242] One embodiment provides a method for preparing a pharmaceutical composition, comprising mixing a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof with a pharmaceutically acceptable carrier.

[0243] In certain embodiments, the PARG inhibitory compound as described in Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, is substantially pure in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1% of other small organic molecules, such as unreacted intermediates or synthesis by-products produced in one or more steps of the synthesis method.

[0244] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1 or Tables 2A-2I or a pharmaceutically acceptable salt or solvate thereof.

[0245] One embodiment provides a method for preparing a pharmaceutical composition comprising mixing a compound of Table 1 or Tables 2A-2I or a pharmaceutically acceptable salt or solvate thereof with a pharmaceutically acceptable carrier.

[0246] In certain embodiments, the PARG inhibitory compound described in Table 1 or Tables 2A-2I, or a pharmaceutically acceptable salt or solvate thereof, is substantially pure in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1% of other small organic molecules, such as unreacted intermediates or synthesis by-products produced in one or more steps of the synthesis method.

[0247] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose, or other suitable materials that are easily dissolved in the digestive tract. In some embodiments, suitable non-toxic solid carriers are used, including, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, etc. (see, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21st Edition Mack Pub. Co., Easton, PA (2005)).

[0248] In some embodiments, the PARG inhibitory compound as described in Formula (I) or (Ia) or Table 1 or Tables 2A-2I, or a pharmaceutically acceptable salt or solvate thereof, is formulated for administration by injection. In some cases, the injection formulation is an aqueous formulation. In some cases, the injection formulation is a non-aqueous formulation. In some cases, the injection formulation is an oil-based formulation, such as sesame oil, etc.

[0249] The dosage of the composition comprising at least one PARG inhibitory compound as described herein varies depending on the condition of the subject or patient (eg, human). In some embodiments, these factors include general health, age, and other factors.

[0250] The pharmaceutical composition is applied in a manner suitable for the disease to be treated (or prevented). Suitable dosage and suitable duration and frequency of application will be determined by factors such as the patient's condition, the type and severity of the patient's disease, the concrete form of the active ingredient and the method of administration. Typically, suitable dosage and treatment regimen provide one or more compositions of the amount sufficient to provide treatment and / or prevention benefits (e.g., improved clinical outcomes, such as more frequent complete or partial remissions, or longer disease-free survival and / or total survival, or mitigation of symptom severity). Optimal dose is typically determined using experimental models and / or clinical trials. Optimal dose depends on the patient's body mass, body weight or blood volume.

[0251] Oral dosages generally range from about 1.0 mg to about 1000 mg, one to four or more times a day.

[0252] Treatment

[0253] One embodiment provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0254] One embodiment provides a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating cancer or a neoplastic disease.

[0255] One embodiment provides a pharmaceutical composition comprising a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient for use in a method for treating cancer or a neoplastic disease.

[0256] One embodiment provides a use of a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for treating cancer or tumor diseases.

[0257] In some embodiments, a method of treating cancer in a patient in need thereof is provided, comprising administering to the patient a compound of Formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating cancer in a patient in need thereof is provided, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient.

[0258] One embodiment provides a compound of Table 1 or Tables 2A-2I, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0259] One embodiment provides a compound of Table 1 or Tables 2A-2I, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer or a neoplastic disease.

[0260] One embodiment provides a pharmaceutical composition comprising a compound of Table 1 or Tables 2A-2I or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient for use in a method of treating cancer or a neoplastic disease.

[0261] One embodiment provides use of a compound of Table 1 or Tables 2A-2I or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for treating cancer or a neoplastic disease.

[0262] In some embodiments, a method of treating cancer in a patient in need thereof is provided, comprising administering to the patient a compound of Table 1 or Tables 2A-2I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating cancer in a patient in need thereof is provided, comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1 or Tables 2A-2I, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0263] Provided herein are methods wherein the pharmaceutical composition is administered orally. Provided herein are methods wherein the pharmaceutical composition is administered by injection.

[0264] One embodiment provides a method of inhibiting a PARG enzyme, comprising contacting the PARG enzyme with a compound of formula (I) or (Ia) or Table 1 or Tables 2A-2I. Another embodiment provides the method of inhibiting a PARG enzyme, wherein the PARG enzyme is contacted in an in vivo environment. Another embodiment provides the method of inhibiting a PARG enzyme, wherein the PARG enzyme is contacted in an in vitro environment.

[0265] Other embodiments and uses will be apparent to those skilled in the art in light of this disclosure.The following examples are provided merely as illustrations of various embodiments and should not be construed as limiting the invention in any way.

[0266] Example

[0267] I. Chemical Synthesis

[0268] In some embodiments, the PARG inhibitory compounds disclosed herein are synthesized according to the following examples. As used below and throughout the description of the present invention, unless otherwise indicated, the following abbreviations should be understood to have the following meanings:

[0269] ACN Acetonitrile

[0270] ℃ Celsius

[0271] δ H Chemical shift downfield of tetramethylsilane in parts per million

[0272] DCM Dichloromethane (CH 2 Cl 2 )

[0273] DIAD Diisopropyl azodicarboxylate

[0274] DIEA Diisopropylethylamine

[0275] DMF Dimethylformamide

[0276] DMSO Dimethyl sulfoxide

[0277] EA Ethyl acetate

[0278] EtOAc Ethyl acetate

[0279] ESI Electrospray ionization

[0280] Et Ethyl

[0281] g

[0282] h hour

[0283] HPLC High Performance Liquid Chromatography

[0284] Hz Hertz

[0285] J Coupling constant (NMR spectroscopy)

[0286] LCMS Liquid chromatography mass spectrometry

[0287] μ micro

[0288] m multiple peak (spectrum); meter; millimeter

[0289] M Moore

[0290] M + Ions of the parent molecule

[0291] Me Methyl

[0292] MsCl Methanesulfonyl chloride

[0293] MHz Megahertz

[0294] min

[0295] mol mole; molecular (measured in mol wt)

[0296] mL milliliters

[0297] MS mass spectrometry

[0298] nm nanometer

[0299] NMR Nuclear Magnetic Resonance

[0300] pH The electrical potential of hydrogen; a measure of the acidity or alkalinity of an aqueous solution

[0301] PE Petroleum Ether

[0302] RT Room temperature

[0303] s singlet (spectrum)

[0304] t triplet (spectrum)

[0305] SFC Supercritical Fluid Chromatography

[0306] T Temperature

[0307] TFA Trifluoroacetic acid

[0308] THF Tetrahydrofuran

[0309] TPP Triphenylphosphine

[0310] Representative synthetic route 1

[0311] Example 46: (R)-1-methyl-4-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-5-oxo-1,2,4,5-tetrahydroimidazo[1,2-a]quinazoline-7-sulfonamide

[0312]

[0313] Step 1

[0314] A solution of 1,3-dihydroquinazoline-2,4-dione (15.0g, 92.5mmol) in chlorosulfonic acid (50mL) was stirred at 60 ° C for 4h. The mixture was allowed to cool to room temperature and then poured into water / ice. The precipitated solid was collected by filtration and washed with water (2x 100mL). The resulting solid was dried under vacuum to obtain 2,4-dioxo-1,3-dihydroquinazoline-6-sulfonyl chloride (16.0g, 66%) as a white solid. LCMS (ESI) m / z: 259 (MH).

[0315] Step 2

[0316] At room temperature, TEA (37.2g, 368mmol) was added to a solution of 1-methylcyclopropyl-1-amine hydrochloride (7.92g, 73.6mmol) in DCM (100mL), and 2,4-dioxo-1,3-dihydroquinazoline-6-sulfonyl chloride (16.0g, 61.3mmol) was then added in batches. The resulting mixture was stirred at room temperature for 2h. The resulting mixture was filtered. The precipitated solid was collected by filtration and washed with water (3x 50mL). The resulting solid was dried under vacuum to obtain N-(1-methylcyclopropyl)-2,4-dioxo-1,3-dihydroquinazoline-6-sulfonamide (17.5g, 82%) as a light yellow solid. LCMS (ESI) m / z: 294 (MH).

[0317] Step 3

[0318] At 0 °C, N-(1-methylcyclopropyl)-2,4-dioxo-1,3-dihydroquinazoline-6-sulfonamide (17 g, 57.5 mmol) was added to POCl 3 DIEA (18.6 g, 1434 mmol) was added dropwise to the stirred mixture in (50.0 mL). The resulting mixture was stirred at 105 ° C for 6 h. The resulting mixture was concentrated under reduced pressure. The reaction was diluted with cold water (200 mL) at 0 ° C. The resulting mixture was extracted with EtOAc (3x 200 mL). The combined organic layers were washed with saturated NaHCO 3 The aqueous solution (3 x 200 mL) was washed and washed with anhydrous Na 2 SO 4 The residue was purified by silica gel column chromatography and eluted with PE / EtOAc (1:1) to give 2,4-dichloro-N-(1-methylcyclopropyl)quinazoline-6-sulfonamide (8.00 g, 42%) as a light yellow solid. LCMS (ESI) m / z: 332 [M+H] + .

[0319] Step 4

[0320] To a solution of 2,4-dichloro-N-(1-methylcyclopropyl)quinazoline-6-sulfonamide (8g, 24.0mmol) in THF (60mL) and water (60mL) was added NaOH (4.58g, 114mmol). The solution was stirred at room temperature for 1h. The mixture was acidified to 3 with HCl (aqueous solution). The precipitated solid was collected by filtration and washed with water (3x 50mL). The filtrate was concentrated under reduced pressure to give 2-chloro-N-(1-methylcyclopropyl)-4-oxo-3H-quinazoline-6-sulfonamide (6.5g, 86%) as a light yellow solid. LCMS (ESI) m / z: 314 [M+H] + .

[0321] Step 5

[0322] A solution of 2-chloro-N-(1-methylcyclopropyl)-4-oxo-3H-quinazoline-6-sulfonamide (1.00 g, 2.81) in DMF (10 mL) and DME (10 mL) was treated with K 2 CO 3 The mixture was stirred at room temperature for 5 h. The reaction was quenched with water (50 mL) at room temperature. The mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL) and purified by anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (9:1) to give 2-chloro-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-3-yl)methyl]-4-oxoquinazoline-6-sulfonamide (430 mg, 37%) as a white solid. LCMS (ESI) m / z: 408 [M+H] + .

[0323] Step 6

[0324] To a solution of 2-chloro-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-3-yl)methyl]-4-oxoquinazoline-6-sulfonamide (400 mg, 0.98 mmol) in DMSO (4 mL) was added (S)-1-aminopropan-2-ol (105 mg, 1.40 mmol) and Et 3N (298 mg, 2.94 mmol). The resulting mixture was stirred at 100 ° C for 2 h. The reaction was quenched by water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3x 30 mL). The combined organic layer was washed with brine (30 mL) and washed with anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (9:1) to give (S)-2-((2-hydroxypropyl)amino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazoline-6-sulfonamide (300 mg, 66%) as an off-white solid. LCMS (ESI) m / z: 447 [M+H] + .

[0325] Step 7

[0326] To a solution of (S)-2-((2-hydroxypropyl)amino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazoline-6-sulfonamide (100 mg, 0.22 mmol) in DCM (5 mL) was added Et 3 N (67.7 mg, 0.67 mmol), and then CH 3 SO 2 Cl (51.9 mg, 0.45 mmol). The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with water (10 mL) at room temperature. The resulting mixture was extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (20 mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC [column: XBridge Shield RP18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 18% B to 45% B, 45% B in 7 min; wavelength: 220 nm] to obtain (R)-1-methyl-4-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-5-oxo-1,2,4,5-tetrahydroimidazo[1,2-a]quinazoline-7-sulfonamide (35 mg, 36%). LCMS (ESI) m / z: 429.10 [M+H] + . 1H NMR (400MHz, CD 3 OD):8.42(s,1H),8.00(dd,J 1 =8.8,2.0Hz,1H),7.67(s,1H),7.54(s,1H),7.20(d,J=8.8Hz,1H),5.03-4.96(m,2H),4.78-4.73(m,1H),4.19-4.1 1(m,1H),3.83(s,3H),3.65-3.62(m,1H),1.40(d,J=6.0Hz,3H),1.16(s,3H),0.72-0.69(m,2H),0.45-0.39(m,2H).

[0327] The following compounds in Table 3 were prepared using procedures similar to those described in Representative Synthesis Route 1 of Example 46 using appropriate starting materials.

