Pyrimidine compounds and their use as USP1 inhibitors

Abstract

This provides pyrimidine compounds and their use as USP1 inhibitors. [Solution] This specification provides a specific heterocyclic aromatic compound, such as a compound of formula (I), as a ubiquitin-specific processing protease 1 (USP1) inhibitor, a pharmaceutical composition containing the compound, and a method of using the compound or pharmaceutical composition in the treatment of a disease or disorder.

Description

[Technical Field]

[0001] This application claims priority to International Application PCT / CN2023 / 107498, filed on 14 July 2023, which is incorporated herein by reference in its entirety for all purposes.

[0002] This specification provides certain pyrimidine heterocyclic aromatic compounds, such as the compound of formula (I) as a ubiquitin-specific processing protease 1 (USP1) inhibitor, pharmaceutical compositions containing the compound, and methods of using the compound or pharmaceutical composition in the treatment of a disease or disorder. [Background technology]

[0003] Ubiquitin (Ub) is a highly conserved 76-amino acid peptide that binds to target proteins post-transcriptionally. The ubiquitin-proteasome system (UPS) is the major proteolytic system that controls proteolysis and also regulates many cellular processes in eukaryotic cells. Polyubiquitination of ubiquitin via a surface lysine-48 (K48) or lysine-11 (K11) residue often results in proteolysis via the 26S proteasome. In contrast, monoubiquitination or polyubiquitin chains linked via other lysines are always involved in DNA damage and repair, cell cycle progression, apoptosis, receptor-mediated endocytosis, and signal transduction. Like other post-translational modifications, ubiquitination is a reversible process, and there is a family of enzymes called deubiquitinating enzymes (DUBs) that act on ubiquitinated substrates to catalyze the removal of the ubiquitin moiety.

[0004] One of the most well-characterized human DUBs is ubiquitin-specific protease 1 (USP1), which plays a crucial role in the cellular response to DNA damage. USP1, along with its cofactor UAF1 (USP1-related factor 1), acts to specifically remove monoubiquitin signaling during the DNA repair process. Monoubiquitinated FANCIFANCD2 heterodimer is one such substrate, involved in the repair of interstrand crosslinks via the Fanconi anemia pathway. A second DNA repair-related process, damage overcoming synthesis (TLS), is also regulated by USP1, further supporting the important function of this DUB in the DNA damage response. A key USP1 substrate in TLS is monoubiquitinated PCNA (proliferating cell nuclear antigen). By restoring PCNA monoubiquitination, USP1 may contribute to preventing unintended recruitment of TLS polymerases and thus help maintain genomic stability. Knockdown of USP1 results in elevated levels of FANCD2-Ub and PCNA-Ub, as well as increased cellular sensitivity to interchain crosslinking agents such as mitomycin C (MMC). Mutations and altered expression of deubiquitinating enzymes have been found to be associated with many human diseases, including cancer. There is a need for the development of safe and effective therapies targeting deubiquitinating enzymes. [Overview of the Initiative]

[0005] In one embodiment, a specific pyrimidine heterocyclic aromatic compound is provided herein as a ubiquitin-specific processing protease 1 (USP1) inhibitor. In one embodiment, the compound has a pyrimidine core structure.

[0006] In one embodiment, the compound of formula (I) is provided herein.

[0007] [ka] or a stereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, where X 1 , X 2 , X3 , R, R 1 , R 2 , R 3 Rings L and A are as defined herein or elsewhere.

[0008] Pharmaceutical compositions comprising the compounds provided herein and pharmaceutically acceptable excipients are also provided herein.

[0009] Furthermore, this specification also provides a method for inhibiting the USP1 protein, which includes contacting the USP1 protein with a compound or pharmaceutical composition provided herein.

[0010] Also provided herein are methods for treating USP1 protein-mediated disorders or cancer, comprising administering a therapeutically effective amount of a compound or pharmaceutical composition provided herein to a subject having the disease or cancer.

[0011] Furthermore, the use of compounds or pharmaceutical compositions provided herein in the manufacture of pharmaceuticals for the prevention or treatment of USP1 protein-mediated disorders or cancer is also provided herein. [Brief explanation of the drawing]

[0012] [Figure 1] The dose-dependent antitumor effects of compound 30 on the vehicle are demonstrated at different doses and schedules. [Modes for carrying out the invention]

[0013] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in which the invention pertains. All patents, applications, published applications and other publications are incorporated by reference in their entirety. If there are multiple definitions of a term herein, the definition in this section shall prevail unless otherwise specified.

[0014] As used herein, and in the specification and the appended claims, the indefinite articles "a" and "an" and the definite article "the" refer to plural and singular subjects, unless the context clearly indicates otherwise.

[0015] As used herein, the terms “comprising” and “including” are interchangeable. The terms “comprising” and “including” should be interpreted as specifying the presence of the mentioned feature or component, but not as excluding the presence or addition of one or more features or components, or groups thereof. Furthermore, the terms “comprising” and “including” are intended to include examples encompassed by the term “consisting of.” Therefore, the term “consisting of” may be used instead of the terms “comprising” and “including” to provide more specific embodiments.

[0016] As used herein, the term “or” should be interpreted as an inclusive “or” meaning any one or any combination thereof. Thus, “A, B, or C” means any of the following: B; C; A and B; A and C; B and C; B and C. Exceptions to this definition arise only if the combination of elements, functions, processes, or actions is in any way inherently mutually exclusive.

[0017] In this specification, the term "and / or" as used in phrases such as "A and / or B" is intended to include both A and B; A or B; A (alone); and B (alone). Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to include the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0018] Note that if there is a discrepancy between the structure shown and the name of that structure, the structure shown is given greater weight.

[0019] As used herein, unless otherwise specified, the term "alkyl" refers to a saturated, straight-chain or branched-chain hydrocarbon chain radical consisting only of carbon and hydrogen atoms. In one embodiment, the alkyl group has, for example, 1 to 24 carbon atoms (C1-C 24 alkyl), 4 to 20 carbon atoms (C4-C 20 alkyl), 6 to 16 carbon atoms (C6-C 16 alkyl), 6 to 9 carbon atoms (C6-C9 alkyl), 1 to 15 carbon atoms (C1-C 15 alkyl), 1 to 12 carbon atoms (C1-C 12 alkyl), 1 to 8 carbon atoms (C1-C8 alkyl) or 1 to 6 carbon atoms (C1-C6 alkyl), and is bonded to the remainder of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, etc. Unless otherwise specified, the alkyl group is optionally substituted.

[0020] As used herein, unless otherwise specified, the term "alkenyl" refers to a straight-chain or branched-chain hydrocarbon chain radical consisting only of carbon and hydrogen atoms and containing one or more carbon-carbon double bonds. The term "alkenyl" also includes radicals having "cis" and "trans" configurations, or "E" and "Z" configurations, as will be understood by those skilled in the art. In one embodiment, the alkenyl group has, for example, 2 to 24 carbon atoms (C2-C 24 alkenyl), 4 to 20 carbon atoms (C4-C 20 alkenyl), 6 to 16 carbon atoms (C6-C 16 alkenyl), 6 to 9 carbon atoms (C6-C9 alkenyl), 2 to 15 carbon atoms (C2-C 15 alkenyl), 2 to 12 carbon atoms (C2-C12 Alkenyl groups have 2 to 8 carbon atoms (C2-C8 alkenyls) or 2 to 6 carbon atoms (C2-C6 alkenyls) and are bonded to the rest of the molecule by single bonds. Examples of alkenyl groups include, but are not limited to, ethenyl, prop-1-enyl, buta-1-enyl, penta-1-enyl, and penta-1,4-dienyl. Unless otherwise specified, alkenyl groups are optionally substituted.

[0021] As used herein, unless otherwise specified, the term "alkynyl" refers to a linear or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms and containing one or more carbon-carbon triple bonds. In one embodiment, the alkynyl group is, for example, 2 to 24 carbon atoms (C2 to C2). 24 Alkynyl group), 4 to 20 carbon atoms (C4 to C 20 Alkynyl group), 6-16 carbon atoms (C6-C6) 16 Alkynyl group), 6-9 carbon atoms (C6-C9 alkynyl group), 2-15 carbon atoms (C2-C 15 Alkynyl group), 2 to 12 carbon atoms (C2 to C 12 Alkynyl groups have 2 to 8 carbon atoms (C2-C8 alkynyl groups) or 2 to 6 carbon atoms (C2-C6 alkynyl groups) and are bonded to the rest of the molecule by single bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and pentynyl. Unless otherwise specified, alkynyl groups can be substituted arbitrarily.

[0022] As used herein, unless otherwise specified, the terms “cycloalkyl” or “carbocyclyl” refer to saturated, non-aromatic monocyclic or polycyclic hydrocarbon radicals consisting only of carbon and hydrogen atoms. Cycloalkyl groups may include condensed, crosslinked, or spirocyclic systems. In one embodiment, a cycloalkyl group may have, for example, 3 to 15 ring carbon atoms (C3 to C 15 Cycloalkyls, having 3 to 10 ring carbon atoms (C3-C 10Cycloalkyl groups are those having 3 to 8 ring carbon atoms (C3-C8 cycloalkyl groups). The cycloalkyl group is attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl radicals include, but are not limited to, adamantyl, norbornyl, dekalinyl, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Unless otherwise specified, cycloalkyl groups are optionally substituted.

[0023] As used herein, “phenyl equivalent” refers to a moiety or functional group that exhibits physical, biological, and / or chemical properties similar to those of a phenyl group. Examples of phenyl equivalents include, but are not limited to, cubane, bicyclo[1.1.1]pentane (BCP), bicyclo[2.2.1]heptane, bicyclo[2.1.1]hexane, bicyclo[2.2.2]octane, adamantane, norbornene, closo-1,2-carborane, closo-1,7-carborane, and closo-1,12-carborane.

[0024] As used herein, unless otherwise specified, the term “aryl” refers to monocyclic and / or polycyclic aromatic groups containing at least one aromatic hydrocarbon ring. In certain embodiments, the aryl has 6 to 18 ring carbon atoms or (C6 to C6) 18 (aryl), having 6 to 14 ring carbon atoms (C6 to C 14 (aryl), or having 6 to 10 ring carbon atoms (C6 to C 10(aryl). Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azlenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. The term "aryl" also refers to a bicyclic, tricyclic, or other polycyclic hydrocarbon ring, where at least one of the rings is aromatic and the others may be saturated, partially unsaturated, or aromatic, e.g., dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). Unless otherwise specified, aryl groups are optionally substituted.

[0025] As used herein, unless otherwise specified, the term “heteroaryl” means a monocyclic and / or polycyclic aromatic group comprising at least one aromatic ring, the at least one aromatic ring comprising one or more heteroatoms (e.g., 1, 1 or 2, 1-3, or 1-4) independently selected from O, S, and N. A heteroaryl can be bonded to the main structure by any heteroatom or carbon atom. In certain embodiments, a heteroaryl has 5-20, 5-15, or 5-10 ring atoms. The term “heteroaryl” also means a bicyclic, tricyclic, or other polycyclic ring, wherein at least one of the rings is aromatic, and the others may be saturated, partially unsaturated, or aromatic, the at least one aromatic ring comprising one or more heteroatoms independently selected from O, S, and N. Examples of monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanil, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, and triazinyl. Examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranil, indolidinyl, benzofuranil, isobenzofuranil, chromonyl, coumalinyl, sinnolinyl, quinoxalinyl, indazolyl, purinyl, pyrrolopyridinyl, flupyridinyl, thienopyridinyl, dihydroisoindolyl, and tetrahydroquinolinyl. Examples of tricyclic heteroaryl groups include, but are not limited to, carbazolyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridine, and xanthenyl. Unless otherwise specified, heteroaryl groups may be substituted as desired.

[0026] As used herein, unless otherwise specified, the term “heterocyclyl” refers to a monocyclic and / or polycyclic non-aromatic group containing one or more heteroatoms (e.g., one, one or two, one to three, or one to four) independently selected from nitrogen, oxygen, phosphorus, and sulfur. A heterocyclyl may be bonded to the main structure by any heteroatom or carbon atom. A heterocyclyl group can be a monocyclic, bicyclic, tricyclic, tetracyclic, or other polycyclic ring system, where the polycyclic ring system can be condensed, bridged, or spirocyclic. A heterocyclyl polycyclic ring system may contain one or more heteroatoms in one or more rings. A heterocyclyl group can be saturated or partially unsaturated. A saturated heterocycloalkyl group may be called a “heterocycloalkyl.” A partially unsaturated heterocycloalkyl group can be called a "heterocycloalkenyl" if the heterocyclil contains at least one double bond, or a "heterocycloalkynyl" if the heterocyclil contains at least one triple bond. In one embodiment, the heterocyclil has, for example, 3 to 18 ring atoms (3 to 18-membered heterocyclil), 4 to 18 ring atoms (4 to 18-membered heterocyclil), 5 to 18 ring atoms (3 to 18-membered heterocyclil), 4 to 8 ring atoms (4 to 8-membered heterocyclil), or 5 to 8 ring atoms (5 to 8-membered heterocyclil). Examples of heterocyclyl groups include, but are not limited to, oxetanyl, azetidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, isoxazolidinyl, isothiazolidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, dihydropyridinyl, tetrahydropyridinyl, tetrahydrothiapyranyl, tetrahydrothiopyranyl, piperazinyl, and piperidinyl. Unless otherwise specified, heterocyclyl groups are substituted as desired.

[0027] Where used herein, numerical ranges such as "3 to 18" always refer to each integer within a given range. For example, "a heterocyclyl having 3 to 18 ring atoms" means that the heterocyclyl group can consist of 18 or fewer ring atoms, such as 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms, and so on. Similarly, C1 to C6 alkyl means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms.

[0028] As used herein, unless otherwise specified, the “cycloalkylalkyl” group is a radical of the formula :-alkyl-cycloalkyl, where alkyl and cycloalkyl are defined above. Substituted cycloalkylalkyl groups may be substituted with the alkyl, cycloalkyl, or both alkyl and cycloalkyl moieties of the group. Representative cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cyclopentylpropyl, and cyclohexylpropyl.

[0029] As used herein, unless otherwise specified, the “aralkyl” group is a radical of the formula :-alkyl-aryl, where alkyl and aryl are defined above. Substituted aralkyl groups may be substituted with the alkyl, aryl, or both alkyl and aryl moieties of the group. Typical aralkyl groups include, but are not limited to, the benzyl and phenethyl groups, as well as aralkyl groups in which the aryl group is condensed with a cycloalkyl group (e.g., indan-4-ylethyl).

[0030] Where used herein, unless otherwise specified, other similar compound terms reflect the above descriptions of “cycloalkylalkyl” and “aralkyl.” For example, a “heterocyclylalkyl” group is a radical of the formula:-alkyl-heterocyclyl, where alkyl and heterocyclyl are defined above. A “heteroarylalkyl” group is a radical of the formula:-alkyl-heteroaryl, where alkyl and heteroaryl are defined above. A “heterocycloalkylalkyl” group is a radical of the formula:-alkyl-heterocycloalkyl, where alkyl and heterocycloalkyl are defined above.

[0031] As used herein, unless otherwise specified, the terms “halogen,” “halide,” or “halo” refer to fluorine (F), chlorine (Cl), bromine (Br), and / or iodine (I). As used herein, unless otherwise specified, the terms “haloalkyl,” “haloalkenyl,” “haloalkynyl,” and “haloalkoxy” refer to alkyl, alkenyl, alkynyl, and alkoxy structures substituted with one or more halo groups or combinations thereof.

[0032] As used herein, unless otherwise specified, the term “alkoxy” refers to an -O-(alkyl) group, where alkyl is defined above. As used herein, unless otherwise specified, the term “aryloxy” refers to an -O-(aryl) group, where aryl is defined above.

[0033] As used herein, unless otherwise specified, the term "alkylsulfonyl" refers to -SO2-alkyl, where alkyl is defined above.

[0034] As used herein, unless otherwise specified, the terms "carboxyl" and "carboxy" refer to the -COOH group.

[0035] As used herein, unless otherwise specified, the term "acyl" refers to -C(O)-R x It refers to R x R may be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is defined above. In certain embodiments, R x It may be unsubstituted or substituted with one or more substituents.

[0036] As used herein, unless otherwise specified, the term "amino" means -N(R y )(R y ) refers to each R y -N(R y )(R y ) The group consists of two R groups other than hydrogen y If present, they can bond with nitrogen atoms to form a ring. In one embodiment, the ring is a 3, 4, 5, 6, 7, or 8-membered ring. In one embodiment, one or more ring atoms are heteroatoms independently selected from O, S, and N. The term "amino" also refers to N-oxide (-N+(R y )(R y This also includes )O-). In a particular embodiment, each R y or -N(R y )(R y The ring formed by ) can independently be unsubstituted or substituted with one or more substituents.

[0037] As used herein, unless otherwise specified, the terms "amide," "amido," or "carboxamide" refer to -C(O)N(R) y )2 or -NR y C(O)R y This refers to, and in the formula, each R y-C(O)N(R y ) The two units have two Rs other than hydrogen y If present, it may bond with a nitrogen atom to form a ring. In one embodiment, the ring is a 3, 4, 5, 6, 7, or 8-membered ring. In one embodiment, one or more ring atoms are heteroatoms independently selected from O, S, and N. In a particular embodiment, each R y or -N(R y )(R y The ring formed by ) may independently be unsubstituted or substituted with one or more substituents.

[0038] As used herein, unless otherwise specified, the term "aminoalkyl" refers to -(alkyl)-(amino), where alkyl and amino are defined above. As used herein, unless otherwise specified, the term "aminoalkoxy" refers to -O-(alkyl)-(amino), where alkyl and amino are defined above.

[0039] As used herein, unless otherwise specified, the term "alkylamino" refers to -NH(alkyl) or -N(alkyl)(alkyl), where alkyl is defined above. Examples of such alkylamino groups include, but are not limited to, -NHCH3, -NHCH2CH3, -NH(CH2)2CH3, -NH(CH2)3CH3, -NH(CH2)4CH3, -NH(CH2)5CH3, -N(CH3)2, -N(CH2CH3)2, -N((CH2)2CH3)2, and -N(CH3)(CH2CH3).

[0040] As used herein, unless otherwise specified, the terms "sulfanil," "sulfide," or "thio" are -SR z It refers to R zR can be, but is not limited to, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is defined above. In certain embodiments, R z It may be unsubstituted or substituted with one or more substituents.

[0041] As used herein, unless otherwise specified, the terms "sulfonyl" or "sulfone" refer to -S(O)2-R m It refers to R m R can be, but is not limited to, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is defined above. In certain embodiments, R m It may be unsubstituted or substituted with one or more substituents.

[0042] As used herein, unless otherwise specified, the terms "sulfonamide" or "sulfonamide" refer to -S(=O)2-N(R y )2 or -N(R y )-S(=O)2-R y This refers to, and in the formula, each R y -S(=O)2-N(R y ) Two units have two Rs other than hydrogen y If present, they can bond with nitrogen atoms to form a ring. In one embodiment, the ring is a 3, 4, 5, 6, 7, or 8-membered ring. In one embodiment, one or more ring atoms are heteroatoms independently selected from O, S, and N. In a particular embodiment, each R y or -N(R y )(R y The ring formed by ) may independently be unsubstituted or substituted with one or more substituents.

[0043] As used herein, unless otherwise specified, the term "cyano" refers to the -CN radical.

[0044] As used herein, unless otherwise specified, the term "nitro" refers to the -NO2 radical.

[0045] As used herein, unless otherwise specified, the term "oxo" refers to the =O radical.

[0046] As used herein, unless otherwise specified, the term "oxy" refers to an -O- radical.

[0047] As used herein, unless otherwise specified, the term "hydroxyl" refers to the -OH radical.

[0048] As used herein, unless otherwise specified, the term "carbonyl" refers to a -C(O)- radical.

[0049] As used herein, unless otherwise specified, the term "mercapto" refers to the -SH radical.

[0050] Where used herein, unless otherwise specified, the terms “optional” or “optionally” (e.g., optionally substituted) mean that the events of the situation described thereafter may or may not occur, and that the description includes both cases in which such events or situations occur and cases in which they do not. For example, “optionally substituted alkyl” means that the alkyl radical may or may not be substituted, and that the description includes both substituted alkyl radicals and unsubstituted alkyl groups.

