Inhibitor of PARG

Abstract

Provided herein are inhibitors of PARG, pharmaceutical compositions comprising an inhibitory compound, and methods for using a PARG inhibitory compound for the treatment of a disease.

Description

Technical Field

[0001] Cross - Reference to Related Applications

[0001] This application claims the benefit of U.S. Patent Application No. 63 / 343,005, filed May 17, 2022, and incorporates it by reference in its entirety.

Background Art

[0002]

[0002] Poly(ADP - ribose) glycohydrolase (PARG) is an enzyme involved in DNA replication and repair, and cells in which PARG is depleted or inhibited show high sensitivity to DNA - damaging agents. PARG inhibitors are expected to have utility as cancer therapeutics, either as monotherapies or in combination with therapeutic agents or radiation therapy.

Summary of the Invention

Problems to be Solved by the Invention

[0003]

[0003] Provided herein are inhibitors of PARG, pharmaceutical compositions comprising the inhibitory compounds, and methods for using the inhibitory compounds for the treatment of diseases.

Means for Solving the Problems

[0004]

[0004] One embodiment is a compound having the structure of formula (I), or a pharmaceutically acceptable salt or solvate thereof:

[0005]

Chemical Formula

[0006] (wherein, A is hydrogen, halo, - OH, - CN, optionally substituted C1 - C6 alkoxy, - N(R 9)2. selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted (carbocyclic) alkynyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, and optionally substituted aryl; n is 1, 2, or 3; X is O or NR 6 ; Y is N, C-H, or C-F; Z is -N(H)- or -CH(R 8 )-; G is a bond, optionally substituted cycloalkylene, or optionally substituted heterocycloalkylene; R 1 is selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkylalkyl, optionally substituted aralkyl, optionally substituted heterocyclic alkyl, and optionally substituted heteroaralkyl; R 2 and R 3 are independently selected from the group consisting of 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 heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, and optionally substituted aryl; R 2 and R 3 may combine to form an optionally substituted carbocyclic or heterocyclic ring; R 4 and R 5is independently selected from the group consisting of 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; R 4 and R 5 are joined to form an optionally substituted carbocyclic or heterocyclic ring, or R 3 and R 4 may be joined 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'-bi(cyclopropane)-1-yl; R 8 is hydrogen, halo, or optionally substituted alkyl; each R 9 is independently hydrogen or optionally substituted C1-C6 alkyl).

[0007]

[0005] 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.

[0008]

[0006] One embodiment provides a method of treating a disease or disorder in a patient in need thereof, the method comprising administering to the patient a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides a method wherein the disease or disorder is cancer.

[0009] Incorporation by reference All publications, patents, and patent applications cited in this specification are hereby incorporated by reference herein for the specific purpose identified herein.

DETAILED DESCRIPTION OF THE INVENTION

[0010]

[0008] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a number of such agents, reference to "the cell" includes reference to one or more cells (or a number of cells) and their equivalents known to those skilled in the art, etc. When ranges are used herein with respect to physical properties, such as molecular weight, or chemical properties, such as chemical formula, all combinations and subcombinations of the ranges and specific embodiments therein are intended to be included. The term "about", when referring to a number or numerical range, means that the recited number or numerical range is an approximation within the variation of the experiment (or within the statistical experimental error), and thus, in some cases, the number or numerical range may vary by 1% to 15% of the recited number or numerical range. Related terms such as "comprising" (and "comprise" or "comprises" or "having" or "including") are intended not to exclude, in other particular embodiments, for example, embodiments of any composition, composition of matter, method, or process described herein, from consisting of or consisting essentially of the recited features.

[0011] Definitions

[0009] As used in this specification and the appended claims, unless otherwise specified, the following terms have the meanings set forth below.

[0012]

[0010] "Amino" refers to the -NH2 group.

[0011] "Cyano" refers to the -CN group.

[0012] "Nitro" refers to the -NO2 group.

[0013]

[0013] "Oxo" refers to the -O- group.

[0014] "Oxo" refers to the =O group.

[0015] "Thioxo" refers to the =S group.

[0014]

[0016] "Imino" refers to the =N-H group.

[0017] "Oximo" refers to the =N-OH group.

[0018] "Hydrazino" refers to the =N-NH2 group.

[0015]

[0019] "Alkyl" consists of only carbon and hydrogen atoms, is unsaturated, and is a straight-chain or branched hydrocarbon chain group having 1 to 15 carbon atoms (e.g., C1 to C 15 alkyl). In certain embodiments, alkyl contains 1 to 13 carbon atoms (e.g., C1 to C 13 alkyl). In certain embodiments, alkyl contains 1 to 8 carbon atoms (e.g., C1 to C8 alkyl). In other embodiments, alkyl contains 1 to 5 carbon atoms (e.g., C1 to C5 alkyl). In other embodiments, alkyl contains 1 to 4 carbon atoms (e.g., C1 to C4 alkyl). In other embodiments, alkyl contains 1 to 3 carbon atoms (e.g., C1 to C3 alkyl). In other embodiments, alkyl contains 1 to 2 carbon atoms (e.g., C1 to C2 alkyl). In other embodiments, alkyl contains 1 carbon atom (e.g., C1 alkyl). In other embodiments, alkyl contains 5 to 15 carbon atoms (e.g., C5 to C 15(alkyl). In other embodiments, the alkyl contains 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl contains 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl contains 3 to 5 carbon atoms (e.g., C3-C5 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 is bonded to the rest of the molecule by a single bond. Unless specifically specified otherwise herein, the alkyl group may have one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, 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) and may be substituted by, and each R ais independently hydrogen, alkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclic alkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclic (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclic alkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (which may be 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 a -CF3 group.

[0016]

[0020] "Alkoxy" refers to a group bonded through the oxygen atom of the formula -O-alkyl, where alkyl is the alkyl chain defined above.

[0021] "Alkenyl" refers to a straight-chain or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having 2 to 12 carbon atoms. In certain embodiments, alkenyl contains 2 to 8 carbon atoms. In other embodiments, alkenyl contains 2 to 4 carbon atoms. Alkenyl is bonded to the remainder of the molecule by a single bond and is, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless specifically specified otherwise herein, an alkenyl group may be substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, 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) and may be substituted by each R ais independently hydrogen, alkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclic alkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclic (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclic alkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0017]

[0022] "Alkynyl" consists of only carbon and hydrogen atoms, contains at least one carbon-carbon triple bond, and refers to a straight-chain or branched hydrocarbon chain group having 2 to 12 carbon atoms. In certain embodiments, alkynyl contains 2 to 8 carbon atoms. In other embodiments, alkynyl contains 2 to 6 carbon atoms. In other embodiments, alkynyl contains 2 to 4 carbon atoms. Alkynyl is bonded to the remainder of the molecule by a single bond and is, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless specifically stated otherwise herein, an alkynyl group may have one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, 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) may be substituted, and each R a is independently hydrogen, alkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclic alkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclic (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclic alkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0018]

[0023] "Alkylene" or "alkylene chain" refers to a straight-chain or branched divalent hydrocarbon chain consisting only of carbon and hydrogen, containing no unsaturation, having 1 to 12 carbon atoms, to which the remainder of the molecule is bonded as a group, for example, methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is bonded to the remainder of the molecule via a single bond and to the group via a single bond. The bonding points of the alkylene chain to the remainder of the molecule and to the group are via one carbon of the alkylene chain or via any two carbons within the chain. In certain embodiments, alkylene contains 1 to 8 carbon atoms (e.g., C1-C8 alkylene). In other embodiments, alkylene contains 1 to 5 carbon atoms (e.g., C1-C5 alkylene). In other embodiments, alkylene contains 1 to 4 carbon atoms (e.g., C1-C4 alkylene). In other embodiments, alkylene contains 1 to 3 carbon atoms (e.g., C1-C3 alkylene). In other embodiments, alkylene contains 1 to 2 carbon atoms (e.g., C1-C2 alkylene). In other embodiments, alkylene contains 1 carbon atom (e.g., C1 alkylene). In other embodiments, alkylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkylene). In other embodiments, alkylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkylene). In other embodiments, alkylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkylene). Unless specifically stated otherwise herein, the alkylene chain has one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, 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(Ra )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) may be substituted, and each R a is independently hydrogen, alkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclic alkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclic (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclic alkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0019]

[0024] "Alkenylene" or "alkenylene chain" refers to a divalent hydrocarbon chain that consists only of carbon and hydrogen, contains at least one carbon-carbon double bond, has a straight or branched structure with 2 to 12 carbon atoms, and is bonded to the rest of the molecule through a single bond. The alkenylene chain is bonded to the rest of the molecule through a single bond and to the group through a single bond. In certain embodiments, alkenylene contains 2 to 8 carbon atoms (e.g., C2-C8 alkenylene). In other embodiments, alkenylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, alkenylene contains 2 to 4 carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, alkenylene contains 2 to 3 carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, alkenylene contains 2 carbon atoms (e.g., C2 alkenylene). In other embodiments, alkenylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkenylene). In other embodiments, alkenylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkenylene). Unless specifically stated otherwise herein, the alkenylene chain may have one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, 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 (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2) and -S(O) t N(Ra ) It may be substituted by 2(t is 1 or 2), and each R a is independently hydrogen, alkyl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclic alkyl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), aryl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclic (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclic alkyl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl).

[0020]

[0025] "Alkynylene" or "alkynylene chain" refers to a straight-chain or branched divalent hydrocarbon chain consisting only of carbon and hydrogen, having at least one carbon-carbon triple bond, and having 2 to 12 carbon atoms, with the remainder of the molecule bonded to a group. The alkynylene chain is bonded to the remainder of the molecule through a single bond and to a group through a single bond. In certain embodiments, alkynylene contains 2 to 8 carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, alkynylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, alkynylene contains 2 to 4 carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, alkynylene contains 2 to 3 carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, alkynylene contains 2 carbon atoms (e.g., C2 alkynylene). In other embodiments, alkynylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, alkynylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkynylene). Unless specifically specified otherwise herein, the alkynylene chain may have one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, 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(Ra )2 (where t is 1 or 2) may be substituted, and each R a is independently hydrogen, alkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclic alkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclic (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclic alkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0021]

[0026] "Aryl" refers to a group derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon atoms of 5 to 18 carbon atoms, and at least one of the rings of the ring system is completely unsaturated, that is, according to the Hückel theory, it is cyclic and contains a delocalized (4n + 2)π electron system. The 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 specifically specified otherwise in this specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") refers to alkyl which may be substituted, alkenyl which may be substituted, alkynyl which may be substituted, 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 -O-R 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 (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2) and -R b -S(O) t N(R a )2 (t is 1 or 2), which means it may be substituted by one or more substituents independently selected from, and each R ais independently hydrogen, alkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), and each R b is independently a direct bond or a linear or branched alkylene or alkenylene chain, and R c is a linear or branched alkylene or alkenylene chain, and R a R b or R c substituents are unsubstituted unless otherwise indicated.

[0022]

[0027] “Aralkyl” refers to a group of the formula -R c -aryl, where R c is, for example, an alkylene chain as defined above such as methylene, ethylene, etc. The alkylene chain portion of the aralkyl group may be substituted as described above for the alkylene chain. The aryl portion of the aralkyl group may be substituted as described above for the aryl group.

[0023]

[0028] “Aralkenyl” refers to a group of the formula -R d -aryl, where R dis the alkenylene chain defined above. The aryl portion of the aralkenyl group may be substituted as described above for the aryl group. The alkenylene chain portion of the aralkenyl group may be substituted as defined above for the alkenylene group.

[0024]

[0029] "Aralkynyl" refers to a group of the formula -R e -aryl, where R e is the alkynylene chain defined above. The aryl portion of the aralkynyl group may be substituted as described above for the aryl group. The alkynylene chain portion of the aralkynyl group may be substituted as defined above for the alkynylene chain.

[0025]

[0030] "Aralkoxy" refers to a group bonded through an oxygen atom of the formula -O-R c -aryl, where R c is, for example, an alkylene chain such as methylene, ethylene, etc., defined above. The alkylene chain portion of the aralkyl group may be optionally substituted as described above for the alkylene chain. The aryl portion of the aralkyl group may be substituted as described above for the aryl group.

[0026]

[0031] "Carbocyclic" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting of only carbon and hydrogen atoms, including a fused ring system or a bridged ring system having 3 to 15 carbon atoms. In certain embodiments, carbocyclic contains 3 to 10 carbon atoms. In other embodiments, carbocyclic contains 5 to 7 carbon atoms. Carbocyclic is bonded to the remainder of the molecule by a single bond. Carbocyclic is saturated (i.e., contains only C-C single bonds) or unsaturated (i.e., contains one or more double bonds or triple bonds). A fully saturated carbocyclic group is also referred to as "cycloalkyl". Examples of monocyclic cycloalkyl include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclic is also referred to as "cycloalkenyl". Examples of monocyclic cycloalkenyl include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Examples of polycyclic carbocyclic groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise indicated specifically herein, the term "carbocyclic" may be substituted alkyl, substituted alkenyl, substituted alkynyl, halo, 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 -O-R c -C(O)N(R a )2、-Rb -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 (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2) and -R b -S(O) t N(R a )2(t is 1 or 2), and means optionally substituted by one or more substituents independently selected from a carbocyclic group, where each R a is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), each R b is independently a direct bond or a linear or branched alkylene or alkenylene chain, R c is a linear or branched alkylene or alkenylene chain, R a, R b or R c The substituents of, unless otherwise indicated, are unsubstituted.

[0027]

[0032] "Carbocyclic alkyl" refers to a group of the formula -R c -carbocyclic, where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclic group may be substituted as defined above.

[0028]

[0033] "Carbocyclic alkynyl" refers to a group of the formula -R c -carbocyclic, where R c is an alkynylene chain as defined above. The alkynylene chain and the carbocyclic group may be substituted as defined above.

[0029]

[0034] "Carbocyclic alkoxy" refers to a group bonded through the oxygen atom of the formula -O-R c -carbocyclic, where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclic group may be substituted as defined above.

[0030]

[0035] "Halo" or "halogen" refers to a bromo substituent, a chloro substituent, a fluoro substituent or an iodo substituent.

[0036] "Fluoroalkyl" refers to an alkyl group as defined above substituted by one or more fluoro groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl group may be substituted as defined above for the alkyl group.