[0328] Table 3

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337] Example 61: (R)-1-methyl-4-((1-methyl-1H-pyrazol-4-yl)methyl-d2)-N-(1-methylcyclopropyl)-5-oxo-1,2,4,5-tetrahydroimidazo[1,2-a]quinazoline-7-sulfonamide

[0338]

[0339] Step 1

[0340] To a stirred solution of methyl 1-methylpyrazole-4-carboxylate (1.0 g, 7.1 mmol) in THF (20 mL) was added LiAlD in portions at 0 °C under nitrogen atmosphere. 4(0.6 g, 14.3 mmol). The resulting mixture was stirred at 0°C under a nitrogen atmosphere for 1 h. The reaction was stirred at room temperature with Na 2 SO 4 10H 2 O (1 g) was quenched. The resulting mixture was filtered and the filter cake was washed with MeCN (3 x 10 mL). The resulting mixture was concentrated under reduced pressure to give (1-methylpyrazol-4-yl) (2H 2 ) methanol (757 mg, 93%). LCMS (ESI) m / z: 115.0 [M+H] + .

[0341] Step 2

[0342] At room temperature, to (1-methylpyrazol-4-yl)(2H 2 )methanol (600 mg, 5.3 mmol) in MeCN (10 mL) was stirred and thionyl chloride (2501.3 mg, 21 mmol) was added in portions. The resulting mixture was stirred at 50 °C for 20 h. The resulting mixture was concentrated under reduced pressure to give 4-[chloro(2H 2 )methyl]-3,5-dimethyl-1,2-oxazole (360 mg, 52%). LCMS (ESI) m / z: 133.0 [M+H] + .

[0343] Step 3

[0344] At room temperature, 2-chloro-N-(1-methylcyclopropyl)-4-oxo-3H-quinazoline-6-sulfonamide (150 mg, 0.48 mmol) and 4-[chloro(2H 2 To a stirred solution of DME (4 mL) and DMF (1 mL) was added K 2 CO 3 (132 mg, 0.96 mmol) and LiBr (83 mg, 0.96 mmol). The resulting mixture was stirred at 50 ° C for 2 h. The reaction was quenched with water (40 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine (2 x 20 mL) and washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (50%-70%) to give 2-chloro-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl) (2H 2)methyl]-4-oxoquinazoline-6-sulfonamide (138 mg, 70%). LCMS (ESI) m / z: 410.0 [M+H] + .

[0345] Step 4

[0346] At room temperature, 2-chloro-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl) (2H 2 To a stirred solution of (S)-1-amino-2-propanol (30.3 mg, 0.41 mmol) and TEA (102.2 mg, 1 mmol) in DMSO (6 mL) was added (S)-1-amino-2-propanol (30.3 mg, 0.41 mmol) and TEA (102.2 mg, 1 mmol) in batches. The resulting mixture was stirred at 50 ° C for 2 h. The reaction was quenched with water (40 mL) at room temperature. The resulting mixture was extracted with EtOAc (3x 30 mL). The combined organic layer was washed with brine (2x 30 mL) and dried over anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using MeOH / CH 2 Cl 2 (10%-20%) to give 2-{[(2S)-2-hydroxypropyl]amino}-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl) (2H 2 )methyl]-4-oxoquinazoline-6-sulfonamide (122 mg, 81%). LCMS (ESI) m / z: 449.0 [M+H] + .

[0347] Step 5

[0348] To a stirred solution of 2-{[(2S)-2-hydroxypropyl]amino}-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)(2H2)methyl]-4-oxoquinazoline-6-sulfonamide (120 mg, 0.27 mmol) in DCM (5 mL) was added MsCl (92 mg, 0.81 mmol) and TEA (81.2 mg, 0.81 mmol) in portions at room temperature. The resulting mixture was stirred at 35 °C for 2 h. The reaction was quenched with water (20 mL) at room temperature. The resulting mixture was washed with CH 2 Cl 2 The combined organic layers were washed with brine (2 x 20 mL) and purified by anhydrous Na 2 SO 4After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by XBridge Prep OBD C18 column with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 55% B, 55% B in 8 min; wavelength: 220 nm) was purified by preparative HPLC to give (R)-1-methyl-4-((1-methyl-1H-pyrazol-4-yl)methyl-d2)-N-(1-methylcyclopropyl)-5-oxo-1,2,4,5-tetrahydroimidazo[1,2-a]quinazoline-7-sulfonamide (30 mg, 26%). LCMS (ESI) m / z: 431.00 [M+H] + . 1 H NMR (400MHz, CD 3 OD)δ8.42(d,J=2.4Hz,1H),7.99(dd,J=8.8,2.4Hz,1H),7.68(s,1H),7.55(s,1H),7.20(d,J=8.8Hz,1H),4.77-4.71(m,1H), 4.18-4.13(m,1H),3.82(s,3H),3.65-3.61(m,1H),1.40(d,J=6.4Hz,3H),1.16(s,3H),0.74-0.67(m,2H),0.46-0.39(m,2H).

[0349] The following compounds in Table 4 were prepared using procedures similar to those described in Example 61 using appropriate starting materials.

[0350] Table 4

[0351]

[0352]

[0353] Representative synthetic route 2

[0354] Example 45: (R)-1-ethyl-4-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-5-oxo-1,2,4,5-tetrahydroimidazo[1,2-a]quinazoline-7-sulfonamide

[0355]

[0356] To a mixture of 2-{[2-hydroxybutyl]amino}-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-3-yl)methyl]-4-oxoquinazoline-6-sulfonamide (130 mg, 0.28 mmol) in DCM (2 mL) was added SOCl 2 (167 mg, 1.40 mmol). The mixture was stirred at room temperature for 2 h. To the above mixture was added NaOH (226 mg, 5.63 mmol) in water (1 mL) dropwise at 0 °C over 10 min. The resulting mixture was stirred at room temperature for an additional 2 h. The aqueous layer was extracted with DCM (3 x 15 mL). The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 7% B to 21% B, 21% B in 11 min; wavelength: 254 / 220 nm) to give 22 mg of racemic (1-ethyl-N-(1-methylcyclopropyl)-4-[(1-methylpyrazol-4-yl)methyl]-5-oxo-1H,2H-imidazo[1,2-a]quinazoline-7-sulfonamide.

[0357] The racemate was purified by chiral HPLC [column: Lux 5um cellulose-4, 2.12*25cm, 5μm; mobile phase A: Hex (10mM NH 3 -MeOH), mobile phase B: EtOH:ACN=5:1; flow rate: 20 mL / min; gradient: 30% B in 28 min; wavelength: 220 / 286 nm; RT1 (min): 18.325; RT2 (min): 23.1] to obtain (1R)-1-ethyl-N-(1-methylcyclopropyl)-4-[(1-methylpyrazol-4-yl)methyl]-5-oxo-1H,2H-imidazo[1,2-a]quinazoline-7-sulfonamide (6.2 mg, 32%) and (1S)-1-ethyl-N-(1-methylcyclopropyl)-4-[(1-methylpyrazol-4-yl)methyl]-5-oxo-1H,2H-imidazo[1,2-a]quinazoline-7-sulfonamide (10.7 mg, 56%). LCMS (ESI) m / z: 443.25 [M+H] + .

[0358] The following compounds in Table 5 were prepared using procedures similar to those described in Representative Synthetic Route 2 of Example 45 using appropriate starting materials.

[0359] Table 5

[0360]

[0361] Representative synthetic route 3

[0362] Example 46: (R)-1-methyl-4-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-5-oxo-1,2,4,5-tetrahydroimidazo[1,2-a]quinazoline-7-sulfonamide

[0363]

[0364] Also provided herein is an alternative route for Example 46, which illustrates an alternative ring closure method. To a solution of (S)-2-((2-hydroxypropyl)amino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazoline-6-sulfonamide (85mg, 0.19mmol) in THF (2mL) was added triphenylphosphine (96mg, 0.36mmol). The solution was cooled to 0°C and DIAD (73mg, 0.36mmol) was added dropwise. The reaction was stirred at room temperature for 16h. The mixture was concentrated under vacuum. The residue was purified by silica gel column, eluted with MeOH / DCM (0-15%) to give the crude product, which was further purified by HPLC.

[0365] The following compounds in Table 6 were prepared using procedures similar to those described in Representative Synthetic Route 3 of Example 46 using appropriate starting materials.

[0366] Table 6

[0367]

[0368] Representative synthetic route 4

[0369] Example 52: (R)-1,4-dimethyl-N-(1-methylcyclopropyl)-5-oxo-1,2,4,5-tetrahydroimidazo[1,2-a]quinazoline-7-sulfonamide

[0370]

[0371] Step 1

[0372] To a stirred solution of 5-bromoanthranilic acid (10 g, 46.3 mmol) and methyl isothiocyanate (4.1 g, 55.5 mmol) in ethanol (200 mL) was added Et 3N (4.7 g, 46.3 mmol). The reaction was stirred at 80 °C for 2 h. The reaction was poured into water (500 mL). The aqueous layer was extracted with EtOAc (2 x 200 mL) and the combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified by CH 2 Cl 2 / MeOH (6:1) to give 6-bromo-3-methyl-2-sulfanylidene-1H-quinazolin-4-one (5.6 g, 45%) as a white solid.

[0373] Step 2:

[0374] At room temperature, 6-bromo-3-methyl-2-sulfanylidene-1H-quinazolin-4-one (5.6 g, 20.7 mmol) was added to POCl 3 Add PCl (50 mL) to the mixture 5 (6.4 g, 31.1 mmol). The reaction was heated to reflux and stirred for 2 h. The reaction was concentrated under reduced pressure. The solid was rinsed with hexane (50 mL) and dried under vacuum to give 6-bromo-2-chloro-3-methylquinazolin-4-one (2.6 g, 46%) as a brown solid.

[0375] Step 3:

[0376] To a stirred solution of 6-bromo-2-chloro-3-methylquinazolin-4-one (2.6 g, 9.36 mmol) and (2S)-1-aminopropan-2-ol (0.84 g, 11.2 mmol) in DMSO (50 mL) was added Et 3 N (2.8 g, 28.1 mmol). The solution was stirred at 100 ° C for 2 h. The reaction was quenched by water (100 mL). The aqueous layer was extracted with EtOAc (2x100 mL), and the combined organic layers were washed with brine (100 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified by CH 2 Cl 2 / MeOH (5:1) to give 6-bromo-2-{[(2S)-2-hydroxypropyl]amino}-3-methylquinazolin-4-one (2.2 g, 74%) as a brown solid.

[0377] Step 4

[0378] At 0°C, 6-bromo-2-{[(2S)-2-hydroxypropyl]amino}-3-methylquinazolin-4-one (2.2 g, 7.07 mmol) and PPh 3(2.8 g, 10.6 mmol) was added dropwise to a stirred solution of (2.1 g, 10.6 mmol) in THF (50 mL). The solution was stirred for 2 h at 0 ° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1: 1) to give (1R)-7-bromo-1,4-dimethyl-1H,2H-imidazo[1,2-a]quinazolin-5-one (1.0 g, 48%) as a yellow solid.

[0379] Step 5

[0380] To a stirred mixture of (1R)-7-bromo-1,4-dimethyl-1H,2H-imidazo[1,2-a]quinazolin-5-one (1 g, 3.4 mmol) and benzyl mercaptan (0.51 g, 4.08 mmol) in toluene (20 mL) were added TEA (1 g, 10.2 mmol), XantPhos (0.39 g, 0.68 mmol) and Pd 2 (dba) 3 (0.31 g, 0.34 mmol). The resulting mixture was stirred at 90 ° C under a nitrogen atmosphere for 3 h. The reaction was quenched with water (120 mL) at room temperature. The resulting mixture was extracted with EtOAc (3x120 mL). The combined organic layers were washed with brine (2x 150 mL) and washed with anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / EA (3:2) to give (1R)-7-(benzylsulfanyl)-1,4-dimethyl-1H,2H-imidazo[1,2-a]quinazolin-5-one (700 mg, 61%) as a yellow solid. LCMS (ESI) m / z: 338.0 [M+H] + .

[0381] Step 6

[0382] To a mixture of (1R)-7-(benzylsulfanyl)-1,4-dimethyl-1H,2H-imidazo[1,2-a]quinazolin-5-one (700 mg, 2.07 mmol) in DCM (10 mL) was added 1,3-dichloro-5,5-dimethyl-2-methylideneimidazolidin-4-one (809 mg, 4.15 mmol), acetic acid (0.15 mL) and H 2 O (0.1 mL). The mixture was stirred at room temperature for 3 h. The reaction was quenched with water (30 mL) at room temperature. The resulting mixture was washed with CH 2 Cl 2 (3 x 30 mL) extraction. The combined organic layers were washed with anhydrous Na 2 SO4 The residue was purified by silica gel column chromatography, eluted with PE / EA (1:2) to give (1R)-1,4-dimethyl-5-oxo-1H,2H-imidazo[1,2-a]quinazoline-7-sulfonyl chloride (210 mg, 32%) as a brown solid. LCMS (ESI) m / z: 314.0 [M+H]+.