[0051] When a group described in this specification is said to be "substituted", it may be substituted with any suitable substituent(s). Exemplary examples of substituents include, but are not limited to, those found in the exemplary compounds and embodiments disclosed herein, and halogen (chloro, iodo, bromo, or fluoro); alkyl; alkenyl; alkynyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; amide; guanidine; enamine; aminocarbonyl; acyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aryloxyamine, aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxo (=O); B(OH)2, O(alkyl)aminocarbonyl; cycloalkyl which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or heterocyclyl which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, azetidinyl, imidazolidinyl, or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); spirocylryl; aryloxy; aralkyloxy; heteroaryloxy; heterocyclyloxy; and heterocyclylalkoxy.

[0052] As used herein, unless otherwise specified, the term “isomer” refers to different compounds having the same molecular formula. “Stereoisomers” are isomers that differ only in the way their atoms are arranged in space. “Atropisomers” are stereoisomers resulting from bound rotation around a single bond. “Enantiomers” are pairs of stereoisomers that are mirror images of each other and cannot be superimposed. A mixture of any proportion of enantiomer pairs may be known as a “racemic” mixture. “Diastereoisomers” are stereoisomers that have at least two chiral atoms but are not mirror images of each other. Absolute stereochemistry can be determined according to the Cahn-Ingold-Prelog R-S system. If a compound is an enantiomer, the stereochemistry at each chiral carbon can be determined by either R or S. Divided compounds with unknown absolute configuration can be called (+) or (-) depending on the direction in which they rotate plane-polarized light within the wavelength of the sodium D line (dextrorotatory or levorotatory). However, the sign of optical rotation, i.e., (+) and (-), is independent of the absolute configuration of the molecule, i.e., R and S. Certain compounds described herein contain one or more chiral centers and thus may give rise to enantiomers, diastereomers, and other stereoisomers that can be defined as (R)- or (S)- with respect to the absolute stereochemistry at each chiral atom. The chemicals, pharmaceutical compositions and methods of the present invention mean that they include all such possible isomers, including racemic mixtures, optically substantially pure forms and intermediate mixtures. Optically active (R)- and (S)- isomers can be prepared, for example, using chiral synthons or chiral reagents, or they can be divided using the prior art.

[0053] As used herein, unless otherwise specified, the term "enantiomeric purity" or "enantiomer purity" refers to a qualitative or quantitative measure of a purified enantiomer. The enantiomeric purity of a compound described herein may be described in terms of enantiomeric excess (ee), which indicates the extent to which a sample contains one enantiomer in a greater amount than the other. A racemic mixture has 0% ee, while a single, completely pure enantiomer has 100% ee. Examples of enantiomeric purity include at least about 10%, at least about 12%, at least about 14%, at least about 16%, at least about 18%, at least about 20%, at least about 22%, at least about 24%, at least about 26%, at least about 28%, at least about 30%, at least about 32%, at least about 34%, at least about 36%, at least about 38%, at least about 40%, at least about 42%, at least about 44%, at least about 46%, at least about 48%, at least about 50%, at least about 52%, at least about 54%, at least about 56%, at least about 58%, at least about 60%, at least about 62%, at least about 64%, at least about 66%, at least about 68%, at least about 70%, at least about 72%, at least about 74%, at least about 76%, at least about 78%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% ee. Similarly, "diastereomeric purity" may be described in terms of diastereomeric excess (de), which indicates the extent to which a sample contains one diastereoisomer in a greater amount than the others.

[0054] As used herein, unless otherwise specified, the term “substantially purified enantiomer” means a compound in which one enantiomer is more enriched than the other, preferably in which the other enantiomer constitutes less than about 20%, less than about 10%, less than about 5%, or less than about 2% of the total enantiomer. In one embodiment, a substantially purified enantiomer has an enantiomer excess of at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, or at least about 99.9% of the S enantiomer. In one embodiment, the substantially purified enantiomer has an enantiomer excess of at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, or at least about 99.9% of the R enantiomer.

[0055] "Stereoisomers" may also include E and Z isomers, or mixtures thereof, as well as cis and trans isomers, or mixtures thereof. In certain embodiments, the compounds described herein are isolated as either the E or Z isomer. In other embodiments, the compounds described herein are a mixture of the E and Z isomers.

[0056] As used herein, unless otherwise specified, the term “pharmaceutically acceptable salt” includes both acid addition salts and base addition salts.

[0057] Examples of pharmaceutically acceptable acid addition salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and organic acids, such as acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonate, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2 Examples of acidic acids that can be used include, but are not limited to, oxo-glutaric acid, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucinic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid.

[0058] Examples of pharmaceutically acceptable base addition salts include, but are not limited to, salts prepared by the addition of inorganic or organic bases to free acid compounds. Examples of salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. In one embodiment, the inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts, and magnesium salts. Examples of salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins (e.g., ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamin, choline, betaine, benetamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc.). In one embodiment, the organic base is isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0059] As used herein, unless otherwise specified, the term “subject” refers to animals including, but not limited to, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms “subject” and “patient” are used interchangeably herein with respect to mammalian subjects, such as human subjects. In one embodiment, the subject is a mammal. In one embodiment, the subject is a human.

[0060] As used herein, unless otherwise specified, the terms “to treat,” “to treat,” and “treatment” refer to the eradication or improvement of a disease or disorder, or one or more symptoms associated with a disease or disorder. Generally, treatment is performed after the onset of a disease or disorder. In certain embodiments, the terms refer to minimizing the progression or worsening of a disease or disorder resulting from the administration of one or more prophylactic or therapeutic agents to a subject with a disease or disorder.

[0061] As used herein, unless otherwise specified, the terms “prevent,” “prevent,” and “prevention” refer to the prevention of the onset, recurrence, or spread of a disease or disorder, or one or more of its symptoms. Generally, prevention is carried out before the onset of the disease or disorder.

[0062] As used herein, unless otherwise specified, the term “therapeutic dose” means an amount of the compound sufficient to prevent or, to some extent, alleviate the onset of one or more symptoms of the disorder, disease, or condition being treated, when administered. The term “therapeutic dose” also refers to an amount of the compound sufficient to induce a biological or medical response in a cell, tissue, system, animal, or human, as sought by researchers, veterinarians, physicians, or clinicians.

[0063] Where used herein, unless otherwise specified, "IC" refers to "IC" 50 The term "maximum response" refers to the amount, concentration, or dose of a compound required to inhibit such response by 50% in an assay measuring the maximum response.

[0064] As used herein, unless otherwise specified, the terms “pharmaceutically acceptable carrier,” “pharmaceutically acceptable excipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” refer to a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulant. In one embodiment, each component is “pharmaceutically acceptable” in the sense that it is compatible with other components of a pharmaceutical formulation, suitable for use in contact with human and animal tissues or organs without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, and is commensurate with a reasonable benefit / risk ratio. Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams &Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and See Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004.

[0065] Unless otherwise specified, the structures shown herein also include compounds that differ only in the presence of one or more isotopic enriched atoms. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, respectively. 2 H, 3 H, 13 C, 14 C, 15 N, 18 O,17 O, 31 P, 32 P, 35 S, 18 F, and 36 Examples include the substitution or enrichment of hydrogen by deuterium or tritium in one or more atoms in a molecule, or in one or more atoms in a molecule 13 C or 14 Compounds having the structure of the present invention, except for carbon substitution or enrichment by C, are within the scope of this disclosure. In one embodiment, provided herein are isotope-labeled compounds in which one or more hydrogen atoms are substituted or enriched with deuterium. In one embodiment, provided herein are isotope-labeled compounds having one or more hydrogen atoms substituted or enriched with tritium. In one embodiment, provided herein are, 13 An isotope-labeled compound having one or more carbon atoms substituted or enriched with C. In one embodiment, provided herein is: 14 It is an isotope-labeled compound having one or more carbon atoms substituted or enriched with C.

[0066] Where used herein, unless otherwise specified, the terms “about” or “approximately” mean the allowable error of a particular value as determined by those skilled in the art, which depends in part on how that value is measured or determined.

[0067] In certain embodiments, the terms “about” or “approximately” mean within 1, 2, 3, or 4 standard deviations. In certain embodiments, the terms “about” or “approximately” mean within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0068] compound In one embodiment, certain pyrimidine heterocyclic aromatic compounds as ubiquitin-specific processing protease 1 (USP1) inhibitors are provided herein. In one embodiment, the compound has a pyrimidine core structure.

[0069] In one embodiment, what is provided herein is a compound of formula (I),

[0070]

Chemical formula

[0071] In one embodiment, R 1 is alkyl. In one embodiment, R 1 is an alkoxy. In one embodiment, R 1 is a halogen. In one embodiment, R 1 is cyano. In one embodiment, R 1 , NR c R d In one embodiment, R 1 is -C(=O)NHR d In one embodiment, R 1 is -NHC(=O)R c In one embodiment, R 1 is a cycloalkyl group. In one embodiment, R 1 is a cycloalkyloxy. In one embodiment, R 1 is a haloalkyloxy. In one embodiment, R 1 is a heterocycline. In one embodiment, R 1 is an arrow. In one embodiment, R 1 is a heteroaryl compound. In one embodiment, R 1 It is a haloalkyl compound.

[0072] In one embodiment, R 1is a C1-C6 alkyl group. In one embodiment, R 1 is a C1-C6 alkoxy. In one embodiment, R 1 is N(C1-C6 alkyl)2. In one embodiment, R 1 is -C(=O)-NH-(C1~C6 alkyl). In one embodiment, R 1 is -C(=O)-NH-(C3~C8 cycloalkyl). In one embodiment, R 1 is -C(=O)N(C1-C6 alkyl)2. In one embodiment, R 1 is -NHC(=O)-(C1~C6 alkyl). In one embodiment, R 1 is a C3-C8 cycloalkyl group. In one embodiment, R 1 is a C3-C8 cycloalkyloxy. In one embodiment, R 1 is a C1-C6 haloalkyloxy. In one embodiment, R 1 R is a 3-8 member heterocycline. In one embodiment, R 1 C6~C 10 It is an arrow. In one embodiment, R 1 is a 5-10 member heteroaryl. In one embodiment, R 1 These are C1-C6 haloalkyl groups.

[0073] In one embodiment, R 1 is methyl. In one embodiment, R 1 is ethyl. In one embodiment, R 1 is propyl or isopropyl. In one embodiment, R 1 is n-butyl, isobutyl, or tert-butyl. In one embodiment, R 1 is a pentill. In one embodiment, R 1 is hexyl. In one embodiment, R 1 is cyclopropyl. In one embodiment, R 1 is cyclobutyl. In one embodiment, R 1 is methoxy. In one embodiment, R1 is ethoxy. In one embodiment, R 1 R is propyloxy or isopropyloxy. In one embodiment, R 1 is cyclopropyl oxy. In one embodiment, R 1 is cyclobutyloxy. In one embodiment, R 1 is 2,2,2-trifluoroethoxy. In one embodiment, R 1 is trifluoromethoxy. In one embodiment, R 1 is NH2. In one embodiment, R 1 is NH(CH3). In one embodiment, R 1 is N(CH3)2. In one embodiment, R 1 It is trifluoromethyl.

[0074] In one embodiment, R c is hydrogen. In one embodiment, R c is alkyl. In one embodiment, R c is an alkoxy. In one embodiment, R c is a cycloalkyl group. In one embodiment, R c is a heterocycline. In one embodiment, R c is an arrow. In one embodiment, R c is a heteroaryl compound. In one embodiment, R c It is a halogen.

[0075] In one embodiment, R c is a C1-C6 alkyl group. In one embodiment, R c is a C1-C6 alkoxy. In one embodiment, R c is a C3-C8 cycloalkyl group. In one embodiment, R c R is a 3-8 member heterocycline. In one embodiment, R c C6~C 10 It is an arrow. In one embodiment, R cis a 5-10 member heteroaryl. In one embodiment, R c is fluoro. In one embodiment, R c is chloro. In one embodiment, R c It is Bromo.

[0076] In one embodiment, R d is hydrogen. In one embodiment, R d is alkyl. In one embodiment, R d is an alkoxy. In one embodiment, R d is a cycloalkyl group. In one embodiment, R d is a heterocycline. In one embodiment, R d is an arrow. In one embodiment, R d is a heteroaryl compound. In one embodiment, R d It is a halogen.

[0077] In one embodiment, R d is a C1-C6 alkyl group. In one embodiment, R d is a C1-C6 alkoxy. In one embodiment, R d is a C3-C8 cycloalkyl group. In one embodiment, R d R is a 3-8 member heterocycline. In one embodiment, R d C6~C 10 It is an arrow. In one embodiment, R d is a 5-10 member heteroaryl. In one embodiment, R d is fluoro. In one embodiment, R d is chloro. In one embodiment, R d It is Bromo.

[0078] In one embodiment, R c and R d Both are hydrogen. In one embodiment, R c and R d Both are alkyl. In one embodiment, R cand R d Both are C1-C6 alkyl groups. In one embodiment, R c and R d Both are methyl.

[0079] In one embodiment, R is hydrogen. In one embodiment, R is a halogen. In one embodiment, R is an alkyl. In one embodiment, R is a cycloalkyl. In one embodiment, R is a heterocyclyl. In one embodiment, R is an aryl. In one embodiment, R is a heteroaryl. In one embodiment, R is an alkoxy. In one embodiment, R is a cycloalkyloxy. In one embodiment, R is a heterocyclyloxy. In one embodiment, R is an aryloxy. In one embodiment, R is a heteroaryloxy. In one embodiment, R is a cycloalkylalkyl. In one embodiment, R is a heterocyclylalkyl. In one embodiment, R is an aralkyloxy. In one embodiment, R is a heteroarylalkyloxy. In one embodiment, R is an amide.

[0080] In one embodiment, R is a C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocycline, or C6-C 10 Aryl, 5-10 member heteroaryl, C1-C6 alkoxy, C3-C8 cycloalkyloxy, 4-8 member heterocyclyloxy, C6-C 10 Aryloxy, 5-10 member heteroaryloxy, (C3-C8 cycloalkyl)-(C1-C2 alkyl)-, (4-8 member heterocyclyl)-(C1-C2 alkyl)-, (C6-C 10(aryl)-, (C1-C2 alkyl)-, (5-10 member heteroaryl)-(C1-C2 alkyl)-, (C3-C8 cycloalkyl)-(C1-C2 alkyloxy)-, (4-8 member heterocyclyl)-(C1-C2 alkyloxy)-, (C6-C 10 The formula is aryl)-(C1-C2 alkyloxy)- or (5-10 member heteroaryl)-(C1-C2 alkyloxy)-, where each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl moiety in R can be independently and arbitrarily substituted.

[0081] In one embodiment, R is a 5- to 10-membered heteroaryl. In one embodiment, R is a 5 or 6-membered heteroaryl. In one embodiment, R is a 5 or 6-membered nitrogen-containing heteroaryl. In one embodiment, R is a 5 or 6-membered nitrogen and oxygen-containing heteroaryl. In one embodiment, R is a 5 or 6-membered nitrogen-containing heteroaryl, where nitrogen is the only heteroatom of the heteroaryl. In one embodiment, R is imidazolyl. In one embodiment, R is pyrazolyl. In one embodiment, R is triazolyl. In one embodiment, R is pyridyl. In one embodiment, R is pyrimidinyl. In one embodiment, R is triazinyl. In one embodiment, R is pyridazinyl. In one embodiment, R is pyrazinyl. In one embodiment, R is a 5 or 6-membered nitrogen-containing heteroaryl, where the heteroaryl contains at least one heteroatom other than nitrogen. In one embodiment, R is oxazolyl. In one embodiment, R is isoxazolyl. In one embodiment, R is thiazolyl. In another embodiment, R is isothiazolyl.

[0082] In one embodiment, R is one or more R 4 It is arbitrarily replaced by each R 4This includes deuterium, halogens, nitro, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted deuterated alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, haloalkyl, optionally substituted alkoxy, optionally substituted deuterated alkoxy, haloalkyloxy, acyl; optionally substituted cycloalkyloxy, optionally substituted heterocyclyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl, optionally substituted spiroheterocyclyl, optionally substituted spirocyclyl, optionally substituted cross-linked heterocyclyl, optionally substituted cross-linked carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, The following are independently selected from optionally substituted alkoxyalkyls, optionally substituted (alkylamino)alkyls, optionally substituted (dialkylamino)alkyls, optionally substituted cyanoalkyls, optionally substituted (carboxamide)alkyls, optionally substituted mercaptoalkyls, optionally substituted (cycloalkylamino)alkyls, optionally substituted cycloalkylalkyloxys, optionally substituted heterocyclylalkyloxys, optionally substituted aralkyloxys, optionally substituted heteroarylalkyloxys, aminos, optionally substituted alkylaminos, optionally substituted dialkylaminos, (hydroxyalkyl)aminos, carboxys, amides, carboxamides, optionally substituted sulfonamides, optionally substituted alkylcarbonyls, optionally substituted arylcarbonyls, optionally substituted alkylsulfonyls, optionally substituted arylsulfonyls, and optionally substituted alkylthios.

[0083] In one embodiment, R is two R 4 It is replaced by (i) a position adjacent to the bond point of R to ring A, and (ii) a position separated from the bond point of R to ring A by one ring atom. 4It is replaced by. In one embodiment, the two positions are on the same side of the bond point of R to ring A. In one embodiment, the two positions are on opposite sides of the bond point of R to ring A.

[0084] In one embodiment, R is three R 4 It is replaced by (i) a position adjacent to the bond point of R to ring A, (ii) a position one ring atom away from the bond point of R to ring A, and (iii) a position two ring atoms away from the bond point of R to ring A. 4 It has been replaced with.

[0085] In one embodiment, R is

[0086] [ka] In one embodiment, R is

[0087] [ka] In one embodiment, R is

[0088] [ka] In one embodiment, R is

[0089] [ka] In one embodiment, R is

[0090] [ka] In one embodiment, R is

[0091] [ka] In one embodiment, R is

[0092] [ka] That is the case.

[0093] In one embodiment, R 4 is one or more R 5 It is arbitrarily replaced by R. In one embodiment, 4 is non-substitutable. In one embodiment, R 4 is one R 5 It is replaced by R 4 This is two R's 5 It has been replaced with.

[0094] In one embodiment, each R 5 These include halogens, nitros, cyano groups, hydroxy, sulfhydryls, alkyls, alkenyls, alkynyls, cycloalkyls, heterocyclyls, aryls, heteroaryls, haloalkyls, alkoxys, acyls, cycloalkyloxys, heterocyclyloxys, heterocyclylcarbonyls, aryloxys, heteroaryloxys, cycloalkylalkyls, heterocyclylalkyls, spiroheterocyclyls, aralkyls, heteroarylalkyls, hydroxyalkyls, carboxyalkyls, alkoxyalkyls, aminoalkyls, (alkylamino)alkyls, (dialkylamino)alkyls, cyanoalkyls, (carboxamyl) (D)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, oxo, carboxy, amide, carboxamide, sulfonamide, formyl, carbamoyl, sulfamoyl, alkylcarbonyl, haloalkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, and alkylthio are independently selected from R 5 is optionally substituted and / or two R 5These, together with the same ring carbon atom to which they are bonded, form optionally substituted C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl groups, and / or two R groups bonded to different carbon atoms. 5 They come together to form a optionally substituted bridging ring.

[0095] In one embodiment, each R 5 is independently selected from fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, oxo, cyclopropyl, cyclopropylcarbonyl, isopropylcarbonyl, cyclobutylcarbonyl, formyl, acetyl, trifluoroacetyl, propionyl, amino, hydroxy, sulfhydryl, oxetanyl, oxetane-3-carbonyl, azetidinyl, methylsulfonyl, ethylsulfonyl, aminomethylsulfonyl, methylsulfinyl, ethylsulfinyl, carbamoyl, benzoyl, sulfamoyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, thiophenyl, piperidinyl, piperazinyl, tetrahydrothiapyranil, and tetrahydrothiopyranil, R 5 is optionally substituted and / or two R 5 These, together with the same ring carbon atom to which they are bonded, form optionally substituted cyclobutyl or azetidinyl, and / or two R atoms bonded to different carbon atoms. 5 These combine to form optionally substituted azabicycloheptyl or diazabicycloheptyl.