[0031]

[0037] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring group containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless specifically specified otherwise herein, the heterocyclyl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a spiro ring system, a fused ring system, or a bridged ring system. The heteroatoms of the heterocyclyl group may be oxidized. One or more nitrogen atoms, if present, may be quaternized. The heterocyclyl group is partially saturated or fully saturated. The heterocyclyl is attached to the remainder of the molecule through any atom of the ring. Examples of such heterocyclyl groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. In some embodiments, the heterocyclyl group includes 2-oxa-7-azaspiro[3.5]nonanyl. Unless specifically specified otherwise herein, the term "heterocyclyl" may be 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)ORa 、 -R b -C(O)N(R a )2, -R b -O-R 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 (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2) and -R b -S(O) t N(R a )2 (t is 1 or 2), and is optionally substituted by one or more substituents selected from, and means including the heterocyclyl group defined above, each R a is, independently, hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), and each Rb is, independently, a direct bond or a linear or branched alkylene or alkenylene chain, and R c is a linear or branched alkylene or alkenylene chain, and R a , R b , or R c substituents are each unsubstituted unless otherwise indicated.

[0032]

[0038] "N - heterocyclyl" or "N - bonded heterocyclyl" refers to a heterocyclyl group as defined above that contains at least one nitrogen, and the point of attachment of the remainder of the molecule of the heterocyclyl group is via a nitrogen atom of the heterocyclyl group. The N - heterocyclyl group may be substituted as described above for the heterocyclyl group. Examples of such N - heterocyclyl groups include, but are not limited to, 1 - morpholinyl, 1 - piperidinyl, 1 - piperazinyl, 1 - pyrrolidinyl, pyrazolidinyl, and imidazolidinyl.

[0033]

[0039] "C - heterocyclyl" or "C - bonded heterocyclyl" refers to a heterocyclyl group as defined above that contains at least one heteroatom, and the point of attachment of the remainder of the molecule of the heterocyclyl group is via a carbon atom of the heterocyclyl group. The C - heterocyclyl group may be substituted as described above for the heterocyclyl group. Examples of such C - heterocyclyl groups include, but are not limited to, 2 - morpholinyl, 2 - piperidinyl or 3 - piperidinyl or 4 - piperidinyl, 2 - piperazinyl, 2 - pyrrolidinyl or 3 - pyrrolidinyl, etc.

[0034]

[0040] "heterocyclylalkyl" refers to a group of the formula - R c -heterocyclyl, and R cis the alkylene chain defined above. When the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be bonded to the alkyl group through a nitrogen atom. The alkylene chain of the heterocyclylalkyl group may be substituted as defined above for the alkylene chain. The heterocyclyl moiety of the heterocyclylalkyl group may be substituted as defined above for the heterocyclyl group.

[0035]

[0041] "Heterocyclylalkoxy" has the formula -O-R c - represents a group bonded through the oxygen atom of the heterocyclyl, and R c is the alkylene chain defined above. When the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be bonded to the alkyl group through a nitrogen atom. The alkylene chain of the heterocyclylalkoxy group may be substituted as defined above for the alkylene chain. The heterocyclyl moiety of the heterocyclylalkoxy group may be substituted as defined above for the heterocyclyl group.

[0036]

[0042] "Heteroaryl" refers to a group derived from an aromatic ring group having 3 to 18 ring members containing 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and at least one of the rings of the ring system is completely unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π electron system in accordance with Hückel's theory. Heteroaryl includes fused ring systems or bridged ring systems. The heteroatoms of the heteroaryl group may be oxidized. One or more nitrogen atoms, if present, may be quaternized. Heteroaryl is attached to the remainder of the molecule through any atom of the ring. Examples of heteroaryl include azepinyl, acridinyl, benzimidazolyl, benzoindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 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]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-Methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, 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, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[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 thiophenyl (i.e., thienyl) are included, but not limited to these. 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 specifically specified otherwise herein, the term "heteroaryl" means 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(Ra ) 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 -O-R 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 (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2) and -R b -S(O) t N(R a ) 2 (t is 1 or 2) and is optionally substituted by one or more substituents selected from, a heteroaryl group as defined above, meaning that each R ais independently hydrogen, alkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), and each R b is independently a direct bond or a linear or branched alkylene or alkenylene chain, and R c is a linear or branched alkylene or alkenylene chain, and R a R b or R c substituents are unsubstituted unless otherwise indicated.

[0037]

[0043] “N - heteroaryl” refers to a heteroaryl group as defined above that contains at least one nitrogen, and the point of attachment to the remainder of the molecule of the heteroaryl group is via a nitrogen atom of the heteroaryl group. The N - heteroaryl group may be substituted as described above for the heteroaryl group.

[0038]

[0044] “C - heteroaryl” refers to a heteroaryl group as defined above, and the point of attachment to the remainder of the molecule of the heteroaryl group is via a carbon atom of the heteroaryl group. The C - heteroaryl group may be substituted as described above for the heteroaryl group.

[0039]

[0045] "Heteroarylalkyl" refers to a group of the formula -R c -heteroaryl, where R c is an alkylene chain as defined above. When the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl may be bonded to the alkyl group through a nitrogen atom. The alkylene chain of the heteroarylalkyl group may be substituted as defined above for the alkylene chain. The heteroaryl moiety of the heteroarylalkyl group may be substituted as defined above for the heteroaryl group.

[0040]

[0046] "Heteroarylalkoxy" refers to a group bonded through an oxygen atom of the formula -O-R c -heteroaryl, where R c is an alkylene chain as defined above. When the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl may be bonded to the alkyl group through a nitrogen atom. The alkylene chain of the heteroarylalkoxy group may be substituted as defined above for the alkylene chain. The heteroaryl moiety of the heteroarylalkoxy group may be substituted as defined above for the heteroaryl group.

[0041]

[0047] The compounds disclosed in this specification, in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomers defined in terms of absolute stereochemistry such as (R)- or (S)-. Unless otherwise specified, it is intended that all stereoisomers of the compounds disclosed in this specification are contemplated by this disclosure. When the compounds described herein contain an alkene double bond and are not otherwise specified, this disclosure is intended to include both geometric isomers (e.g., cis or trans) of the E and Z forms. Similarly, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are intended to be included. The term "geometric isomer" refers to the geometric isomers of the E or Z form of an alkene double bond (e.g., cis or trans). The term "positional isomer" refers to structural isomers around a central ring, e.g., ortho-isomers, meta-isomers, and para-isomers around a benzene ring.

[0042]

[0048] 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

[0043]

Chem.

[0044] and the like, but are not limited thereto.

[0049] "Tautomer" refers to a molecule in which a proton shift is possible from one atom of the molecule to another atom of the same molecule. The compounds shown in this specification exist as tautomers in certain embodiments. In situations where tautomerization is possible, a chemical equilibrium of tautomers exists. The exact ratio of tautomers depends on several factors including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibria include

[0045]

Chem.

[0046] is included.

[0050] The compounds disclosed herein, in some embodiments, for example, 2 H, 3 H, 11 C, 13 C and / or 14 C, are used in the form of various enriched isotopes, such as those with a concentrated content. In a particular embodiment, the compound is deuterated at at least one position. Such deuterated forms can be made by the procedures described in U.S. Patent No. 5,846,514 and U.S. Patent No. 6,334,997. As described in U.S. Patent No. 5,846,514 and U.S. Patent No. 6,334,997, deuteration can improve metabolic stability and / or efficacy, and thus can extend the duration of action of the drug.

[0047]

[0051] Unless otherwise indicated, the structures shown herein are intended to include compounds that differ only in the presence of one or more isotope-enriched atoms. For example, except for the substitution of hydrogen with deuterium or tritium, or the substitution of carbon with 13 C- or 14 C-enriched carbon, compounds having this structure are within the scope of this disclosure.

[0048]

[0052] The compounds of the present disclosure may contain unnatural ratios of atomic isotopes with respect to one or more atoms that make up such compounds. For example, the compound may be labeled with isotopes such as, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). 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, 125 All isotope substitutions with O, F, S, Cl, Br, and I are contemplated. In some embodiments, 18 isotope substitution with F is contemplated. All isotope variations of the compounds of the invention are included within the scope of the invention, whether or not radioactive.

[0049]

[0053] In certain embodiments, the compounds disclosed herein have some or all of the 1 H atoms replaced with 2 H atoms. Methods for synthesizing deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0050]

[0054] Deuterium-substituted compounds are synthesized using a variety of methods such as those 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, page 110; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601 - 21; and Evans, Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1 - 2), 9 - 32.

[0051]

[0055] The deuterated starting materials are readily available and are subjected to the synthetic methods described herein provided for the synthesis of deuterium-containing compounds. A number of deuterium-containing reagents and building blocks are commercially available from chemical vendors such as Aldrich Chemical.

[0052]

[0056] Deuterium transfer reagents suitable for use in nucleophilic substitution reactions such as iodomethane-d3 (CD3I) are readily available and can be used to transfer deuterium-substituted carbon atoms to a reaction substrate under nucleophilic substitution reaction conditions. The use of CD3I is merely illustrated as an example in the following reaction scheme.

[0053]

Chemical formula

[0054]

[0057] Deuterium transfer reagents such as lithium aluminum deuteride (LiAlD4) are used to transfer deuterium to a reaction substrate under reducing conditions. The use of LiAlD4 is merely illustrated as an example in the following reaction scheme.

[0055]

Chemical formula

[0056]

[0058] Deuterium gas and a palladium catalyst are used to reduce unsaturated carbon-carbon bonds and to carry out reductive substitution of aryl carbon-halogen bonds as merely illustrated as an example in the following reaction scheme.

[0057]

Chemical formula

[0058]

[0059] 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 atoms. In one embodiment, the level of deuterium incorporation is determined by a synthetic method in which a deuterated building block is used as a starting material.

[0059]

[0060] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. Any pharmaceutically acceptable salt of any one of the PARG inhibitory compounds described herein is intended to encompass 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.

[0060]

[0061] "Pharmaceutically acceptable acid addition salts" are not biologically or otherwise undesirable and refer to those salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc., which retain the biological effects and properties of the free base. Also included are salts formed with organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, such as 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, etc. Thus, representative salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Salts of amino acids such as argininates, gluconates, and galacturonates are also contemplated (see, for example, Berge S.M. et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 66:1-19 (1997)). The acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base form with a sufficient amount of the desired acid to form the salt, according to methods and techniques well known to those of ordinary skill in the art.

[0061]

[0062] "Pharmaceutically acceptable base addition salts" refer to those salts that retain the biological effects and properties of the free acid and are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are formed, in some embodiments, with metals or amines such as alkali metals, alkaline earth metals, or organic amines. Salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc. Salts derived from organic bases include 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, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc., but are not limited to these. See Berge et al., supra.

[0062]

[0063] "Pharmaceutically acceptable solvates" refer to compositions in a solvate form. In some embodiments, the solvate contains the solvent in either a stoichiometric or non-stoichiometric amount and is formed during a process of manufacture with a pharmaceutically acceptable solvent, such as water, ethanol, etc. When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcoholate is formed. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein exist in either a non-solvated form or a solvated form.

[0063]

[0064] The terms "subject" or "patient" include mammals. Examples of mammals include members of the mammalian groups: humans, non-human primates such as chimpanzees, other apes and monkey species; livestock such as cows, horses, sheep, goats, pigs; companion animals such as rabbits, dogs, and cats; laboratory animals such as rodents including rats, mice and guinea pigs, but are not limited to these. In one aspect, the mammal is a human.

[0064]

[0065] As used herein, "treatment" or "treating", or "palliating" or "ameliorating" are used interchangeably. These terms refer to an approach for obtaining a beneficial or desired result, including but not limited to a therapeutic and / or prophylactic effect. "Therapeutic effect" means the eradication or amelioration of a primary disease being treated. Also, a therapeutic effect is achieved by the eradication or amelioration of one or more physiological symptoms associated with the primary disease such that improvement is observed in the patient, even though the patient still suffers from the primary disease. For a prophylactic effect, the composition is administered, in some embodiments, to a patient at risk of developing a particular disease, or a patient in whom one or more physiological symptoms of the disease have been reported, even if the disease has not been diagnosed. Poly(ADP-ribose) glycohydrolase

[0066] Single-strand DNA breaks (SSBs) are the most frequently occurring type of lesion in cells, and poly(ADP-ribose) glycohydrolase (PARG), together with poly(ADP-ribose) polymerase (PARP), is involved with numerous other proteins in another repair mechanism called single-strand break repair and base excision repair. PARG and PARP are involved in DNA replication and repair, and cells in which PARG is depleted or inhibited show high sensitivity to DNA-damaging agents. PARG can reverse the action of the PARP enzyme by hydrolyzing the ribose linkage present in poly(ADP-ribose) (PAR). PARG is a primary hydrolase involved in the degradation of PAR, using both endoglycohydrolase and exoglycohydrolase activities, and is one of the hydrolases responsible for the rapid removal of the ADP-ribose moiety from modified proteins to recycle NAD + back to the cell system.

[0065]

[0067] PARG inhibition may confer a therapeutic advantage in PARP inhibitor-resistant cells. Furthermore, PARG depletion has been reported to lead to a gene expression pattern that is significantly different from that of PARP depletion in breast cancer cells. Current models indicate that PARG depletion leads to PARP-dependent effects in DNA repair, but recent studies have shown a mechanistic divergence from PARP inhibition. After genotoxic stimulation, PARG depletion leads to a decrease in NAD levels, in contrast to PARP depletion, which results in lung cancer cell death that can lead to energy deficiency.

[0066]

[0068] PARG exists as a single gene with isoforms in the nucleus, mitochondria, and cytosol. The only other known protein with glycohydrolase activity that is localized to the mitochondria is ARH3. Although mainly known for its direct role in DNA repair, PARG strongly affects PAR signaling in the splicing, transcription, and epigenetic pathways. PARG can also play a role in preventing the accumulation of cytoplasmic PAR and parthanatos, a PAR-mediated type of cell death. The accumulation of perturbed replication intermediates can lead to synthetic lethality in certain situations. PARG inhibitors can be used as a cancer treatment, either as a single agent or in combination with therapeutic agents or radiotherapy.

[0067]

[0069] When other mechanisms of DNA repair are non-functional, cancer cells may proliferate by utilizing specific DNA repair pathways. Tumors carrying mutations in proteins involved in double-strand break repair are often highly sensitive to PARP inhibitors for SSB repair. There is already some evidence that PARG depletion inhibits SSB repair and reduces the survival rate of BRCA2-deficient cells. However, other tumor mutations can result in deficiencies in the double-strand DNA repair machinery (so-called "BRCA-ness"), thereby making tumor cells sensitive to PARG inhibition.