[0383] Step 7

[0384] To a solution of 1-methylcyclopropyl-1-amine hydrochloride (86.4 mg, 0.80 mmol) in DCM (10 mL) was added TEA (203 mg, 2.0 mmol) at room temperature. The mixture was stirred for 15 min and then (1R)-1,4-dimethyl-5-oxo-1H,2H-imidazo[1,2-a]quinazoline-7-sulfonyl chloride (210 mg, 0.67 mmol) was added. The solution was stirred at room temperature for 3 h. The reaction was quenched with water (30 mL) at room temperature. The resulting mixture was washed with CH 2 Cl 2 (3 x 40 mL) extraction. The combined organic layers were washed with anhydrous Na 2 SO 4 The crude product was dried and concentrated under reduced pressure. The crude product was purified by XBridge Shield RP18 OBD column with the following conditions (column: XBridge Shield RP18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 25% B to 60% B in 10 min, wavelength: 220 nm) was purified by preparative HPLC to give (1R)-1,4-dimethyl-N-(1-methylcyclopropyl)-5-oxo-1H,2H-imidazo[1,2-a]quinazoline-7-sulfonamide (26.0 mg, 11%). LCMS (ESI) m / z: 349.00 [M+H] + . 1 H NMR (400MHz, CD 3 OD)δ8.41(s,1H),8.01(d,J=8.8Hz,1H),7.05(d,J=8.8Hz,1H),4.37-4.29(m,1H),4.26(t,J=9.2Hz,1H),3.70 -3.64(m,1H),3.41(s,3H),1.38(d,J=6.4Hz,3H),1.15(d,J=0.8Hz,3H),0.73-0.67(m,2H),0.44-0.38(m,2H).

[0385] The following compounds in Table 7 were prepared using procedures similar to those described in Representative Synthetic Route 4 of Example 52 using appropriate starting materials.

[0386] Table 7

[0387]

[0388] The following compounds in Table 8 were prepared using procedures similar to those described in Representative Synthetic Route 4 (Steps 5-7) of Example 52 using appropriate starting materials.

[0389] Table 8

[0390]

[0391] Representative synthetic route 5

[0392] Example 1: (R)-4-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)methyl)-1-methyl-N-(1-methylcyclopropyl)-5-oxo-1,2,4,5-tetrahydroimidazo[1,2-a]quinazoline-7-sulfonamide

[0393]

[0394] Step 1

[0395] To a stirred mixture of 2-chloro-N-(1-methylcyclopropyl)-4-oxo-3H-quinazoline-6-sulfonamide (170 mg, 0.54 mmol) and (1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}pyrazol-4-yl)methanol (166 mg, 0.65 mmol) in THF (10 mL) was added PPh in portions at room temperature. 3 (213mg, 0.81mmol) and DEAD (164mg, 0.81mmol). The resulting mixture was stirred at room temperature for 12h. The resulting mixture was concentrated under reduced pressure. The residue was purified by trans-flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 60% to 80% gradient in 10min; detector, UV 254nm) to obtain 3-[(1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}pyrazol-4-yl)methyl]-2-chloro-N-(1-methylcyclopropyl)-4-oxoquinazoline-6-sulfonamide (100mg, 33%). LCMS (ESI) m / z:552[M+H] + .

[0396] Step 2

[0397] To a stirred mixture of 3-[(1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}pyrazol-4-yl)methyl]-2-chloro-N-(1-methylcyclopropyl)-4-oxoquinazoline-6-sulfonamide (100 mg, 0.18 mmol) and (2S)-1-aminopropan-2-ol (16.3 mg, 0.22 mmol) in DMSO (10 mL) was added TEA (54.9 mg, 0.54 mmol) in portions at room temperature. The resulting mixture was stirred at 100° C. for 2 h. The mixture was passed through a column with the following conditions (column, C18 silica gel; mobile phase, in water (10 mmol / L NH 4 HCO 3 ) in MeCN, 50% to 70% gradient in 10 min; detector, UV 254 nm) to give 3-[(1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}pyrazol-4-yl)methyl]-2-{[(2S)-2-hydroxypropyl]amino}-N-(1-methylcyclopropyl)-4-oxoquinazoline-6-sulfonamide (50 mg, 47%). LCMS (ESI) m / z: 591 [M+H] + .

[0398] Step 3

[0399] To a stirred mixture of 3-[(1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}pyrazol-4-yl)methyl]-2-{[(2S)-2-hydroxypropyl]amino}-N-(1-methylcyclopropyl)-4-oxoquinazoline-6-sulfonamide (50 mg, 0.08 mmol) and MsCl (24 mg, 0.21 mmol) in DCM (5 mL) was added TEA (21.4 mg, 0.21 mmol) in portions at room temperature. The resulting mixture was stirred at 35 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by chromatography on a column with the following conditions (column, C18 silica gel; mobile phase, in water (10 mmol / L NH 4 HCO 3 ) in MeCN, 40% to 60% gradient in 10 min; detector, UV 254 nm) to give (1R)-4-[(1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}pyrazol-4-yl)methyl]-1-methyl-N-(1-methylcyclopropyl)-5-oxo-1H,2H-imidazo[1,2-a]quinazoline-7-sulfonamide (30 mg, 65%). LCMS (ESI) m / z: 573 [M+H] + .

[0400] Step 4

[0401] To a stirred mixture of (1R)-4-[(1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}pyrazol-4-yl)methyl]-1-methyl-N-(1-methylcyclopropyl)-5-oxo-1H,2H-imidazo[1,2-a]quinazoline-7-sulfonamide (30 mg, 0.05 mmol) in THF (5 mL) was added TBAF (13.7 mg, 0.05 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for 2 h. The crude product was purified by chromatography on a column having the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, Mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 35% B, 35% B in 7 min; wavelength: 220 nm; RT1 (min): 6.45) was purified by preparative HPLC to give (1R)-4-{[1-(2-hydroxyethyl)pyrazol-4-yl]methyl}-1-methyl-N-(1-methylcyclopropyl)-5-oxo-1H,2H-imidazo[1,2-a]quinazoline-7-sulfonamide (12.3 mg, 54%). LCMS (ESI) m / z: 459.10 [M+H] + . 1 H-NMR (300 MHz, DMSO-d 6 )δ:8.25(d,J=2.1Hz,1H),8.07(s,1H),7.93(dd,J 1 =8.4,2.1Hz,1H),7.71(s,1H),7.45(s,1H),7.28(d,J=9.0Hz,1H),4.99-4.85(m,3H),4.75(s,1H),4.11-4.01(m,3 H),3.68-3.67(m,2H),3.57-3.55(m,1H),1.32(d,J=6.3Hz,3H),1.06(s,3H),0.61-0.59(m,2H),0.37-0.34(m,2H).

[0402] Representative synthetic route 6

[0403] Example 53: (R)-4-((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)methyl)-1-methyl-N-(1-methylcyclopropyl)-5-oxo-1,2,4,5-tetrahydroimidazo[1,2-a]quinazoline-7-sulfonamide

[0404]

[0405] Step 1

[0406] To a stirred mixture of (1R)-4-{[1-(2-hydroxyethyl)pyrazol-4-yl]methyl}-N-isopropyl-1-methyl-5-oxo-1H,2H-imidazo[1,2-a]quinazoline-7-sulfonamide (40 mg, 0.09 mmol) and MsCl (25.7 mg, 0.22 mmol) in DCM (5 mL) was added TEA (27.2 mg, 0.27 mmol) in portions at room temperature. The resulting mixture was stirred at 35 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified by chromatography on CH 2 Cl 2 The mixture was eluted with MeOH (10%-15%) to give 2-(4-{[(1R)-1-methyl-7-[(1-methylcyclopropyl)sulfamoyl]-5-oxo-1H,2H-imidazo[1,2-a]quinazolin-4-yl]methyl}pyrazol-1-yl)ethyl methanesulfonate (10 mg, 21%). LCMS (ESI) m / z: 537 [M+H] + .

[0407] Step 2

[0408] To a stirred mixture of 2-(4-{[(1R)-1-methyl-7-[(1-methylcyclopropyl)sulfamoyl]-5-oxo-1H,2H-imidazo[1,2-a]quinazolin-4-yl]methyl}pyrazol-1-yl)ethyl methanesulfonate (10 mg, 0.02 mmol) and dimethylamine hydrochloride (1.8 mg, 0.023 mmol) in DMF (2 mL) was added K in portions at room temperature. 2 CO 3 (7.7 mg, 0.057 mmol). The resulting mixture was stirred at 70 °C for 16 h. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on a column with the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 55% B, 55% B in 7 min; wavelength: 220 nm; RT1 (min): 6.23) was purified by preparative HPLC to give (1R)-4-({1-[2-(dimethylamino)ethyl]pyrazol-4-yl}methyl)-1-methyl-N-(1-methylcyclopropyl)-5-oxo-1H,2H-imidazo[1,2-a]quinazoline-7-sulfonamide (3.9 mg, 40%). LCMS (ESI) m / z: 486.30 [M+H]+ . 1 H-NMR (400 MHz, DMSO-d 6 )δ:8.24(d,J=2.4Hz,1H),8.03(s,1H),7.90(dd,J=8.4,2.0Hz,1H),7.72(s,1 H),7.41(s,1H),7.23(d,J=8.8Hz,1H),4.97-4.85(m,2H),4.75-4.66(m,1H),4 .14-4.01(m,3H),3.51(dd,J=13.6,3.6Hz,1H),2.58(t,J=6.4Hz,2H),2.12(s, 6H), 1.31 (d, J = 6.4Hz, 3H), 1.07 (s, 3H), 0.62-0.57 (m, 2H), 0.40-0.35 (m, 2H).

[0409] Representative synthetic route 7

[0410] Example 57: (R)-4-((1-(difluoromethyl)-1H-pyrazol-4-yl)methyl)-1-methyl-N-(1-methylcyclopropyl)-5-oxo-1,2,4,5-tetrahydroimidazo[1,2-a]quinazoline-7-sulfonamide

[0411]

[0412] A solution of Example 6 (20 mg, 0.05 mmol) in DMF (5 mL) was treated with NaHCO 3 (8mg, 0.1mmol) was treated for 5min, then difluoromethyl sodium chloroformate (8mg, 0.05mmol) was added dropwise at room temperature. The reaction mixture was stirred at 100°C for 16h. The reaction was quenched by adding water (5mL) at room temperature. The resulting mixture was extracted with EtOAc (3x 50mL). The combined organic layer was washed with brine (3x 50mL) and filtered through anhydrous Na 2 SO 4Dry. After filtration, the filtrate was concentrated under reduced pressure. The crude product was quickly purified by reverse phase with the following conditions (column: YMC-Actus Triart C18, 30*150mm, 5μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL / min; gradient: 25% B to 45% B, 45% B in 7min; wavelength: 254 / 220nm; RT1(min): 5.92) to obtain (1R)-4-{[1-(difluoromethyl)pyrazol-4-yl]methyl}-1-methyl-N-(1-methylcyclopropyl)-5-oxo-1H,2H-imidazo[1,2-a]quinazoline-7-sulfonamide (2.3mg, 10%). LCMS(ESI)m / z:465.00[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.28–8.19(m,2H),8.05(s,1H),7.91(dd,J=9.2,6.9Hz,1H),7.77(d,J=21.3H z,2H),7.25(d,J=8.7Hz,1H),4.99(q,J=14.5Hz,2H),4.73(ddp,J=8.9,6.1,3.1 ,2.6Hz,1H),4.06(dd,J=13.7,9.3Hz,1H),3.52(dd,J=13.7,3.6Hz,1H),1.33(d ,J=6.2Hz,3H),1.08(s,3H),0.61(q,J=4.0Hz,2H),0.39(dd,J=5.0,2.2Hz,2H).