[0096] In one embodiment, R 5 is one or more R 6 It is arbitrarily replaced by R. In one embodiment, 5 is non-substitutable. In one embodiment, R 5 is one R 6 It is replaced by R 5 This is two R's 6 It has been replaced with.

[0097] In one embodiment, each R 6 This is independently selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkyl, alkoxy, acyl; cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (carboxamide)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxy, amide, carboxamide, sulfonamide, alkylcarbonyl, arylcarbonyl, formyl, carbamoyl, alkylsulfonyl, arylsulfonyl, and alkylthio, R 6 It has been arbitrarily replaced.

[0098] In one embodiment, each R 6 R is independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, carbamoyl, methylsulfonyl, ethylsulfonyl, formyl, acetyl, propionyl, methoxy, ethoxy, isopropoxy, tert-butoxy, amino, methylamino, ethylamino, dimethylamino, hydroxy, carboxamide, acetamide, propionamide, carbamoyl, methylsulfonyl, ethylsulfonyl, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranil, oxetanyl, azetidinyl, isoxazolidinyl, and pyrrolidinyl. 6 It has been arbitrarily replaced.

[0099] In one embodiment, R 6 is one or more R7 It is arbitrarily replaced by R. In one embodiment, 6 is non-substitutable. In one embodiment, R 6 is one R 7 It is replaced by R 6 This is two R's 7 It has been replaced with.

[0100] In one embodiment, each R 7 These are independently selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkyl, alkoxy, oxo, acyl, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, hydroxyalkyloxy, carboxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (carboxamide)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxy, amide, carboxamide, sulfonamide, alkylcarbonyl, arylcarbonyl, formyl, carbamoyl, alkylsulfonyl, arylsulfonyl, and alkylthio.

[0101] In one embodiment, each R 7 These are independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, acetyl, oxo, hydroxy, sulfhydryl, oxetanyl, azetidinyl, imidazolidinyl, methylsulfonyl, methylamino, dimethylamino, methoxy, ethoxy, isopropoxy, tert-butoxy, and hydroxyethoxy.

[0102] In one embodiment, X1 , X 2 , and X 3 At least one of them is N.

[0103] In one embodiment, X 1 In one embodiment, X 1 CR x1 In one embodiment, X 1 is CH. In one embodiment, R x1 is a C1-C6 alkyl group. In one embodiment, R x1 is methyl. In one embodiment, R x1 is ethyl. In one embodiment, R x1 is propyl (e.g., n-propyl or isopropyl). In one embodiment, R x1 is butyl (e.g., n-butyl, isobutyl, or tert-butyl). In one embodiment, R x1 is a pentill. In one embodiment, R x1 It is hexyl.

[0104] In one embodiment, X 2 In one embodiment, X 2 CR x2 In one embodiment, X 2 is CH. In one embodiment, R x2 is a C1-C6 alkyl group. In one embodiment, R x2 is methyl. In one embodiment, R x2 is ethyl. In one embodiment, R x2 is propyl (e.g., n-propyl or isopropyl). In one embodiment, R x2 is butyl (e.g., n-butyl, isobutyl, or tert-butyl). In one embodiment, R x2 is a pentill. In one embodiment, R x2 It is hexyl.

[0105] In one embodiment, X 3In one embodiment, X 3 CR x3 In one embodiment, X 3 is CH. In one embodiment, R x3 is a C1-C6 alkyl group. In one embodiment, R x3 is methyl. In one embodiment, R x3 is ethyl. In one embodiment, R x3 is propyl (e.g., n-propyl or isopropyl). In one embodiment, R x3 is butyl (e.g., n-butyl, isobutyl, or tert-butyl). In one embodiment, R x3 is a pentill. In one embodiment, R x3 It is hexyl.

[0106] In one embodiment, X 1 CR x1 X 2 CR x2 In one embodiment, X 1 CR x1 X 2 In one embodiment, X 1 N is X 2 CR x2 In one embodiment, X 1 N is X 2 In one embodiment, X 1 CR x1 X 3 CR x3 In one embodiment, X 1 CR x1 X 3 In one embodiment, X 1 is N and X 3 CR x3 In one embodiment, X 1 N is X 3 In one embodiment, X 2 CR x2 X 3CR x3 In one embodiment, X 2 CR x2 X 3 In one embodiment, X 2 N is X 3 CR x3 In one embodiment, X 2 N is X 3 It is N.

[0107] In one embodiment, X 1 N is X 2 N is X 3 CR x3 In one embodiment, X 1 N is X 2 N is X 3 is CH. In one embodiment, X 1 N is X 2 CR x2 X 3 In one embodiment, X 1 N is X 2 CH is, X 3 In one embodiment, X 1 CR x1 X 2 N is X 3 In one embodiment, X 1 CH is, X 2 N is X 3 It is N.

[0108] In one embodiment, R 2 and R 3Each of these is independently selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (carboxamide)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxy, amide, carboxamide, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, and alkylthio, R 2 or R 3 Each alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl moiety within the molecule is independently and arbitrarily substituted with one or more C1-C6 alkyl groups, halogens, or deuterium.

[0109] In one embodiment, R 2 and R 3 Each of these is independently selected from halogen, nitro, cyano, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 member heterocyclyl, 5-10 member aryl, 5-10 member heteroaryl, C1-C6 alkoxy, C3-C8 cycloalkyloxy, 3-8 member heterocyclyloxy, 5-10 member aryloxy, 5-10 member heteroaryloxy, (C3-C8 cycloalkyl)(C1-C6 alkyl), and (3-8 member heterocyclyl)(C1-C6 alkyl).

[0110] In one embodiment, R 2cyano, amino, methylamino, dimethylamino, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, cyclopropoxy, cyclobutoxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, chloro, fluoro, 1-fluoropropan-2-yl, (S)-1-fluoropropan-2-yl, (R)-1-f Selected from ruolopropan-2-yl, hydroxyethyl, 1-methoxy-2-methylpropan-2-yl, 1-methoxypropan-2-yl, (S)-1-methoxypropan-2-yl, (R)-1-methoxypropan-2-yl, 1-(methoxymethyl)cyclopropyl, 1-hydroxypropan-2-yl, oxetane-3-yl, tetrahydrofuran-3-yl, 1-methylcyclopropyl, methyl deuterium, ethyl deuterium, isopropyl deuterium, methoxy deuterium, and ethoxy deuterium.

[0111] In one embodiment, R 2 is a cycloalkyl group. In one embodiment, R 2 is a C3-C8 cycloalkyl group. In one embodiment, R 2 is cyclopropyl. In one embodiment, R 2 It is cyclobutyl.

[0112] In one embodiment, R 3cyano, amino, methylamino, dimethylamino, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, cyclopropoxy, cyclobutoxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, chloro, fluoro, 1-fluoropropan-2-yl, (S)-1-fluoropropan-2-yl, (R)-1-f Selected from ruolopropan-2-yl, hydroxyethyl, 1-methoxy-2-methylpropan-2-yl, 1-methoxypropan-2-yl, (S)-1-methoxypropan-2-yl, (R)-1-methoxypropan-2-yl, 1-(methoxymethyl)cyclopropyl, 1-hydroxypropan-2-yl, oxetane-3-yl, tetrahydrofuran-3-yl, 1-methylcyclopropyl, methyl deuterium, ethyl deuterium, isopropyl deuterium, methoxy deuterium, and ethoxy deuterium.

[0113] In one embodiment, R 3 is an alkoxy. In one embodiment, R 3 is a C1-C6 alkoxy. In one embodiment, R 3 is methoxy. In one embodiment, R 3 It is ethoxy.

[0114] In one embodiment, R 2 It is a cycloalkyl, and R 3 is an alkoxy. In one embodiment, R 2 It is a C3-C8 cycloalkyl group, and R 3 is a C1-C6 alkoxy. In one embodiment, R 2 It is cyclopropyl, and R 3 It is methoxy.

[0115] In one embodiment, X 1 N is X 2 CR x2 X 3 CR x3And R 2 It is a cycloalkyl, and R 3 is an alkoxy. In one embodiment, X 2 N is X 1 CR x1 X 3 CR x3 And R 2 It is a cycloalkyl, and R 3 is an alkoxy. In one embodiment, X 3 N is X 1 CR x1 X 2 CR x2 And R 2 It is a cycloalkyl, and R 3 is an alkoxy. In one embodiment, X 1 N is X 2 N is X 3 CR x3 And R 2 It is a cycloalkyl, and R 3 is an alkoxy. In one embodiment, X 1 N is X 2 N is X 3 CH is, R 2 It is a cycloalkyl, and R 3 is an alkoxy. In one embodiment, X 1 N is X 2 CR x2 X 3 N is R 2 It is a cycloalkyl, and R 3 is an alkoxy. In one embodiment, X 1 N is X 2 CH is, X 3 N is R 2 It is a cycloalkyl, and R 3 is an alkoxy. In one embodiment, X 2 N is X 3 N is X 1 CR x1 And R 2It is a cycloalkyl, and R 3 is an alkoxy. In one embodiment, X 2 N is X 3 N is X 1 CH is, R 2 It is a cycloalkyl, and R 3 It is an alkoxy.

[0116] In one embodiment, the compound of formula (II) is provided herein.

[0117] [ka] During the ceremony X 4 is N or CR x4 And R x4 These are hydrogen, C1-C6 alkyl, or halogen. X 5 is N or CR x5 And R x5 These are hydrogen, C1-C6 alkyl, or halogen. R a1 This is selected from deuterium, halogen, nitro, cyano, hydroxy, alkyl, cycloalkyl, haloalkyl, alkoxy, and haloalkyloxy. R a2These are deuterium, halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, deuterated alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkyl, alkoxy, deuterated alkoxy, haloalkyloxy, acyl; cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, spiroheterocyclyl, spirocyclyl, cross-linked heterocyclyl, cross-linked carbocyclyl, aralkyl, heteroarylalkyl, alkoxyalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (carboxamide)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxy, amide, carboxamide, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, and alkylthio, R a2 It has been arbitrarily replaced.

[0118] Ring A, L, R 1 , R 2 , and R 3 Each of them is as defined above, Alternatively, it may be a stereoisomer, a mixture of such stereoisomers, a solvate, or a pharmaceutically acceptable salt thereof.

[0119] In one embodiment, X 4 In one embodiment, X 4 CR x4 In one embodiment, X 4 is CH. In one embodiment, R x4 is a halogen. In one embodiment, R x4 is fluoro. In one embodiment, R x4 is chloro. In one embodiment, R x4 is bromo. In one embodiment, R x4is iodine. In one embodiment, R x4 is a C1-C6 alkyl group. In one embodiment, R x4 is ethyl. In one embodiment, R x4 is propyl (e.g., n-propyl or isopropyl). In one embodiment, R x4 is butyl (e.g., n-butyl, isobutyl, or tert-butyl). In one embodiment, R x4 is a pentill. In one embodiment, R x4 It is hexyl.

[0120] In one embodiment, X 5 In one embodiment, X 5 CR x5 In one embodiment, X 5 is CH. In one embodiment, R x5 is a halogen. In one embodiment, R x5 is fluoro. In one embodiment, R x5 is chloro. In one embodiment, R x5 is bromo. In one embodiment, R x5 is iodine. In one embodiment, R x5 is a C1-C6 alkyl group. In one embodiment, R x5 is ethyl. In one embodiment, R x5 is propyl (e.g., n-propyl or isopropyl). In one embodiment, R x5 is butyl (e.g., n-butyl, isobutyl, or tert-butyl). In one embodiment, R x5 is a pentill. In one embodiment, R x5 It is hexyl.

[0121] In one embodiment, X 4 is N, and X 5 CR x5 In one embodiment, X 4 N is X 5 In one embodiment, X4 CR x4 X 5 In one embodiment, X 4 CR x4 X 5 CR x5 That is the case.

[0122] In one embodiment, X 4 is N, and X 5 is CH. In one embodiment, X 4 N is X 5 In one embodiment, X 4 CH is, X 5 In one embodiment, X 4 CH is, X 5 It is CH.

[0123] In one embodiment, R a1 The following are selected from cyano, nitro, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoropropan-2-yl, 2-fluoroethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethoxy, and trifluoromethoxy.

[0124] In one embodiment, R a2Fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, 1-fluoropropan-2-yl, 2-fluoroethyl, formyl, acetyl, propionyl, amino, methylamino, ethylamino, dimethylamino, 2,2-difluoroethoxy, cyclopropoxy, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranil, oxetanyl, azetidinyl, pyrrolidinyl, dihydropyridinyl, tetrahydropyridinyl, tetrahydrothiapyranil, Selected from tetrahydrothiopyranyl, morpholinyloxy, piperidinyloxy, piperazinyloxy, tetrahydropyranyloxy, oxetanyloxy, azetidinyloxy, pyrrolidinyloxy, dihydropyridinyloxy, tetrahydropyridinyloxy, tetrahydrothiapyranyloxy, morpholinylmethyl, piperidinylmethyl, piperazinylmethyl, tetrahydropyranylmethyl, oxetanylmethyl, azetidinylmethyl, pyrrolidinylmethyl, dihydropyridinylmethyl, tetrahydropyridinylmethyl, tetrahydrothiapyranylmethyl, azaspiroheptyl, azabicycloheptyl, diazabicycloheptyl, methoxymethyl, methylaminomethyl, deuterium methyl, deuterium ethyl, deuterium isopropyl, deuterium methoxy, and deuterium ethoxy, R a2 It has been arbitrarily replaced.

[0125] In one embodiment, R a2 is one or more R 5 It is arbitrarily replaced by R. In one embodiment, a2 is non-substitutable. In one embodiment, R a2 is one R 5 It is replaced by R a2 This is two R's 5 It has been replaced with.

[0126] In one embodiment, each R 5 These include halogens, nitro, cyano, hydroxy, sulfhydryl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkyl, alkoxy, acyl, cycloalkyloxy, heterocyclyloxy, heterocyclylcarbonyl, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, spiroheterocyclyl, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (carboxamide ) Alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, oxo, carboxy, amide, carboxamide, sulfonamide, formyl, carbamoyl, sulfamoyl, alkylcarbonyl, haloalkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, and alkylthio are independently selected from R 5 is optionally substituted and / or two R 5 These, together with the same ring carbon atom to which they are bonded, form optionally substituted C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl groups, and / or two R groups bonded to different carbon atoms. 5 They combine to form arbitrarily substituted bridging rings.

[0127] In one embodiment, each R 5R is independently selected from fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, oxo, cyclopropyl, cyclopropylcarbonyl, isopropylcarbonyl, cyclobutylcarbonyl, formyl, acetyl, trifluoroacetyl, propionyl, amino, hydroxy, sulfhydryl, oxetanyl, oxetane-3-carbonyl, azetidinyl, methylsulfonyl, ethylsulfonyl, aminomethylsulfonyl, methylsulfinyl, ethylsulfinyl, carbamoyl, benzoyl, sulfamoyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, thiophenyl, piperidinyl, piperazinyl, tetrahydrothiapyranil and tetrahydrothiopyranil, 5 is optionally substituted and / or two R 5 These, together with the same ring carbon atom to which they are bonded, form optionally substituted cyclobutyl or azetidinyl, and / or two R atoms bonded to different carbon atoms. 5 These combine to form optionally substituted azabicycloheptyl or diazabicycloheptyl.

[0128] In one embodiment, R 5 is one or more R 6 It is arbitrarily replaced by R. In one embodiment, 5 is non-substitutable. In one embodiment, R 5 is one R 6 It is replaced by R 5 This is two R's 6 It has been replaced with.

[0129] In one embodiment, each R 6This is independently selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkyl, alkoxy, acyl; cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (carboxamide)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxy, amide, carboxamide, sulfonamide, alkylcarbonyl, arylcarbonyl, formyl, carbamoyl, alkylsulfonyl, arylsulfonyl, and alkylthio, R 6 This can be replaced as desired.

[0130] In one embodiment, each R 6 R is independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, carbamoyl, methylsulfonyl, ethylsulfonyl, formyl, acetyl, propionyl, methoxy, ethoxy, isopropoxy, tert-butoxy, amino, methylamino, ethylamino, dimethylamino, hydroxy, carboxamide, acetamide, propionamide, carbamoyl, methylsulfonyl, ethylsulfonyl, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranil, oxetanyl, azetidinyl, isoxazolidinyl and pyrrolidinyl, 6 It has been arbitrarily replaced.

[0131] In one embodiment, R 6 is one or more R 7 It is arbitrarily replaced by R. In one embodiment, 6 is non-substitutable. In one embodiment, R6 is one R 7 It is replaced by R 6 This is two R's 7 It has been replaced with.

[0132] In one embodiment, each R 7 The following are independently selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkyl, alkoxy, oxo, acyl, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, hydroxyalkyloxy, carboxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (carboxamide)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxy, amide, carboxamide, sulfonamide, alkylcarbonyl, arylcarbonyl, formyl, carbamoyl, alkylsulfonyl, arylsulfonyl, and alkylthio.

[0133] In one embodiment, each R 7 The following are independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, acetyl, oxo, hydroxy, sulfhydryl, oxetanyl, azetidinyl, imidazolidinyl, methylsulfonyl, methylamino, dimethylamino, methoxy, ethoxy, isopropoxy, tert-butoxy, and hydroxyethoxy.

[0134] In one embodiment, R a2 is methyl. In one embodiment, R a2 is methoxy. In one embodiment, R a2is dimethylamino. In one embodiment, R a2 is cyclopropyl. In one embodiment, R a2 is fluoro. In one embodiment, R a2 teeth,

[0135] [ka] In one embodiment, R a2 teeth,

[0136] [ka] In one embodiment, R a2 teeth,

[0137] [ka] In one embodiment, R a2 teeth,

[0138] [ka] In one embodiment, R a2 teeth,

[0139] [ka] In one embodiment, R is the case. a2 teeth,

[0140] [ka] In one embodiment, R a2 teeth,

[0141] [ka] In one embodiment, R a2 teeth,

[0142] [ka] In one embodiment, R a2 teeth,

[0143] [ka] In one embodiment, R a2 teeth,

[0144] [ka] In one embodiment, R a2 teeth,

[0145] [ka] In one embodiment, R a2 teeth,

[0146] [ka] In one embodiment, R a2 teeth,

[0147] [ka] In one embodiment, R a2 teeth,

[0148] [ka] In one embodiment, R a2 teeth,

[0149] [ka] In one embodiment, R a2 It is.

[0150] [ka] In one embodiment, R a2 teeth,

[0151] [ka] In one embodiment, R a2 teeth,

[0152] [ka] In one embodiment, R a2 teeth,

[0153] [ka] In one embodiment, R a2 teeth,

[0154] [ka] In one embodiment, R a2 teeth,

[0155] [ka] In one embodiment, R a2 teeth,

[0156] [ka] In one embodiment, R a2 teeth,

[0157] [ka] In one embodiment, R a2 teeth,

[0158] [ka] In one embodiment, R a2 teeth,

[0159] [ka] In one embodiment, R a2 teeth,

[0160] [ka] In one embodiment, R a2 teeth,

[0161] [ka] In one embodiment, R a2 teeth,

[0162] [ka] In one embodiment, R a2 teeth,

[0163] [ka] In one embodiment, R a2 teeth,

[0164] [ka] In one embodiment, R a2 teeth,

[0165] [ka] In one embodiment, R a2 teeth,

[0166] [ka] In one embodiment, R a2 teeth,

[0167] [ka] In one embodiment, R a2 teeth,

[0168] [ka] In one embodiment, R a2 teeth,

[0169] [ka] In one embodiment, R a2 teeth,

[0170] [ka] In one embodiment, R a2 teeth,

[0171] [ka] In one embodiment, R a2 teeth,

[0172] [ka] In one embodiment, R a2 teeth,

[0173] [ka] In one embodiment, R a2 teeth,

[0174] [ka] In one embodiment, R a2 teeth,

[0175] [ka] In one embodiment, R a2 teeth,

[0176] [ka] In one embodiment, R a2 teeth,

[0177] [ka] In one embodiment, R a2 teeth,

[0178] [ka] In one embodiment, R a2 teeth,

[0179] [ka] In one embodiment, R a2 teeth,

[0180] [ka] In one embodiment, R a2 teeth,

[0181] [ka] In one embodiment, R a2 teeth,

[0182] [ka] In one embodiment, R a2 teeth,

[0183] [ka] In one embodiment, R a2 teeth,

[0184] [ka] In one embodiment, R a2 teeth,

[0185] [ka] In one embodiment, R a2 teeth,

[0186] [ka] In one embodiment, R a2 teeth,

[0187] [ka] In one embodiment, R a2 teeth,

[0188] [ka] In one embodiment, R a2 teeth,

[0189] [ka] In one embodiment, R a2 teeth,

[0190] [ka] In one embodiment, R a2 teeth,

[0191] [ka] That is the case.