[0068]

[0070] PARG depletion has been studied in many mouse and human model systems. Mouse cells lacking or depleted of PARG show high sensitivity to experimental and clinical DNA-damaging agents. However, this suggests specificity for PARG function in certain pathways of DNA damage repair and chemotherapy and radiotherapy, as a lack of PARG does not make cells sensitive to all agents (e.g., gemcitabine, camptothecin). In humans, PARG depletion makes cells from lung, cervical, and pancreatic cancers sensitive to γ-irradiation or experimental DNA-damaging agents (e.g., hydrogen peroxide, methyl methanesulfonate).

[0069]

[0071] In humans, the PARG gene is located on a single chromosome at locus 10q11.23 - 21, but may undergo alternative splicing, and PARG 111 , PARG 102 , PARG 99 , PARG 60 , PARG 55 and so on, resulting in various PARG isoforms. The various PARG isoforms can be localized to various intracellular locations. For example, the largest isoform, PARG - 111 is localized in the nucleus and can be translocated to the cytoplasm. PARG 111 has four domains, namely, the PARG catalytic domain, the macrodomain, the region controlling natural denaturation, and the hinge domain. PARG 102 and PARG 99 lacking a part of the N - terminal domain can be localized in the cytoplasm and have a perinuclear distribution that can translocate to the nucleus. PARG 102 and PARG 99 have a higher degree of overall cell activity. PARG 60 and PARG 55 can be localized within mitochondria and lack catalytic activity.

[0070]

[0072] PARG can function together with PARP for DNA repair. The PARP family of enzymes has at least 17 members, among which PARP1 - 3 are localized in the nucleus and are involved in many cellular processes. Nuclear PARP enzymes are part of DNA repair and are also involved in 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 way in which PARP1 - 3 function is by adding large - scale post - translational modifications to other proteins and themselves, and PARG can reverse this. By inhibiting PARG, the reaction rate of depolymerization can be changed, and as a result, proteins are inappropriately modified.

[0071] PARG enzyme function

[0073] PARG and PARP can work together to promote downstream cellular processes. The exoglycohydrolase activity of PARG involves binding to the two most distal ADP-ribose residues within the PARG chain, resulting in free PAR and mono-ADP-ribose moieties. Mono-ADP-ribose is metabolized to AMP and ribose 5'-phosphate by ADP-ribose pyrophosphohydrolase. Subsequently, AMP is utilized in cell signaling pathways while ribose can be utilized for other biomolecules such as, but not limited to, DNA and RNA. PARG endoglycohydrolase activity can occur via excessive PARP activity which would result in the generation of free PAR chains. Free PAR chains may be associated with apoptosis and function to signal cell death.

[0072]

[0074] PARG also functions to maintain a stable level of PAR to protect cells against parthanatos, which is triggered by the release of apoptosis-inducing factor (AIF) from mitochondria to the nucleus. Within the nuclear chromatin environment, AIF can cause large-scale DNA fragmentation and chromatin condensation, potentially leading to cell death. Depletion of PARG can prevent the release of AIF from mitochondria to protect against oxidative stress-induced parthanatos. PARG can also have a useful function in telomere maintenance by negatively regulating access to telomeric DNA by reversing the ADP-ribosylation of the telomere-specific protein TRF1. This leads to PARG contributing to the repair and replication control of telomeres.

[0073]

[0075] PARP enzymes can fulfill many functions of DNA repair, such as, but not limited to, single-strand DNA breaks. Therefore, PARP inhibitors have been studied for cancers with defects in the DNA damage response mechanism (Pilger et al., Genes Dev. 2021). The immune response of PARP is related to DNA repair, and DNA lesions can activate antitumor 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 relationship between PARP inhibitors for use in DNA damage responses, their therapeutic use with immune checkpoint inhibitors, or their use as biomarkers.

[0074]

[0076] PARP enzymes can catalyze the addition of PAR subunits to receptor proteins and themselves. PARP inhibitors have been studied for cancer treatment and have been successful in treatment of ovarian, breast, and prostate cancers. PARP inhibitors have been found to treat defects in the homologous recombination DNA repair pathway, particularly BRCA1 and BRCA2 mutant tumors (Ding et al., Cell Reports 2018; Reislander et al., Nature Comm. 2019). Thus, BRCA mutant cells are dependent on PARP-mediated DNA repair and survival and may therefore be sensitive to PARP inhibition.

[0075]

[0077] PARP inhibitors have also shown clinical efficacy in subjects with BRCA mutations. PARP inhibitors that can elicit local and systemic anti-tumor immunity can participate in the innate immune response through the stimulator of interferon genes (STING)-dependent pathway (Ding et al., Cell Reports 2018; Reislander et al., Nature Comm. 2019). Studies have found that STING-dependent type I interferon (IFN) signaling may mediate the therapeutic effect of PARP inhibition in BRCA1-deficient tumors. Furthermore, treatment with PARP inhibitors can stimulate the upregulation of IFN signaling genes in vitro and in vivo, and it has been found that it can promote the upregulation of the innate immune response in BRCA1-deficient tumors or BRCA2-deficient tumors (Reislander et al., Nature Comm. 2019).

[0076]

[0078] PARP inhibitors exhibit synthetic lethality associated with loss of BRCA function and can be used for therapeutic treatment of ovarian cancer for monotherapy treatment in patients with germline or somatic BRCA1 mutations and BRCA2 mutations, or can be used as maintenance therapy after platinum chemotherapy in subjects with platinum-sensitive recurrent disease (Ding et al., Cell Reports 2018). Further studies suggest that adding a PD-1 blocker can extend the activity of PARP inhibitors by overcoming the increase in the expression of PD-L1 in tumor cells that occurs when cells are treated with PARP inhibitors alone (Ding et al., Cell Reports 2018). Prior art PARG inhibitors

[0079] PARG inhibitors have not been studied to the extent of PARP inhibitors. Clinical resistance to PARP inhibitors has already been explained, and therefore, it is necessary to discover alternative inhibitors that target the DNA damage repair pathway. The aforementioned PARG inhibitors include bicyclic aryl compounds and heteroaryl compounds described in WO2016 / 092326, WO2016 / 097749, WO2021 / 055744, WO2018 / 237296, WO2020 / 023802, and WO2020 / 205646. There remains a need to find alternative PARG inhibitors that have strong independent efficacy regarding the DNA cleavage repair cycle and a synergistic effect with PARP inhibitors.

[0077] PARG inhibitory compound

[0080] In one aspect, provided herein is a PARG inhibitory compound.

[0081] One embodiment is a compound having the structure of formula (I), or a pharmaceutically acceptable salt or solvate thereof:

[0078]

Chemical formula

[0079] (wherein, A is selected from the group consisting of 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 carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted (carbocyclic) alkynyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, and optionally substituted aryl; n is 1, 2, or 3; X is O, or NR 6 ; Y is N, C-H, or C-F; Z is -N(H)- or -CH(R8 )-and; G is an optionally substituted cycloalkylene or an optionally substituted heterocycloalkylene; R 1 is selected from the group consisting of 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 are independently selected from the group consisting of 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; R 2 and R 3 may combine to form an optionally substituted carbocyclic or heterocyclic ring; R 4 and R 5 are independently selected from the group consisting of 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; R 4 and R 5 may combine to form an optionally substituted carbocyclic or heterocyclic ring, or R 3 and R 4 may combine to form an optionally substituted carbocyclic or heterocyclic ring; R 6 is selected from hydrogen, OH, or optionally substituted C1-C5 alkyl; R 7is optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted 1,1'-bi(cyclopropane)-1-yl; R 8 is hydrogen, halo, or optionally substituted alkyl; each R 9 is independently hydrogen or optionally substituted C1-C6 alkyl).

[0080]

[0082] Another embodiment provides a compound of formula (I) wherein A is hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

[0083] Another embodiment provides a compound of formula (I) wherein A is halo, -OH, or -CN, or a pharmaceutically acceptable salt or solvate thereof.

[0081]

[0084] Another embodiment provides a compound of formula (I) wherein A is optionally substituted C1-C6 alkoxy or -N(R 9 )2, or a pharmaceutically acceptable salt or solvate thereof.

[0082]

[0085] Another embodiment provides a compound of formula (I) wherein A is selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, and optionally substituted carbocyclylalkyl, or a pharmaceutically acceptable salt or solvate thereof.

[0083]

[0086] Another embodiment provides a compound of formula (I) wherein A is optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or a pharmaceutically acceptable salt or solvate thereof.

[0084]

[0087] Another embodiment provides a compound of formula (I) wherein A is selected from optionally substituted heteroaryl or optionally substituted aryl, or a pharmaceutically acceptable salt or solvate thereof.

[0085]

[0088] One embodiment is a compound of formula (I) having the structure of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:

[0086]

Chemical Formula

[0087] (wherein, n is 1, 2, or 3; X is O, or NR 6 ; Y is N, C-H, or C-F; Z is -N(H)- or -CH(R 8 ); G is a bond, an optionally substituted cycloalkylene, or an optionally substituted heterocycloalkylene; R 1 is selected from the group consisting of 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 are independently selected from the group consisting of 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; R 2 and R 3 may combine to form an optionally substituted carbocyclic or heterocyclic ring; R 4 and R 5is independently selected from the group consisting of 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; R 4 and R 5 are joined to form an optionally substituted carbocyclic or heterocyclic ring, or R 3 and R 4 may be joined 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'-bi(cyclopropane)-1-yl; R 8 is hydrogen, halo, or optionally substituted alkyl).

[0088]

[0089] Another embodiment provides a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. Another embodiment provides a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 or 3.

[0089]

[0090] Another embodiment provides a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein X is O. Another embodiment provides a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein X is NR 6 is provided.

[0090]

[0091] Another embodiment provides a compound of formula (I) or formula (Ia) wherein Y is N, or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides a compound of formula (I) or formula (Ia) wherein Y is C-H, or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides a compound of formula (I) or formula (Ia) wherein Y is C-F, or a pharmaceutically acceptable salt or solvate thereof.

[0091]

[0092] Another embodiment provides a compound of formula (I) or formula (Ia) wherein R 1 is optionally substituted alkyl, or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides a compound of formula (I) or formula (Ia) wherein R 1 is optionally substituted C1-C4 alkyl, or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides a compound of formula (I) or formula (Ia) wherein R 1 is optionally substituted C1-C4 alkyl and is substituted with at least one substituent selected from -CN, -OR 8 , halo, oxo, -N(R 8 )2, or -CON(R 8 )2; each R 8 is independently hydrogen or optionally substituted C1-C4 alkyl, or a pharmaceutically acceptable salt or solvate thereof.

[0092]

[0093] Another embodiment provides a compound of formula (I) or formula (Ia) wherein R 1 is optionally substituted heteroalkyl, or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides a compound of formula (I) or formula (Ia) wherein R 1 is optionally substituted heteroalkyl and the heteroaryl is selected from 5- or 6-membered heteroaryl, or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides a compound of formula (I) or formula (Ia) wherein R 1is an optionally substituted heteroalkyl, and the heteroaryl is selected from 5-membered nitrogen-containing heteroaryl, a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides a compound of formula (I) or formula (Ia), 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. Another embodiment provides a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 5-membered nitrogen-containing heteroaryl is optionally substituted pyrazole. Another embodiment provides a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 5-membered nitrogen-containing heteroaryl is substituted with at least optionally substituted C1-C5 alkyl. Another embodiment provides a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C5 alkyl is optionally substituted C1 alkyl.

[0093]

[0094] Another embodiment provides that R 1 is an optionally substituted heteroalkyl, and the alkylene is optionally substituted C1-C4 alkylene, a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C4 alkylene is -CH2-.

[0094]

[0095] Another embodiment provides that R 1Provided are compounds of formula (I) or formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein the aralkyl may be substituted. Another embodiment provides compounds of formula (I) or formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein the aralkyl which may be substituted contains a phenyl which may be substituted. Another embodiment provides compounds of formula (I) or formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein the aralkyl which may be substituted contains a C1-C4 alkylene which may be substituted. Another embodiment provides compounds of formula (I) or formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein the C1-C4 alkylene which may be substituted is -CH2-. Another embodiment provides compounds of formula (I) or formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein the heteroaryl is a 6-membered nitrogen-containing heteroaryl. Another embodiment provides compounds of formula (I) or formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein the 6-membered nitrogen-containing heteroaryl is a pyridine or pyrazine which may be substituted.

[0095]

[0096] Another embodiment provides that R 1 is a C4-C7 cycloalkylalkyl which may be substituted, of a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides compounds of formula (I) or formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein the cycloalkylalkyl which may be substituted is a cyclopropylmethyl which may be substituted.

[0096]

[0097] Another embodiment provides that R 1Provided are compounds of formula (I) or formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein the heterocyclylalkyl may be substituted. Another embodiment provides compounds of formula (I) or formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein the heterocyclylalkyl which may be substituted is optionally substituted oxetan-3-ylmethyl or optionally substituted pyrazolon-3-ylmethyl.

[0097]

[0098] Another embodiment provides compounds of formula (I) or formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein R 4 is hydrogen.

[0099] Another embodiment provides compounds of formula (I) or formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein R 5 is hydrogen.

[0098]

[0100] Another embodiment provides compounds of formula (I) or formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein R 3 is hydrogen.

[0101] Another embodiment provides compounds of formula (I) or formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein R 2 is not hydrogen. Another embodiment provides compounds of formula (I) or formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein R 2 is optionally substituted C1-C5 alkyl. Another embodiment provides compounds of formula (I) or formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein the optionally substituted C1-C5 alkyl is optionally substituted C1-C2 alkyl.

[0099]

[0102] Another embodiment provides compounds of formula (I) or formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein R 2 and R 3 are both optionally substituted C1-C5 alkyl.

[0100]

[0103] Another embodiment provides a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 and R 3 are combined to form an optionally substituted carbocyclic or heterocyclic ring.

[0101]

[0104] Another embodiment provides a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is optionally substituted C1-C5 alkynyl.

[0102]

[0105] Another embodiment provides a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is optionally substituted heterocyclyl.

[0103]

[0106] Another embodiment provides a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 is optionally substituted C3-C5 cycloalkyl. Another embodiment provides that the optionally substituted cycloalkyl is

[0104]

Chemical formula

[0105] and R 8 is selected from the group consisting of hydrogen, -CH3, -CH2F, -CHF2, -CF3, -CN, cyclopropyl, -CH2CH3, -CH(CH3)2, and -C(CH3)3, and provides a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt or solvate thereof.

[0106]

[0107] Another embodiment provides a compound of formula (I) or formula (Ia) wherein G is a bond, or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides a compound of formula (I) or formula (Ia) wherein G is an optionally substituted cycloalkylene, or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides a compound of formula (I) or formula (Ia) wherein G is an optionally substituted heterocycloalkylene, or a pharmaceutically acceptable salt or solvate thereof.