[0413] Representative synthetic routes 8

[0414] Example 2: (R)-N-(1-cyanocyclopropyl)-1-methyl-4-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-1,2,4,5-tetrahydroimidazo[1,2-a]quinazoline-7-sulfonamide

[0415] Step 1

[0416] To a stirred solution of 2-chloro-3H-quinazolin-4-one (1 g, 5.53 mmol) and 4-(bromomethyl)-1-methylpyrazole (0.97 g, 5.54 mmol) in DMF (1 mL) and DME (4 mL) was added K in portions at room temperature. 2 CO 3(1.53 g, 11.1 mmol). The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was diluted with water (100 mL). The aqueous layer was extracted with EtOAc (2 x 200 mL) and the combined organic phases were concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: 275 [M+H] + .

[0417] Step 2

[0418] To a stirred solution of 2-chloro-3-[(1-methylpyrazol-4-yl)methyl]quinazolin-4-one (1 g, 3.64 mmol) and (2S)-1-aminopropan-2-ol (0.27 g, 3.64 mmol) in DMSO was added Et 3 N (1.1 g, 10.9 mmol). The resulting mixture was stirred at 100 °C for 1 h. The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (20 mL) and purified by anhydrous Na 2 SO 4 After drying, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: 314 [M+H] + .

[0419] Step 3

[0420] To a stirred solution of 2-{[(2S)-2-hydroxypropyl]amino}-3-[(1-methylpyrazol-4-yl)methyl]quinazolin-4-one (500 mg, 1.59 mmol) and MsCl (457 mg, 3.99 mmol) in DCM was added TEA (484 mg, 4.78 mmol) in portions at room temperature. The resulting mixture was stirred at 35 °C for 5 h. The resulting mixture was diluted with water (20 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified by CH 2 Cl 2 / MeOH (10:1) to give (1R)-1-methyl-4-[(1-methylpyrazol-4-yl)methyl]-1H,2H-imidazo[1,2-a]quinazolin-5-one (200 mg, 42%). LCMS (ESI) m / z: 296 [M+H] + .

[0421] Step 4

[0422] A mixture of (1R)-1-methyl-4-[(1-methylpyrazol-4-yl)methyl]-1H,2H-imidazo[1,2-a]quinazolin-5-one (200 mg, 0.67 mmol) and chlorosulfonic acid (2 mL) was stirred at 60 °C for 1 h. The reaction was quenched with water / ice at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0423] Step 5

[0424] (1R)-1-methyl-4-[(1-methylpyrazol-4-yl)methyl]-5-oxo-1H,2H-imidazo[1,2-a]quinazoline-7-sulfonic acid (100 mg, 0.26 mmol) and DMF (0.1 mL) were dissolved in SOCl 2 The solution in (3 mL) was stirred at 60 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: 394 [M+H] + .

[0425] Step 6

[0426] To a stirred solution of (1R)-1-methyl-4-[(1-methylpyrazol-4-yl)methyl]-5-oxo-1H,2H-imidazo[1,2-a]quinazoline-7-sulfonyl chloride (50 mg, 0.13 mmol) and 1-aminocyclopropane-1-carbonitrile (12.5 mg, 0.15 mmol) in DCM (2 mL) was added pyridine (30 mg, 0.38 mmol) in batches at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water (10 mL) and extracted with DCM (2 x 10 mL). The combined organic layers were washed with acetic acid (2 x 10 mL) and purified by anhydrous Na 2 SO 4 Dry. After filtration, the filtrate was concentrated under reduced pressure. The crude product (10 mg) was purified by preparative HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 11% B to 19% B, 19% B in 7 min; wavelength: 254 / 220 nm; RT1 (min): 4.82) to obtain (1R)-N-(1-cyanocyclopropyl)-1-methyl-4-[(1-methylpyrazol-4-yl)methyl]-5-oxo-1H,2H-imidazo[1,2-a]quinazoline-7-sulfonamide (1.7 mg, 3%). LCMS (ESI) m / z: 440.05 [M+H] + . 1 H NMR (400MHz, CD3 OD)δ8.38(d,J=2.2Hz,1H),7.96(dd,J=8.8,2.2Hz,1H),7.58(s,1H),7.46(s,1H),7.18(d,J=8.8Hz,1H),4.98–4.85(m,2H),4 .08(dd,J=13.3,9.4Hz,1H),3.95(q,J=7.2Hz,1H),3.73(s,3H),3.57–3.54(m,1H),1.35–1.27(m,5H),1.18(t,J=7.2Hz,2H).

[0427] The following compounds in Table 9 were prepared using procedures similar to those described in Representative Synthetic Route 8 of Example 2 using appropriate starting materials.

[0428] Table 9

[0429]

[0430] Representative synthetic routes 9

[0431] Example 114: (R)-1-methyl-4-(1-(1-methyl-1H-pyrazol-4-yl)cyclopropyl)-N-(1-methylcyclopropyl)-5-oxo-1,2,4,5-tetrahydroimidazo[1,2-a]quinazoline-7-sulfonamide

[0432]

[0433] Step 1

[0434] To a solution of 2-amino-5-bromobenzoic acid (1.5 g, 7.17 mmol) in DMF (40 mL) was added HATU (3 g, 7.89 mmol), DIPEA (1.7 mL, 10 mmol) and 1-(1-methyl-1H-pyrazol-4-yl)cyclopropyl-1-amine (984 mg, 7.17 mmol) and reacted at room temperature for 1.10 h. Water was added and the formed precipitate (ppt) was filtered. The filtrate was extracted with EtOAc. The organic layer was concentrated and purified by silica gel chromatography (0-18% MeOH / DCM) to obtain the product (2.3 g, 96%).

[0435] Step 2

[0436] 2-Amino-5-bromo-N-[1-(1-methyl-1H-pyrazol-4-yl)cyclopropyl]benzamide (1 g, 2.98 mmol) was added in CH 3To the mixture in CN (13.6 mL) was added CDI (869 mg, 5.36 mmol) and DMAP (36.4 mg, 0.3 mmol). The reaction was stirred at room temperature for 20 min and then at 55 ° C for 5.45 h. The solvent was evaporated in vacuo, water was added and the white precipitate formed was filtered (ppt). The precipitate was washed with 1M HCl and then with water and dried to obtain the product (681.2 mg, 63%).

[0437] Step 3

[0438] To a solution of 6-bromo-3-[1-(1-methyl-1H-pyrazol-4-yl)cyclopropyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione (601 mg, 1.66 mmol) in toluene (9.6 mL) was added Et 3 N (0.7 mL, 5 mmol), BnSH (0.2 mL, 2 mmol), dioxane (0.4 mL) and the reaction was heated to 4% N. 2 Degas and backfill. Next, Xantphos (193 mg, 0.33 mmol), Pd 2 (dba) 3 (152 mg, 0.16 mmol), treated with N 2 Degas and backfill, and heat at 90°C for 1.45h. The crude reaction mixture was purified by silica gel chromatography (0-100% EtOAc / hexanes and then 100% MeOH / DCM) to afford the product (599 mg, 89%). LCMS (ESI) m / z: 405 [M+H] + .

[0439] Step 4

[0440] To a microwave vial was added 6-(benzylsulfanyl)-3-[1-(1-methyl-1H-pyrazol-4-yl)cyclopropyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione (300 mg, 0.74 mmol), DMF (0.3 mL), BOP (590 mg, 1.34 mmol), DBU (0.2 mL, 1.48 mmol) and the reaction mixture was stirred at room temperature for 2 h. Additional BOP (165 mg), DBU (65 ul) were added and reacted at room temperature for 1 h. Further BOP (211.4 mg), DBU (0.1 mL) were added and the reaction was stirred for another 1.20 h. To the reaction mixture was added (2S)-1-aminopropan-2-ol (0.5 mL, 6.5 mmol) and reacted at room temperature for 10 min and then heated in a microwave at 80 °C for 1 h. Water was added to the reaction mixture and extracted with EtOAc. The crude product was purified by silica gel chromatography (0-100% EtOAc / hexanes, then 0-100% MeOH / DCM) to afford the product (239.1 mg, 70%). LCMS (ESI) m / z: 462 [M+H] + .

[0441] Step 5

[0442] To a mixture of 2-{[(2S)-2-hydroxypropyl]amino}-3-[1-(1-methyl-1H-pyrazol-4-yl)ethyl]-3,4-dihydroquinazolin-4-one (239 mg, 0.52 mmol) in DCM (10.7 mL) was added Et 3 N (0.2 mL, 1.5 mmol) and MsCl (0.1 mL, 1.29 mmol). The reaction mixture was stirred at room temperature for 1.10 h and then heated at 35 ° C for 2.20 h. Water was added and extracted with DCM and EtOAc. The crude product was purified by silica gel chromatography (0-37% MeOH / DCM) to obtain the product (95.1 mg, 41%). LCMS (ESI) m / z: 444 [M+H] + .

[0443] Step 6

[0444] At 0°C, (1R)-7-(benzylsulfanyl)-1-methyl-4-[1-(1-methyl-1H-pyrazol-4-yl)cyclopropyl]-1H,2H,4H,5H-imidazo[1,2-a]quinazolin-5-one (45 mg, 0.1 mmol) was added to CH 3 CN (0.4 mL) was added with 1 drop of H 2O, 1 drop of AcOH, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (22 mg, 0.1 mmol) and reacted at 0°C for 2.30 h. The reaction mixture was used directly in the next step. LCMS (ESI) m / z: 420 [M+H] + .

[0445] Step 7

[0446] The crude reaction mixture from the previous step was cooled to 0 °C and 1-methylcyclopropan-1-amine hydrochloride (30 mg, 0.28 mmol) and Et 3 N (0.2 mL, 1.43 mmol). The reaction was stirred at 0 °C for 1 h. The solvent was evaporated in vacuo and the crude reaction mixture was purified by preparative HPLC to obtain the product (5.1 mg, 13%). LCMS (ESI) m / z: 455.00 [M+H] + . 1 H NMR (400MHz, CD 3 OD)δ8.43(s,1H),8.03-8.00(m,1H),7.64(d,J=8.0Hz,1H),7.50(d,J=8.0Hz,1H),7.28 -7.24(m,1H),4.76-4.74(m,1H),4.20-4.16(m,1H),3.81(s,3H),3.69-3.63(m,1H),1. 51-1.45(m,5H),1.41-1.38(m,2H),1.16(s,3H),0.71-0.69(m,2H),0.45-0.42(m,2H).

[0447] Representative synthetic route 10

[0448] Example 123: (R)-1-methyl-4-((1-methyl-5-oxopyrrolidin-3-yl)methyl)-N-(1-methylcyclopropyl)-5-oxo-1,2,4,5-tetrahydroimidazo[1,2-a]quinazoline-7-sulfonamide

[0449]

[0450] Step 1

[0451] A solution of 4-(aminomethyl)-1-methylpyrrolidin-2-one (100 mg, 0.78 mmol) in DCM (10 mL) was treated with 4-nitrophenyl chloroformate (173 mg, 0.86 mmol) for 2 min, and then DIEA (111 mg, 0.86 mmol) was added in portions at -60 ° C. The resulting mixture was stirred at -20 ° C for 30 min. The reaction was quenched at room temperature by adding water (30 mL). The resulting mixture was washed with CH 2 Cl 2 The combined organic layers were washed with brine (1 x 50 mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to obtain 4-nitrophenyl N-[(1-methyl-5-oxopyrrolidin-3-yl)methyl]carbamate (212 mg, 93%). LCMS (ESI) m / z: 294.0 [M+H] + .

[0452] Step 2

[0453] To a stirred mixture of methyl 5-(chlorosulfonyl)-2-fluorobenzoate (2.5 g, 9.90 mmol) and 1-methylcyclopropan-1-amine hydrochloride (1.17 g, 10.9 mmol) in DCM (50 mL) was added EtOH dropwise at room temperature. 3 N (3.00 g, 29.7 mmol). The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (5:1) to give methyl 2-fluoro-5-[(1-methylcyclopropyl)sulfamoyl]benzoate (2.6 g, 92%). LCMS (ESI) m / z: 288.0 [M+H] + .

[0454] Step 3

[0455] At room temperature, DIEA (3.54 g, 27.4 mmol) was added dropwise to a stirred mixture of 2-fluoro-5-[(1-methylcyclopropyl)sulfamoyl]benzoic acid methyl ester (2.63 g, 9.14 mmol) and N-[(2R)-2-aminopropyl]carbamic acid tert-butyl ester (1.75 g, 10 mmol) in DMSO (50 mL). The resulting mixture was stirred overnight at 60 ° C. The reaction was quenched at room temperature by adding water (200 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layer was washed with brine (1 x 300 mL) and purified by anhydrous Na 2 SO 4After filtration, the filtrate was concentrated under reduced pressure to obtain methyl 2-{[(2R)-1-[(tert-butyloxycarbonyl)amino]propan-2-yl]amino}-5-[(1-methylcyclopropyl)sulfamoyl]benzoate (3.5 g, 87%). LCMS (ESI) m / z: 442.0 [M+H] + .