[0192] In one embodiment, ring A is an aryl compound. In one embodiment, ring A is C6~C 10 It is an aryl ring. In one embodiment, ring A is phenyl. In one embodiment, ring A is

[0193] [ka] That is the case.

[0194] In one embodiment, ring A is a heteroaryl. In one embodiment, ring A is a 5- to 10-membered heteroaryl. In one embodiment, ring A is a 5 or 6-membered heteroaryl. In one embodiment, nitrogen is the only heteroatom contained in the heteroaryl. In one embodiment, ring A is pyridyl. In one embodiment, ring A is

[0195] [ka] In one embodiment, ring A is

[0196] [ka] That is the case.

[0197] In one embodiment, ring A is a cycloalkyl group. In one embodiment, ring A is a C3-C8 cycloalkyl group. In one embodiment, ring A is a C5-C6 cycloalkyl group. In one embodiment, ring A is a cyclopentyl group. In one embodiment, ring A is a cyclohexyl group.

[0198] In one embodiment, ring A is a heterocyclyl. In one embodiment, ring A is a 5- to 10-membered heterocyclyl. In one embodiment, ring A is a 5 or 6-membered heterocyclyl. In one embodiment, nitrogen is the only heteroatom contained in the heterocyclyl. In one embodiment, ring A is pyrrolidinyl. In one embodiment, ring A is

[0199] [ka] In one embodiment, ring A is piperidinyl. In one embodiment, ring A is

[0200] [ka] In one embodiment, ring A is piperidinyl.

[0201] In one embodiment, ring A is a phenyl equivalent. In one embodiment, ring A is cubane. In one embodiment, ring A is

[0202] [ka] That is the case.

[0203] In one embodiment, ring A is one or more R 8 It is arbitrarily substituted with in the formula. 8 The ring A is independently selected from halogens, cyano, alkyl, amino, alkylamino, dialkylamino, hydroxy, and alkoxy, and each alkyl, alkylamino, dialkylamino, or alkoxy moiety is independently and optionally substituted with one or more halogens, hydroxy, or alkoxy. In one embodiment, ring A is unsubstituted. In one embodiment, ring A has one R 8 It is replaced by. In one embodiment, ring A has two R 8It is substituted with. Unless otherwise specified, the substitution state of ring A described herein does not take the R group into consideration.

[0204] In one embodiment, each R 8 The compound is independently selected from fluoro, chloro, cyano, methoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy, hydroxyethoxy, and methoxyethoxy.

[0205] In one embodiment, ring A is

[0206] [ka] In one embodiment, ring A is

[0207] [ka] In one embodiment, ring A is

[0208] [ka] In one embodiment, ring A is

[0209] [ka] In one embodiment, ring A is

[0210] [ka] In one embodiment, ring A is

[0211] [ka] In one embodiment, ring A is

[0212] [ka] In one embodiment, ring A is

[0213] [ka] In one embodiment, ring A is

[0214] [ka] In one embodiment, ring A is

[0215] [ka] In one embodiment, ring A is

[0216] [ka] In one embodiment, ring A is

[0217] [ka] In one embodiment, ring A is

[0218] [ka] In one embodiment, ring A is

[0219] [ka] In one embodiment, ring A is

[0220] [ka] In one embodiment, ring A is

[0221] [ka] In one embodiment, ring A is

[0222] [ka] In one embodiment, ring A is

[0223] [ka] That is the case.

[0224] As shown herein, unless otherwise specified, the bond on the left side of the ring A structure is to the carbon atom between L and ring A, and the bond on the right side is to the R group.

[0225] In one embodiment, R a2 It is piperidinyl, and R 5 This is Ashir.

[0226] In one embodiment, the compound of formula (III) is provided herein.

[0227] [ka] During the ceremony R a3 These are selected from halogens, haloalkyls, nitros, cyanos, hydroxys, alkyls, alkoxys, and cycloalkyls. R a4is selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkyl, alkoxy, acyl, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (carboxamide)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxy, amide, carboxamide, sulfonamide, alkylcarbonyl, arylcarbonyl, formyl, carbamoyl, alkylsulfonyl, arylsulfonyl, and alkylthio, R a4 It can be arbitrarily replaced, L, R 1 , R 2 , and R 3 Each of them is as defined above, Alternatively, it may be a stereoisomer, a mixture of such stereoisomers, a solvate, or a pharmaceutically acceptable salt thereof.

[0228] In one embodiment, R a3 The following are selected from cyano, nitro, hydroxy, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, isopropoxy, and tert-butoxy.

[0229] In one embodiment, R a4R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, trifluoromethyl, carbamoyl, methylsulfonyl, ethylsulfonyl, formyl, acetyl, propionyl, methoxy, ethoxy, isopropoxy, tert-butoxy, amino, methylamino, ethylamino, dimethylamino, hydroxy, carboxamide, acetamide, propionamide, carbamoyl, methylsulfonyl, ethylsulfonyl, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranil, oxetanyl, azetidinyl, isoxazolidinyl, and pyrrolidinyl. a4 It has been arbitrarily replaced.

[0230] In one embodiment, R a4 is one or more R 9 It is arbitrarily replaced by R. In one embodiment, a4 is non-substitutable. In one embodiment, R a4 is one R 9 It is replaced by R a4 This is two R's 9 It has been replaced with.

[0231] In one embodiment, each R 9These are independently selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkyl, alkoxy, oxo, acyl, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, hydroxyalkyloxy, carboxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (carboxamide)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxy, amide, carboxamide, sulfonamide, alkylcarbonyl, arylcarbonyl, formyl, carbamoyl, alkylsulfonyl, arylsulfonyl, and alkylthio.

[0232] In one embodiment, each R 9 The following are independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, acetyl, oxo, hydroxy, sulfhydryl, oxetanyl, azetidinyl, imidazolidinyl, methylsulfonyl, methylamino, dimethylamino, methoxy, ethoxy, isopropoxy, tert-butoxy, and hydroxyethoxy.

[0233] In one embodiment, R a4 is methyl. In one embodiment, R a4 is ethyl. In one embodiment, R a4 is isopropyl. In one embodiment, R a4 is cyclopropyl. In one embodiment, R a4 is an amino acid. In one embodiment, R a4 is methylamino. In one embodiment, R a4is hydroxymethyl. In one embodiment, R a4 is trifluoromethyl. In one embodiment, R a4 is methylsulfonyl ethyl. In one embodiment, R a4 teeth,

[0234] [ka] In one embodiment, R a4 teeth,

[0235] [ka] In one embodiment, R a4 teeth,

[0236] [ka] In one embodiment, R a4 teeth,

[0237] [ka] In one embodiment, R a4 teeth,

[0238] [ka] In one embodiment, R a4 teeth,

[0239] [ka] In one embodiment, R a4 teeth,

[0240] [ka] In one embodiment, R a4 teeth,

[0241] [ka] In one embodiment, R a4 teeth,

[0242] [ka] In one embodiment, R a4 teeth,

[0243] [ka] In one embodiment, R a4 teeth,

[0244] [ka] In one embodiment, R a4 teeth,

[0245] [ka] In one embodiment, R a4 teeth,

[0246] [ka] In one embodiment, R a4 teeth,

[0247] [ka] In one embodiment, R a4 teeth,

[0248] [ka] In one embodiment, R a4 teeth,

[0249] [ka] In one embodiment, R a4 teeth,

[0250] [ka] In one embodiment, R a4 teeth,

[0251] [ka] In one embodiment, R a4 teeth,

[0252] [ka] That is the case.

[0253] In one embodiment, L is NR b In one embodiment, L is NH. In one embodiment, L is N(C1-C6 alkyl). In one embodiment, L is O. In one embodiment, L is S.

[0254] In one embodiment, R b is methyl. In one embodiment, R b is ethyl. In one embodiment, R b is propyl (e.g., n-propyl or isopropyl). In one embodiment, R b is butyl (e.g., n-butyl, isobutyl, or tert-butyl). In one embodiment, R b is a pentill. In one embodiment, R b It is hexyl.

[0255] In one embodiment of formula (II) or (III), R 1 is an alkoxy. In one embodiment of formula (II) or (III), R2 is a cycloalkyl. In one embodiment of formula (II) or (III), R 3 It is methoxy.

[0256] In one embodiment, the compound provided herein is a single enantiomer. In one embodiment, the compound provided herein is a single diastereoisomer. In one embodiment, the compound provided herein is a mixture of enantiomers. In one embodiment, the compound provided herein is a mixture of diastereoisomers. In one embodiment, the compound provided herein is a racemic compound.

[0257] In one embodiment, the compounds provided herein have an enantiomer excess of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, or at least about 99.9%. In one embodiment, the compound is a substantially purified enantiomer. In one embodiment, the compound is a substantially purified enantiomer of the S configuration. In one embodiment, the compound is a substantially purified enantiomer of the R configuration.

[0258] In one embodiment, the compound has an enantiomeric excess of at least about 80% S-configuration. In one embodiment, the compound has an enantiomeric excess of at least about 90% S-configuration. In one embodiment, the compound has an enantiomeric excess of at least about 92% S-configuration. In one embodiment, the compound has an enantiomeric excess of at least about 94% S-configuration. In one embodiment, the compound has an enantiomeric excess of at least about 96% S-configuration. In one embodiment, the compound has an enantiomeric excess of at least about 98% S-configuration. In one embodiment, the compound has an enantiomeric excess of at least about 99% S-configuration. In one embodiment, the compound has an enantiomeric excess of at least about 99.5% S-configuration. In one embodiment, the compound has an enantiomeric excess of at least about 99.9% S-configuration.

[0259] In one embodiment, the compound has an enantiomeric excess of at least about 80% R-configuration. In one embodiment, the compound has an enantiomeric excess of at least about 90% R-configuration. In one embodiment, the compound has an enantiomeric excess of at least about 92% R-configuration. In one embodiment, the compound has an enantiomeric excess of at least about 94% R-configuration. In one embodiment, the compound has an enantiomeric excess of at least about 96% R-configuration. In one embodiment, the compound has an enantiomeric excess of at least about 98% R-configuration. In one embodiment, the compound has an enantiomeric excess of at least about 99% R-configuration. In one embodiment, the compound has an enantiomeric excess of at least about 99.5% R-configuration. In one embodiment, the compound has an enantiomeric excess of at least about 99.9% R-configuration.

[0260] In one embodiment, the compound is one of the compounds listed in Table 1, or a pharmaceutically acceptable salt thereof.

[0261] Table 1 [Table 1-1]

[0262] (Continued from Table 1) [Table 1-2]

[0263] (Continued from Table 1) [Table 1-3]

[0264] (Continued from Table 1) [Table 1-4]

[0265] Where used herein, unless otherwise specified, if the stereochemical configuration of a chiral center in a compound provided herein is described stereospecifically (e.g., having a widget and / or dash bond) without further designation, or designated as "R" (or "R") or "S" (or "S"), it means that the absolute stereochemistry is known. For some compounds, the stereochemical configuration at the indicated center means that the compound itself is isolated as a single stereoisomer and is enantiomerically pure, but the absolute stereochemistry is undetermined (even if the bond is described stereospecifically), * If the column conditions for separation of "R" are described in the synthesis protocol, and only one stereocenter is present or indicated, then the first to elute from the column or " * It is specified as "S" (the second to elute from the column if the separation column conditions are described in the synthesis protocol and only one stereocenter is present or indicated). * When a compound designated as "R" is converted to another compound, the resulting compound is *The "R" designation originates from the starting material.

[0266] In one embodiment, the compounds provided herein are USP1 inhibitors that reduce the level of USP1 protein and / or inhibit or reduce at least one biological activity of the USP1 protein.

[0267] In one embodiment, the compounds provided herein specifically bind to the USP1 protein. In one embodiment, the compounds provided herein specifically bind to the USP1 protein in the USP1-UAF1 complex. In one embodiment, the compounds provided herein specifically bind to USP1 mRNA. In one embodiment, the compounds provided herein specifically bind to the USP1 protein (alone or in the USP1-UAF1 complex) or USP1 mRNA. In one embodiment, the compounds provided herein specifically bind to UAF1 (alone or in the USP1-UAF1 complex) and inhibit or reduce the formation or activity of the USP1-UAF1 complex.

[0268] In one embodiment, and without being bound by any particular theory, the S-enantiomer of the compounds provided herein has a higher binding affinity to the USP1 protein than the R-enantiomer. In one embodiment, the S-enantiomer has a binding affinity to the USP1 protein that is at least 1.5, 2, 3, 4, 5, 6, 8, 10, 20, 30, 50, or 100 times higher than the R-enantiomer.

[0269] In one embodiment, and without being bound by any particular theory, the R-enantiomer of the compounds provided herein has a higher binding affinity to the USP1 protein than the S-enantiomer. In one embodiment, the R-enantiomer has a binding affinity to the USP1 protein that is at least 1.5, 2, 3, 4, 5, 6, 8, 10, 20, 30, 50, or 100 times higher than the S-enantiomer.

[0270] In one embodiment, the compounds provided herein reduce the formation of the USP1-UAF1 complex. In one embodiment, the compounds provided herein reduce the activity of the USP1-UAF1 complex. In one embodiment, the compounds provided herein reduce the deubiquitinating enzyme activity of USP1. In one embodiment, the compounds provided herein increase monoubiquitinated PCNA. In one embodiment, the compounds provided herein increase monoubiquitinated FANCD2.

[0271] In one embodiment, the compounds provided herein increase monoubiquitinated FANCI.

[0272] In one embodiment, the compounds provided herein do not bind to other deubiquitinating enzymes, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1). In one embodiment, the compounds provided herein bind to deubiquitinating enzymes, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1) with an affinity at least about 5 times, at least about 10 times, at least about 20 times, or at least about 100 times lower than the affinity to USP1 (i.e., the K of the compounds provided herein to other deubiquitinating enzymes, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1)). D (This is at least approximately 5 times, at least approximately 10 times, at least approximately 20 times, or at least approximately 100 times higher than the KD ratio for USP1.)

[0273] In one embodiment, the compounds provided herein, when measured using the assay described in U.S. Patent Application Publication No. 2017 / 0145012, have ICs of less than about 50 nM, about 50 nM to about 200 nM, about 200 nM to about 2 μM, or greater than 2 μM. 50 Alternatively, when measured using the assay disclosed, for example, in Liang et al., Nat Chem Biol 10:289-304 (2014), IC50 ranges from 50 nM to 1000 nM. 50Therefore, it inhibits USP1 deubiquitinating enzyme activity. In one embodiment, the compounds provided herein, when measured using the assay disclosed in Chen, et al., Chem Biol., 18(11):1390-1400 (2011), exhibit IC50. 50 This inhibits USP1 deubiquitinase activity. In one embodiment, the compounds provided herein do not inhibit the activity of other deubiquitinases, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1), or the compounds provided herein do not inhibit USP1 deubiquitinase activity. 50 Compared to that, ICs are at least approximately 5 times, at least approximately 10 times, at least approximately 20 times, or at least approximately 100 times higher. 50 This inhibits the activity of other deubiquitinating enzymes, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1).

[0274] In one embodiment, the compounds provided herein bind to the USP1 protein with affinities in the range of about 1 pM to about 100 μM, about 1 pM to about 1 μM, about 1 pM to about 500 nM, or about 1 pM to about 100 nM. In some embodiments, the compounds provided herein bind to the USP1 protein with affinity to about 1 pM to about 100 μM, about 1 nM to about 100 μM, about 1 μM to about 100 μM, about 1 μM to about 50 μM, about 1 μM to about 40 μM, about 1 μM to about 30 μM, about 1 μM to about 20 μM, or about 1 μM to about 10 μM, about 1 μM, about 5 μM, about 10 μM, about 15 μM, about 20 μM, about 25 μM, about 30 μM, about 35 μM, about 40 μM, about 45 μM, about 50 μM, about 60 μM, about 70 μM, about 80 μM, about 90 μM, or about 100 μM. In some embodiments, the compounds provided herein are available in concentrations of approximately 100 nM to 1 μM, approximately 100 nM to 900 nM, approximately 100 nM to 800 nM, approximately 100 nM to 700 nM, approximately 100 nM to 600 nM, approximately 100 nM to 500 nM, approximately 100 nM to 400 nM, approximately 100 nM to 300 nM, approximately 100 nM to 200 nM, approximately 200 nM to 1 μM, and approximately It binds to the USP1 protein with affinity levels of approximately 300 nM to 1 μM, 400 nM to 1 μM, 500 nM to 1 μM, 600 nM to 1 μM, 700 nM to 1 μM, 800 nM to 1 μM, 900 nM to 1 μM, 100 nM, 200 nM, 300 nM, 400 nM, 500 nM, 600 nM, 700 nM, 800 nM, or 900 nM.In some embodiments, the compounds provided in specification are approximately 1 nM to approximately 100 nM, approximately 1 nM to approximately 90 nM, approximately 1 nM to approximately 80 nM, approximately 1 nM to approximately 70 nM, approximately 1 nM to approximately 60 nM, approximately 1 nM to approximately 50 nM, approximately 1 nM to approximately 40 nM, approximately 1 nM to approximately 30 nM, approximately 1 nM to approximately 20 nM, approximately 1 nM to approximately 10 nM, approximately 10 nM to approximately 100 nM, approximately 20 nM to approximately 100 nM, approximately 30 nM to approximately 100 nM, approximately 40 nM to approximately 100 nM, The compounds bind to the USP1 protein with affinity of approximately 50 nM to 100 nM, 60 nM to 100 nM, 70 nM to 100 nM, 80 nM to 100 nM, 90 nM to 100 nM, 1 nM, 2 nM, 3 nM, 4 nM, 5 nM, 6 nM, 7 nM, 8 nM, 9 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, or 100 nM. In some embodiments, the compounds provided herein bind to the USP1 protein with affinity of less than 1 μM, less than 500 nM, less than 100 nM, less than 10 nM, or less than 1 nM. In one embodiment, the compounds provided herein bind to the USP1 protein with an affinity of less than 1 nM.