[0107]

[0108] Another embodiment provides a compound of formula (I) wherein Z is -N(H)-, or a pharmaceutically acceptable salt or solvate thereof.

[0109] One embodiment provides a PARG inhibitory compound having the structure shown in Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0108]

Table 1-1

[0109]

Table 1-2

[0110]

Table 1-3

[0111]

Table 1-4

[0112]

Table 1-5

[0113]

Table 1-6

[0114]

Table 1-7

[0115]

Table 1-8

[0116]

Table 1-9

[0117]

Table 1-10

[0118]

Table 1-11

[0119]

Table 1-12

[0120]

Table 1-13

[0121]

Table 1-14

[0122]

Table 1-15

[0123]

Table 1-16

[0124]

Table 1-17

[0125]

Table 1-18

[0126]

Table 1-19

[0127]

Table 1-20

[0128]

Table 1-21

[0129]

Table 1-22

[0130]

Table 1-23

[0131]

Table 1-24

[0132]

Table 1-25

[0133]

Table 1-26

[0134] Another embodiment provides a PARG inhibitory compound having the structures shown in Tables 2A - 2I, or a pharmaceutically acceptable salt or solvate thereof.

[0135]

Table 2 - 1

[0136]

Table 2 - 2

[0137]

Table 2 - 3

[0138]

Table 2 - 4

[0139]

Table 2 - 5

[0140]

Table 2 - 6

[0141]

Table 3

[0142]

Table 4

[0143]

Table 5

[0144]

Table 6

[0145]

Table 7

[0146]

Table 8

[0147]

Table 9

[0148]

Table 10

[0149] Preparation of the compound

[0111] The compounds used in the synthetic chemical reactions described in this specification are manufactured according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemical substances and / or compounds described in the chemical literature. "Commercially available chemical substances" are 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, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Company (Pittsburgh, PA), Fisons Chemicals (Loughborough, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), 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 Chemical USA, Inc. (Richmond, VA).

[0150] For a detailed description of the synthesis of reactants useful for the preparation of the compounds described herein, or for treatises that explain the preparation and provide references to appropriate reference books and papers, for example, "Synthetic Organic Chemistry", John Wiley & Sons, New York; S.R. Sandler et al., "Organic Functional Group Preparations", 2nd Edition, Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions", 2nd Edition, W.A. Benjamin Inc., Menlo Park, Calif. 1972; T.L. 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 are included. Additional appropriate reference books and papers for a detailed description of the synthesis of reactants useful for the preparation of the compounds described herein, or for treatises that explain the preparation and provide references, for example, Fuhrhop, J. and Penzlin G., "Organic Synthesis: Concepts, Methods, Starting Materials", Revised and Enlarged 2nd Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V., "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R.C., "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. (ed.) "Modern Carbonyl Chemistry" (2000), Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai’s 1992 Guide to the Chemistry of Functional Groups" (1992), Interscience, ISBN: 0-471-93022-9; Solomons, T.W.G. "Organic Chemistry", 7th Edition (2000), John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C. "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 in total; "Organic Reactions" (1942 - 2000), John Wiley & Sons, over 55 volumes; and "Chemistry of Functional Groups", John Wiley & Sons, 73 volumes in total are included.

[0151]

[0113] Specific reactants and similar reactants are in some cases identified through indices of known chemical substances prepared by the American Chemical Society's Chemical Abstracts Service, which are available in most public and university libraries, and also through online databases (for details, contact the American Chemical Society, Washington, D.C.). Chemical substances that are known but not commercially available in catalogs are in some cases prepared by custom chemical synthesis companies, and many standard chemical substance suppliers (e.g., those mentioned above) offer custom synthesis services. A useful reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P.H. Stahl and C.G. Wermuth, "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0152] General synthetic scheme

[0114] The PARG inhibitory compounds disclosed herein can be prepared by a variety of synthetic routes including, but not limited to, the routes described in Scheme I or II below.

[0153]

Chemical formula

[0154]

[0115] When 2,4 - quinazolinone derivative 1.1 is reacted with chlorosulfonic acid, chlorosulfonyl derivative 1.2 is obtained. Reacting compound 1.2 with a substituted amine gives sulfonamide 1.3. Chlorinating compound 1.3 gives dichloroquinazoline derivative 1.4, which undergoes selective hydrolysis at the 4 - position when treated with an aqueous base. 2 - chloroquinazoline 1.5 is substituted at the amide nitrogen by treatment with a suitable electrophile under basic conditions to give compound 1.6. The cyclization of the 5 - membered imidazole ring is initiated by substitution of the chloro group by reaction with a suitable amino alcohol to give 2 - aminoquinazoline derivative 1.7. The ring - closure of the imidazole ring to obtain the target compound 1.8 is achieved under Mitsunobu conditions (e.g., DEAD, PPh3), or alternatively, by activation of the alcohol as a suitable leaving group such as conversion to a methanesulfonate or chlorination with SOCl2, followed by ring - closure by treatment with a base. One of ordinary skill in the art will recognize that using a 1,2 - amino alcohol gives a 5 - membered imidazole compound 1.8, while using a 1,3 - amino alcohol gives a similar 6 - membered compound. Similarly, using a 1,4 - amino alcohol gives a similar 7 - membered compound. In this case, a single stereoisomer of the target compound is desired, and chiral chromatography using supercritical fluid chromatography can be used. Alternatively, if necessary, a non - racemic chiral starting material such as an amino alcohol may be used.

[0155]

Chem.

[0156]

[0116] Anthranilic acid derivative 2.1 is condensed with alkyl isothiocyanate to obtain 2-thioxo-2,3-dihydroquinazolin-4(1H)-one derivative 2.2. Chlorination gives compound 2.3, which undergoes substitution with amino alcohol to obtain quinazolinone derivative 2.4. The ring closure of the imidazole ring to obtain compound 2.5 is achieved under Mitsunobu conditions (e.g., DIAD, PPh3), or alternatively, by activation of the alcohol as a suitable leaving group with a reagent such as methanesulfonyl chloride (MeSO2Cl) or thionyl chloride (SOCl2), followed by ring closure with treatment with a base. One skilled in the art will recognize that using a 1,2-amino alcohol gives a 5-membered imidazole compound 2.5, while using a 1,3-amino alcohol gives a similar 6-membered compound. Similarly, using a 1,4-amino alcohol gives a similar 7-membered compound. Palladium-catalyzed thiolation of imidazole compound 2.5 gives sulfide 2.6, which undergoes oxidative chlorination to obtain sulfonyl chloride 2.7. Reacting the sulfonyl chloride with a suitable amine gives the target compound 2.8.

[0157]

[0117] One skilled in the synthesis of organic compounds will recognize that depending on the nature of the substituents in groups R 1 ~R 5 and R 7 , modifications of Scheme I or II may be required. Such changes may include, for example, the use of protecting groups to change the reactivity of the substituents or to change the time and temperature for the reaction. Further modifications of the compounds of formula 1.8 or 2.8 can be carried out to reach the desired PARG inhibitory compound. In this event, a single stereoisomer of the target compound is desired, and chiral chromatography using supercritical fluid chromatography can be used. Alternatively, a non-racemic chiral starting material such as an amino alcohol may be used if necessary.

[0158]

[0118] When using appropriate starting materials, the PARG inhibitory compounds according to formula (I) or (Ia), or described herein in Tables 1 or 2A - 2I, can be synthesized using the methods described in Schemes I or II.

[0159] Pharmaceutical composition

[0119] In certain embodiments, the PARG inhibitory compounds described herein are administered as pure chemical substances. In other embodiments, the PARG inhibitory compounds described herein are combined with a pharmaceutically suitable or pharmaceutically 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) selected based on, for example, the selected route of administration and standard pharmaceutical practice as described in Remington: The Science and Practice of Pharmacy (Gennaro, 21st edition, Mack Pub. Co., Easton, PA (2005)).

[0160]

[0120] Provided herein is a pharmaceutical composition comprising at least one PARG inhibitory compound described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other components of the composition and not harmful to the recipient (i.e., the subject or patient) of the composition.

[0161]

[0121] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt or solvate thereof.

[0162]

[0122] One embodiment provides a method for preparing a pharmaceutical composition comprising the step of mixing a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0163]

[0123] In certain embodiments, the PARG inhibitory compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, is substantially pure and 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 organic small molecules, such as unreacted intermediates, or synthetic by-products made in one or more steps of the synthetic method, for example.

[0164]

[0124] 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.

[0165]

[0125] One embodiment provides a method for preparing a pharmaceutical composition comprising the step of mixing a compound of Table 1 or Tables 2A - 2I, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0166]

[0126] In certain embodiments, the PARG inhibitory compound of Table 1 or Tables 2A - 2I, or a pharmaceutically acceptable salt or solvate thereof, is substantially pure and 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 organic small molecules, such as unreacted intermediates, or synthetic by-products made in one or more steps of the synthetic method, for example.

[0167]

[0127] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard gelatin or soft gelatin, methylcellulose, or another suitable material that readily dissolves in the gastrointestinal tract. In some embodiments, a suitable non-toxic solid carrier is used, including, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, 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)).

[0168]

[0128] In some embodiments, the PARG inhibitory compounds described in formula (I) or formula (Ia) or Tables 1 or 2A - 2I, or a pharmaceutically acceptable salt or solvate thereof, are 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 oily formulation, such as sesame oil, etc.

[0169]

[0129] The dosage of the composition comprising at least one PARG inhibitory compound described herein varies depending on the condition of the subject or patient (e.g., human). In some embodiments, such factors include general health status, age, and other factors.

[0170]

[0130] The pharmaceutical composition is administered in a manner suitable for the disease to be treated (or prevented). The appropriate dosage, appropriate duration, and frequency of administration are determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. Generally, the appropriate dosage and treatment plan provide the composition in an amount sufficient to provide a therapeutic and / or prophylactic effect (e.g., improvement of a clinical outcome, such as more frequent complete or partial remission, or a longer disease-free and / or overall survival period, or reduction in the severity of symptoms). The optimal dosage is generally determined using experimental models and / or clinical trials. The optimal dosage depends on the body mass, weight, or blood volume of the patient.

[0171]

[0131] Oral dosages are typically in the range of about 1.0 mg to about 1000 mg, one to four times a day, or more. Method of treatment

[0132] One embodiment provides a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a human or animal body.

[0172]

[0133] One embodiment provides a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a cancer or neoplastic disease.

[0173]

[0134] One embodiment provides a pharmaceutical composition comprising a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient, for use in a method of treating a cancer or neoplastic disease.

[0174]

[0135] One embodiment provides the use of a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a cancer or neoplastic disease.

[0175]

[0136] In some embodiments, there is provided a method of treating cancer in a patient in need of cancer treatment, the method comprising administering to the patient a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, there is provided a method of treating cancer in a patient in need of cancer treatment, the method comprising administering to the patient a pharmaceutical composition comprising a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0176]

[0137] 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 a human or animal body.

[0177]

[0138] 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.

[0178]

[0139] 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.

[0179]

[0140] One embodiment provides the use of a compound of Table 1 or Tables 2A - 2I, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or a neoplastic disease.

[0180]

[0141] In some embodiments, provided is a method of treating cancer in a patient in need thereof, the method 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, provided is a method of treating cancer in a patient in need thereof, the method 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.

[0181]

[0142] Provided herein are methods in which the pharmaceutical composition is administered orally. Provided herein are methods in which the pharmaceutical composition is administered by injection.

[0143] One embodiment provides a method of inhibiting a PARG enzyme, the method comprising contacting the PARG enzyme with a compound of formula (I) or (Ia) or Table 1 or Tables 2A - 2I. Another embodiment provides a method of inhibiting a PARG enzyme, the method comprising contacting the PARG enzyme in an in vivo setting. Another embodiment provides a method of inhibiting a PARG enzyme, the method comprising contacting the PARG enzyme in an in vitro setting.

[0182]

[0144] Other embodiments and uses will be apparent to those skilled in the art in light of the present disclosure. The following examples are given merely as illustrations of various embodiments and should not be construed in any way as limiting the invention.

Examples

[0183] I. Chemical Synthesis

[0145] 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 invention, the following abbreviations should be understood to have the following meanings, unless otherwise indicated: ACN Acetonitrile ℃ Degrees Celsius δH Chemical shifts in parts per million from tetramethylsilane on the low magnetic field side DCM Dichloromethane (CH2Cl2) DIAD Diisopropyl azodicarboxylate DIEA Diisopropylethylamine DMF Dimethylformamide DMSO Dimethyl sulfoxide EA Ethyl acetate EtOAc Ethyl acetate ESI Electrospray ionization Et Ethyl g Gram h Hour HPLC High performance liquid chromatography Hz Hertz J Coupling constant (in NMR spectroscopy) LCMS Liquid chromatography mass spectrometry μ Micro m Multiplet (of spectrum); meter; milli M Molar concentration M + Parent molecular ion Me Methyl MsCl Methanesulfonyl chloride MHz Megahertz min Minute mol Mole; molecule (in mol wt) mL Milliliter MS Mass spectrometry nm Nanometer NMR Nuclear magnetic resonance pH Hydrogen ion exponent; measure of acidity or basicity of an aqueous solution PE Petroleum ether RT Room temperature s Singlet (of spectrum) t Triplet (of spectrum) SFC Supercritical fluid chromatography T Temperature TFA Trifluoroacetic acid THF Tetrahydrofuran TPP Triphenylphosphine Typical synthetic route 1 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

[0184] [Chemical Structure]

[0185] Step 1

[0146] A solution of 1,3-dihydroquinazoline-2,4-dione (15.0 g, 92.5 mmol) in chlorosulfonic acid (50 mL) was stirred at 60 °C for 4 h. The mixture was cooled to room temperature and then poured onto water / ice. The precipitated solid was collected by filtration and washed with water (2 × 100 mL). The obtained solid was dried under vacuum to give 2,4-dioxo-1,3-dihydroquinazoline-6-sulfonyl chloride (16.0 g, 66%) as a white solid. LCMS (ESI) m / z: 259 (M-H).

[0186] Step 2

[0147] TEA (37.2 g, 368 mmol) was added to a solution of 1-methylcyclopropane-1-amine hydrochloride (7.92 g, 73.6 mmol) in DCM (100 mL), and then 2,4-dioxo-1,3-dihydroquinazoline-6-sulfonyl chloride (16.0 g, 61.3 mmol) was added portionwise at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was filtered. The precipitated solid was collected by filtration and washed with water (3 × 50 mL). The obtained solid was dried under vacuum to give N-(1-methylcyclopropyl)-2,4-dioxo-1,3-dihydroquinazoline-6-sulfonamide (17.5 g, 82%) as a pale yellow solid. LCMS (ESI) m / z: 294 (M-H).