[0456] Step 4

[0457] A mixture of methyl 2-{[(2R)-1-[(tert-butyloxycarbonyl)amino]propan-2-yl]amino}-5-[(1-methylcyclopropyl)sulfamoyl]benzoate (500 mg, 1.13 mmol) and HCl in 1,4-dioxane (1032 mg, 11.32 mmol) in THF (10 mL) was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified by CH 2 Cl 2 / MeOH (4:1) to give methyl 2-{[(2R)-1-aminopropan-2-yl]amino}-5-[(1-methylcyclopropyl)sulfamoyl]benzoate (322 mg, 83%). LCMS (ESI) m / z: 342.0 [M+H] + .

[0458] Step 5

[0459] To a stirred mixture of methyl 2-{[(2R)-1-aminopropan-2-yl]amino}-5-[(1-methylcyclopropyl)sulfamoyl]benzoate (212 mg, 0.62 mmol) and 4-nitrophenyl N-[(1-methyl-5-oxopyrrolidin-3-yl)methyl]carbamate (218.5 mg, 0.74 mmol) in DCM (10 mL) was added EtOH dropwise at room temperature. 3 N (138.2 mg, 1.37 mmol). The resulting mixture was stirred at 40°C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified by CH 2 Cl 2 / MeOH (12:1) to give methyl 2-{[(2R)-1-({[(1-methyl-5-oxopyrrolidin-3-yl)methyl]carbamoyl}amino)propan-2-yl]amino}-5-[(1-methylcyclopropyl)sulfamoyl]benzoate (275 mg, 89%). LCMS (ESI) m / z: 496.0 [M+H] + .

[0460] Step 6

[0461] Methyl 2-{[(2R)-1-({[(1-methyl-5-oxopyrrolidin-3-yl)methyl]carbamoyl}amino)propan-2-yl]amino}-5-[(1-methylcyclopropyl)sulfamoyl]benzoate (200 mg, 0.40 mmol) and POCl 3 A mixture of (309.4 mg, 2.02 mmol) in toluene (8 mL) and DCE (2 mL) was stirred at 60°C overnight. The reaction mixture was passed through a column with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 m; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min mL / min; gradient: 9% B to 27% B in 10 min; wavelength: 254 nm / 220 nm nm; RT1 (min): 12.4) was purified by preparative HPLC to give (1R)-1-methyl-4-[(1-methyl-5-oxopyrrolidin-3-yl)methyl]-N-(1-methylcyclopropyl)-5-oxo-1H,2H-imidazo[1,2-a]quinazoline-7-sulfonamide (60 mg, 33%). LCMS (ESI) m / z: 446.0 [M+H] + .

[0462] Step 7

[0463] The racemate (60 mg) was passed through a column with the following conditions (column: CHIRALPAK IA, 2*25 cm, 5 μm; mobile phase A: MtBE (10 mM NH 3 -MeOH), mobile phase B: MeOH--HPLC; flow rate: 20 mL / min; gradient: isocratic 30; wavelength: 220 / 286 nm; RT1 (min): 6; RT2 (min): 10; sample solvent: MeOH--HPLC; injection volume: 0.5 mL) was purified by preparative CHIRAL-HPLC to obtain isomer A (7.6 mg, 13%) and isomer B (15.5 mg, 26%). LCMS (ESI) m / z: 446.25 [M+H] + .

[0464] Isomer A: 1 H NMR (400 MHz, methanol-d 4)δ8.40(m,1H),7.22(m,1H),4.76(m,1H),4.72–4.80(m,1H),4.18–4.02(m,3 H),3.64–3.51(m,2H),3.33(d,J=14.2,7.0Hz,1H),2.94–3.04(m,3H),2.84( s,1H),2.52(dd,J=16.9,8.8Hz,1H),2.32(dd,J=17.0,6.4Hz,1H),1.43(dd, J=6.2,0.8Hz,3H),1.21–1.10(m,3H),0.68–0.74(m,2H),0.41–0.46(m,2H).

[0465] Isomer B: 1 H NMR (400 MHz, DMSO-d 6 )δ8.24(d,J=2.2Hz,1H),8.03(s,1H),7.92(dd,J=8.7,2.3Hz,1H),7.25(d,J=8.8Hz,1H), 4.66–4.76(m,1H),4.06–3.95(m,3H),3.47(dd,J=13.7,3.5Hz,1H),3.40(dd,J=9.8,7.8Hz ,1H),3.22–3.14(m,1H),2.93–2.83(m,1H),2.69(s,3H),2.34(dd,J=16.7,8.8Hz,1H),2. 17–2.05(m,1H),1.32(d,J=6.1Hz,3H),1.09(s,3H),0.58–0.64(m,2H),0.44–0.35(m,2H).

[0466] The following compounds in Table 10 were prepared using procedures similar to those described in Representative Synthetic Route 10 of Example 123 using appropriate starting materials.

[0467] Table 10

[0468]

[0469] Representative synthetic route 11

[0470] Example 130: (R)-N,N-dimethyl-4-(1-methyl-4-((1-methyl-1H-pyrazol-4-yl)methyl)-7-(N-(1-methylcyclopropyl)sulfamoyl)-5-oxo-1,2,4,5-tetrahydroimidazo[1,2-a]quinazolin-9-yl)piperazine-1-carboxamide

[0471]

[0472] Step 1

[0473] A solution of 8-bromo-1,3-dihydroquinazoline-2,4-dione (20g, 82.9mmol) in chlorosulfonic acid (200mL) was stirred at 80°C overnight. The reaction was quenched by adding ice (1000g) at 0°C. The precipitated solid was collected by filtration and washed with water (3x100 mL). The resulting solid was dried under vacuum to obtain 8-bromo-2,4-dioxo-1,3-dihydroquinazoline-6-sulfonyl chloride (30g) as a white solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: 339,341 [M+H] + .

[0474] Step 2

[0475] A solution of 8-bromo-2,4-dioxo-1,3-dihydroquinazoline-6-sulfonyl chloride (30 g, 88.3 mmol), 1-methylcyclopropane-1-amine hydrochloride (11.4 g, 106 mmol) and TEA (26.8 g, 265 mmol) in DCM (500 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified by CH 2 Cl 2 / EA (1:1) to give 8-bromo-N-(1-methylcyclopropyl)-2,4-dioxo-1,3-dihydroquinazoline-6-sulfonamide (25 g, 76%). LCMS (ESI) m / z: 374, 376 [M+H] + .

[0476] Step 3

[0477] At 90°C, under nitrogen atmosphere, 8-bromo-N-(1-methylcyclopropyl)-2,4-dioxo-1,3-dihydroquinazoline-6-sulfonamide (25 g, 66.8 mmol), bis(pinacolato)diboron (33.9 g, 133.6 mmol), AcOK (19.7 g, 200.4 mmol) and Pd(dppf)Cl were added. 2 A solution of (4.89 g, 6.68 mmol) in 1,4-dioxane (300 mL) was stirred at 90° C. overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified by CH 2 Cl 2 / PE (1:1) to give 6-[(1-methylcyclopropyl)sulfamoyl]-2,4-dioxo-1,3-dihydroquinazolin-8-ylboronic acid (17 g, 75%). LCMS (ESI) m / z: 340 [M+H] + .

[0478] Step 4

[0479] A solution of 6-[(1-methylcyclopropyl)sulfamoyl]-2,4-dioxo-1,3-dihydroquinazolin-8-ylboronic acid (8 g, 23.6 mmol), N,N-dimethylpiperazine-1-carboxamide (3.71 g, 23.6 mmol), copper(II) acetate (4.28 g, 23.6 mmol) and DIEA (9.15 g, 70.8 mmol) in DCM (200 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified by CH 2 Cl 2 / MeOH (9:1) was eluted to give N,N-dimethyl-4-{6-[(1-methylcyclopropyl)sulfamoyl]-2,4-dioxo-1,3-dihydroquinazolin-8-yl}piperazine-1-carboxamide as a white solid, which was further purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column 30*150mm, 5m; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL / min mL / min; gradient: 26% B to 40% B in 10min; wavelength: 254nm / 220nm; RT1(min): 12.97) to give N,N-dimethyl-4-{6-[(1-methylcyclopropyl)sulfamoyl]-2,4-dioxo-1,3-dihydroquinazolin-8-yl}piperazine-1-carboxamide (300mg, 3%). LCMS (ESI) m / z: 451 [M+H] + .

[0480] Step 5

[0481] N,N-dimethyl-4-{6-[(1-methylcyclopropyl)sulfamoyl]-2,4-dioxo-1,3-dihydroquinazolin-8-yl}piperazine-1-carboxamide (300 mg, 0.67 mmol) and DIEA (172.1 mg, 1.33 mmol) were dissolved in POCl 3 The mixture in 4% paraformaldehyde (20 mL) was stirred at 105 ° C overnight. The resulting mixture was concentrated under reduced pressure. The reaction was quenched by adding water / ice (150 mL) at 0 ° C. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 10 mL) and dried over anhydrous Na 2 SO 4The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. This produced 4-{2,4-dichloro-6-[(1-methylcyclopropyl)sulfamoyl]quinazolin-8-yl}-N,N-dimethylpiperazine-1-carboxamide (260 mg). The crude product was used directly in the next step without further purification.

[0482] Step 6

[0483] 4-{2,4-dichloro-6-[(1-methylcyclopropyl)sulfamoyl]quinazolin-8-yl}-N,N-dimethylpiperazine-1-carboxamide (260 mg, 0.53 mmol) and NaOH (42.7 mg, 1.1 mmol) were dissolved in THF (10 mL) and H 2 The mixture was stirred at 0 °C for 30 min in 2% CO (10 mL). The mixture was acidified to pH 2 with concentrated HCl. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 50 mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to obtain 4-{2-chloro-6-[(1-methylcyclopropyl)sulfamoyl]-4-oxo-3H-quinazolin-8-yl}-N,N-dimethylpiperazine-1-carboxamide (110 mg, 44%).

[0484] Step 7

[0485] 4-{2-chloro-6-[(1-methylcyclopropyl)sulfamoyl]-4-oxo-3H-quinazolin-8-yl}-N,N-dimethylpiperazine-1-carboxamide (110 mg, 0.23 mmol), 4-(bromomethyl)-1-methyl-1H-pyrazole hydrobromide (60 mg, 0.23 mmol), K 2 CO 3 A mixture of 4-nitropropene (64.8 mg, 0.47 mmol) and LiBr (40.7 mg, 0.47 mmol) in DME (10 mL) and DMF (2.5 mL) was stirred at room temperature overnight. The reaction was quenched by adding water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (4 x 50 mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to obtain 4-{2-chloro-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxoquinazolin-8-yl}-N,N-dimethylpiperazine-1-carboxamide (80 mg, 61%). LCMS (ESI) m / z: 564 [M+H] + .

[0486] Step 8

[0487] A mixture of 4-{2-chloro-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxoquinazoline-8-yl}-N,N-dimethylpiperazine-1-carboxamide (80 mg, 0.14 mmol), (2S)-1-aminopropan-2-ol (12.8 mg, 0.17 mmol) and TEA (43.1 mg, 0.43 mmol) in DMSO (5 mL) was stirred at 50 ° C for 30 min. The reaction was quenched at room temperature by adding water (100 mL). The resulting mixture was extracted with EtOAc (3x 100 mL). The combined organic layer was washed with brine (5x 50 mL) and dried over anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to obtain 4-(2-{[(2S)-2-hydroxypropyl]amino}-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxoquinazolin-8-yl)-N,N-dimethylpiperazine-1-carboxamide (50 mg, 59%). LCMS (ESI) m / z: 602 [M+H] + .