[0275] In one embodiment, the compounds provided herein are ICs with a concentration of about 1 pM to about 100 μM, or about 1 pM to about 1 μM, or about 1 pM to about 500 nM, or about 1 pM to about 100 nM. 50 This inhibits USP1 activity. In one embodiment, the compounds provided herein are ICs in concentrations of about 1 pM to about 100 μM, about 1 nM to about 100 μM, about 1 μM to about 100 μM, about 1 μM to about 50 μM, about 1 μM to about 40 μM, about 1 μM to about 30 μM, about 1 μM to about 20 μM, or about 1 μM to about 10 μM, about 1 μM, about 5 μM, about 10 μM, about 15 μM, about 20 μM, about 25 μM, about 30 μM, about 35 μM, about 40 μM, about 45 μM, about 50 μM, about 60 μM, about 70 μM, about 80 μM, about 90 μM, or about 100 μM. 50This inhibits USP1 activity. In some embodiments, the compounds provided herein are available in concentrations of about 100 nM to about 1 μM, about 100 nM to about 900 nM, about 100 nM to about 800 nM, about 100 nM to about 700 nM, about 100 nM to about 600 nM, about 100 nM to about 500 nM, about 100 nM to about 400 nM, about 100 nM to about 300 nM, about 100 nM to about 200 nM, and about 200 nM. ICs with a microfilament of approximately M to 1 μM, approximately 300 nM to 1 μM, approximately 400 nM to 1 μM, approximately 500 nM to 1 μM, approximately 600 nM to 1 μM, approximately 700 nM to 1 μM, approximately 800 nM to 1 μM, approximately 900 nM to 1 μM, approximately 100 nM, approximately 200 nM, approximately 300 nM, approximately 400 nM, approximately 500 nM, approximately 600 nM, approximately 700 nM, approximately 800 nM, or approximately 900 nM 50 This inhibits USP1 activity. In some embodiments, the compounds provided herein are available in concentrations of approximately 1 nM to approximately 100 nM, approximately 1 nM to approximately 90 nM, approximately 1 nM to approximately 80 nM, approximately 1 nM to approximately 70 nM, approximately 1 nM to approximately 60 nM, approximately 1 nM to approximately 50 nM, approximately 1 nM to approximately 40 nM, approximately 1 nM to approximately 30 nM, approximately 1 nM to approximately 20 nM, approximately 1 nM to approximately 10 nM, approximately 10 nM to approximately 100 nM, approximately 20 nM to approximately 100 nM, approximately 30 nM to approximately 100 nM, and approximately 40 nM. ICs with a molecular weight of approximately M to 100nM, approximately 50nM to 100nM, approximately 60nM to 100nM, approximately 70nM to 100nM, approximately 80nM to 100nM, approximately 90nM to 100nM, approximately 1nM, approximately 2nM, approximately 3nM, approximately 4nM, approximately 5nM, approximately 6nM, approximately 7nM, approximately 8nM, approximately 9nM, approximately 10nM, approximately 20nM, approximately 30nM, approximately 40nM, approximately 50nM, approximately 60nM, approximately 70nM, approximately 80nM, approximately 90nM, or approximately 100nM. 50 This inhibits USP1 activity. In one embodiment, the compounds provided herein have IC50 concentrations of less than 1 μM, less than 500 nM, less than 100 nM, less than 10 nM, or less than 1 nM. 50 This inhibits USP1 activity. In one embodiment, the compounds provided herein have an IC50 of less than 1 nM. 50 This inhibits USP1 activity.

[0276] In one embodiment, although not bound by any particular theory, regarding the inhibition of USP1 activity, the IC of the S enantiomer of the compound provided herein 50 This is the R enantiomer IC 50 Lower than. In one embodiment, with respect to inhibition of USP1 activity, IC of the R enantiomer 50 This is the IC of the S enantiomer. 50 It is at least 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 8 times, 10 times, 20 times, 30 times, 50 times, or 100 times higher than [the other value].

[0277] In one embodiment, although not bound by any particular theory, regarding the inhibition of USP1 activity, the IC of the R enantiomer of the compound provided herein 50 This is the IC of the S enantiomer. 50 It is lower than. In one embodiment, regarding the inhibition of USP1 activity, the IC of the S enantiomer 50 This is the R enantiomer IC 50 It is at least 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 8 times, 10 times, 20 times, 30 times, 50 times, or 100 times higher than [the other value].

[0278] How to use In one embodiment, the compounds provided herein can be used to inhibit the activity of the USP1 protein. In one embodiment, a method for inhibiting the USP1 protein is provided herein, comprising contacting the USP1 protein with the compounds provided herein. The contact can be performed in vitro or in vivo. In one embodiment, the contact is performed in a subject suffering from a USP1 protein-mediated disorder.

[0279] In one embodiment, the compounds provided herein can be used to treat USP1 protein-mediated disorders. In one embodiment, provided herein is a method for treating a USP1 protein-mediated disorder or cancer, comprising administering a therapeutically effective amount of the compounds or pharmaceutical compositions provided herein to a subject having the disorder or cancer. A USP1 protein-mediated disorder is any pathological condition in which the USP1 protein is known to play a role. In one embodiment, a USP1 protein-mediated disorder is a proliferative disorder such as cancer.

[0280] In one embodiment, this specification provides a method for treating diseases and disorders using compounds provided herein. Exemplary diseases and disorders that can be treated with compounds provided herein include, but are not limited to, cancer.

[0281] In one embodiment, the foregoing provides a method for treating cancer, comprising administering to a subject having cancer a therapeutically effective amount of a compound or pharmaceutical composition provided herein.

[0282] In one embodiment, cancer is a hematological cancer, lymphoma, DNA damage repair pathway deficiency cancer, homologous recombination deficiency cancer, cancer containing cancer cells having a mutation in the gene encoding p53, or cancer containing cancer cells having a loss-of-function mutation in the gene encoding p53. In one embodiment, cancer is a cancer containing cancer cells having a mutation in the gene encoding p53. In one embodiment, cancer is a cancer containing cancer cells having a loss-of-function mutation in the gene encoding p53. In one embodiment, cancer is a cancer containing cancer cells having a mutation in the gene encoding BRCA1. In one embodiment, cancer is a cancer containing cancer cells having a mutation in the gene encoding BRCA2. In one embodiment, cancer is a cancer containing cancer cells having a loss-of-function mutation in the gene encoding ATM.

[0283] In one embodiment, the cancer is a solid tumor. In one embodiment, the cancer is lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, or breast cancer. In one embodiment, the cancer is non-small cell lung cancer (NSCLC), osteosarcoma, ovarian cancer, or breast cancer. In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is triple-negative breast cancer.

[0284] In one embodiment, the cancers treated with the compounds provided herein are selected from the group consisting of bone cancers, including osteosarcoma and chondrosarcoma; brain cancers, including glioma, glioblastoma, astrocytoma, medulloblastoma, and meningioma; soft carcinomas, including rhabdoid and sarcoma; kidney cancer; bladder cancer; skin cancers, including melanoma; and lung cancers, including non-small cell lung cancer; colon cancer, uterine cancer; nervous system cancers; head and neck cancers; pancreatic cancer; and cervical cancer.

[0285] In one embodiment, the method provided herein is a method for treating cancer, comprising administering a therapeutically effective amount of a compound provided herein to a subject having cancer, wherein the cancer comprises cancer cells with elevated levels of RAD18. In one embodiment, the elevated level of RAD18 is an elevated level of RAD18 protein. In one embodiment, the elevated level of RAD18 is an elevated level of RAD18 mRNA. In one embodiment, the elevated level of RAD18 (e.g., RAD18 protein and / or RAD18 mRNA) is detected before administration (e.g., in a cancer sample obtained from the subject). That is, in one embodiment, the cancer in the subject is tested for RAD18 protein or mRNA before initiating treatment with a USP1 inhibitor such as a compound provided herein.

[0286] In one embodiment, such a method comprises (a) identifying the cancer in the subject as a USP1 inhibitor-sensitive cancer, and then (b) administering a therapeutically effective dose of the compound provided herein to the subject.

[0287] In one embodiment, such a method comprises (a) detecting the level of RAD18 (e.g., RAD18 protein and / or RAD18 mRNA) in cancer cells (e.g., in a cancer sample obtained from a subject), and then (b) administering a therapeutically effective amount of the compound provided herein to a subject having cancer, including cancer cells with elevated levels of RAD18.

[0288] In one embodiment, such a method includes administering a therapeutically effective amount of the compound provided herein to a subject having triple-negative breast cancer.

[0289] In one embodiment, the compounds provided herein are used to treat cancer, which is homologous recombination-deficient cancer. In one embodiment, the compounds provided herein are used to treat cancer, which comprises cancer cells having a mutation in the gene encoding p53. In one embodiment, the compounds provided herein are used to treat cancer, which comprises cancer cells having a loss-of-function mutation in the gene encoding p53. In one embodiment, the compounds provided herein are used to treat cancer that does not have a defect in the homologous recombination pathway.

[0290] In one embodiment, the compound provided herein is used to treat cancer, which is a BRCA1 mutant cancer. In one embodiment, the compound provided herein is used to treat cancer, which is a BRCA2 mutant cancer. In one embodiment, the compound provided herein is used to treat cancer, which is a BRCA1 mutant cancer and a BRCA2 mutant cancer. In one embodiment, the cancer is neither a BRCA1 mutant cancer nor a BRCA2 mutant cancer. In one embodiment, the cancer is a BRCA1-deficient cancer. In one embodiment, the cancer is a BRCA2-deficient cancer. In one embodiment, the cancer is a BRCA1-deficient cancer and a BRCA2-deficient cancer.

[0291] In one embodiment, the compounds provided herein are used to treat cancer, which is ATM-mutated cancer. In one embodiment, the cancer is not ATM-mutated cancer. In one embodiment, the cancer is ATM-deficient cancer.

[0292] In one embodiment, the compounds provided herein are used to treat cancer, which is PARP inhibitor-resistant or refractory cancer. In one embodiment, the cancer is PARP inhibitor-resistant or refractory BRCA1 mutation cancer. In one embodiment, the cancer is PARP inhibitor-resistant or refractory BRCA1 deficiency cancer. In one embodiment, the cancer is PARP inhibitor-resistant or refractory BRCA2 mutation cancer. In one embodiment, the cancer is PARP inhibitor-resistant or refractory BRCA2 deficiency cancer.

[0293] In one embodiment, the cancer is a BRCA1 and / or BRCA2 mutant cancer, and the cancer includes cells with elevated levels of RAD18. In one embodiment, the elevated level of RAD18 is at least as high as the RAD18 protein and / or mRNA level in ES2 cells. In one embodiment, the elevated level of RAD18 is higher than the RAD18 protein and / or mRNA level in HEP3B217 cells. In one embodiment, triple-negative breast cancer is a BRCA1 and / or BRCA2 mutant cancer.

[0294] In one embodiment, the cancer is a solid tumor. In one embodiment, the cancer is a hematological / lymphatic cancer. In one embodiment, the cancer is a DNA damage repair pathway deficiency cancer. In one embodiment, the cancer is a homologous recombination deficiency cancer. In one embodiment, the cancer comprises cancer cells having a mutation in the gene encoding p53. In one embodiment, the cancer comprises cancer cells having a loss-of-function mutation in the gene encoding p53. In one embodiment, the cancer is selected from the group consisting of non-small cell lung cancer (NSCLC), osteosarcoma, ovarian cancer, and breast cancer (including triple-negative breast cancer). In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is triple-negative breast cancer.

[0295] In one embodiment, the compounds provided herein are used in combination with one or more additional therapeutic agents for the treatment of cancer. It has been reported that p53 status determines PARP inhibitor sensitization (Sa et al., Genome Biology, (2019) 20:253), and BRCA1 / 2 status predicts the clinical efficacy of PARP inhibitors (Audeh et al., Lancet (2010) 376(9737), 245-51). In one embodiment, without being bound by any particular theory, p53-mutated cancers and BRCA-mutated cancers have increased sensitivity to USP1 inhibitors. Therefore, in one embodiment, the compounds provided herein are used in combination with PARP inhibitors for the treatment of cancer.

[0296] In one embodiment, the compounds provided herein are provided for use as pharmaceuticals, for example, for the treatment of cancer, or for use in the preparation of pharmaceuticals. In one embodiment, the compounds provided herein are provided for use in a method for treating cancer.

[0297] Pharmaceutical composition Pharmaceutical compositions comprising the compounds provided herein and pharmaceutically acceptable excipients are also provided herein.

[0298] In one embodiment, the compounds provided herein are administered to mammals in the form of raw chemical substances without other components. In one embodiment, the compounds provided herein are administered to mammals as part of a pharmaceutical composition containing the compounds conjugated with a suitable pharmaceutically acceptable carrier (see, for example, Gennaro, Remington: The Science and Practice of Pharmacy with Facts and Comparisons: Drug facts Plus, 20th ed. (2003); Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed., Lippencott Williams and Wilkins (2004); Kibbe et al., Handbook of Pharmaceutical Excipients, 3rd ed., Pharmaceutical Press (2000)). Such carriers can be selected from pharmaceutically acceptable excipients and adjuvants.

[0299] In one embodiment, the pharmaceutical compositions provided herein may be prepared as liquid suspensions or solutions using liquids such as oils, water, alcohols, and combinations thereof.

[0300] In one embodiment, the pharmaceutical compositions provided herein may be prepared as sterile injectable preparations, which may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art.

[0301] In one embodiment, the pharmaceutical compositions provided herein may be administered orally in any orally acceptable dosage form, including capsules, tablets, aqueous suspensions, or liquids.

[0302] In one embodiment, the pharmaceutical composition provided herein may be administered in the form of a suppository for rectal administration.

[0303] In one embodiment, the pharmaceutical compositions provided herein may also be administered topically, particularly when the therapeutic target includes areas or organs easily accessible by topical application, such as diseases of the eyes, skin, or lower intestines. Topical application for the lower intestines may be achieved by rectal suppositories (see above) or suitable enema formulations. Topical transdermal patches may also be used. For topical application, the pharmaceutical compositions may be formulated in suitable ointments, lotions, or creams containing the active ingredient suspended or dissolved in one or more carriers.

[0304] In one embodiment, the pharmaceutical compositions provided herein may also be formulated as a micronized suspension in isotonic pH-adjusted sterile saline, or as a solution in isotonic pH-adjusted sterile saline, for ophthalmic administration, with or without preservatives such as benzylalkonium chloride. In one embodiment, for ophthalmic use, the pharmaceutical compositions may be formulated as an ointment such as petrolatum.

[0305] In one embodiment, the pharmaceutical compositions provided herein may also be administered by nasal aerosol or inhalation. Such compositions may be prepared according to techniques well known in the field of pharmaceutical formulations and may be prepared as solutions in physiological saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0306] In one embodiment, the pharmaceutical composition used for in vivo administration may be sterile. In one embodiment, this is achieved, for example, by filtration through a sterile filtration membrane.

[0307] In one embodiment, the pharmaceutical compositions provided herein include all compositions in which the compounds provided herein are bound to one or more pharmaceutically acceptable carriers. In one embodiment, the compounds provided herein are present in the composition in an amount effective to achieve its intended therapeutic purpose.

[0308] In one embodiment, the pharmaceutical compositions provided herein can be administered to any patient who may experience the beneficial effects of the compounds provided herein. In one embodiment, the patient is a mammal, such as a human or a companion animal. In one embodiment, the patient is a human.

[0309] In one embodiment, a kit is also provided herein, comprising the compounds provided herein (or compositions comprising the compounds provided herein), packaged in a manner that facilitates their use in carrying out the methods provided herein. In one embodiment, the kit comprises the compounds provided herein (or compositions comprising the compounds provided herein), packaged in a container such as a sealed bottle or vessel, with a label indicating the use of the compounds or compositions for carrying out the methods provided herein affixed to the container or included in the kit. In one embodiment, the compounds or compositions are packaged in unit dosage forms. In one embodiment, the kit further comprises a device suitable for administering the compounds or compositions according to an intended route of administration. In one embodiment, the kit comprises the compounds provided herein and instructions for administering the compounds to a patient having cancer. [Examples]

[0310] Specific embodiments of the claimed subject matter are illustrated by the following non-limiting embodiments.

[0311] The disclosed compounds can generally be synthesized by the following general procedures or by appropriate combinations of generally known synthetic methods. Techniques useful for synthesizing these compounds are readily apparent and available to those skilled in the art based on this disclosure. Many of the optionally substituted starting compounds and other reactants are commercially available or readily prepared by those skilled in the art using commonly used synthetic methods.

[0312] The following examples are intended to illustrate specific methods for preparing the disclosed compounds and are not intended to limit the range of reactions or reaction sequences that may be used when preparing the compounds provided herein.

[0313] Synthesis method In one embodiment, the foregoing describes a process (Method 1) for preparing the compound provided herein, comprising the following steps.

[0314] [ka] X is a halogen such as Br, Cl, or I.

[0315] Step 1 is carried out in the presence of a suitable organic base such as triethylamine or diisopropylethylamine, a suitable inorganic base such as sodium hydride, and in a suitable organic solvent such as THF, ethanol, or isopropanol, at a suitable temperature such as approximately -10 to approximately 120°C.

[0316] Step 2 is carried out at a suitable temperature, such as about 40 to about 120°C, in the presence of a suitable organic base such as triethylamine or diisopropylethylamine, a suitable inorganic base such as sodium carbonate or potassium phosphate, a suitable palladium catalyst such as CATACXIUMI A, Pd G3, or Pd(dppf)Cl2, and a suitable solvent combination such as dimethoxyethane / water or dioxane / water.

[0317] Several methods for preparing the compounds provided herein are illustrated in the following examples. Unless otherwise noted, all starting materials are obtained from commercial suppliers and used without further purification, or can be synthesized by those skilled in the art using well-known methods.

[0318] [Table 2-1]

[0319] (Continuation of the table above) [Table 2-2]

[0320] (Continuation of the table above) [Table 2-3]

[0321] Preparation of intermediates In some cases, for intermediates used in subsequent reaction steps as crude or partially purified intermediates, the molar amount of such intermediate in the subsequent reaction step is not mentioned, or alternatively, an estimated or theoretical molar amount of such intermediate in the subsequent reaction step is given in the reaction protocol described below.

[0322] Preparation of Intermediate 1

[0323] [ka]

[0324] A mixture of 3-bromo-2-chloro-6-(trifluoromethyl)pyridine (625.6 mg, 2.40 mmol, 1 equivalent), (1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridine-4-yl)boronic acid (600 mg, 2.64 mmol, 1.1 equivalent), Cs2CO3 (1.57 g, 4.80 mmol, 2 equivalents), and Pd(dppf)Cl2 (175.7 mg, 240.22 μmol, 0.1 equivalent) in dioxane (12 mL) and H2O (3 mL) was degassed, purged three times with N2, and then stirred under an N2 atmosphere at 90°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with 100 mL of H2O, and extracted with 200 mL (100 mL x 2) of EA. The combined organic layers were washed with 100 mL of NaCl aqueous solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was subjected to flash column chromatography on silica gel (eluent: A: petroleum ether, B: ethyl acetate, 0% B to 20% B in A. TLC: petroleum ether: ethyl acetate = 5:1, R f The mixture was purified using a method involving a concentration of 0.3 to obtain intermediate 1 (612.7 mg, 1.55 mmol, yield 64.53%, purity 91.784%) as a yellow oily substance.

[0325] Preparation of Intermediate 2

[0326] [ka]

[0327] A mixture of dioxane (12 mL) and intermediate 1 (612.7 mg, 1.69 mmol, 1 equivalent) in H2O (3 mL), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (474.4 mg, 2.03 mmol, 1.2 equivalents), Cs2CO3 (1.10 g, 3.38 mmol, 2 equivalents), and ditert-butyl(cyclopentyl)phosphine dichloropalladium iron (110.1 mg, 168.89 μmol, 0.1 equivalent) was degassed, purged three times with N2, and then stirred at 100°C for 16 hours under an N2 atmosphere. The reaction mixture was cooled to room temperature, diluted with 100 mL of H2O, and extracted with 200 mL (100 mL x 2) of EA. The combined organic layers were washed with 100 mL of aqueous NaCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography on silica gel (eluent: A: petroleum ether, B: ethyl acetate, 0% B to 34% B in A; TLC: petroleum ether: ethyl acetate = 1:1, Rf = 0.5) to obtain intermediate 2 (616.1 mg, 1.38 mmol, yield 81.98%, purity 97.632%) as a yellow solid.

[0328] Preparation of Intermediate 3

[0329] [ka]

[0330] To a solution of intermediate 2 (500 mg, 1.15 mmol, 1 equivalent) in MeOH (10 mL), Pd / C (244.9 mg, 230.18 μmol, 10% purity, 0.2 equivalents) and NH3.H2O (17 μL, 115.09 μmol, 25% purity, 0.1 equivalents) were added. The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 35°C for 16 hours under H2 (15 psi). The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was separated by preparative HPLC (basic conditions, column: Waters Xbridge BEH C18 150). * 25mm *The mixture was purified by 5 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 44%~64% over 10 minutes (B) to obtain intermediate 3 (231 mg, 495.43 μmol, yield 43.05%, purity 93.610%) as a white solid.

[0331] Preparation of intermediate 4

[0332] [ka]

[0333] To a mixture of intermediate 3 (231 mg, 529.25 μmol, 1 equivalent) in THF (5 mL), NaH (42.3 mg, 1.06 mmol, 60% purity, 2 equivalents) was added under N2 at 0°C, and the mixture was stirred at 0°C for 0.5 hours. 2,4-dichloro-5-methoxypyrimidine (189.4 mg, 1.06 mmol, 2 equivalents) was added, and the mixture was stirred at 0°C for 3.5 hours. The reaction mixture was quenched by adding 10 mL of saturated NH4Cl, then diluted with 40 mL of H2O, and extracted with 120 mL of EA (40 mL x 3). The combined organic layers were washed with 30 mL of brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash column chromatography on silica gel (eluent: A: petroleum ether, B: ethyl acetate, 0% B to 53% B in A; TLC: petroleum ether: ethyl acetate = 1:1, Rf = 0.6) to obtain intermediate 4 (306.7 mg, 521.15 μmol, yield 98.47%, purity 98.386%) as a colorless oil.