[0187] Step 3

[0148] In POCl3 (50.0 mL), to a stirred mixture of N-(1-methylcyclopropyl)-2,4-dioxo-1,3-dihydroquinazoline-6-sulfonamide (17 g, 57.5 mmol), DIEA (18.6 g, 143.4 mmol) was added dropwise at 0 °C. 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 (3 × 200 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (3 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give 2,4-dichloro-N-(1-methylcyclopropyl)quinazoline-6-sulfonamide (8.00 g, 42%) as a pale yellow solid. LCMS (ESI) m / z: 332 [M+H] + .

[0188] Step 4

[0149] To a solution of 2,4-dichloro-N-(1-methylcyclopropyl)quinazoline-6-sulfonamide (8 g, 24.0 mmol) in THF (60 mL) and water (60 mL), NaOH (4.58 g, 114 mmol) was added. The solution was stirred at room temperature for 1 h. The mixture was acidified to pH 3 with HCl (aqueous solution). The precipitated solid was collected by filtration and washed with water (3 × 50 mL). The filtrate was concentrated under reduced pressure to give 2-chloro-N-(1-methylcyclopropyl)-4-oxo-3H-quinazoline-6-sulfonamide (6.5 g, 86%) as a pale yellow solid. LCMS (ESI) m / z: 314 [M+H] + .

[0189] Step 5 In DMF (10 mL) and DME (10 mL), a solution of 2-chloro-N-(1-methylcyclopropyl)-4-oxo-3H-quinazoline-6-sulfonamide (1.00 g, 2.81 mmol) was treated with K2CO3 (0.78 g, 5.62 mmol), followed by the addition of LiBr (0.49 g, 5.62 mmol) and 4-(bromomethyl)-1-methylpyrazole hydrobromide (0.72 g, 2.81 mmol). The resulting mixture was stirred at room temperature for 5 h. The reaction was quenched at room temperature with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting 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] + .

[0190] Step 6

[0151] In DMSO (4 mL), to a solution of 2-chloro-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-3-yl)methyl]-4-oxoquinazoline-6-sulfonamide (400 mg, 0.98 mmol) were added (S)-1-aminopropan-2-ol (105 mg, 1.40 mmol) and Et3N (298 mg, 2.94 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 2 h. The reaction was quenched at room temperature with water (20 mL). The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting 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] + .

[0191] Step 7

[0152] 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 Et3N (67.7 mg, 0.67 mmol), followed by the addition of CH3SO2Cl (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 × 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. 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 NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 18% B to 45% B in 7 min, 45% B; wavelength: 220 nm] to give (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] + 。 1 H NMR (400 MHz, CD3OD): 8.42 (s, 1H), 8.00 (dd, J1 = 8.8, 2.0 Hz, 1H), 7.67 (s, 1H), 7.54 (s,1H), 7.20 (d, J = 8.8 Hz, 1H), 5.03 - 4.96 (m, 2H), 4.78 - 4.73 (m, 1H), 4.19 - 4.11 (m, 1H), 3.83 (s, 3H), 3.65 - 3.62 (m, 1H), 1.40 (d, J = 6.0 Hz, 3H), 1.16 (s, 3H), 0.72 - 0.69 (m, 2H), 0.45 - 0.39 (m, 2H). Using the same procedure as described for representative synthetic route 1 for Example 46 and using appropriate starting materials, the following compounds in Table 3 were prepared.

[0192]

Table 11-1

[0193]

Table 11-2

[0194]

Table 11-3

[0195]

Table 11-4

[0196]

Table 11-5

[0197]

Table 11-6

[0198]

Table 11-7

[0199]

Table 11-8

[0200]

Table 11-9

[0201] 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

[0202]

Chem.

[0203] Step 1

[0154] To a stirred solution of methyl 1-methylpyrazole-4-carboxylate (1.0 g, 7.1 mmol) in THF (20 mL) was added LiAlD4 (0.6 g, 14.3 mmol) portionwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. The reaction was quenched at room temperature with Na2SO4·10H2O (1 g). The resulting mixture was filtered and the filter cake was washed with MeCN (3 × 10 mL). The resulting mixture was concentrated under reduced pressure to give (1-methylpyrazol-4-yl)(2H2)methanol (757 mg, 93%). LCMS (ESI) m / z: 115.0 [M+H] + 。

[0204] Step 2

[0155] To a stirred solution of (1-methylpyrazol-4-yl)(2H2)methanol (600 mg, 5.3 mmol) in MeCN (10 mL) was added thionyl chloride (2501.3 mg, 21 mmol) portionwise at room temperature. The resulting mixture was stirred at 50 °C for 20 h. The resulting mixture was concentrated under reduced pressure to give 4-[chloro(2H2)methyl]-3,5-dimethyl-1,2-oxazole (360 mg, 52%). LCMS (ESI) m / z: 133.0 [M+H] + 。

[0205] Step 3 In DME (4 mL) and DMF (1 mL), to a stirred solution of 2-chloro-N-(1-methylcyclopropyl)-4-oxo-3H-quinazoline-6-sulfonamide (150 mg, 0.48 mmol) and 4-[chloro(2H2)methyl]-1-methylpyrazole (126.8 mg, 0.96 mmol) at room temperature, K2CO3 (132 mg, 0.96 mmol) and LiBr (83 mg, 0.96 mmol) were added portionwise. The resulting mixture was stirred at 50 °C for 2 h. The reaction was quenched at room temperature with water (40 mL). The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA / PE (50% - 70%) to give 2-chloro-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)(2H2)methyl]-4-oxoquinazoline-6-sulfonamide (138 mg, 70%). LCMS (ESI) m / z: 410.0 [M+H] + .

[0206] Step 4

[0157] In DMSO (6 mL), to a stirred solution of 2-chloro-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)(2H2)methyl]-4-oxoquinazoline-6-sulfonamide (138 mg, 0.34 mmol) at room temperature, (S)-1-amino-2-propanol (30.3 mg, 0.41 mmol) and TEA (102.2 mg, 1 mmol) were added portionwise. The resulting mixture was stirred at 50 °C for 2 h. The reaction was quenched at room temperature with water (40 mL). The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH / CH2Cl2 (10% - 20%) to give 2-{[(2S)-2-hydroxypropyl]amino}-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)(2H2)methyl]-4-oxoquinazoline-6-sulfonamide (122 mg, 81%). LCMS (ESI) m / z: 449.0 [M+H] + 。

[0207] Step 5

[0158] In 5 mL of DCM, MsCl (92 mg, 0.81 mmol) and TEA (81.2 mg, 0.81 mmol) were added portionwise 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) at room temperature. The resulting mixture was stirred at 35 °C for 2 h. The reaction was quenched at room temperature with water (20 mL). The resulting mixture was extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B - 55% B in 8 min, 55% B; wavelength: 220 nm) 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 (400 MHz, CD3OD) δ 8.42 (d, J = 2.4 Hz, 1H), 7.99 (dd, J = 8.8, 2.4 Hz, 1H), 7.68 (s, 1H), 7.55 (s, 1H), 7.20 (d, J = 8.8 Hz, 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 = 6.4 Hz, 3H), 1.16 (s, 3H), 0.74 - 0.67 (m, 2H), 0.46 - 0.39 (m, 2H).

[0159] Using a procedure similar to that described in Example 61 and using appropriate starting materials, the following compounds in Table 4 were prepared.

[0208]

Table 12-1

[0209]

Table 12-2

[0210] Typical synthetic route 2 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

[0211]

Chemical formula

[0212]

[0160] 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), SOCl2 (167 mg, 1.40 mmol) was added. The mixture was stirred at room temperature for 2 h. To the above mixture, NaOH (226 mg, 5.63 mmol) in water (1 mL) was added 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 × 15 mL). The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under 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: from 7% B to 21% B in 11 min, 21% B; wavelength: 254 / 220 nm) to obtain 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.

[0213]

[0161] The racemate was separated by chiral HPLC [column: Lux 5um cellulose-4, 2.12 × 25 cm, 5 μm; mobile phase A: Hex (10 mM NH3-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] + 。

[0214]

[0162] Using the same procedure as described for representative synthetic route 2 for Example 45 and using appropriate starting materials, the following compounds in Table 5 were prepared.

[0215]

Table 13

[0216] Representative synthetic route 3 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

[0217]

Chemical formula

[0218]

[0163] An alternative route to Example 46 illustrating an alternative ring closure method is also provided herein. 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 (85 mg, 0.19 mmol) in THF (2 mL) was added triphenylphosphine (96 mg, 0.36 mmol). The solution was cooled to 0 °C and DIAD (73 mg, 0.36 mmol) was added dropwise. The reaction was stirred at room temperature for 16 h. The mixture was concentrated under vacuum. The residue was purified by silica gel column eluting with MeOH / DCM (0 - 15%) to give the crude product, which was further purified by HPLC.

[0219]

[0164] Using the same procedure as described for representative synthetic route 3 for Example 46 and using appropriate starting materials, the following compounds in Table 6 were prepared.

[0220]

Table 14

[0221] Typical synthetic route 4 Example 52: (R)-1,4-Dimethyl-N-(1-methylcyclopropyl)-5-oxo-1,2,4,5-tetrahydroimidazo[1,2-a]quinazoline-7-sulfonamide

[0222]

Chemical Structure

[0223] Step 1

[0165] 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 Et3N (4.7 g, 46.3 mmol). The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was poured into water (500 mL). The aqueous layer was extracted with EtOAc (2 × 200 mL), and the combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (6:1) to give 6-bromo-3-methyl-2-sulfanylidene-1H-quinazolin-4-one (5.6 g, 45%) as a white solid.

[0224] Step 2:

[0166] To a mixture of 6-bromo-3-methyl-2-sulfanylidene-1H-quinazolin-4-one (5.6 g, 20.7 mmol) in POCl3 (50 mL) was added PCl5 (6.4 g, 31.1 mmol) at room temperature. The reaction mixture was heated to reflux and stirred for 2 h. The reaction mixture was concentrated under reduced pressure. The solid was washed 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.

[0225] Step 3:

[0167] 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 Et3N (2.8 g, 28.1 mmol). The solution was stirred at 100 °C for 2 h. The reaction was quenched with water (100 mL). The aqueous layer was extracted with EtOAc (2 × 100 mL), the combined organic layers were washed with brine (100 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (5:1) to give 6-bromo-2-{[(2S)-2-hydroxypropyl]amino}-3-methylquinazolin-4-one (2.2 g, 74%) as a brown solid.

[0226] Step 4

[0168] To a stirred solution of 6-bromo-2-{[(2S)-2-hydroxypropyl]amino}-3-methylquinazolin-4-one (2.2 g, 7.07 mmol) and PPh3 (2.8 g, 10.6 mmol) in THF (50 mL) was added DIAD (2.1 g, 10.6 mmol) dropwise at 0 °C. The solution was stirred at 0 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting 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.

[0227] Step 5

[0169] In toluene (20 mL), 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), TEA (1 g, 10.2 mmol), Xantphos (0.39 g, 0.68 mmol) and Pd2(dba)3 (0.31 g, 0.34 mmol) were added. The resulting mixture was stirred at 90 °C for 3 h under a nitrogen atmosphere. The reaction was quenched with water (120 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 120 mL). The combined organic layers were washed with brine (2 × 150 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting 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] + 。

[0228] Step 6

[0170] 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), 1,3-dichloro-5,5-dimethyl-2-methylideneimidazolidin-4-one (809 mg, 4.15 mmol), acetic acid (0.15 mL) and H2O (0.1 mL) were added. 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 extracted with CH2Cl2 (3 × 30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:2) to give (1R)-1,4-dimethyl-5-oxo-1H,2H-imidazo[1,2-a]quinazolin-7-sulfonyl chloride (210 mg, 32%) as a brown solid. LCMS (ESI) m / z: 314.0 [M+H]+.

[0229] Step 7

[0171] In DCM (10 mL), TEA (203 mg, 2.0 mmol) was added to a solution of 1-methylcyclopropane-1-amine hydrochloride (86.4 mg, 0.80 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 at room temperature with water (30 mL). The resulting mixture was extracted with CH2Cl2 (3 × 40 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: XBridge Shield RP18 OBD column, 19 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 25% B to 60% B in 10 min; wavelength: 220 nm) 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 (400 MHz, CD3OD) δ 8.41 (s, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H), 4.37 - 4.29 (m, 1H), 4.26 (t, J = 9.2 Hz, 1H), 3.70 - 3.64 (m, 1H), 3.41 (s, 3H), 1.38 (d, J = 6.4 Hz, 3H), 1.15 (d, J = 0.8 Hz, 3H), 0.73 - 0.67 (m, 2H), 0.44 - 0.38 (m, 2H).

[0172] Using a procedure similar to that described for representative synthetic route 4 for Example 52 and using appropriate starting materials, the following compounds in Table 7 were prepared.

[0230]

Table 15

[0231]

[0173] Using the same procedure (Steps 5 to 7) as described for Representative Synthetic Route 4 for Example 52 and using appropriate starting materials, the following compounds in Table 8 were prepared.

[0232]

Table 16

[0233] Representative Synthetic Route 5 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

[0234]

Chemical formula

[0235] Step 1 In THF (10 mL), PPh3 (213 mg, 0.81 mmol) and DEAD (164 mg, 0.81 mmol) were added portionwise 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) at room temperature. The resulting mixture was stirred at room temperature for 12 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 60% to 80% in 10 min; detector, UV 254 nm to give 3-[(1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}pyrazol-4-yl)methyl]-2-chloro-N-(1-methylcyclopropyl)-4-oxoquinazoline-6-sulfonamide (100 mg, 33%). LCMS (ESI) m / z: 552 [M+H] + .

[0236] Step 2 In DMSO (10 mL), 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) was added TEA (54.9 mg, 0.54 mmol) portionwise at room temperature. The resulting mixture was stirred at 100 °C for 2 h. The mixture was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 50% to 70% 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] + .