[0488] Step 9

[0489] A solution of 4-(2-{[(2S)-2-hydroxypropyl]amino}-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxoquinazolin-8-yl)-N,N-dimethylpiperazine-1-carboxamide (50 mg, 0.08 mmol), MsCl (28.5 mg, 0.25 mmol) and TEA (42 mg, 0.41 mmol) in DCM (5 mL) was stirred at room temperature overnight. The reaction was quenched at room temperature by adding water (5 mL). The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: Xselect CSH F-phenyl OBD column 30*250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min mL / min; gradient: 2% B to 19% B in 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 12.57) to give N,N-dimethyl-4-[(1R)-1-methyl-7-[(1-methylcyclopropyl)sulfamoyl]-4-[(1-methylpyrazol-4-yl)methyl]-5-oxo-1H,2H-imidazo[1,2-a]quinazolin-9-yl]piperazine-1-carboxamide (10.1 mg, 21%). LCMS (ESI) m / z: 584.30 [M+H] + .1 H NMR (400 MHz, DMSO-d 6 )δ8.11(d,J=2.2Hz,1H),8.01(s,1H),7.79(d,J=2.2Hz,1H),7.68(s,1H),7.41(s,1H),5 .29-5.20(m,1H),5.00-4.90(m,2H),3.93(dd,J=13.6,8.4Hz,1H),3.77(s,3H),3.69(d, J=12.4Hz,1H),3.47(dd,J=17.1,12.9Hz,2H),3.16(q,J=10.8Hz,2H),3.06-2.93(m,3H) ,2.79(s,6H),2.35-2.26(m,1H),1.08-1.02(m,6H),0.61(q,J=10.8Hz,2H),0.38(s,2H).

[0490] Representative synthetic route 12

[0491] Example 131: (R)-1-methyl-9-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-5-oxo-1,2,4,5-tetrahydroimidazo[1,2-a]quinazoline-7-sulfonamide

[0492]

[0493] To a solution of (1R)-9-bromo-1-methyl-N-(1-methylcyclopropyl)-4-[(1-methylpyrazol-4-yl)methyl]-5-oxo-1H,2H-imidazo[1,2-a]quinazoline-7-sulfonamide (50 mg, 0.099 mmol) and 1-methyl-3,6-dihydro-2H-pyridin-4-ylboronic acid (20.8 mg, 0.15 mmol) in 1,4-dioxane (4 mL) and H2O was added at room temperature. 2 To the stirred mixture in 2% O (0.4 mL) was added K 2 CO 3 (40.9 mg, 0.3 mmol) and Pd(dppf)Cl 2 (7.21 mg, 0.010 mmol). The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 2 h. The residue was purified by preparative TLC (10% MeOH / CH 2 Cl 2 ) was purified and purified by the following conditions (column: XBridge Shield RP18 OBD column 30*150mm, 5m; mobile phase A: water (10mmol / LNH4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min mL / min; gradient: 15% B to 35% B in 10 min; wavelength: 254 nm / 200 nm; RT1 (min): 10.78) was further purified by preparative HPLC to give (1R)-1-methyl-9-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-N-(1-methylcyclopropyl)-4-[(1-methylpyrazol-4-yl)methyl]-5-oxo-1H,2H-imidazo[1,2-a]quinazoline-7-sulfonamide (2 mg, 4%). LCMS (ESI) m / z: 524.35 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.22(d,J=2.3Hz,1H),8.03(s,1H),7.69(d,J=2.2Hz,1H),7.59(d,J=2.3Hz,1H),7.41(d,J=2.3Hz,1H), 6.00(s,1H),4.95(q,J=14.2Hz,2H),4.58(d,J=7.9Hz,1H),3.88(dd,J=13.4,8.1Hz,1H),3.77(d,J=2.2Hz, 3H),3.48(d,J=13.6Hz,1H),3.17(d,J=17.5Hz,1H),2.90(d,J=17.4Hz,1H),2.66(d,J=11.6Hz,2H),2.41(d ,J=18.0Hz,1H),2.29(s,3H),2.05(s,1H),1.07–0.96(m,6H),0.59(d,J=5.8Hz,2H),0.38(d,J=2.1Hz,2H).

[0494] The following compounds in Table 11 were prepared using procedures similar to those described in Representative Synthetic Route 12 of Example 131 using appropriate starting materials.

[0495] Table 11

[0496]

[0497] Representative synthetic route 13

[0498] Example 132: (R)-1,9-dimethyl-4-((1-methyl-1H-pyrazol-4-yl)methyl-d2)-N-(1-methylcyclopropyl)-5-oxo-1,2,4,5-tetrahydroimidazo[1,2-a]quinazoline-7-sulfonamide

[0499]

[0500] (1R)-9-bromo-1-methyl-N-(1-methylcyclopropyl)-4-[(1-methylpyrazol-4-yl)(2H2)methyl]-5-oxo-1H,2H-imidazo[1,2-a]quinazoline-7-sulfonamide (50 mg, 0.098 mmol), trimethyl-1,3,5,2,4,6-trioxatriborinane (14.8 mg, 0.12 mmol), P(t-Bu) 3 PdG 3(5.61mg, 0.01mmol), P(t-Bu) 3 .HBF 4 (3.1 mg, 0.010 mmol), Cs 2 CO 3 A solution of 1,4-dihydro- ... 2 SO 4 Dry. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: Sunfire prep C18 column, 30*150mm, 5m; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL / min mL / min; gradient: isocratic 11% B to 31% B in 10min; wavelength: 254nm / 220nm; RT1(min): 12.48) to obtain (1R)-1,9-dimethyl-N-(1-methylcyclopropyl)-4-[(1-methylpyrazol-4-yl)(2H2)methyl]-5-oxo-1H,2H-imidazo[1,2-a]quinazoline-7-sulfonamide (1.4mg, 3%). LCMS(ESI)m / z:445.05[M+H] + . 1 H NMR (400 MHz, methanol-d 4 )δ8.38(d,J=2.3Hz,1H),7.84(d,J=2.3Hz,1H),7.70(s,1H),7.56(s,1H),5.18(m,1H),4.01(dd,J=13.2,8.2Hz,1H),3.8 3(s,3H),3.59(d,J=13.3Hz,1H),2.61(s,3H),1.19(d,J=6.3Hz,3H),1.15(s,3H),0.75–0.67(m,2H),0.46–0.39(m,2H).

[0501] Representative synthetic route 14

[0502] Example 137: (R)-9-Bromo-1-methyl-4-((1-methyl-1H-pyrazol-4-yl)methyl-d2)-N-(1-methylcyclopropyl)-5-oxo-1,2,4,5-tetrahydroimidazo[1,2-a]quinazoline-7-sulfonamide

[0503]

[0504] Step 1

[0505] 8-Bromo-N-(1-methylcyclopropyl)-2,4-dioxo-1,3-dihydroquinazoline-6-sulfonamide (5 g, 13.4 mmol) and DIEA (3.45 g, 26.7 mmol) were dissolved in POCl 3 The mixture in 4% paraformaldehyde (100 mL) was stirred at 105 ° C overnight. The resulting mixture was concentrated under reduced pressure. The reaction was quenched by adding water / ice (150 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 50 mL) and washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. This gave 8-bromo-2,4-dichloro-N-(1-methylcyclopropyl)quinazoline-6-sulfonamide (5 g), which was used directly in the next step without further purification.

[0506] Step 2

[0507] At 0 °C, 8-bromo-2,4-dichloro-N-(1-methylcyclopropyl)quinazoline-6-sulfonamide (2 g, 4.86 mmol) was dissolved in THF (20 mL) and H 2 NaOH (0.39 g, 9.7 mmol) was added dropwise to the stirred mixture in 4% paraformaldehyde (20 mL). The resulting mixture was stirred at 0 ° C for 30 min. The mixture was acidified to pH 6 with concentrated HCl. The reaction was quenched by adding water (200 mL) at 0 ° C. The resulting mixture was extracted with EtOAc (3 x 250 mL). The combined organic layers were washed with brine (2 x 50 mL) and purified by anhydrous Na 2 SO 4 Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (45%-55%) to give 8-bromo-2-chloro-N-(1-methylcyclopropyl)-4-oxo-3H-quinazoline-6-sulfonamide (500 mg). LCMS (ESI) m / z: 392, 394 [M+H] + .

[0508] Step 3

[0509] 8-Bromo-2-chloro-N-(1-methylcyclopropyl)-4-oxo-3H-quinazoline-6-sulfonamide (300 mg, 0.76 mmol), 4-[bromo(2H2)methyl]-1-methylpyrazole (270.5 mg, 1.53 mmol), LiBr (132.7 mg, 1.53 mmol) and K 2 CO 3 A solution of 4-(316.8 mg, 2.29 mmol) in DME (10 mL) and DMF (2.5 mL) was stirred at room temperature overnight. The resulting mixture was diluted with water (100 mL) and then extracted with EtOAc (300 mL). The combined organic layers were washed with water (100 mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to obtain 8-bromo-2-chloro-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)(2H2)methyl]-4-oxoquinazoline-6-sulfonamide (300 mg). LCMS (ESI) m / z: 488, 490 [M+H] + .

[0510] Step 4

[0511] 8-Bromo-2-chloro-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)(2H2)methyl]-4-oxoquinazoline-6-sulfonamide (300 mg, 0.61 mmol), (2S)-1-aminopropan-2-ol (55.3 mg, 0.74 mmol) and Et 3 A solution of N (186.3 mg, 1.84 mmol) in DMSO (20 mL) was stirred at 50 °C for 30 min. The resulting mixture was diluted with water (100 mL) and then extracted with EtOAc (300 mL). The combined organic layers were washed with water (100 mL) and dried over anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give 8-bromo-2-{[(2S)-2-hydroxypropyl]amino}-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)(2H2)methyl]-4-oxoquinazoline-6-sulfonamide (250 mg). LCMS (ESI) m / z: 527, 529 [M+H] + .

[0512] Step 5

[0513] 8-Bromo-2-{[(2S)-2-hydroxypropyl]amino}-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)(2H2)methyl]-4-oxoquinazoline-6-sulfonamide (300 mg, 0.57 mmol), MsCl (130.3 mg, 1.14 mmol) and Et 3 A solution of N (172.7 mg, 1.71 mmol) in DCM (20 mL) was stirred at room temperature overnight. The resulting mixture was diluted with water (100 mL) and then extracted with EtOAc (300 mL). The combined organic layers were washed with water (100 mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified by CH 2 Cl 2 / MeOH (10:1) to give (1R)-9-bromo-1-methyl-N-(1-methylcyclopropyl)-4-[(1-methylpyrazol-4-yl)(2H2)methyl]-5-oxo-1H,2H-imidazo[1,2-a]quinazoline-7-sulfonamide (150 mg, 52%). LCMS (ESI) m / z: 509.05, 511.00 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.29(d,J=2.0Hz,1H),8.18(s,1H),8.11(d,J=2.0Hz,1H),7.68(s,1H),7.41(s,1H),5.73–5.64(m,1H),3.97-3.9 1(m,1H),3.75(s,3H),3.54-3.51(m,1H),1.21(d,J=6.4Hz,3H),1.09(s,3H),0.64-0.59(m,2H),0.44-0.39(m,2H).

[0514] Representative synthetic route 15

[0515] Example 138: (R)-9-cyano-1-methyl-4-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-5-oxo-1,2,4,5-tetrahydroimidazo[1,2-a]quinazoline-7-sulfonamide

[0516]

[0517] At room temperature, (1R)-9-bromo-1-methyl-N-(1-methylcyclopropyl)-4-[(1-methylpyrazol-4-yl)methyl]-5-oxo-1H,2H-imidazo[1,2-a]quinazoline-7-sulfonamide (50 mg, 0.1 mmol) and Zn(CN) were added. 2 To a stirred mixture of Pd(PPh) (13.9 mg, 0.12 mmol) in DMF (2 mL) was added portionwise 3 ) 4 (11.4 mg, 0.01 mmol). The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 12 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (2 x 30 mL) and purified by anhydrous Na 2 SO 4 Dry. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep Phenyl OBD column 19*250mm, 5m; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL / min mL / min; gradient: 23% B to 40% B in 10min; wavelength: 254nm / 220nm nm; RT1 (min): 10.54) to obtain (1R)-9-cyano-1-methyl-N-(1-methylcyclopropyl)-4-[(1-methylpyrazol-4-yl)methyl]-5-oxo-1H,2H-imidazo[1,2-a]quinazoline-7-sulfonamide (0.7mg, 1.5%). LCMS (ESI) m / z: 454.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.41(d,J=2.4Hz 1H),8.22(s,J=2.4Hz 1H),7.68(s,1H),7.41(m,1H),5.35-5.25(m,1H),5.02-4.84(m,2H),4.09-4.02(m,1H),3.76(s ,3H),3.63-3.55(m,1H),1.42-1.30(m,3H),1.11(s,3H),0.66-0.57(m,2H),0.47-0.38(m,2H).