[0334] The following intermediates were synthesized using a method similar to that described above for intermediate 4.

[0335] [Table 3-1]

[0336] (Continuation of the table above) [Table 3-2]

[0337] Preparation of intermediate 5

[0338] [ka]

[0339] A mixture of intermediate 4 (306.7 mg, 529.70 μmol, 1 equivalent), 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (292.5 mg, 1.06 mmol, 2 equivalents), Na2CO3 (112.2 mg, 1.06 mmol, 2 equivalents), and CATACXIUM(R)A Pd G3 (38.5 mg, 52.97 μmol, 0.1 equivalent) in DME (8 mL) and H2O (2 mL) was degassed, purged three times with N2, and then stirred at 90°C for 2 hours under an N2 atmosphere. The reaction mixture was cooled to room temperature, diluted with 40 mL of H2O, and extracted with 60 mL (20 mL x 3) of EA. The combined organic layers were washed with 30 mL of NaCl aqueous solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was then subjected to preparative HPLC (basic conditions; column: Waters Xbridge C18 150). * 50mm * 10um; Mobile phase: [Water (NH 3. [H2O)-ACN]; gradient: Purified by 70%~100% B) over 11 minutes to obtain intermediate 5 (171.1 mg, 247.00 μmol, yield 46.63%, purity 100%) as a white solid.

[0340] The following intermediates were synthesized using a method similar to that described above for intermediate 5.

[0341] [Table 4]

[0342] Preparation of intermediate 6

[0343] [ka]

[0344] To a solution of intermediate 5 (171.1 mg, 247.00 μmol, 1 equivalent) in DCM (1 mL), TFA (0.5 mL, 6.73 mmol, 27.25 equivalents) was added at room temperature. The resulting reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain intermediate 6 (200 mg, crude product, TFA), which was used in the next step without further purification.

[0345] The following intermediates were synthesized using a method similar to that described above for intermediate 6.

[0346] [Table 5]

[0347] Preparation of intermediate 10

[0348] [ka]

[0349] To a solution of intermediate 6 (150 mg, crude composition, TFA) in DCM (2 mL), DIEA (55 μL, 318.41 μmol, 3 equivalents) and 2-[tert-butoxycarbonyl(methyl)amino]acetic acid (40.1 mg, 212.27 μmol, 2 equivalents) were added. Then, T4P (114.7 mg, 159.21 μmol, 50% purity, 1.5 equivalents) was added in small amounts. The resulting mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to obtain a residue, which was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent 0 / 1~80 / 20 ethyl acetate / petroleum ether gradient, 35 mL / min) to obtain intermediate 10 (55 mg, 66.39 μmol, yield 62.55%, purity 92.2%) as a white solid.

[0350] The following intermediates were synthesized using a method similar to that described above for intermediate 10.

[0351] [Table 6]

[0352] Preparation of intermediate 11

[0353] [ka]

[0354] A mixture of 3-bromo-2-chloro-6-(trifluoromethyl)pyridine (2 g, 7.68 mmol, 1 equivalent) and (1-methyl-2-oxo-4-pyridyl)boronic acid (1.17 g, 7.68 mmol, 1 equivalent) in dioxane (20 mL) and H2O (5 mL) was degassed, purged three times with N2, and then Pd(dppf)Cl2 (561.9 mg, 767.93 μmol, 0.1 equivalent) and Na2CO3 (1.63 g, 15.36 mmol, 2 equivalents) were added. The mixture was stirred at 90°C for 12 hours under an N2 atmosphere. The reaction mixture was cooled to room temperature, poured into H2O (50 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain intermediate 11 (1.4 g, 4.80 mmol, yield 62.53%, purity 99%) as a brown solid.

[0355] Preparation of intermediate 12

[0356] [ka]

[0357] A mixture of intermediate 11 (250 mg, 866.09 μmol, 1 equivalent) and [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (202.7 mg, 866.09 μmol, 1 equivalent) in DME (2 mL) and H2O (0.5 mL) was degassed, purged three times with N2, and Cs2CO3 (564.3 mg, 1.73 mmol, 2 equivalents) and ditert-butyl(cyclopentyl)phosphine dichloropalladium iron (56.4 mg, 86.61 μmol, 0.1 equivalent) were added. The mixture was degassed again, purged three times with N2, and stirred at 95°C for 12 hours under an N2 atmosphere. The reaction mixture was cooled to room temperature, diluted with H2O (40 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, ethyl acetate / methanol = 1 / 0 to 10 / 1; TLC: ethyl acetate:methanol = 10:1, Rf = 0.5) to obtain intermediate 12 (260 mg, 707.13 μmol, yield 81.65%, purity 98%) as a brown solid.

[0358] Preparation of intermediate 14

[0359] [ka]

[0360] A mixture of 3-bromo-2-chloro-6-(trifluoromethyl)pyridine (940 mg, 3.61 mmol, 1 equivalent), 2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (979.4 mg, 4.33 mmol, 1.2 equivalents), and an aqueous solution of Na2CO3 (2 M, 2.71 mL, 1.5 equivalents) in n-BuOH (8.4 mL) was degassed, purged three times with N2, and then Pd(PPh3)4 (417 mg, 360.93 μmol, 0.1 equivalent) was added. The mixture was stirred at 130°C for 15 minutes under an N2 atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was purified by FCC (ISCO®; 12g SepaFlash® silica flash column, 3% EA, 40mL / min at PE / EA, PE / EA = 5:1, Rf = 0.8) to obtain the crude product, which was then purified by FCC (ISCO®; 4g SepaFlash® silica flash column, 0-7% EA, 20mL / min at PE / EA, PE / EA = 7:1, Rf = 0.6) to obtain intermediate 14 (550mg, 1.70 mmol, yield 47.07%, purity 86.4%) as a yellow oily substance.

[0361] Preparation of intermediate 15

[0362] [ka]

[0363] A mixture of dioxane (4 mL), intermediate 14 (550 mg, 1.97 mmol, 1 equivalent), (4-methoxycarbonylphenyl)boronic acid (424.6 mg, 2.36 mmol, 1.2 equivalents), and Cs2CO3 (1.28 g, 3.93 mmol, 2 equivalents) in H2O (1 mL) was degassed, purged three times with N2, and then Pd(dppf)Cl2 (128.1 mg, 196.63 μmol, 0.1 equivalent) was added. The mixture was stirred at 100°C for 4 hours under an N2 atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was purified by FCC (ISCO®; 12g SepaFlash® silica flash column, 40mL / min, 7% PE / EA, EA.PE / EA=3:1, Rf=0.5) to obtain intermediate 15 (602mg, 1.55 mmol, yield 78.79%, purity 97.64%) as a white oily substance.

[0364] Preparation of intermediate 16

[0365] [ka]

[0366] To a 10 mL solution of methyl intermediate 15 (602 mg, 1.59 mmol, 1 equivalent) in DCM, m-CPBA (684.5 mg, 3.17 mmol, 80% purity, 2 equivalents) was added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with dichloromethane (50 mL) and washed with aqueous Na2SO3 solution (30 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by FCC (ISCO®; 12 g SepaFlash® silica flash column, 30% EA, PE / EA at 40 mL / min; PE / EA = 1:1, Rf = 0.5) to obtain intermediate 16 (588 mg, 1.37 mmol, yield 86.61%, purity 96.156%) as a white solid.

[0367] Preparation of intermediate 17

[0368] [ka]

[0369] The mixture of intermediate 16 (288 mg, 700.06 μmol, 1 equivalent) in MeOH (3 mL) was degassed, purged three times with H2, and then Pd / C (372.5 mg, 350.03 μmol, purity 10%, 0.5 equivalent) was added. The mixture was stirred at 25°C for 2 hours under an H2 (15 psi) atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 17 (260 mg, 574.83 μmol, yield 82.11%, purity 91.4%) as a white solid.

[0370] Preparation of intermediate 18

[0371] [ka]

[0372] The mixture of intermediate 17 (210 mg, 507.97 μmol, 1 equivalent) in THF (3 mL) was degassed, purged three times with N2, and then LiBH4 (2 M, 761 μL, 3.00 equivalents) was added dropwise, and the mixture was stirred at 40°C for 4 hours under an N2 atmosphere. The mixture was quenched by dropwise addition of HCl (10%, 100 mL) under an N2 atmosphere, and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain intermediate 18 (220 mg, crude product) as a white solid, which was used in the next step without further purification.

[0373] Preparation of intermediate 20

[0374] [ka]

[0375] To a suspension of CuBr2 (6.90 g, 30.91 mmol, 1.45 mL, 1.15 equivalents) in MeCN (120 mL), t-BuONO (3.88 g, 37.63 mmol, 4.48 mL, 1.4 equivalents) was added dropwise at 0°C. Then, a solution of [4-[3-amino-6-(trifluoromethyl)-2-pyridyl]phenyl]methanol (7.21 g, 26.88 mmol, 1 equivalent) in MeCN (40 mL) was added dropwise. The mixture was stirred at 0°C for 1 hour, then slowly warmed to 20°C and stirred for 12 hours. The reaction mixture was diluted with H2O (200 mL) and acidified to pH=5-6 with 1 M HCl solution. The mixture was extracted with EA (200 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was then subjected to flash column chromatography on 80 g of silica gel (eluent: A: petroleum ether, B: ethyl acetate, 0% B to 26% B in A, 80 mL / min. TLC: petroleum ether:ethyl acetate = 3:1, R f The intermediate was purified using (0.35) to obtain intermediate 20 (8.36 g, 24.67 mmol, yield 91.77%, purity 98%) as a brown oily substance.

[0376] Preparation of intermediate 21

[0377] [ka]

[0378] A mixture of intermediate 20 (100 mg, 301.10 μmol, 1 equivalent), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-yl]ethanone (90.7 mg, 361.32 μmol, 1.2 equivalents), and K3PO4 (127.8 mg, 602.20 μmol, 2 equivalents) in H2O (0.5 mL) and dioxane (2 mL) was degassed, purged three times with N2, and then CATACXIUM(R)A Pd G3 (21.9 mg, 30.11 μmol, 0.1 equivalent) was added and the mixture was stirred at 100°C for 2 hours under an N2 atmosphere. The reaction mixture was cooled to room temperature, H2O (40 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This was purified by FCC (ISCO®; 4g SepaFlash® silica flash column, 0-20% MeOH, 30 mL / min DCM / MeOH; DCM / MeOH = 5:1, Rf = 0.4) to obtain intermediate 21 (94 mg, 249.75 μmol, yield 82.95%) as a white solid.

[0379] Preparation of intermediate 23

[0380] [ka]

[0381] A mixture of intermediate 20 (500 mg, 1.51 mmol, 1 equivalent), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate (500 mg, 1.69 mmol, 1.13 equivalents), Cs2CO3 (981 mg, 3.01 mmol, 2 equivalents), cyclopentyl(diphenyl)phosphine dichloropalladium iron (110.1 mg, 150.55 μmol, 0.1 equivalent), and H2O (2.5 mL) in dioxane (10 mL) was degassed, purged three times with N2, and then stirred at 90°C under an N2 atmosphere for 16 hours. The reaction mixture was cooled to room temperature, diluted with 50 mL of H2O, and extracted with 100 mL (50 mL x 2) of EA. The combined organic layers were washed with 50 mL of aqueous NaCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography on silica gel (eluent: A: petroleum ether, B: ethyl acetate, 0% B to 40% B in A; TLC: petroleum ether: ethyl acetate = 1:1, Rf = 0.5) to obtain intermediate 23 (609.5 mg, 1.39 mmol, yield 92.35%, purity 95.901%) as a yellow oily substance.

[0382] Preparation of intermediate 24

[0383] [ka]

[0384] To a solution of intermediate 23 (500 mg, 1.19 mmol, 1 equivalent) in MeOH (25 mL), Pd / C (253.1 mg, 237.86 μmol, 10% purity, 0.2 equivalents) and NH3.H2O (18.32 μL, 118.93 μmol, 25% purity, 0.1 equivalents) were added. The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 35°C for 16 hours under H2 (15 psi). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 24 (600 mg, 1.37 mmol, 95.76% yield, 96.22% purity) as a colorless oil, which was used in the next step without further purification.

[0385] Preparation of intermediate 28

[0386] [ka]

[0387] A stirring rod, intermediate 12 (330 mg, 915.83 μmol, 1 equivalent), Pd / C (97.4 mg, 91.58 μmol, 10% purity, 0.1 equivalent), and MeOH (10 mL) were added to a hydrogenation bottle under an N2 atmosphere. The suspension was degassed under vacuum, purged three times under an Ar atmosphere, and then purged three times with hydrogen. The resulting mixture was stirred under H2 (40 Psi) at 25°C for 24 hours. The mixture was filtered through a Celite pad, and the filtrate cake was washed with methanol (30 mL x 3). The combined filtrate was concentrated under reduced pressure to obtain intermediate 28 (215 mg, 590.07 μmol, yield 64.43%) as a yellow solid, which was used in the next step without further purification.

[0388] Preparation of intermediate 30

[0389] [ka]

[0390] A mixture of 2-chloro-6-(trifluoromethyl)pyridine-3-carbaldehyde (500 mg, 2.39 mmol, 1 equivalent), 1-piperazine-1-yleuthanone (458.7 mg, 3.58 mmol, 1.5 equivalents), and AcOH (136 μL, 2.39 mmol, 1 equivalent) in MeOH (3 mL) was stirred for 30 minutes. Then, NaBH3CN (299.8 mg, 4.77 mmol, 2 equivalents) was added, and the mixture was stirred at 25°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent 0 / 1 to 1 / 1 ethyl acetate / petroleum ether gradient, 30 mL / min) to obtain intermediate 30 (600 mg, 1.86 mmol, yield 78.16%) as a white solid.

[0391] Preparation of intermediate 31

[0392] [ka]

[0393] Intermediate 30 (580 mg, 1.80 mmol, 1 equivalent), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (633 mg, 2.70 mmol, 1.5 equivalents), K3PO4 (1.15 g, 5.41 mmol, 3 equivalents), a mixture of [2-(2-aminophenyl)phenyl]palladium(1+); bis(1-adamantyl)-butyl-phosphine; methanesulfonate (131.2 mg, 180.28 μmol, 0.1 equivalents) in H2O (2 mL) and dioxane (6 mL) was stirred at 95°C for 1 hour. The reaction mixture was cooled to room temperature, H2O (40 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by flash silica gel chromatography (ISCO®; 4g SepaFlash® silica flash column, eluent 0 / 1~90 / 10 ethyl acetate / petroleum ether gradient, 30 mL / min) to obtain intermediate 31 (280 mg, 711.74 μmol, yield 39.48%) as a white solid.

[0394] Preparation of intermediate 33

[0395] [ka]

[0396] A mixture of intermediate 20 (500 mg, 1.51 mmol, 1 equivalent), tert-butyl 3-methyleneazetidine-1-carboxylate (509.5 mg, 3.01 mmol, 2 equivalents), and TEA (628 μL, 4.52 mmol, 3 equivalents) in MeCN (4 mL) was mixed with Pd(OAc)2 (33.8 mg, 150.55 μmol, 0.1 equivalent) and tris-o-tolylphosphan (91.6 mg, 301.10 μmol, 0.2 equivalents) under N2 conditions. The mixture was then stirred at 100°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 4g SepaFlash® silica flash column, eluent 0 / 1~50 / 50 ethyl acetate / petroleum ether gradient, 30 mL / min) to obtain intermediate 33 (530 mg, 1.26 mmol, yield 83.74%) as a colorless gum.

[0397] Preparation of intermediate 34

[0398] [ka]

[0399] A mixture of intermediate 33 (500 mg, 1.51 mmol, 1 equivalent), tert-butyl 3-methyleneazetidine-1-carboxylate (509.5 mg, 3.01 mmol, 2 equivalents), and TEA (628 μL, 4.52 mmol, 3 equivalents) in MeCN (4 mL) was mixed with Pd(OAc)2 (33.8 mg, 150.55 μmol, 0.1 equivalent) and tris-o-tolylphosphan (91.6 mg, 301.10 μmol, 0.2 equivalents) under N2 conditions. The mixture was then stirred at 100°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 4g SepaFlash® silica flash column, eluent 0 / 1~50 / 50 ethyl acetate / petroleum ether gradient, 30 mL / min) to obtain intermediate 34 (530 mg, 1.26 mmol, yield 83.74%) as a colorless gum.

[0400] Preparation of intermediate 36

[0401] [ka]

[0402] A mixture of intermediate 35 (150 mg, 265.49 μmol, 1 equivalent), 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (146.6 mg, 530.99 μmol, 2 equivalents), K3PO4 (169 mg, 796.48 μmol, 3 equivalents), and CATACXIUM(R)A Pd G3 (19.3 mg, 26.55 μmol, 0.1 equivalent) in H2O (0.5 mL) and dioxane (1.5 mL) was stirred at 100°C for 0.5 hours. The reaction mixture was cooled to room temperature, H2O (40 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by flash silica gel chromatography (ISCO®; 4g SepaFlash® silica flash column, eluent gradient 0 / 1~40 / 60 ethyl acetate / petroleum ether, 30 mL / min) to obtain intermediate 36 (140 mg, 206.28 μmol, yield 77.70%) as a colorless gum.

[0403] The following intermediates were synthesized using a method similar to that described above for intermediate 36.

[0404] [Table 7]

[0405] Preparation of intermediate 38

[0406] [ka]

[0407] To a solution of oxetane-3-amine (200 mg, 2.74 mmol, 1 equivalent) and DIEA (953 μL, 5.47 mmol, 2 equivalents) in THF (3 mL), phenyl carbochloride (343 μL, 2.74 mmol, 1 equivalent) was added dropwise. The resulting mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0 / 1~50 / 50 ethyl acetate / petroleum ether gradient, 40 mL / min) to obtain intermediate 38 (410 mg, 2.12 mmol, yield 77.56%, purity 100%) as a white solid.

[0408] Preparation of intermediate 39

[0409] [ka]

[0410] To a solution of intermediate 20 (2.4 g, 7.23 mmol, 1 equivalent) in THF (20 mL), tert-butyl-chlorodimethyl-silane (1.33 mL, 10.84 mmol, 1.5 equivalents) and TEA (2.01 mL, 14.45 mmol, 2 equivalents) were added, and the reaction mixture was stirred at 25°C for 16 hours. H2O (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~4 / 1) to obtain intermediate 39 (3.17 g, 7.09 mmol, yield 81.71%, purity 99.78%) as a white solid.

[0411] Preparation of intermediate 40

[0412] [ka]

[0413] To a solution of intermediate 39 (400 mg, 896.11 μmol, 1 equivalent) and 4-methylpiperidine-4-ol (206.4 mg, 1.79 mmol, 2 equivalents) in toluene (5 mL), t-BuONa (344.4 mg, 3.58 mmol, 4 equivalents) was added. The suspension was degassed under vacuum and purged three times under an N2 atmosphere. Then, BINAP (55.8 mg, 89.61 μmol, 0.1 equivalent) and Pd2(dba)3 (82 mg, 89.61 μmol, 0.1 equivalent) were added. The mixture was degassed under vacuum, purged three times under an N2 atmosphere, and stirred at 110°C for 12 hours. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with 60 mL (20 mL x 3) of ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography on 4 g of silica gel (eluent: A: petroleum ether, B: ethyl acetate, 0% B to 28% B in A; TLC: petroleum ether: ethyl acetate = 3:1, Rf = 0.4) to obtain intermediate 40 (460 mg, 890.07 μmol, yield 99.33%, purity 93%) as a yellow oily substance.

[0414] Preparation of intermediate 41

[0415] [ka]

[0416] Intermediate 40 (460 mg, 957.06 μmol, 1 equivalent) and TBAF (1 M, 1.44 mL, 1.5 equivalents) were dissolved in THF (5 mL), and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with H2O (30 mL x 3) and saturated NaCl aqueous solution (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain intermediate 41 (460 mg, crude product) as a yellow oily substance, which was used in the next step without further purification.