[0237] Step 3

[0176] 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 dropwise TEA (21.4 mg, 0.21 mmol) 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 reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 40% to 60% 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] + 。

[0238] Step 4

[0177] In THF (5 mL), 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), TBAF (13.7 mg, 0.05 mmol) was added portionwise at room temperature. The resulting mixture was stirred at room temperature for 2 h. The crude product was purified by preparative HPLC using the following conditions (column: YMC-Actus Triart C18 ExRS, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 35% B in 7 min, 35% B; wavelength: 220 nm; RT1 (min): 6.45) 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 1H-NMR (300 MHz, DMSO-d6) δ: 8.25 (d, J = 2.1 Hz, 1H), 8.07 (s, 1H), 7.93 (dd, J1 = 8.4, 2.1 Hz, 1H), 7.71 (s, 1H), 7.45 (s, 1H), 7.28 (d, J = 9.0 Hz, 1H), 4.99 - 4.85 (m, 3H), 4.75 (s, 1H), 4.11 - 4.01 (m, 3H), 3.68 - 3.67 (m, 2H), 3.57 - 3.55 (m, 1H), 1.32 (d, J = 6.3 Hz, 3H), 1.06 (s, 3H), 0.61 - 0.59 (m, 2H), 0.37 - 0.34 (m, 2H). Typical Synthetic Route 6 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

[0239]

Chem.

[0240] Step 1

[0178] 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) portionwise 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 eluting with MeOH (10% - 15%) in CH2Cl2 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] + 。

[0241] Step 2

[0179] In a stirred mixture of DMF (2 mL), 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) at room temperature, K2CO3 (7.7 mg, 0.057 mmol) was added portionwise. 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 preparative HPLC using the following conditions (column: YMC-Actus Triart C18 ExRS, 30×150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 55% B in 7 min, 55% B; wavelength: 220 nm; RT1 (min): 6.23) 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 1H-NMR (400 MHz, DMSO-d6) δ: 8.24 (d, J = 2.4 Hz, 1H), 8.03 (s, 1H), 7.90 (dd, J = 8.4, 2.0 Hz, 1H), 7.72 (s, 1H), 7.41 (s, 1H), 7.23 (d, J = 8.8 Hz, 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, 3.6 Hz, 1H), 2.58 (t, J = 6.4 Hz, 2H), 2.12 (s, 6H), 1.31 (d, J = 6.4 Hz, 3H), 1.07 (s, 3H), 0.62 - 0.57 (m, 2H), 0.40 - 0.35 (m, 2H). Representative synthetic route 7 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

[0242]

Chem.

[0243]

[0180] In DMF (5 mL), a solution of Example 6 (20 mg, 0.05 mmol) was treated with NaHCO3 (8 mg, 0.1 mmol) at room temperature under a nitrogen atmosphere for 5 min, and then sodium difluoromethyl carbonochloridate (8 mg, 0.05 mmol) was added dropwise at room temperature. The reaction mixture was stirred at 100 °C for 16 h. The reaction was quenched by adding water (5 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography using the following conditions (column: YMC-Actus Triart C18, 30 × 150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 25% B to 45% B in 7 min, 45% B; wavelength: 254 / 220 nm; 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 (2.3 mg, 10%). LCMS (ESI) m / z: 465.00 [M+H] + 。 11H NMR (400 MHz, DMSO-d6) δ 8.28 - 8.19 (m, 2H), 8.05 (s, 1H), 7.91 (dd, J = 9.2, 6.9 Hz, 1H), 7.77 (d, J = 21.3 Hz, 2H), 7.25 (d, J = 8.7 Hz, 1H), 4.99 (q, J = 14.5 Hz, 2H), 4.73 (ddp, J = 8.9, 6.1, 3.1, 2.6 Hz, 1H), 4.06 (dd, J = 13.7, 9.3 Hz, 1H), 3.52 (dd, J = 13.7, 3.6 Hz, 1H), 1.33 (d, J = 6.2 Hz, 3H), 1.08 (s, 3H), 0.61 (q, J = 4.0 Hz, 2H), 0.39 (dd, J = 5.0, 2.2 Hz, 2H). Representative synthetic route 8 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

[0244]

Chemical formula

[0245] Step 1

[0181] 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) at room temperature, K2CO3 (1.53 g, 11.1 mmol) was added portionwise. 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 × 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] + 。

[0246] Step 2

[0182] In DMSO, 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) was added portionwise Et3N (1.1 g, 10.9 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 1 h. The resulting mixture was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with water (20 mL) and dried over anhydrous Na2SO4. After filtration, 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] + 。

[0247] Step 3

[0183] In DCM, 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) was added portionwise TEA (484 mg, 4.78 mmol) 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 eluting with CH2Cl2 / 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] + 。

[0248] Step 4

[0184] 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 at room temperature with water / ice. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0249] Step 5

[0185] In SOCl2 (3 mL), a solution of (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) 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] + 。

[0250] Step 6

[0186] 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) portionwise 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 × 10 mL). The combined organic layers were washed with acetic acid (2 × 10 mL) and dried over anhydrous Na2SO4. 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 in 7 min, 19% B; wavelength: 254 / 220 nm; RT1 (min): 4.82) to give (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] + 。 11H NMR (400 MHz, CD3OD) δ 8.38 (d, J = 2.2 Hz, 1H), 7.96 (dd, J = 8.8, 2.2 Hz, 1H), 7.58 (s, 1H), 7.46 (s, 1H), 7.18 (d, J = 8.8 Hz, 1H), 4.98 - 4.85 (m, 2H), 4.08 (dd, J = 13.3, 9.4 Hz, 1H), 3.95 (q, J = 7.2 Hz, 1H), 3.73 (s, 3H), 3.57 - 3.54 (m, 1H), 1.35 - 1.27 (m, 5H), 1.18 (t, J = 7.2 Hz, 2H).

[0187] Using the same procedure as described in Representative Synthetic Route 8 for Example 2 and using appropriate starting materials, the following compounds in Table 9 were prepared.

[0251]

Table 17

[0252] Representative Synthetic Route 9 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

[0253]

Chemical Structure

[0254] Step 1

[0188] A solution of 2-amino-5-bromobenzoic acid (1.5 g, 7.17 mmol) in DMF (40 mL) was added with HATU (3 g, 7.89 mmol), DIPEA (1.7 mL, 10 mmol) and 1-(1-methyl-1H-pyrazol-4-yl)cyclopropan-1-amine (984 mg, 7.17 mmol), and reacted at room temperature for 1.10 h. Water was added, and the formed 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%).

[0255] Step 2

[0189] To a mixture of 2-amino-5-bromo-N-[1-(1-methyl-1H-pyrazol-4-yl)cyclopropyl]benzamide (1 g, 2.98 mmol) in CH3CN (13.6 mL) were added CDI (869 mg, 5.36 mmol) and DMAP (36.4 mg, 0.3 mmol). The reaction mixture 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 formed white ppt was filtered. The precipitate was washed with 1M HCl and then with water and dried to obtain the product (681.2 mg, 63%).

[0256] Step 3

[0190] 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) were added Et3N (0.7 mL, 5 mmol), BnSH (0.2 mL, 2 mmol), dioxane (0.4 mL), the reaction mixture was degassed and refilled with N2. Next, Xantphos (193 mg, 0.33 mmol), Pd2(dba)3 (152 mg, 0.16 mmol) were added, degassed and refilled with N2, and heated at 90 °C for 1.45 h. The crude reaction mixture was purified by silica gel chromatography (0 - 100% EtOAc / hex, then 100% MeOH / DCM) to obtain the product (599 mg, 89%). LCMS (ESI) m / z: 405 [M + H] + 。

[0257] Step 4

[0191] To a microwave vial, 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), and DBU (0.2 mL, 1.48 mmol) were added, and the reaction mixture was stirred at room temperature for 2 h. Additional BOP (165 mg) and DBU (65 μL) were added, and the reaction was carried out at room temperature for 1 h. Further, BOP (211.4 mg) and DBU (0.1 mL) were added, and the reaction mixture was stirred for an additional 1.20 h. To this reaction mixture, (2S)-1-aminopropan-2-ol (0.5 mL, 6.5 mmol) was added, and the reaction was carried out at room temperature for 10 min, and then heated at 80 °C for 1 h using a microwave oven. Water was added to the reaction mixture, and the mixture was extracted with EtOAc. The crude product was purified by silica gel chromatography (0 - 100% EtOAc / hexane, and then 0 - 100% MeOH / DCM) to obtain the product (239.1 mg, 70%). LCMS (ESI) m / z: 462 [M+H] + 。

[0258] Step 5

[0192] 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), Et3N (0.2 mL, 1.5 mmol) and MsCl (0.1 mL, 1.29 mmol) were added. 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 the mixture was 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] + 。

[0259] Step 6

[0193] In CH3CN (0.4 mL), to a solution of (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) at 0 °C, 1 drop of H2O and 1 drop of AcOH were added, and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (22 mg, 0.1 mmol) was added. The reaction was carried out at 0 °C for 2.30 h. The reaction mixture was used directly in the next step. LCMS (ESI) m / z: 420 [M+H] + 。

[0260] Step 7

[0194] The crude reaction mixture from the previous step was cooled to 0 °C, and 1-methylcyclopropane-1-amine hydrochloride (30 mg, 0.28 mmol) and Et3N (0.2 mL, 1.43 mmol) were added. 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 give the product (5.1 mg, 13%). LCMS (ESI) m / z: 455.00 [M+H] + 。 1 H NMR (400 MHz, CD3OD) δ 8.43 (s, 1H), 8.03 - 8.00 (m, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 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). Representative Synthetic Route 10 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

[0261]

Chem.

[0262] Step 1

[0195] In DCM (10 mL), a solution of 4-(aminomethyl)-1-methylpyrrolidin-2-one (100 mg, 0.78 mmol) was treated with 4-nitrophenyl carbonochloridate (173 mg, 0.86 mmol) for 2 min, and then, at -60 °C, DIEA (111 mg, 0.86 mmol) was added portionwise. The resulting mixture was stirred at -20 °C for 30 min. The reaction was quenched at room temperature by the addition of water (30 mL). The resulting mixture was extracted with CH2Cl2 (3 × 30 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 4-nitrophenyl N-[(1-methyl-5-oxopyrrolidin-3-yl)methyl]carbamate (212 mg, 93%). LCMS (ESI) m / z: 294.0 [M+H] + 。

[0263] Step 2

[0196] To a stirred mixture of methyl 5-(chlorosulfonyl)-2-fluorobenzoate (2.5 g, 9.90 mmol) and 1-methylcyclopropane-1-amine hydrochloride (1.17 g, 10.9 mmol) in DCM (50 mL) was added dropwise Et3N (3.00 g, 29.7 mmol) at room temperature. 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 eluting 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] + 。

[0264] Step 3

[0197] In DMSO (50 mL), to a stirred mixture of methyl 2-fluoro-5-[(1-methylcyclopropyl)sulfamoyl]benzoate (2.63 g, 9.14 mmol) and tert-butyl N-[(2R)-2-aminopropyl]carbamate (1.75 g, 10 mmol) was added DIEA (3.54 g, 27.4 mmol) dropwise at room temperature. The resulting mixture was stirred at 60 °C overnight. The reaction was quenched at room temperature by the addition of water (200 mL). The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (1 × 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give methyl 2-{[(2R)-1-[(tert-butoxycarbonyl)amino]propan-2-yl]amino}-5-[(1-methylcyclopropyl)sulfamoyl]benzoate (3.5 g, 87%). LCMS (ESI) m / z: 442.0 [M+H] + .

[0265] Step 4

[0198] In THF (10 mL), a mixture of methyl 2-{[(2R)-1-[(tert-butoxycarbonyl)amino]propan-2-yl]amino}-5-[(1-methylcyclopropyl)sulfamoyl]benzoate (500 mg, 1.13 mmol) and HCl (1032 mg, 11.32 mmol) in 1,4-dioxane was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / 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] + .

[0266] Step 5

[0199] In DCM (10 mL), 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), Et3N (138.2 mg, 1.37 mmol) was added dropwise at room temperature. 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 eluting with CH2Cl2 / 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] + .

[0267] Step 6

[0200] In toluene (8 mL) and DCE (2 mL), a mixture of 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 POCl3 (309.4 mg, 2.02 mmol) was stirred at 60 °C overnight. The reaction mixture was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C18 column 30×150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 9% B to 27% B in 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 12.4) 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]+ .

[0268] Step 7

[0201] The racemate (60 mg) was purified by preparative chiral-HPLC using the following conditions (column: Chiral PAK IA, 2 × 25 cm, 5 μm; mobile phase A: MtBE (10 mM NH3-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) to obtain isomer A (7.6 mg, 13%) and isomer B (15.5 mg, 26%). LCMS (ESI) m / z: 446.25 [M+H] + .

[0269]

[0202] Isomer A: 1 H NMR (400 MHz, methanol-d4) δ 8.40 (m, 1H), 7.22 (m, 1H), 4.76 (m, 1H), 4.72 - 4.80 (m, 1H), 4.18 - 4.02 (m, 3H), 3.64 - 3.51 (m, 2H), 3.33 (d, J = 14.2, 7.0 Hz, 1H), 2.94 - 3.04 (m, 3H), 2.84 (s, 1H), 2.52 (dd, J = 16.9, 8.8 Hz, 1H), 2.32 (dd, J = 17.0, 6.4 Hz, 1H), 1.43 (dd, J = 6.2, 0.8 Hz, 3H), 1.21 - 1.10 (m, 3H), 0.68 - 0.74 (m, 2H), 0.41 - 0.46 (m, 2H).

[0203] Isomer B: 11H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 2.2 Hz, 1H), 8.03 (s, 1H), 7.92 (dd, J = 8.7, 2.3 Hz, 1H), 7.25 (d, J = 8.8 Hz, 1H), 4.66 - 4.76 (m, 1H), 4.06 - 3.95 (m, 3H), 3.47 (dd, J = 13.7, 3.5 Hz, 1H), 3.40 (dd, J = 9.8, 7.8 Hz, 1H), 3.22 - 3.14 (m, 1H), 2.93 - 2.83 (m, 1H), 2.69 (s, 3H), 2.34 (dd, J = 16.7, 8.8 Hz, 1H), 2.17 - 2.05 (m, 1H), 1.32 (d, J = 6.1 Hz, 3H), 1.09 (s, 3H), 0.58 - 0.64 (m, 2H), 0.44 - 0.35 (m, 2H).

[0204] Using the same procedure as described in Representative Synthetic Route 10 for Example 123 and using appropriate starting materials, the following compound in Table 10 was prepared.

[0270]

Table 18

[0271] Representative Synthetic Route 11

[0205] 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

[0272]

Chemical Structure

[0273] Step 1

[0206] In chlorosulfonic acid (200 mL), a solution of 8-bromo-1,3-dihydroquinazoline-2,4-dione (20 g, 82.9 mmol) was stirred at 80 °C overnight. The reaction was quenched at 0 °C by the addition of ice (1000 g). The precipitated solid was collected by filtration and washed with water (3 × 100 mL). The obtained solid was dried under vacuum to give 8-bromo-2,4-dioxo-1,3-dihydroquinazoline-6-sulfonyl chloride (30 g) 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] + .