[0518] Intermediate Synthesis Intermediate 1-4-(Bromomethyl)pyrazole-1-carboxylic acid tert-butyl ester

[0519]

[0520] At room temperature, tert-butyl 4-(hydroxymethyl)pyrazole-1-carboxylate (2.00 g, 10.1 mmol) and CBr 4 To a stirred mixture of PPh (6.7 g, 20.2 mmol) in DCM (100 mL) was added portionwise 3 (5.3 g, 20.2 mmol). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc (40%-45%) in PE to give tert-butyl 4-(bromomethyl)pyrazole-1-carboxylate (0.80 g) as a light yellow liquid.

[0521] Intermediate 1 was used in the synthesis of Example 6.

[0522] Intermediate 2-1-aminobut-3-yn-2-ol hydrochloride

[0523]

[0524] Step 1

[0525] at -78 °C in N 2 To a solution of tert-butyl (2-oxoethyl)carbamate (5 g, 31.4 mmol) in THF (50 mL) was added dropwise bromo(ethynyl)magnesium (0.5 M in THF, 157 mL, 78.5 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at -78 °C for 20 min. At room temperature, the resulting mixture was stirred for 1 h under a nitrogen atmosphere. The reaction was heated with saturated NH 4 Cl aqueous solution (20 mL) was quenched, and the mixture was then extracted with EtOAc (500 mL). The combined organic extracts were washed with brine (200 mL) and washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to obtain tert-butyl N-(2-hydroxybut-3-yn-1-yl)carbamate (4.5 g, 77%) as a light yellow oil. LCMS (ESI) m / z: 186 [M+H] + .

[0526] Step 2

[0527] A mixture of tert-butyl N-(2-hydroxybut-3-yn-1-yl)carbamate (4.5 g, 24.3 mmol) and HCl in 1,4-dioxane (40 ml) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to obtain 1-aminobut-3-yn-2-ol hydrochloride (3 g) as a light yellow solid. LCMS (ESI) m / z: 86 [M+H] + .

[0528] Intermediate 2 was used in the synthesis of Examples 9, 10, 15, 16, 27, 28, 33, 34, 43, 71, and 72.

[0529] Examples 59 and 60 were synthesized using appropriate starting materials similar to Intermediate 2.

[0530] Intermediate 3-4-(Chloromethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole

[0531]

[0532] Step 1

[0533] To a solution of 1-methyl-3-(trifluoromethyl)pyrazole-4-carboxylic acid (2 g, 10.3 mmol) in THF (20 mL) was added LiAlH in portions at room temperature. 4 (0.78 g, 20.6 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction was heated at room temperature with Na 2 SO 4 10H 2 The resulting mixture was filtered and the filter cake was washed with THF (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and used in CH 2 Cl 2 The mixture was eluted with MeOH (0%-10%) to give [1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methanol (300 mg) as a yellow liquid. LCMS (ESI) m / z: 181 [M+H] + .

[0534] Step 2

[0535] To a solution of [1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methanol (300 mg, 1.67 mmol) in acetonitrile (10 mL) was added thionyl chloride (396 mg, 3.33 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for 4 h. The resulting mixture was concentrated under reduced pressure to give 4-(chloromethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole (200 mg), which was used directly in the next step without further purification. LCMS (ESI) m / z: 199 [M+H] + .

[0536] Intermediate 3 was used in the synthesis of Example 55.

[0537] Intermediate 4-2-chloro-N-(1-methylcyclopropyl)-4-oxo-3-(3-(trimethylsilyl)prop-2-yn-1-yl)-3,4-dihydroquinazoline-6-sulfonamide

[0538]

[0539] At room temperature, 2-chloro-N-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazoline-6-sulfonamide (0.3 g, 0.96 mmol) and K 2 CO 3 To a stirred mixture of (264 mg, 1.91 mmol) in DMF (8 mL) was added LiBr (166 mg, 1.91 mmol) and (3-bromoprop-1-yn-1-yl)trimethylsilane (219 mg, 1.15 mmol) dropwise. The mixture was stirred at 50 °C for 2 h. The resulting mixture was extracted with PE (3 x 50 mL). The combined organic layers were washed with brine (20 mL) and purified by anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to give 2-chloro-N-(1-methylcyclopropyl)-4-oxo-3-(3-(trimethylsilyl)prop-2-yn-1-yl)-3,4-dihydroquinazoline-6-sulfonamide (0.12 g, 29%) as a white solid. LCMS (ESI) m / z: 424 [M+H] + .

[0540] Example 58 was synthesized using Intermediate 4 and Steps 6-7 of Representative Synthetic Route 1 of Example 46.

[0541] Intermediate 5-2-(4-(Chloromethyl)-1H-pyrazol-1-yl)acetonitrile

[0542]

[0543] Step 1

[0544] At 0 ° C, under a nitrogen atmosphere, imidazole (1.7 g, 24.5 mmol) was added in batches to a stirred mixture of 1H-pyrazol-4-ylmethanol (1.2 g, 12.2 mmol) and TBDMSCl (2.8 g, 18.3 mmol) in DMF (20 mL). The mixture was stirred at room temperature for 1 h. The reaction was quenched at room temperature by adding water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine (3 x 10 mL) and washed with anhydrous Na 2 SO 4 The residue was purified by column chromatography on silica gel using PE / EA (5:1) as eluent and concentrated under reduced pressure to give 4-(((tert-butyldimethylsilyl)oxy)methyl)-1H-pyrazole (1.2 g, 46%) as a colorless oil.

[0545] Step 2

[0546] A solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-1H-pyrazole (1.2 g, 5.6 mmol) in THF (10 mL) was treated with NaH (0.16 g, 6.8 mmol) for 30 min at 0°C under nitrogen atmosphere, and then 2-bromoacetonitrile (1 g, 8.5 mmol) was added dropwise at room temperature. The mixture was stirred overnight at room temperature under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 5 mL) and purified by anhydrous Na 2 SO 4 The residue was purified by column chromatography on silica gel using PE / EA (5:1) as eluent and concentrated under reduced pressure to give 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)-1H-pyrazol-1-yl)acetonitrile (850 mg, 60%) as a colorless oil.

[0547] Step 3

[0548] At room temperature, under a nitrogen atmosphere, a mixture of 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)-1H-pyrazol-1-yl)acetonitrile (310 mg, 1.23 mmol) and formic acid (1.5 mL) in water (10 mL) was stirred for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (5 mL). The resulting mixture was concentrated under reduced pressure to obtain 2-(4-(hydroxymethyl)-1H-pyrazol-1-yl)acetonitrile (210 mg, 17%) as a white solid. The crude product was used directly in the next step without further purification.

[0549] Step 4

[0550] At room temperature, under nitrogen atmosphere, a mixture of 2-(4-(hydroxymethyl)-1H-pyrazol-1-yl)acetonitrile (90 mg, 0.66 mmol) and thionyl chloride (156 mg, 1.31 mmol) in MeCN (2 mL) was stirred overnight. The resulting mixture was concentrated under reduced pressure to obtain 2-(4-(chloromethyl)-1H-pyrazol-1-yl)acetonitrile (40 mg, 39%) as a white solid. The crude product was used directly in the next step without further purification.

[0551] Intermediate 5 was used in the synthesis of Example 66.

[0552] Intermediate 6-2-amino-1-(2,4-dimethyl-1,3-thiazol-5-yl)ethanol

[0553]

[0554] Step 1

[0555] At room temperature, a mixture of 2,4-dimethyl-1,3-thiazole-5-carboxaldehyde (1 g, 7.1 mmol) in nitromethane (20 mL) was stirred for 12 h. The reaction was quenched at room temperature by adding water / ice (50 mL). The resulting mixture was extracted with EtOAc (3x80 mL). The combined organic layers were washed with brine (2x 80 mL) and purified by anhydrous Na 2 SO 4 Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254nm). To obtain 1-(2,4-dimethyl-1,3-thiazol-5-yl)-2-nitroethanol (1.0 g, 70%) as an orange solid. LCMS (ESI) m / z: 203.0 [M+H] + .

[0556] Step 2

[0557] 1-(2,4-dimethyl-1,3-thiazol-5-yl)-2-nitroethanol (250 mg, 1.2 mmol), NH 4 Cl (331 mg, 6.2 mmol) and Fe (69 mg, 1.2 mmol) in CH 3 CH 2 OH (5.0 mL), H 2 The mixture in 4% 4-nitropropene (0.5mL) was stirred at 80 ° C for 2h. The reaction was quenched by adding water / ice (20mL) at room temperature. The resulting mixture was filtered and the filter cake was washed with MeCN (3x50mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 10min; detector, UV 254nm) to obtain 2-amino-1-(2,4-dimethyl-1,3-thiazol-5-yl)ethanol (150mg, 70%) as a white solid. LCMS (ESI) m / z: 173.0 [M+H] + .

[0558] Intermediate 6 was used in the synthesis of Example 82.

[0559] Intermediate 7-1-amino-4-cyclopropylbut-3-yn-2-ol

[0560]

[0561] Step 1

[0562] To a stirred solution of ethynylcyclopropane (1 g, 15 mmol) in anhydrous THF (20 mL) was added n-BuLi (1.1 g, 16.6 mmol) at -78 °C for 30 min. Phthalimide acetaldehyde (3.15 g, 16.6 mmol) was added dropwise to the mixture at -78 °C over 15 min. The resulting mixture was stirred at room temperature for another 2 h. After the reaction was complete, the resulting mixture was stirred by adding saturated NH 4 Cl solution (20mL) quenched. The aqueous layer was extracted with ethyl acetate (300mL). The combined organic phase was washed with brine (100mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was further purified by silica gel column chromatography (using a gradient of 10 to 30% ethyl acetate in PE) to give the desired compound 2-(4-cyclopropyl-2-hydroxybutan-3-yn-1-yl)isoindole-1,3-dione (0.8g). LCMS (ESI) m / z: 256 [M+H] + .

[0563] Step 2

[0564] At room temperature, hydrazine hydrate (307 mg, 6.3 mmol) was added to a stirred solution of 2-(4-cyclopropyl-2-hydroxybutan-3-yn-1-yl)isoindole-1,3-dione (800 mg, 3.1 mmol) in anhydrous EtOH (25 mL). The reaction mixture was stirred at 70 ° C for 2 h. After the reaction was completed, the reaction mixture was quenched by adding water (10 mL). The aqueous layer was extracted with ethyl acetate (200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was further purified by column chromatography (using a gradient of 10 to 30% MeOH in DCM) to give the desired compound 1-amino-4-cyclopropylbutan-3-yn-2-ol (200 mg). LCMS (ESI) m / z: 126 [M+H] + .

[0565] Intermediate 7 was used in the synthesis of Examples 83 and 84.

[0566] Intermediate 8-4-(Chloromethyl)-1-methyl-1,2,3-triazole

[0567]

[0568] Step 1

[0569] 1-Methyl-1,2,3-triazole-4-carboxylic acid methyl ester (400 mg, 2.8 mmol) and LiAlH 4A solution of (215 mg, 5.7 mmol) in THF (4 mL) was stirred at room temperature for 1 h. The reaction was quenched with saturated sodium thiosulfate at room temperature. The resulting mixture was filtered and the filter cake was washed with THF (2x20 mL). The filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: 114 [M+H] + .

[0570] Step 2

[0571] (1-Methyl-1,2,3-triazol-4-yl)methanol (30 mg, 0.26 mmol) was dissolved in SOCl 2 The solution in (2 mL) was stirred at 70 °C for 1 h. The resulting mixture was concentrated under reduced pressure and used directly in the next step without further purification. LCMS (ESI) m / z: 132 [M+H] + .

[0572] Intermediate 8 was used in the synthesis of Example 90.

[0573] Intermediate 9-3-(Bromomethyl)-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine

[0574]

[0575] A solution of 5H,6H,7H-pyrazolo[3,2-b][1,3]oxazin-3-ylmethanol (800 mg, 5.2 mmol) in HBr was stirred in AcOH (10 mL) at 90 °C under nitrogen overnight. Et 2 A precipitate was formed which was dried to obtain the desired product (700 mg) as a brown solid.

[0576] The crude product was used directly in the next step without further purification.

[0577] Intermediate 9 was used in the synthesis of Example 119. Examples 118, 120, 121 and 122 were synthesized in a similar manner using appropriate starting materials.