[0417] The following intermediates were synthesized by a method similar to that described above for intermediate 41.

[0418] [Table 8]

[0419] Preparation of intermediate 43

[0420] [ka]

[0421] Intermediate 39 (365 mg, 817.70 μmol, 1 equivalent), tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (486.3 mg, 2.45 mmol, 3 equivalents), Cs2CO3 (666 mg, 2.04 mmol, 2.5 equivalents), and [2-(2-aminophenyl)phenyl]-chloropalladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (64.3 mg, 81.77 μmol, 0.1 equivalent) were added to the vial, then the vial was degassed under vacuum and purged three times with an N2 atmosphere. Dioxane (8 mL) was added to the vial, purged again with N2, and the mixture was stirred at 90°C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with H2O (30 mL) and EA (20 mL) * Extraction was performed in step 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was subjected to flash column chromatography on 4 g of silica gel (eluent: A: petroleum ether, B: ethyl acetate, 0% B to 11% B in A, 10 mL / min. TLC: petroleum ether: ethyl acetate = 3:1, R f The intermediate 43 (277 mg, 427.50 μmol, yield 52.28%, purity 87%) was purified using a solution of 0.4) and obtained as a yellow solid.

[0422] Preparation of intermediate 48

[0423] [ka]

[0424] In a 15 mL vial equipped with a stirring rod, the following were added: Intermediate 39 (893 mg, 2 mmol, 1 equivalent) in DME (2 mL), tert-butyl 3-bromoazetidine-1-carboxylate (614 mg, 2.60 mmol, 1.3 equivalents), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (22.4 mg, 20 μmol, 0.01 equivalent), NiCl2.dtbbpy (11.9 mg, 30 μmol, 0.015 equivalents), TTMSS (49.7 mg, 0.2 mmol, 1.00 equivalent), and Na2CO3 (42.4 mg, 0.4 mmol, 2 equivalents). The vial was sealed and placed under nitrogen. The reaction mixture was stirred, irradiated with a 10 W blue LED lamp (3 cm away), and the reaction temperature was maintained at 25 °C for 14 hours using cooling water. The reaction mixture was diluted with 50 mL of H2O and extracted with EA (30 mL x 3). The combined organic layer was washed with saturated NaCl aqueous solution (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 4 / 1; TLC:PE:EA = 3:1, Rf = 0.7) to obtain intermediate 48 (640 mg, 1.05 mmol, yield 52.42%, purity 86%) as a colorless oil.

[0425] Preparation of intermediate 53

[0426] [ka]

[0427] To a solution of 2 g (7.68 mmol, 1 equivalent) of 3-bromo-2-chloro-6-(trifluoromethyl)pyridine and 989.6 mg (6.91 mmol, 0.9 equivalents) of methylpiperidine-4-carboxylate in toluene (20 mL), t-BuONa (1.11 g, 11.52 mmol, 1.5 equivalents) was added. The suspension was degassed under vacuum and purged three times under an N2 atmosphere, and then Pd2(dba)3 (703.2 mg, 767.93 μmol, 0.1 equivalent) and xanthophos (444.3 mg, 767.93 μmol, 0.1 equivalent) were added. The mixture was degassed under vacuum and purged three times under an N2 atmosphere, and stirred at 95°C for 8 hours. The reaction mixture was cooled to room temperature, 80 mL of H2O was added, and the mixture was extracted with ethyl acetate (50 mL x 4). The combined organic layers were washed with 50 mL of saturated NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography on 12 g of silica gel (eluent: A: petroleum ether, B: ethyl acetate, 0% B to 20% B in A, 18 mL / min. TLC: petroleum ether: ethyl acetate = 3:1, Rf = 0.65) to obtain intermediate 53 (270 mg, 711.16 μmol, yield 9.26%, purity 85%) as a yellow oily substance.

[0428] Preparation of intermediate 54

[0429] [ka]

[0430] To a solution of dioxane (2 mL) and intermediate 53 (270 mg, 836.66 μmol, 1 equivalent) in H2O (0.5 mL) and [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (293.7 mg, 1.25 mmol, 1.5 equivalents), Cs2CO3 (545.2 mg, 1.67 mmol, 2 equivalents) was added. The suspension was degassed under vacuum and purged three times under an N2 atmosphere. Then, ditert-butyl(cyclopentyl)phosphan; dichloropalladium; iron (54.5 mg, 83.67 μmol, 0.1 equivalents) was added. The mixture was degassed under vacuum and purged three times under an N2 atmosphere, and stirred at 95°C for 12 hours. The reaction mixture was cooled to room temperature, 20 mL of H2O was added, and the mixture was extracted with ethyl acetate (15 mL x 4). The combined organic layers were washed with 50 mL of saturated NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash column chromatography on 4 g of silica gel (eluent: A: petroleum ether, B: ethyl acetate, 0% B to 45% B in A, 8 mL / min. TLC: petroleum ether: ethyl acetate = 1:1, Rf = 0.4) to obtain intermediate 54 (218 mg, 528.99 μmol, 63.23% yield, 95.7% purity) as a yellow solid.

[0431] Preparation of intermediate 56

[0432] [ka]

[0433] To a stirred solution of intermediate 55 (85 mg, 162.55 μmol, 1 equivalent) and methaneamine hydrochloride (16.4 mg, 243.83 μmol, 1.5 equivalents) in DMF (2 mL), DIEA (84 μL, 487.66 μmol, 3 equivalents) was added. Then, HATU (92.7 mg, 243.83 μmol, 1.5 equivalents) was added at 0°C. The reaction mixture was warmed to 25°C and stirred at 25°C for 8 hours. 20 mL of H2O was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain intermediate 56 (41 mg, crude product) as a pale yellow oily substance, which was used in the next step without further purification.

[0434] Preparation of intermediate 57

[0435] [ka]

[0436] A mixture of dioxane (20 mL) and H2O (5 mL) containing intermediate 1 (1.13 g, 3.11 mmol, 1 equivalent), (4-cyanophenyl)boronic acid (549.2 mg, 3.74 mmol, 1.2 equivalents), Cs2CO3 (2.03 g, 6.23 mmol, 2 equivalents), and ditert-butyl(cyclopentyl)phosphine; dichloropalladium; iron (203 mg, 311.49 μmol, 0.1 equivalent) was degassed, purged three times with N2, and then stirred at 100°C for 16 hours under an N2 atmosphere. The reaction mixture was cooled to room temperature, diluted with 100 mL of H2O, and extracted with 240 mL (80 mL x 3) of EA. The combined organic layers were washed with 200 mL of aqueous NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by flash column chromatography on silica gel (eluent: A: petroleum ether, B: ethyl acetate, 0% B to 40% B in A; TLC: petroleum ether: ethyl acetate = 1:1, Rf = 0.8) to obtain intermediate 57 (1.37 g, 3.04 mmol, yield 89.73%, purity 95.366%) as a yellow solid. The following intermediates were synthesized by a method similar to that described above for intermediate 57.

[0437] [Table 9]

[0438] Preparation of intermediate 58

[0439] [ka]

[0440] To a solution of intermediate 57 (0.2 g, 465.73 μmol, 1 equivalent) in MeOH (5 mL), Pd / C (49.5 mg, 46.57 μmol, 10% purity, 0.1 equivalent) was added under N2 conditions. The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred under H2 (15 psi) at 35°C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 58 (300 mg, crude product) as a colorless oil, which was used in the next step without further purification.

[0441] Preparation of intermediate 59

[0442] [ka]

[0443] To a solution of intermediate 58 (202.8 mg, 465.73 μmol, 1 equivalent) in THF (5 mL), TEA (194 μL, 1.40 mmol, 3 equivalents) and 2,4-dichloro-5-methoxypyrimidine (83.3 mg, 465.73 μmol, 1 equivalent) were added. The mixture was stirred at 60°C for 16 hours. The reaction mixture was diluted with 50 mL of H2O and extracted with 100 mL (50 mL x 2) of HCl. The combined organic layer was washed with 50 mL of aqueous NaCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash column chromatography on silica gel (eluent: A: petroleum ether, B: ethyl acetate, 0% B to 100% B in A; TLC: petroleum ether: ethyl acetate = 3:1, Rf = 0.1) to obtain intermediate 59 (77.2 mg, 102.34 μmol, yield 21.97%, purity 76.626%) as a colorless oil.

[0444] The following intermediates were synthesized using a method similar to that described above for intermediate 59.

[0445] [Table 10]

[0446] Preparation of intermediate 60

[0447] [ka]

[0448] A mixture of intermediate 59 (77.2 mg, 133.56 μmol, 1 equivalent), 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (73.7 mg, 267.12 μmol, 2 equivalents), Na2CO3 (28.3 mg, 267.12 μmol, 2 equivalents), and CATACXIUM(R)A Pd G3 (9.7 mg, 13.36 μmol, 0.1 equivalent) in DME (2 mL) and H2O (0.5 mL) was degassed, purged three times with N2, and then stirred at 90°C for 2 hours under an N2 atmosphere. The reaction mixture was cooled to room temperature, diluted with 60 mL of H2O, and extracted with 100 mL (50 mL x 2) of EA. The combined organic layers were washed with 80 mL of NaCl aqueous solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was then separated by preparative HPLC (basic conditions: column: Waters Xbridge C18 150). * 50mm * The mixture was purified over 10 μm using a mobile phase [water (NH3H2O)-ACN] gradient, yielding 63% to 93% of the solution over 10 minutes. Intermediate 60 (81 mg, 111.62 μmol, 83.57% yield, 95.320% purity) was obtained as a white solid.

[0449] The following intermediates were synthesized using a method similar to that described above for intermediate 60.

[0450] [Table 11]

[0451] Preparation of intermediate 61

[0452] [ka]

[0453] To a solution of intermediate 60 (81 mg, 117.10 μmol, 1 equivalent) in DCM (2 mL), TFA (3.07 g, 26.92 mmol, 2 mL, 229.93 equivalents) was added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain intermediate 61 (100 mg, crude product, TFA) as a yellow oily substance, which was used directly in the next step without further purification.

[0454] The following intermediates were synthesized using a method similar to that described above for intermediate 61.

[0455] [Table 12]

[0456] Preparation of intermediate 62

[0457] [ka]

[0458] A mixture of 1-piperazine-1-yluetanone (320 mg, 2.50 mmol, 1 equivalent), 3-bromo-2-chloro-6-(trifluoromethyl)pyridine (845.2 mg, 3.25 mmol, 1.3 equivalents), t-BuONa (359.9 mg, 3.74 mmol, 1.5 equivalents), and xanthophos (86.6 mg, 149.80 μmol, 0.06 equivalents) in 15 mL of Tol was degassed under vacuum, purged three times under an N2 atmosphere, and then Pd2(dba)3 (45.7 mg, 49.93 μmol, 0.02 equivalents) was added. The mixture was degassed under vacuum, purged three times under an N2 atmosphere, and stirred at 100°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0-100% ethyl acetate / petroleum ether gradient, 40 mL / min) to obtain intermediate 62 (820 mg, 1.82 mmol, yield 72.90%, purity 68.3%) as a yellow oily substance.

[0459] Preparation of intermediate 63

[0460] [ka]

[0461] To a solution of intermediate 62 (820 mg, 2.66 mmol, 1 equivalent) and tert-butyl N-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]carbamate (1.07 g, 3.20 mmol, 1.2 equivalents) in dioxane (15 mL) and H2O (5 mL), K2CO3 (1.10 g, 7.99 mmol, 3 equivalents) was added. The suspension was degassed under vacuum, purged three times under an N2 atmosphere, and then Pd(dppf)Cl2CH2Cl2 (217.6 mg, 266.49 μmol, 0.1 equivalent) was added. The mixture was degassed under vacuum, purged three times under an N2 atmosphere, and stirred at 100°C for 12 hours. The reaction mixture was cooled to room temperature, H2O (80 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0 / 100~90 / 10 ethyl acetate / petroleum ether gradient, 40 mL / min) to obtain intermediate 63 (1.04 g, 2.16 mmol, yield 81.15%, purity 99.5%) as a pale yellow solid.

[0462] Preparation of intermediate 64

[0463] [ka]

[0464] To a solution of intermediate 63 (300 mg, 626.95 μmol, 1 equivalent) in DCM (3 mL), HCl / dioxane (4 M, 3.13 mL, 20 equivalents) was added. The resulting reaction mixture was stirred at 25°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to obtain intermediate 64 (300 mg, crude product, HCl) as a white solid, which was used in the next step without further purification.

[0465] Preparation of intermediate 66

[0466] [ka]

[0467] To a mixture of 2-bromo-6-(trifluoromethyl)pyridine-3-amine (600 mg, 2.49 mmol, 1 equivalent) in DMF (12 mL), NaH (298.7 mg, 7.47 mmol, 60% purity, 3 equivalents) was added under N2 at 0°C, and the mixture was stirred at 25°C for 15 minutes. 1-bromo-2-(2-bromoethoxy)ethane (469 μL, 3.73 mmol, 1.5 equivalents) was added at 25°C, and the mixture was stirred at 80°C for 35 minutes. The reaction mixture was quenched with 10 mL of saturated NH4Cl, water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated lithium chloride solution (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain intermediate 66 (1.35 g, crude product) as a yellow oil, which was used in the next step without further purification.

[0468] Preparation of intermediate 67

[0469] [ka]

[0470] A mixture of dioxane (20 mL) and intermediate 66 (1.35 g, 4.34 mmol, 1 equivalent), tert-butyl N-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]carbamate (1.59 g, 4.77 mmol, 1.1 equivalent), Cs2CO3 (2.83 g, 8.68 mmol, 2 equivalents), and ditert-butyl(cyclopentyl)phosphine dichloropalladium iron (282.8 mg, 433.95 μmol, 0.1 equivalent) in H2O (5 mL) was degassed, purged three times with N2, and then stirred at 100°C for 16 hours under an N2 atmosphere. The reaction mixture was cooled to room temperature, diluted with 100 mL of H2O, and extracted with 200 mL (100 mL x 2) of EA. The combined organic layers were washed with 100 mL of aqueous NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography on silica gel (eluent: A: petroleum ether, B: ethyl acetate, 0% B to 50% B in A; TLC: petroleum ether: ethyl acetate = 1:1, Rf = 0.6) to obtain intermediate 67 (1.40 g, 3.19 mmol, yield 73.52%, purity 100%) as a yellow solid.

[0471] The following intermediates were synthesized using a method similar to that described above for intermediate 67.

[0472] [Table 13]

[0473] Preparation of intermediate 68

[0474] [ka]

[0475] To a 10 mL solution of intermediate 67 (1.4 g, 3.20 mmol, 1 equivalent) in DCM, TFA (7.68 g, 67.31 mmol, 5 mL, 21.03 equivalents) was added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain intermediate 68 (1.6 g, crude product, TFA) as a yellow oily substance, which was used in the next step without further purification.

[0476] The following intermediates were synthesized using a method similar to that described above for intermediate 68.

[0477] [Table 14]

[0478] Preparation of intermediate 70

[0479] [ka]

[0480] To a solution of 5-bromo-2-cyclopropylpyridine (4.5 g, 22.72 mmol, 1 equivalent) in DCM (90 mL), m-CPBA (4.61 g, 22.72 mmol, 85% purity, 1 equivalent) was gradually added at 0°C, and the solution was stirred at 25°C for 12 hours. The mixture was diluted with H2O (100 mL) and adjusted to pH=11 with 10% NaOH aqueous solution. The mixture was extracted with DCM (80 mL x 3). The combined organic layers were washed with saturated Na2S2O3 aqueous solution (150 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was then subjected to flash column chromatography on 80 g of silica gel (eluent: A: petroleum ether, B: ethyl acetate, 0% B to 74% B in A, 80 mL / min. TLC: petroleum ether: ethyl acetate = 1:1, R f The intermediate 70 (3.68 g, 17.16 mmol, yield 75.53%, purity 99.82%) was purified using a solution of 0.2) to obtain a pale yellow oily substance.

[0481] Preparation of intermediate 71

[0482] [ka]

[0483] A mixture of intermediate 70 (3.6 g, 16.82 mmol, 1 equivalent) in POCl3 (12 mL) was stirred at 90°C for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was then adjusted to pH 7 by adding NaHCO3 dropwise, and the mixture was extracted with EA (80 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was subjected to flash column chromatography on 40 g of silica gel (eluent: A: petroleum ether, B: ethyl acetate, 0% B to 1% B in A, 60 mL / min. TLC: petroleum ether: ethyl acetate = 10:1, R f The intermediate 71 (2.41 g, 10.18 mmol, yield 60.51%, purity 98.17%) was purified using a solution of 0.6) to obtain a colorless oil.

[0484] Preparation of intermediate 72

[0485] [ka]

[0486] To a solution of intermediate 71 (2.4 g, 10.32 mmol, 1 equivalent) and (1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridine-4-yl)boronic acid (2.70 g, 11.87 mmol, 1.15 equivalents) in dioxane (60 mL) and H2O (15 mL), Cs2CO3 (6.73 g, 20.64 mmol, 2 equivalents) was added. The suspension was degassed under vacuum and purged three times under an N2 atmosphere. Then, cyclopentyl(diphenyl)phosphine; dichloropalladium; iron (755.2 mg, 1.03 mmol, 0.1 equivalents) were added. The mixture was degassed under vacuum, purged three times under an N2 atmosphere, and stirred at 100°C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with H2O (100 mL) and extracted with EA (80 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was subjected to flash column chromatography on 40 g of silica gel (eluent: A: petroleum ether, B: ethyl acetate, 0% B to 10% B in A, 45 mL / min. TLC: petroleum ether: ethyl acetate = 5:1, R f The intermediate 72 (2.89 g, 7.95 mmol, yield 77.06%, purity 92.16%) was purified using a solution of 0.5) to obtain a pale yellow oily substance.

[0487] Preparation of intermediates 74 and 75

[0488] [ka]

[0489] To a solution of intermediate 73 (400 mg, 996.26 μmol, 1 equivalent) in MeOH (10 mL), Pd / C (150 mg, 140.95 μmol, 10% purity, 1.41 e-1 equivalent) and NH3.H2O (76 μL, 498.13 μmol, 25% purity, 0.5 equivalent) were added. The suspension was degassed under vacuum, purged several times with H2 (15 psi), and the mixture was stirred under H2 at 30°C for 8 hours. The reaction mixture was filtered, and the filter cake was washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure to obtain a mixture of intermediates 74 and 75 (270 mg, crude product) as a white solid, which was used in the next step without further purification.

[0490] Preparation of intermediates 76 and 77

[0491] [ka]

[0492] A mixture of intermediates 74 and 75 (437 mg, crude product) in THF (10 mL) and TEA (298 μL, 2.14 mmol, 2 equivalents) was mixed with 2,4-dichloro-5-methoxypyrimidine (287.9 ​​mg, 1.61 mmol, 1.5 equivalents). The resulting mixture was stirred at 50°C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with H2O (50 mL) and extracted with EA (40 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was subjected to flash column chromatography on 20 g of silica gel (eluent: A: petroleum ether, B: ethyl acetate, 0% B to 50% B in A, 30 mL / min. TLC: petroleum ether: ethyl acetate = 1:1, R f The crude product was purified by (=0.2) to obtain the crude product. The crude product was then separated by SFC (separation conditions: DAIEL CHIRALCEL OJ (250 mm)). * Separation was performed using a mobile phase (30 mm, 10 μm); A: supercritical CO2, B: 0.1% NH3H2OMEOH, A:B = 70:30, 100 mL / min). The pure fraction was collected, and the solvent was evaporated under vacuum to obtain intermediate 76 (R t :1.617 min) and 77 (Rt Intermediate 76 (219 mg, 395.17 μmol, 36.85% yield, 99.26% purity) was obtained as a white solid. Intermediate 77 (207 mg, 362.52 μmol, 33.81% yield, 96.69% purity) was obtained as a white solid.