[0274] Step 2

[0207] In DCM (500 mL), 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) was stirred at room temperature for 2 h. The obtained mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / 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] + .

[0275] Step 3 In 1,4-dioxane (300 mL), a solution of 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)Cl2 (4.89 g, 6.68 mmol) was stirred at 90 °C overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / PE (1:1) to give 6-[(1-methylcyclopropyl)sulfamoyl]-2,4-dioxo-1,3-dihydroquinazoline-8-ylboronic acid (17 g, 75%). LCMS (ESI) m / z: 340 [M+H] + .

[0276] Step 4

[0209] In DCM (200 mL), 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) 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 CH2Cl2 / MeOH (9:1) 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 using the following conditions (column: XBridge Prep OBD C18 column 30×150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 26% B to 40% B in 10 min; wavelength: 254 nm / 220 nm; 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 (300 mg, 3%). LCMS (ESI) m / z: 451 [M+H] + .

[0277] Step 5 In POCl3 (20 mL), a mixture of 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) was stirred at 105 °C overnight. The resulting mixture was concentrated under reduced pressure. The reaction was quenched at 0 °C by the addition of water / ice (150 mL). The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Thereby, 4-{2,4-dichloro-6-[(1-methylcyclopropyl)sulfamoyl]quinazolin-8-yl}-N,N-dimethylpiperazine-1-carboxamide (260 mg) was obtained. The crude product was used directly in the next step without further purification.

[0278] Step 6 In THF (10 mL) and H2O (10 mL), a mixture of 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) was stirred at 0 °C for 30 min. The mixture was acidified to pH 2 with concentrated HCl. The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 4-{2-chloro-6-[(1-methylcyclopropyl)sulfamoyl]-4-oxo-3H-quinazolin-8-yl}-N,N-dimethylpiperazine-1-carboxamide (110 mg, 44%).

[0279] Step 7 In DME (10 mL) and DMF (2.5 mL), a mixture of 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), K2CO3 (64.8 mg, 0.47 mmol) and LiBr (40.7 mg, 0.47 mmol) was stirred at room temperature overnight. The reaction was quenched at room temperature by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (4 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 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] + 。

[0280] Step 8

[0213] In DMSO (5 mL), a mixture of 4-{2-chloro-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxoquinazolin-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) was stirred at 50 °C for 30 min. The reaction was quenched at room temperature by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (5 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 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] + .

[0281] Step 9 A solution of (50 mg, 0.08 mmol) 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, (28.5 mg, 0.25 mmol) of MsCl and (42 mg, 0.41 mmol) of TEA in DCM (5 mL) was stirred overnight at room temperature. The reaction was quenched at room temperature by the addition of water (5 mL). The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using 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; gradient: 2% B to 19% B in 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 12.57) to obtain 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] + . 11H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 2.2 Hz, 1H), 8.01 (s, 1H), 7.79 (d, J = 2.2 Hz, 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, 8.4 Hz, 1H), 3.77 (s, 3H), 3.69 (d, J = 12.4 Hz, 1H), 3.47 (dd, J = 17.1, 12.9 Hz, 2H), 3.16 (q, J = 10.8 Hz, 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 = 10.8 Hz, 2H), 0.38 (s, 2H). Representative synthetic route 12 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

[0282]

Chemical Structure

[0283] In 1,4-dioxane (4 mL) and H2O (0.4 mL), to a stirred mixture 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) were added portionwise at room temperature K2CO3 (40.9 mg, 0.3 mmol) and Pd(dppf)Cl2 (7.21 mg, 0.010 mmol). The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The residue was purified by preparative TLC (10% MeOH / CH2Cl2) and further purified by preparative HPLC using the following conditions (column: XBridge Shield RP18 OBD column 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 15% B to 35% B in 10 min; wavelength: 254 nm / 200 nm; RT1 (min): 10.78) 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] + . 11H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J = 2.3 Hz, 1H), 8.03 (s, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.59 (d, J = 2.3 Hz, 1H), 7.41 (d, J = 2.3 Hz, 1H), 6.00 (s, 1H), 4.95 (q, J = 14.2 Hz, 2H), 4.58 (d, J = 7.9 Hz, 1H), 3.88 (dd, J = 13.4, 8.1 Hz, 1H), 3.77 (d, J = 2.2 Hz, 3H), 3.48 (d, J = 13.6 Hz, 1H), 3.17 (d, J = 17.5 Hz, 1H), 2.90 (d, J = 17.4 Hz, 1H), 2.66 (d, J = 11.6 Hz, 2H), 2.41 (d, J = 18.0 Hz, 1H), 2.29 (s, 3H), 2.05 (s, 1H), 1.07 - 0.96 (m, 6H), 0.59 (d, J = 5.8 Hz, 2H), 0.38 (d, J = 2.1 Hz, 2H).

[0216] Using the same procedure as described in Representative Synthetic Route 12 for Example 131 and using appropriate starting materials, the following compound in Table 11 was prepared.

[0284]

Table 19

[0285] Representative Synthetic Route 13 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

[0286]

Chemical Structure

[0287] In THF (2 mL), a solution of (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)3PdG3 (5.61 mg, 0.01 mmol), P(t-Bu)3.HBF4 (3.1 mg, 0.010 mmol), Cs2CO3 (64 mg, 0.2 mmol) and CsF (29.8 mg, 0.2 mmol) was stirred at 80 °C overnight. The resulting mixture was diluted with water (50 mL) and then extracted with EtOAc (200 mL). The combined organic layers were washed with water (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under 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: from 11% B to 31% B at a uniform concentration in 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 12.48) to give (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 (1.4 mg, 3%). LCMS (ESI) m / z: 445.05 [M+H] + . 11H NMR (400 MHz, methanol-d4) δ 8.38 (d, J = 2.3 Hz, 1H), 7.84 (d, J = 2.3 Hz, 1H), 7.70 (s, 1H), 7.56 (s, 1H), 5.18 (m, 1H), 4.01 (dd, J = 13.2, 8.2 Hz, 1H), 3.83 (s, 3H), 3.59 (d, J = 13.3 Hz, 1H), 2.61 (s, 3H), 1.19 (d, J = 6.3 Hz, 3H), 1.15 (s, 3H), 0.75 - 0.67 (m, 2H), 0.46 - 0.39 (m, 2H). Representative synthetic route 14 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

[0288] [Chemical formula]

[0289] Step 1

[0218] A mixture of 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) in POCl3 (100 mL) was stirred at 105 °C overnight. The resulting mixture was concentrated under reduced pressure. The reaction was quenched at room temperature by the addition of water / ice (150 mL). The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. 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.

[0290] Step 2

[0219] In THF (20 mL) and H2O (20 mL), to a stirred mixture of 8-bromo-2,4-dichloro-N-(1-methylcyclopropyl)quinazoline-6-sulfonamide (2 g, 4.86 mmol) was added NaOH (0.39 g, 9.7 mmol) dropwise at 0 °C. 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 at 0 °C by the addition of water (200 mL). The resulting mixture was extracted with EtOAc (3×250 mL). The combined organic layers were washed with brine (2×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting 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] + 。

[0291] Step 3

[0220] A solution of 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 K2CO3 (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 dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 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] + 。

[0292] Step 4

[0221] In DMSO (20 mL), a solution of 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 Et3N (186.3 mg, 1.84 mmol) 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 Na2SO4. 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] + 。

[0293] Step 5

[0222] In DCM (20 mL), a solution of 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 Et3N (172.7 mg, 1.71 mmol) 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 dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / 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 1H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J = 2.0 Hz, 1H), 8.18 (s, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.68 (s, 1H), 7.41 (s, 1H), 5.73 - 5.64 (m, 1H), 3.97 - 3.91 (m, 1H), 3.75 (s, 3H), 3.54 - 3.51 (m, 1H), 1.21 (d, J = 6.4 Hz, 3H), 1.09 (s, 3H), 0.64 - 0.59 (m, 2H), 0.44 - 0.39 (m, 2H). Representative Synthetic Route 15 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

[0294]

Chemical Structure

[0295]

[0223] To a stirred mixture of DMF (2 mL), (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)2 (13.9 mg, 0.12 mmol) at room temperature was added Pd(PPh3)4 (11.4 mg, 0.01 mmol) portionwise. The resulting mixture was stirred at 100 °C for 12 h under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (2 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XBridge Prep phenyl OBD column 19 × 250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 23% B to 40% B in 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 10.54) to give (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 (0.7 mg, 1.5%). LCMS (ESI) m / z: 454.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 2.4 Hz 1H), 8.22 (s, J = 2.4 Hz 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). Synthesis of Intermediate Intermediate 1 - tert-Butyl 4-(bromomethyl)pyrazole-1-carboxylate

[0296]

Chem.

[0297]

[0224] To a stirred mixture of tert-butyl 4-(hydroxymethyl)pyrazole-1-carboxylate (2.00 g, 10.1 mmol) and CBr4 (6.7 g, 20.2 mmol) in DCM (100 mL) was added PPh3 (5.3 g, 20.2 mmol) portionwise at room temperature. 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 pale yellow liquid.

[0298]

[0225] Intermediate 1 was used for the synthesis of Example 6. Intermediate 2 - 1-Aminobut-3-yn-2-ol hydrochloride

[0299]

Chem.

[0300] Step 1

[0226] In THF (50 mL), to a solution of tert-butyl (2-oxoethyl) carbamate (5 g, 31.4 mmol) was added dropwise bromo(ethynyl)magnesium (0.5 M in THF, 157 mL, 78.5 mmol) at -78 °C under a N2 atmosphere. The reaction mixture was stirred at -78 °C for 20 min. The resulting mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. The reaction was quenched with saturated aqueous NH4Cl solution (20 mL), and then the mixture was extracted with EtOAc (500 mL). The combined organic extracts were washed with brine (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl N-(2-hydroxybut-3-yn-1-yl)carbamate (4.5 g, 77%) as a pale yellow oil. LCMS (ESI) m / z: 186 [M+H] + 。

[0301] Step 2

[0227] 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 give 1-aminobut-3-yn-2-ol hydrochloride (3 g) as a pale yellow solid. LCMS (ESI) m / z: 86 [M+H] + 。

[0302]

[0228] Intermediate 2 was used for the synthesis of Examples 9, 10, 15, 16, 27, 28, 33, 34, 43, 71, 72. Examples 59 and 60 were synthesized using appropriate starting materials similar to Intermediate 2. Intermediate 3 - 4-(Chloromethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole

[0303]

Chemical Structure

[0304] Step 1

[0229] In THF (20 mL), to a solution of 1-methyl-3-(trifluoromethyl)pyrazole-4-carboxylic acid (2 g, 10.3 mmol) at room temperature, LiAlH4 (0.78 g, 20.6 mmol) was added portionwise. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched at room temperature using Na2SO4·10H2O. The resulting mixture was filtered and the filter cake was washed with THF (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH in CH2Cl2 (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] + 。

[0305] Step 2

[0230] In acetonitrile (10 mL), to a solution of [1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methanol (300 mg, 1.67 mmol) at room temperature, thionyl chloride (396 mg, 3.33 mmol) was added portionwise. 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] + 。

[0306]

[0231] Intermediate 3 was used for the synthesis of Example 55. Intermediate 4 - 2-chloro-N-(1-methylcyclopropyl)-4-oxo-3-(3-(trimethylsilyl)prop-2-yn-1-yl)-3,4-dihydroquinazoline-6-sulfonamide

[0307]

Chem.

[0308]

[0232] In a stirred mixture of DMF (8 mL), 2-chloro-N-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazoline-6-sulfonamide (0.3 g, 0.96 mmol) and K2CO3 (264 mg, 1.91 mmol) at room temperature, LiBr (166 mg, 1.91 mmol) and (3-bromoprop-2-yn-1-yl)trimethylsilane (219 mg, 1.15 mmol) were added dropwise. The mixture was stirred at 50 °C for 2 h. The resulting mixture was extracted with PE (3 × 50 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting 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] + 。

[0309]

[0233] Example 58 was synthesized using Representative Synthetic Route 1, Steps 6 - 7 for Intermediate 4 and Example 46. Intermediate 5 - 2-(4-(Chloromethyl)-1H-pyrazol-1-yl)acetonitrile

[0310]

Chemical Structure

[0311] Step 1

[0234] In DMF (20 mL), to a stirred mixture of 1H-pyrazol-4-ylmethanol (1.2 g, 12.2 mmol) and TBDMSCl (2.8 g, 18.3 mmol) was added imidazole (1.7 g, 24.5 mmol) portionwise at 0 °C under a nitrogen atmosphere. The mixture was stirred at room temperature for 1 h. The reaction was quenched at room temperature by the addition of water (50 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) and concentrated under reduced pressure to give 4-(((tert-butyldimethylsilyl)oxy)methyl)-1H-pyrazole (1.2 g, 46%) as a colorless oil.

[0312] Step 2

[0235] 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) at 0 °C for 30 min under a nitrogen atmosphere, followed by the dropwise addition of 2-bromoacetonitrile (1 g, 8.5 mmol) at room temperature. The mixture was stirred at room temperature overnight under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) 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.

[0313] Step 3

[0236] In water (10 mL), 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) was stirred at room temperature for 2 h under a nitrogen atmosphere. 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.

[0314] Step 4

[0237] In MeCN (2 mL), a mixture of 2-(4-(hydroxymethyl)-1H-pyrazol-1-yl)acetonitrile (90 mg, 0.66 mmol) and thionyl chloride (156 mg, 1.31 mmol) was stirred at room temperature overnight under a nitrogen atmosphere. 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.

[0315]

[0238] Intermediate 5 was used for the synthesis of Example 66. Intermediate 6 - 2-Amino-1-(2,4-dimethyl-1,3-thiazol-5-yl)ethanol

[0316]

Chemical formula

[0317] Step 1

[0239] A mixture of 2,4-dimethyl-1,3-thiazole-5-carbaldehyde (1 g, 7.1 mmol) in nitromethane (20 mL) was stirred at room temperature for 12 h. The reaction was quenched at room temperature by the addition of water / ice (50 mL). The resulting mixture was extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (2 × 80 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 10% to 50% in 10 min; detector, UV 254 nm 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] + 。

[0318] Step 2

[0240] A mixture of 1-(2,4-dimethyl-1,3-thiazol-5-yl)-2-nitroethanol (250 mg, 1.2 mmol), NH4Cl (331 mg, 6.2 mmol) and Fe (69 mg, 1.2 mmol) in CH3CH2OH (5.0 mL), H2O (0.5 mL) was stirred at 80 °C for 2 h. The reaction was quenched at room temperature by the addition of water / ice (20 mL). The resulting mixture was filtered and the filter cake was washed with MeCN (3 × 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 10% to 50% in 10 min; detector, UV 254 nm to obtain 2-amino-1-(2,4-dimethyl-1,3-thiazol-5-yl)ethanol (150 mg, 70%) as a white solid. LCMS (ESI) m / z: 173.0 [M+H] + 。

[0319]

[0241] Intermediate 6 was used for the synthesis of Example 82. Intermediate 7 - 1-Amino-4-cyclopropylbut-3-yn-2-ol

[0320] [Chem.]