[0578] II. Biological Evaluation

[0579] Example 1: Nuclear PAR accumulation assay

[0580] Determination of the IC of compounds that inhibit cellular PARG using an immunofluorescence high-content imaging assay targeting nuclear PAR accumulation 50 One day before compound treatment, HeLa cells were plated at 15,000 cells / well in 96-well plates and then treated with different concentrations of test compounds and incubated at 37°C + 5% CO 2Incubate for 1 hour at 4 ° C. After the test compound treatment, methyl methanesulfonate (MMS) was added to a final concentration of 50 μg / mL, and the cells were incubated for another hour. After treatment, the cells were fixed with ice-cold 95% methanol, and the plates were sealed and placed at -20 ° C for 15 minutes. The cells were then washed once with phosphate-buffered saline (PBS) and permeabilized with 0.1% Triton-X 100 at room temperature for 20 minutes. The cells were washed once again with PBS and incubated overnight with anti-poly ADP ribose (PAR) monoclonal antibodies (Millipore Part # AM80 clone 10H) diluted 1:1,000 in 5% fetal bovine serum + 0.1% Tween 20 + PBS. The cells were then washed three times with PBS and then incubated for 1 hour at room temperature with fluorescently conjugated goat anti-mouse antibodies (Invitrogen A32723) diluted 1:500 in 5% FBS + 0.1% Tween 20 + PBS. The cells were washed three times again with PBS, and the nuclei were labeled by incubation with 1 μg / mL DAPI (4′,6-diamidino-2-phenylindole). Nuclear PAR accumulation was evaluated using high-content fluorescence microscopy. Four fields of view for each well were obtained at 20x magnification, resulting in at least 1,000 analyzed cells per well. Using high-content software (CellReporterXpress), the DAPI channel was used to detect and segment the nuclei, and the fluorescence intensity of the PAR-Alexa 488 channel was quantified within the nuclear region. The average intensity of each nucleus and the percentage of PAR-positive cells were quantified. The percentage of PAR-positive cells was identified by having greater anti-PAR labeling above the threshold set for control cells treated with vehicle DMSO. The percentage inhibition of PARG by the test compound was calculated by normalizing the data to 0.1% DMSO and reference compound control values ​​representing 0% and 100% inhibition of enzyme activity, respectively. Concentration response curves and IC were generated using four-parameter logistic curve fitting software 50 value.

[0581] Representative data for exemplary compounds are given in Table 12.

[0582] Table 12

[0583]

[0584]

[0585]

[0586] Note: PAR accumulation is measured by IC 50 The data is specified in the following ranges:

[0587] A:≤0.1μM

[0588] B: >0.1μM to ≤1.0μM

[0589] C: >1.0μM to ≤10μM

[0590] D:>10μM

[0591] III. Preparation of pharmaceutical dosage forms

[0592] Example 1: Oral capsules

[0593] The active ingredient is a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof. Capsules for oral administration are prepared by mixing 1-1000 mg of the active ingredient with starch or other suitable powder blends. The mixture is incorporated into oral dosage units suitable for oral administration, such as hard gelatin capsules.

[0594] Example 2: Solution for injection

[0595] The active ingredient is a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof, and is formulated as a solution in sesame oil at a concentration of 50 mg-eq / mL.

[0596] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested to those skilled in the art are to be included within the spirit and purview of this application and the scope of the appended claims.

Claims

1. A compound or a pharmaceutically acceptable salt or solvate thereof having a structure of formula (I): in, A is selected from hydrogen, halo, -OH, -CN, optionally substituted C1-C6 alkoxy, -N(R 9 )2, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted (carbocyclyl)alkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aryl; n is 1, 2 or 3; X is O or NR 6 ; Y is N, CH or CF; Z is -N(H)- or -CH(R 8 )-; G is a bond, optionally substituted cycloalkylene, or optionally substituted heterocycloalkylene; R 1 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkylalkyl, optionally substituted aralkyl, optionally substituted heterocyclylalkyl, and optionally substituted heteroaralkyl; R 2 and R 3 R is independently selected from hydrogen, halo, -OH, -CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted (cycloalkyl)alkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aryl; optionally, R 2 and R 3 are combined to form an optionally substituted carbocyclic or heterocyclic ring; R 4 and R 5 R is independently selected from hydrogen, halo, -OH, -CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted (cycloalkyl)alkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aryl; optionally, R 4 and R 5 to form an optionally substituted carbocyclic or heterocyclic ring, or R 3 and R 4 are combined to form an optionally substituted carbocyclic or heterocyclic ring; R 6 is selected from hydrogen, OH or optionally substituted C1-C5 alkyl; R 7 is optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted 1,1'-bis(cyclopropyl)-1-yl; R 8 is hydrogen, halo or optionally substituted alkyl; and Each R 9 and R is independently hydrogen or optionally substituted C1-C6 alkyl.

2. A compound or a pharmaceutically acceptable salt or solvate thereof having a structure of formula (Ia): in, n is 1, 2 or 3; X is O or NR 6 ; Y is N, CH or CF; Z is -N(H)- or -CH(R 8 )-; G is a bond, optionally substituted cycloalkylene, or optionally substituted heterocycloalkylene; R 1 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkylalkyl, optionally substituted aralkyl, optionally substituted heterocyclylalkyl, and optionally substituted heteroaralkyl; R 2 and R 3 R is independently selected from hydrogen, halo, -OH, -CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted (cycloalkyl)alkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aryl; optionally, R 2 and R 3 are combined to form an optionally substituted carbocyclic or heterocyclic ring; R 4 and R 5 R is independently selected from hydrogen, halo, -OH, -CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted (cycloalkyl)alkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aryl; optionally, R 4 and R 5 to form an optionally substituted carbocyclic or heterocyclic ring, or R 3 and R 4 are combined to form an optionally substituted carbocyclic or heterocyclic ring; R 6 is selected from hydrogen, OH or optionally substituted C1-C5 alkyl; R 7 is optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted 1,1'-bis(cyclopropyl)-1-yl; and R 8 is hydrogen, halogenated or optionally substituted alkyl.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 or 3.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein X is O.

6. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein X is NR 6 .

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is N.

8. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is CH.

9. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is CF.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted alkyl group.

11. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted C1-C4 alkyl group.

12. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted C1-C4 alkyl group and is substituted by at least one selected from -CN, -OR 8 , halogenated, oxo-, -N(R 8 )2 or -CON(R 8 )2 is substituted by a substituent; wherein each R 8 and R is independently hydrogen or optionally substituted C1-C4 alkyl.

13. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted heteroaralkyl group.

14. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted heteroaralkyl group and the heteroaryl group is selected from a 5-membered or 6-membered heteroaryl group.

15. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted heteroaralkyl group and the heteroaryl group is selected from a 5-membered nitrogen-containing heteroaryl group.

16. The compound of claim 15 or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 5-membered nitrogen-containing heteroaryl is selected from optionally substituted thiazole, optionally substituted oxazole, optionally substituted imidazole, optionally substituted pyrazole, optionally substituted isoxazole, optionally substituted pyrrole, optionally substituted oxadiazole, optionally substituted triazole, optionally substituted thiadiazole or optionally substituted isothiazole.

17. The compound according to any one of claims 14 to 16, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted heteroaralkyl group and the alkylene group is an optionally substituted C1-C4 alkylene group.

18. The compound according to claim 17, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C4 alkylene is -CH2-.

19. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted aralkyl group.

20. The compound according to claim 19, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted aralkyl group comprises an optionally substituted phenyl group.

21. The compound according to claim 19 or 20, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted aralkyl group comprises an optionally substituted C1-C4 alkylene group.

22. The compound according to claim 21, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C4 alkylene is -CH2-.

23. The compound according to claim 14 or a pharmaceutically acceptable salt or solvate thereof, wherein the heteroaryl group is a 6-membered nitrogen-containing heteroaryl group.

24. The compound according to claim 23, or a pharmaceutically acceptable salt or solvate thereof, wherein the 6-membered nitrogen-containing heteroaryl group is an optionally substituted pyridine or pyrazine.

25. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted C4-C7 cycloalkylalkyl group.

26. The compound according to claim 25, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted cycloalkylalkyl is optionally substituted cyclopropylmethyl.

27. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted heterocyclylalkyl group.

28. The compound according to claim 27, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heterocyclylalkyl is optionally substituted oxetanylmethyl or optionally substituted pyrazolonylmethyl.

29. A compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 For hydrogen.

30. A compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 For hydrogen.

31. A compound as described in any one of claims 1 to 30, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 For hydrogen.

32. A compound as described in any one of claims 1 to 30, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Not hydrogen.

33. A compound as described in any one of claims 1 to 30, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is an optionally substituted C1-C5 alkyl group.

34. The compound of claim 33, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C5 alkyl group is an optionally substituted C1-C2 alkyl group.

35. A compound as described in any one of claims 1 to 30, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 and R 3 Each is an optionally substituted C1-C5 alkyl group.

36. The compound of claim 35 or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 and R 3 to form an optionally substituted carbocyclic or heterocyclic ring.

37. A compound as described in any one of claims 1 to 30, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is an optionally substituted C1-C5 alkynyl group.

38. A compound as described in any one of claims 1 to 30, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is an optionally substituted heterocyclic group.

39. A compound as described in any one of claims 1 to 28, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 For hydrogen.

40. A compound as described in any one of claims 1-28 or 39, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 Not hydrogen.

41. A compound as described in any one of claims 1-28 or 39, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is an optionally substituted C1-C5 alkyl group.

42. A compound as described in any one of claims 1-28 or 39, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 and R 5 Each is an optionally substituted C1-C5 alkyl group.

43. A compound as described in any one of claims 1-28 or 39, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 and R 5 to form an optionally substituted carbocyclic or heterocyclic ring.

44. The compound of claims 1-43 or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 is an optionally substituted C3-C5 cycloalkyl group.

45. The compound of claim 44, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted cycloalkyl is: Where R 8 Selected from hydrogen, -CH3, -CH2F, -CHF2, -CF3, -CN, cyclopropyl, -CH2CH3, -CH(CH3)2 and -C(CH3)3.

46. ​​The compound of claim 16 or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 5-membered nitrogen-containing heteroaryl is an optionally substituted pyrazole.

47. The compound of claim 16 or 46, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 5-membered nitrogen-containing heteroaryl is substituted with at least one optionally substituted C1-C5 alkyl.

48. The compound of claim 47, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C5 alkyl group is an optionally substituted C1 alkyl group.

49. A compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein G is a bond.

50. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt or solvate thereof, wherein G is an optionally substituted cycloalkylene.

51. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt or solvate thereof, wherein G is an optionally substituted heterocycloalkylene.

52. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -N(H)-.

53. A compound as described in any one of claims 1, 3-52, or a pharmaceutically acceptable salt or solvate thereof, wherein A is hydrogen.

54. The compound or pharmaceutically acceptable salt or solvate thereof as described in any one of claims 1, 3-52, wherein A is halo or -CN.

55. A compound as described in any one of claims 1, 3-52, or a pharmaceutically acceptable salt or solvate thereof, wherein A is an optionally substituted C1-C6 alkoxy or -N(R 9 )2.

56. A compound as described in any one of claims 1, 3-52, or a pharmaceutically acceptable salt or solvate thereof, wherein A is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, and optionally substituted carbocyclyl alkyl.

57. The compound as described in any one of claims 1, 3-52, or a pharmaceutically acceptable salt or solvate thereof, wherein A is an optionally substituted heterocyclyl or an optionally substituted heterocyclylalkyl.

58. A compound as described in any one of claims 1, 3-52, or a pharmaceutically acceptable salt or solvate thereof, wherein A is selected from optionally substituted heteroaryl or optionally substituted aryl.

59. The compound of claim 17, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C4 alkylene is -CD2-.

60. A compound or a pharmaceutically acceptable salt or solvate thereof as described in Table 1.

61. A compound or a pharmaceutically acceptable salt or solvate thereof as described in any one of Tables 2A-2I.

62. A pharmaceutical composition comprising a compound according to any one of claims 1 to 61 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

63. A method for preparing a pharmaceutical composition comprising mixing a compound as described in any one of claims 1 to 61 or a pharmaceutically acceptable salt or solvate thereof with a pharmaceutically acceptable carrier.

64. A compound as claimed in any one of claims 1 to 61, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating the human or animal body.

65. A compound as described in any one of claims 1 to 61, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer or a neoplastic disease.

66. Use of a compound as described in any one of claims 1 to 61 or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for treating cancer or a tumor disease.

67. A method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvate thereof.

68. A method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound as described in any one of claims 1-61, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

69. A method of inhibiting a PARG enzyme comprising contacting the enzyme with a compound as described in any one of claims 1-61, wherein the PARG enzyme is contacted in an in vitro environment.

70. A method of inhibiting a PARG enzyme comprising contacting the enzyme with a compound as described in any one of claims 1-61, wherein the PARG enzyme is contacted in an in vivo environment.

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