[0321] Step 1

[0242] 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 over 30 min. To the above mixture was added phthalimide acetaldehyde (3.15 g, 16.6 mmol) dropwise at -78 °C over 15 min. The resulting mixture was stirred at room temperature for an additional 2 h. After completion of the reaction, the reaction mixture was quenched by addition of saturated NH4Cl solution (20 mL). The aqueous layer was extracted with ethyl acetate (300 mL). The combined organic phases were washed with brine (100 mL), 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-hydroxybut-3-yn-1-yl)isoindole-1,3-dione (0.8 g). LCMS (ESI) m / z: 256 [M+H] + .

[0322] Step 2

[0243] To a stirred solution of 2-(4-cyclopropyl-2-hydroxybut-3-yn-1-yl)isoindole-1,3-dione (800 mg, 3.1 mmol) in anhydrous EtOH (25 mL) was added hydrazine hydrate (307 mg, 6.3 mmol) at room temperature. The reaction mixture was stirred at 70 °C for 2 h. After completion of the reaction, the reaction mixture was quenched by addition of 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-cyclopropylbut-3-yn-2-ol (200 mg). LCMS (ESI) m / z: 126 [M+H] + .

[0323]

[0244] Intermediate 7 was used for the synthesis of Examples 83 and 84. Intermediate 8 - 4-(Chloromethyl)-1-methyl-1,2,3-triazole

[0324]

Chemical formula

[0325] Step 1

[0245] A solution of methyl 1-methyl-1,2,3-triazole-4-carboxylate (400 mg, 2.8 mmol) and LiAlH4 (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 (2 × 20 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] + .

[0326] Step 2

[0246] A solution of (1-methyl-1,2,3-triazol-4-yl)methanol (30 mg, 0.26 mmol) in SOCl2 (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] + .

[0327]

[0247] Intermediate 8 was used for the synthesis of Example 90. Intermediate 9 - 3-(Bromomethyl)-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine

[0328]

Chemical formula

[0329] A solution of 5H,6H,7H-pyrazolo[3,2-b][1,3]oxazin-3-ylmethanol (800 mg, 5.2 mmol) in HBr (10 mL) in AcOH was stirred at 90 °C overnight under a nitrogen atmosphere. Addition of Et2O formed a precipitate, which was dried to give the desired product as a brown solid (700 mg).

[0330] The crude product was used directly in the next step without further purification.

[0249] Intermediate 9 was used for the synthesis of Example 119. Examples 118, 120, 121 and 122 were synthesized in a similar manner using the appropriate starting materials.

[0331] II. Biological evaluation

[0250] Example 1: Nuclear PAR accumulation assay

[0251] The IC of the compound for the inhibition of cellular PARG was determined using an immunofluorescence high-content imaging assay for nuclear PAR accumulation 50Values were determined. The day before compound treatment, HeLa cells were seeded in 96-well plates at 15,000 cells / well, then treated with various concentrations of the test compound and incubated at 37 °C + 5% CO2 for 1 hour. Following the test compound treatment, methyl methanesulfonate (MMS) was added at a final concentration of 50 μg / mL and the cells were incubated for an additional 1 hour. After treatment, the cells were fixed with ice-cold 95% methanol, 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-X100 for 20 minutes at room temperature. The cells were washed again once with PBS and incubated overnight at 4 °C with an anti-poly ADP ribose (PAR) monoclonal antibody (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 before incubation for 1 hour at room temperature with a fluorescently conjugated goat anti-mouse antibody (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 incubating with 1 μg / mL of DAPI (4’,6-diamidino-2-phenylindole). High-content fluorescence microscopy was used to evaluate PAR accumulation in the nuclei. Four fields per well were acquired at 20x magnification, resulting in at least 1,000 cells being analyzed per well. High-content software (CellReporterXpress) was used to detect the nuclei, segment using the DAPI channel, and quantify the fluorescence intensity in the PAR-Alexa488 channel within the nuclear region. Both the mean intensity of each nucleus and the percentage of PAR-positive cells were quantified. The percentage of PAR-positive cells was identified by having an anti-PAR label greater than the threshold set by the DMSO-treated control cells of the vehicle. The data were normalized by the control values of 0.1% DMSO and the reference compound, representing 0% to 100% inhibition of enzyme activity, respectively, to calculate the percentage of inhibition of PARG by the test compound. A four-parameter logistic curve fitting software was used to generate the concentration-response curve and IC 50 values.

[0332] Representative data for representative compounds are shown in Table 12.

[0333] [Table 20]

[0334] [Table 21]

[0335] III. Preparation of Pharmaceutical Dosage Forms Example 1: Oral Capsules The active ingredient is the compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof. Oral 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 such as hard gelatin capsules suitable for oral administration.

[0336] Example 2: Injectable Solution The active ingredient is the 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 equivalent / mL.

[0337] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested to those skilled in the art are within the spirit and scope of this application and the scope of the appended claims.

Claims

1. Compounds having the structure of formula (I), or pharmaceutically acceptable salts or solvates thereof: 【Chemistry 1】 (In the formula, A is hydrogen, halo, -OH, -CN, optionally substituted C1-C6 alkoxy, -N(R) ９ ) ２ Selected from the group consisting of substituted C1-C6 alkyl, substituted C2-C6 alkenyl, substituted C2-C6 alkynyl, substituted C3-C7 carbocyryl, substituted carbocyrylalkyl, substituted (carbocyryl)alkynyl, substituted heterocyclyl, substituted heterocyclylalkyl, substituted heteroaryl, and substituted aryl; n is 1, 2, or 3; X is O, or NR ６ And; Y is N, C-H, or C-F; Z is -N(H)- or -CH(R ８ ) - and; G is a cycloalkylene that may be bound or substituted, or a heterocycloalkylene that may be substituted; R １ This is selected from the group consisting of 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 are each independently selected from the group consisting of 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; R ２ and R ３ may combine to form an optionally substituted carbocyclic or heterocyclic ring; R ４ and R ５ R is independently selected from the group consisting of 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; ４ and R ５ They bond to form a substituted carbon ring or heterocycle, or R ３ and R ４ They may bond to form a substituted or substituted carbon ring or heterocycle; R ６ is selected from hydrogen, OH, or substituted C1-C5 alkyl groups; R ７ is an optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted 1,1'-bi(cyclopropane)-1-yl; R ８ is hydrogen, a halo, or an optionally substituted alkyl; Each R ９ (These are C1-C6 alkyl groups that may be independently hydrogenated or substituted.)

2. Compounds having the structure of formula (Ia), or pharmaceutically acceptable salts or solvates thereof: 【Chemistry 2】 (In the formula, n is 1, 2, or 3; X is O, or NR ６ And; Y is N, C-H, or C-F; Z is -N(H)- or -CH(R ８ ) - and; G is a cycloalkylene that may be bound or substituted, or a heterocycloalkylene that may be substituted; R １ This is selected from the group consisting of 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 the group consisting of 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; ２ and R ３ They may bond to form a substituted or substituted carbon ring or heterocycle; R ４ and R ５ R is independently selected from the group consisting of 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; ４ and R ５ They bond to form a substituted carbon ring or heterocycle, or R ３ and R ４ They may bond to form a substituted or substituted carbon ring or heterocycle; R ６ is selected from hydrogen, OH, or substituted C1-C5 alkyl groups; R ７ is an optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted 1,1'-bi(cyclopropane)-1-yl; R ８ (wherein it is hydrogen, a halo, or an alkyl group which may be substituted.)

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 X is O.

5. Y is either C-H or The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is C-F.

6. (a) R １ However, it is a heteroaralkyl which may be substituted, and may be (i), (ii) or (iii), (i) R1 is a heteroaralkyl which may be substituted, and the heteroaryl is selected from 5-membered or 6-membered heteroaryls, The heteroaryl is either a six-membered nitrogen-containing heteroaryl or The heteroaryl is a pyridine or pyrazine that may be substituted. (ii) R1 is a substituted heteroaralkyl, and the heteroaryl is selected from substituted five-membered nitrogen-containing heteroaryls, The heteroaryl is a substituted five-membered nitrogen-containing heteroaryl selected from substituted thiazole, substituted oxazole, substituted imidazole, substituted pyrazole, substituted isoxazole, substituted pyrrole, substituted oxadiazole, substituted triazole, substituted thiadiazole, or substituted isothiazole. The heteroaryl is a pyrazole which may be substituted, and / or The heteroaryl is a substituted five-membered nitrogen-containing heteroaryl which is substituted with at least a substituted C1-C5 alkyl, or The heteroaryl is a substituted five-membered nitrogen-containing heteroaryl which is substituted with a substituted C1 alkyl, or (iii) R1 is a substituted heteroaralkyl, and the alkylene is a substituted C1-C4 alkylene. The alkylene is either -CH2- or Alkilen is -CD2-, or (b) R1 is an optionally substituted alkyl, and may be (i) or (ii), (i) R1 is a C1-C4 alkyl that may be substituted, or (ii) R1 is an or otherwise substituted C1-C4 alkyl group, and is substituted with at least one substituent selected from -CN, -OR8, halo, oxo, -N(R8)2, or -CON(R8)2, and each R8 is independently hydrogen or an or otherwise substituted C1-C4 alkyl group, (c) R1 is an aralkyl which may be substituted, The substituted aralkyl may contain a substituted phenyl, and / or (i) or (ii), (i) The substituted aralkyl contains a substituted C1-C4 alkylene, or (ii) The aralkyl which may be substituted contains -CH2- or (d) R1 is a C4-C7 cycloalkylalkyl which may be substituted, The substituted C4-C7 cycloalkylalkyl group may be a substituted cyclopropylmethyl group, or (e) R1 is a heterocyclylalkyl which may be substituted, The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein the substituted heterocyclylalkyl may be a substituted oxetanylmethyl or a substituted pyrazolonylmethyl.

7. (a) R ４ is hydrogen, and / or R5 is hydrogen, R4 is not hydrogen, and R5 is hydrogen. R4 is a C1-C5 alkyl group which may be substituted, and R5 is hydrogen. R4 and R5 are both C1-C5 alkyl groups that may be substituted, or R4 and R5 bond to form a substituted or substituted carbon ring or heterocycle. (b) Whether R2 is not hydrogen, or whether R3 is hydrogen. Is R2 hydrogen, and is R3 hydrogen? R2 is a C1-C5 alkyl group which may be substituted, and R3 is hydrogen. The C1-C5 alkyl group that may be substituted may also be a C1-C2 alkyl group that may be substituted. R2 is a C1-C5 alkynyl which may be substituted, and R3 is hydrogen. R2 is a substituted heterocycline, and R3 is hydrogen. Both R2 and R3 are substituted C1-C5 alkyl groups, or The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 and R3 are bonded to form a substituted or heterocycle.

8. R ７ However, it is a C3-C5 cycloalkyl which may be substituted. A cycloalkyl group that may be substituted is 【Transformation 3】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R 8 may be selected from the group consisting of hydrogen, -CH3, -CH2F, -CHF2, -CF3, -CN, cyclopropyl, -CH2CH3, -CH(CH3)2, and -C(CH3)3.

9. (a) G is a bond, (b) G is a cycloalkylene or (c) The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein G is a heterocycloalkylene which may be substituted.

10. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -N(H)-.

11. (a) A is hydrogen, (b) Whether A is a halo or -CN, (c) A is a substituted C1-C6 alkoxy or -N(R9)2, (d) A is selected from the group consisting of substituted C1-C6 alkyls, substituted C3-C7 carbocyryls, and substituted carbocyrylalkyls, (e) A is a substituted heterocyclyl or a substituted heterocyclylalkyl, or (f) The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein A is selected from an optionally substituted heteroaryl or optionally substituted aryl. 【Request Item 12】 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】 【Chemistry 4-4】 [Chemistry 4-5] [Chemistry 4-6] 【Chemistry 4-7】 【Chemistry 4-8】 【Chemistry 4-9】 【Chemistry 4-10】 【Chemistry 4-11】 【Chemistry 4-12】 【Chemistry 4-13】 【Chemistry 4-14】 【Chemistry 4-15】 【Chemistry 4-16】 【Chemistry 4-17】 【Chemistry 4-18】 【Chemistry 4-19】 Alternatively, it may be selected from the pharmaceutically acceptable salts or solvates thereof, The following structural formula: (A) 【Transformation 5】 Defined as, in the formula, R is, 【Transformation 6】 A compound selected from, or a pharmaceutically acceptable salt or solvate thereof, (B) 【Transformation 7】 Defined as, in the formula, R is, 【Transformation 8】 A compound selected from, or a pharmaceutically acceptable salt or solvate thereof, (C) 【Chemistry 9】 Defined as, in the formula, R is, 【Chemistry 10】 A compound selected from, or a pharmaceutically acceptable salt or solvate thereof, (D) 【Chemistry 11】 Defined as, in the formula, R is, 【Chemistry 12】 A compound selected from, or a pharmaceutically acceptable salt or solvate thereof, (E) 【Chemistry 13】 Defined as, in the formula, R is, 【Chemistry 14】 A compound selected from, or a pharmaceutically acceptable salt or solvate thereof, (F) 【Chemistry 15】 Defined as, in the formula, R is, 【Chemistry 16】 A compound selected from, or a pharmaceutically acceptable salt or solvate thereof, (G) 【Chemistry 17】 Defined as, in the formula, R is, [Chemistry 18] A compound, or a pharmaceutically acceptable salt or solvate thereof, selected from the above, and (H) 【Chemistry 19】 Defined as, in the formula, R is, 【Chemistry 20】 A compound selected from, or a pharmaceutically acceptable salt or solvate thereof, A compound, or a pharmaceutically acceptable salt or solvate thereof.

13. A pharmaceutical composition comprising the compound described in claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

14. Use of the compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a pharmaceutical for the treatment of cancer or neoplasm.

15. A method for inhibiting a PARG enzyme, comprising the step of contacting the enzyme with a compound according to claim 1 or 2, wherein the PARG enzyme is contacted in vitro.

Images