[0493] Preparation of intermediate 82

[0494] [ka]

[0495] To a solution of 2-chloro-6-(trifluoromethyl)pyridine-3-ol (1 g, 5.06 mmol, 1 equivalent) in THF (10 mL), 1-(4-hydroxy-1-piperidyl)ethanone (942.2 mg, 6.58 mmol, 1.3 equivalents), PPh3 (1.73 g, 6.58 mmol, 1.3 equivalents), and DBAD (1.52 g, 6.58 mmol, 1.3 equivalents) were added at 0°C. The mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with 100 mL of H2O and extracted with 200 mL of EA (100 mL x 2). The combined organic layers were washed with 100 mL of aqueous NaCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash column chromatography on silica gel (eluent: A: petroleum ether, B: ethyl acetate, 0% B to 100% B in A; TLC: petroleum ether: ethyl acetate = 0:1, Rf = 0.2) to obtain intermediate 82 (1.28 g, 3.91 mmol, yield 77.34%, purity 99.066%) as a colorless oil.

[0496] Preparation of intermediate 86

[0497] [ka]

[0498] A mixture of 3-bromo-2-chloro-6-fluoropyridine (300 mg, 1.43 mmol, 1 equivalent), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (528.9 mg, 1.71 mmol, 1.2 equivalents), and K3PO4 (907.8 mg, 4.28 mmol, 3 equivalents) in dioxane (3 mL) and H2O (0.75 mL) was degassed, purged three times with N2, and then Pd(dppf)Cl2 (52.1 mg, 71.28 μmol, 0.05 equivalents) was added. The mixture was stirred at 100°C for 1 hour under an N2 atmosphere. The mixture was cooled to room temperature, H2O (40 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by FCC (ISCO®; 4g SepaFlash® silica flash column, 0-100% EA, 30 mL / min, PE / EAPE / EA=3:1, Rf=0.5) to obtain intermediate 86 (392 mg, 1.25 mmol, yield 87.91%) as a white solid.

[0499] Preparation of intermediate 87

[0500] [ka]

[0501] A mixture of dioxane (3 mL), intermediate 86 (392 mg, 1.25 mmol, 1 equivalent), (4-cyanophenyl)boronic acid (221 mg, 1.50 mmol, 1.2 equivalents), and Cs2CO3 (816.7 mg, 2.51 mmol, 2 equivalents) in H2O (0.75 mL) was degassed, purged three times with N2, and then Pd(dppf)Cl2 (81.6 mg, 125.33 μmol, 0.1 equivalent) was added. The mixture was stirred at 100°C for 1 hour under an N2 atmosphere. The mixture was cooled to room temperature, H2O (40 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by FCC (ISCO®; 4g SepaFlash® silica flash column, 0-15% EA, PE / EA at 30 mL / min; PE / EA = 3:1, Rf = 0.5) to obtain intermediate 87 (415 mg, 1.09 mmol, yield 87.27%) as a white solid.

[0502] Preparation of intermediate 88

[0503] [ka]

[0504] A mixture of intermediate 87 (200 mg, 527.11 μmol, 1 equivalent), Pd / C (226.3 mg, 10% purity), and NH3·H2O (16 μL, 105.42 μmol, 25% purity, 0.2 equivalents) in MeOH (5 mL) was degassed, purged three times with H2, and then the mixture was stirred at 40°C for 1 hour under an H2 atmosphere (15 psi). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 88 (160 mg, crude product) as a colorless gum, which was used in the next step without further purification.

[0505] Preparation of intermediate 89

[0506] [ka]

[0507] To a solution of intermediate 88 (310 mg, 804.20 μmol, 1 equivalent) in THF (5 mL), DIEA (311.8 mg, 2.41 mmol, 420.23 μL, 3 equivalents) and 2,4-dichloro-5-methoxypyrimidine (143.9 mg, 804.20 μmol, 1 equivalent) were added at 25°C. The mixture was stirred at 50°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0 / 1~45 / 55 ethyl acetate / petroleum ether gradient, 40 mL / min) to obtain intermediate 89 (130 mg, 211.98 μmol, yield 26.36%, purity 86.1%) as a yellow solid.

[0508] Preparation of Compound 1

[0509] [ka]

[0510] To a solution of intermediate 6 (174.5 mg, 247.00 μmol, 1 equivalent, TFA) in DCM (1 mL), TEA (1 mL, 7.18 mmol, 29.09 equivalents) and Ac2O (23 μL, 247.00 μmol, 1 equivalent) were added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched at 25°C by adding 10 mL of aqueous NH4Cl solution, then diluted with 30 mL of H2O, and extracted with 30 mL of DCM (10 mL x 3). The combined organic layer was washed with 10 mL of aqueous NaCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, dichloromethane:methanol = 10:1, Rf = 0.5) to obtain a pure fraction, and the solvent was evaporated under vacuum. The residue was partitioned into CH3CN (2 mL) and water (10 mL). The mixture was freeze-dried to obtain compound 1 (104.7 mg, 158.97 μmol, yield 64.36%, purity 96.360%) as a white solid.

[0511] The following compounds were synthesized using a method similar to that described above for compound 1.

[0512] [Table 15]

[0513] Preparation of Compound 3

[0514] [ka]

[0515] To a solution of intermediate 6 (211.7 mg, 299.69 μmol, 1 equivalent, TFA) in DCM (2 mL), TEA (1 mL, 7.18 mmol, 23.97 equivalents) and 2-methoxyacetyl chloride (27 μL, 299.69 μmol, 1 equivalent) were added at 0°C. The mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched at 25°C by adding 10 mL of aqueous NH4Cl solution, then diluted with 30 mL of H2O, and extracted with 60 mL (20 mL x 3) of DCM. The combined organic layer was washed with 10 mL of aqueous NaCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was subjected to preparative HPLC (basic conditions; column: Waters Xbridge C18 150). * 50mm * The compound was purified by 10 μm; mobile phase: [water (NH3H2O)-ACN]; gradient: 47%~77% over 11 minutes (B) to obtain compound 3 (37.12 mg, 53.75 μmol, yield 17.93%, purity 96.241%) as a white solid.

[0516] Preparation of Compound 4

[0517] [ka]

[0518] To a solution of intermediate 6 (85.5 mg, 144.36 μmol, 1 equivalent) in MeOH (2 mL), AcOH (16 μL, 288.72 μmol, 2 equivalents) and formaldehyde (107 μL, 1.44 mmol, 10 equivalents) were added at 25°C. After addition, the mixture was stirred at 45°C for 0.5 hours, and then NaBH3CN (18.1 mg, 288.72 μmol, 2 equivalents) was added at 45°C. The resulting mixture was stirred at 45°C for 1.5 hours. The reaction mixture was diluted with dichloromethane (40 mL), basicized to pH=8 with saturated sodium bicarbonate solution (30 mL), and then extracted with dichloromethane (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. Separation of residue by HPLC (FA conditions; column: Phenomenex Luna C18 150) * 25mm * The compound was purified by 10 μm; mobile phase: [water (FA)-ACN]; gradient: 20% to 50% B over 10 minutes to obtain compound 4 (56.49 mg, 90.70 μmol, yield 62.83%, purity 99.623%, 0.3 FA) as a white solid.

[0519] Preparation of compound 5

[0520] [ka]

[0521] A mixture of intermediate 13 (325 mg, 646.29 μmol, 1 equivalent) and 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (321.2 mg, 1.16 mmol, 1.8 equivalents) in DME (4 mL) and H2O (1 mL) was degassed, purged three times with N2, and CATACXIUM® A Pd G3 (47 mg, 64.63 μmol, 0.1 equivalent) and Na2CO3 (137 mg, 1.29 mmol, 2 equivalents) were added to the mixture. The mixture was then degassed again, purged three times with N2, and stirred at 95°C for 2 hours under an N2 atmosphere. The mixture was cooled to room temperature, diluted with H2O (40 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was then subjected to preparative HPLC (column: Waters Xbridge BEH C18 150). * 25mm * The crude product was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 0 / 1; TLC:EA:MeOH = 10:1; Rf = 0.5) to obtain compound 5 (98.16 mg, 159.20 μmol, yield 24.63%, purity 100%) as a white solid.

[0522] The following compounds were synthesized using a method similar to that described above for compound 5.

[0523] [Table 16]

[0524] Preparation of compound 6

[0525] [ka]

[0526] A mixture of dioxane (3 mL), intermediate 19 (156 mg, 295.49 μmol, 1 equivalent), 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (163.1 mg, 590.97 μmol, 2 equivalents), and K3PO4 (125.4 mg, 590.97 μmol, 2 equivalents) in H2O (0.75 mL) was degassed, purged three times with N2, and then CATACXIUM® A Pd G3 (21.5 mg, 29.55 μmol, 0.1 equivalent) was added and the mixture was stirred at 100°C for 1 hour under an N2 atmosphere. The reaction mixture was cooled to room temperature, H2O (40 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by FCC (ISCO®; 4g SepaFlash® silica flash column, 0-70% EA, PE / EA at 25 mL / min) PE / EA=0:1, Rf=0.4) to obtain the product. The product was then separated by preparative HPLC (column: Waters x bridge 150). * The compound was further purified using a 25mm x 5μm filter (mobile phase A: [water (NH4HCO3)-ACN], mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 45%B to 75%B). The pure fraction was collected, and volatile matter was removed under vacuum. The residue was partitioned into ACN (2 mL) and water (10 mL). The solution was freeze-dried to obtain compound 6 (112.8 mg, 175.79 μmol, yield 59.49%, purity 100%) as a white solid.

[0527] The following compounds were synthesized using a method similar to that described above for compound 6.

[0528] [Table 17]

[0529] Preparation of Compound 7

[0530] [ka]

[0531] To a solution of intermediate 6 (81.6 mg, 115.49 μmol, 1 equivalent, TFA) in DCM (2 mL), TEA (1 mL, 7.18 mmol, 62.21 equivalents) and N-methylcarbamoyl chloride (10.8 mg, 115.49 μmol, 1 equivalent) were added at 0°C. The mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched at 25°C by adding 10 mL of aqueous NH4Cl solution, then diluted with 30 mL of H2O, and extracted with 60 mL (20 mL x 3) of DCM. The combined organic layer was washed with 50 mL of aqueous NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was separated by preparative HPLC (basic conditions: column: Waters Xbridge 150). * 25mm * The compound was purified by 5 μm; mobile phase: [water (NH3H2O)-ACN]; gradient: 38%~68% over 10 minutes (B) to obtain compound 7 (32.15 mg, 49.02 μmol, yield 42.44%, purity 99.053%) as a white solid.

[0532] Preparation of compounds 9 and 10

[0533] [ka]

[0534] To a solution of intermediate 27 (163.2 mg, 235.75 μmol, 1 equivalent, TFA) in DCM (2 mL), TEA (2 mL, 14.37 mmol, 60.95 equivalents) and Ac2O (22 μL, 235.75 μmol, 1 equivalent) were added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched at 25°C by adding 10 mL of NH4Cl aqueous solution, then diluted with 30 mL of H2O, and extracted with 60 mL (20 mL x 3) of DCM. The combined organic layers were washed with 40 mL of aqueous NaCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by preparative TLC (SiO2, dichloromethane:methanol = 10:1, Rf = 0.4) to obtain a mixture of compounds 9 and 10 (69.71 mg, 109.80 μmol, yield 46.58%, purity 97.755%) as a white solid.

[0535] [ka]

[0536] The mixture was subjected to supercritical fluid chromatography (column: REG IS(R,R)WHELK-O1 (250mm)). * Separation was performed using a 25mm, 10um mobile phase (CO2-ACN / MeOH (0.1%NH3H2O)); B%: 30%, constant composition elution mode.

[0537] Compound 9 (18.10 mg, 28.40 μmol, 26.11% yield, 97.394% purity) was obtained as a white solid.

[0538] Compound 10 (19.29 mg, 29.78 μmol, yield 27.37%, purity 95.818%) was obtained as a white solid.

[0539] Preparation of compound 11

[0540] [ka]

[0541] To a solution of intermediate 29 (280 mg, 552.37 μmol, 1 equivalent) and 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (152.5 mg, 552.37 μmol, 1 equivalent) in dioxane (10 mL) and H2O (2.5 mL), Na2CO3 (175.6 mg, 1.66 mmol, 3 equivalents) was added. The suspension was degassed under vacuum and purged three times under an N2 atmosphere. Then, CATACXIUM® A Pd G3 (40.2 mg, 55.24 μmol, 0.1 equivalent) was added. The mixture was degassed under vacuum, purged three times under an N2 atmosphere, and stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature, H2O (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was then subjected to preparative HPLC (column: Phenomenex luna C18 150). * 25mm * The crude product was purified by preparative TLC (SiO2, PE:EA=0:1) over 10 minutes to obtain compound 11 (18.63 mg, 30.02 μmol, yield 5.43%, purity 100%) as a white solid.

[0542] Preparation of compound 12

[0543] [ka]

[0544] To a solution of intermediate 6 (120 mg, crude TFA) and 2-(oxetan-3-yl)acetic acid (29.5 mg, 254.73 μmol, 1.5 equivalents) in DCM (1 mL), DIEA (88 μL, 509.46 μmol, 3 equivalents) was added. Then, HATU (96.8 mg, 254.73 μmol, 1.5 equivalents) was added, and the reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to obtain a residue, which was then subjected to preparative HPLC (column: Waters x bridge 150). *The compound was purified using a 25 mm x 5 μm filter (mobile phase A: [water (NH4HCO3)-ACN], mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 43% to 73%). The pure fraction was collected, and volatile matter was removed under vacuum. The residue was partitioned into ACN (2 mL) and water (10 mL). The solution was freeze-dried to obtain compound 12 (10 mg, 13.81 μmol, yield 8.13%, purity 95.389%) as a white solid.

[0545] Preparation of compound 13

[0546] [ka]

[0547] A mixture of intermediate 6 (100 mg, crude product, TFA), 1-bromo-2-methoxyethane (39.3 mg, 283.03 μmol, 26.60 μL, 2 equivalents), and K2CO3 (39.1 mg, 283.03 μmol, 2 equivalents) in MeCN (9 mL) was then added, followed by KI (23.4 mg, 141.52 μmol, 1 equivalent), and the mixture was stirred at 80°C for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product, which was then subjected to preparative HPLC (column: Waters Xbridge 150). * The compound was purified using a 25 mm x 5 μm filter (mobile phase A: [water (NH4HCO3)-ACN], mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 52% to 82%). The pure fraction was collected, and volatile matter was removed under vacuum. The residue was partitioned into ACN (2 mL) and water (10 mL). The solution was freeze-dried to obtain compound 13 (13.54 mg, 20.71 μmol, yield 14.63%, purity 99.517%) as a white solid.

[0548] Preparation of compound 15

[0549] [ka]

[0550] To a solution of intermediate 6 (150 mg, crude, 1 equivalent) in DCM (2 mL), TEA (105 μL, 759.35 μmol, 3 equivalents) was added. Methylsulfonyl methanesulfonate (88.1 mg, 506.23 μmol, 2 equivalents) was added at 0°C. The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm, mobile phase A: water (FA), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 50%B to 80%). The pure fraction was collected and volatile matter was removed under vacuum. The residue was partitioned into acetonitrile (2 mL) and water (10 mL). The solution was freeze-dried to obtain compound 15 (15.88 mg, 23.64 μmol, yield 9.34%, purity 99.83%) as a white solid.

[0551] Preparation of compound 17

[0552] [ka]

[0553] To a solution of intermediate 10 (55 mg, 72.01 μmol, 1 equivalent) in DCM (3 mL), HCl / dioxane (4 M, 3 mL, 166.65 equivalents) was added. The mixture was stirred at 25°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was diluted with saturated NaHCO3 (30 mL) and extracted with EA (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was subjected to preparative HPLC (column: Phenomenex C18 150). * 25mm * The compound was purified using a 10 μm filter (mobile phase A: water (NH4HCO3), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 42% B to 72%). The pure fraction was collected, and volatile matter was removed under vacuum. The residue was partitioned into acetonitrile (2 mL) and water (8 mL). The solution was freeze-dried to obtain compound 17 (10.58 mg, 15.63 μmol, 21.70% yield, 98.04% purity) as a white solid.

[0554] Preparation of compound 18

[0555] [ka]

[0556] A mixture of intermediate 6 (200 mg, crude product), 2-bromo-N-methylacetamide (76.9 mg, 506.23 μmol, 1.5 equivalents), and K2CO3 (139.9 mg, 1.01 mmol, 3 equivalents) in DMF (0.5 mL) was stirred at 100°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a residue, which was then subjected to preparative HPLC (column: Waters X bridge 150). * 25mm * The compound was purified using a 5 μm mobile phase (A: water (NH3·H2O), B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 41%B to 71%). The pure fraction was collected, and volatile matter was removed under vacuum. The residue was partitioned into acetonitrile (2 mL) and water (10 mL). The solution was freeze-dried to obtain compound 18 (17.97 mg, 26.73 μmol, yield 98.72%, purity 98.72%) as a white solid.

[0557] Preparation of compound 19

[0558] [ka]

[0559] To a solution of intermediate 38 (20 mg, 103.52 μmol, 1 equivalent) in MeCN (1 mL), DIEA (54 μL, 310.56 μmol, 3 equivalents) and intermediate 6 (146.3 mg, 103.52 μmol, 1 equivalent, TFA) were added. The mixture was stirred at 60°C for 10 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was separated by preparative HPLC (column: Waters X bridge BEH C18 150). * 25mm *The compound was purified using a 5 μm filter (mobile phase A: water (NH4HCO3), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 36%B to 66%). The pure fraction was collected, and volatile matter was removed under vacuum. The residue was partitioned into acetonitrile (2 mL) and water (8 mL). The solution was freeze-dried to obtain compound 19 (26.79 mg, 36.62 μmol, yield 35.37%, purity 94.54%) as a yellow solid.

[0560] Preparation of compound 22

[0561] [ka]

[0562] A mixture of intermediate 6 (150 mg, crude product, TFA), oxetane-3-carboxylic acid (51.6 mg, 506.23 μmol, 2 equivalents), DIEA (132 μL, 759.35 μmol, 3 equivalents), and T4P (273.5 mg, 379.68 μmol, 50% purity, 1.5 equivalents) in DCM (2 mL) was stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was then subjected to preparative HPLC (column: Waters X bridge 150). * 25mm * The compound was purified using a 5 μm filter (mobile phase A: water (NH3H2O), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 38%B to 68%). The pure fraction was collected, and volatile matter was removed under vacuum. The residue was partitioned into acetonitrile (2 mL) and water (10 mL). The solution was freeze-dried to obtain compound 22 (24.13 mg, 34.11 μmol, 13.48% yield, 95.65% purity) as a white solid.

[0563] The following compounds were synthesized by a method similar to that described above for compound 22.

[0564] [Table 18]

[0565] Preparation of compound 28

[0566] [ka]

[0567] To a solution of intermediate 53 (60 mg, 77.14 μmol, 1 equivalent) in DCM (2 mL), TFA (2 mL, 26.92 mmol, 349.04 equivalents) was added. The mixture was stirred at 25°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was diluted with saturated NaHCO3 aqueous solution (20 mL) and extracted with EA (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was separated by preparative HPLC (column: Phenomenex luna C18 150). * 25mm * The compound was purified using a 10 μm filter (mobile phase A: water (FA), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 19%B to 49%). The pure fraction was collected, and volatile matter was removed under vacuum. The residue was partitioned into acetonitrile (2 mL) and water (8 mL). The solution was freeze-dried to obtain compound 28 (21.96 mg, 29.73 μmol, yield 38.54%, purity 97.97%, FA) as a white solid.

[0568] Preparation of compound 30

[0569] [ka]

[0570] To a solution of intermediate 61 (82.6 mg, 117.10 μmol, 1 equivalent, TFA) in DCM (2 mL), TEA (1 mL, 7.18 mmol, 61.35 equivalents) and Ac2O (11 μL, 117.10 μmol, 1 equivalent) were added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched at 25°C by adding 10 mL of aqueous NH4Cl solution, then diluted with 10 mL of H2O, and extracted with 30 mL (10 mL x 3) of DCM. The combined organic layer was washed with 10 mL of aqueous NaCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by preparative TLC (SiO2, dichloromethane:methanol = 10:1, Rf = 0.5) to obtain a pure fraction, and the solvent was evaporated under vacuum. The residue was partitioned into MeCN (2 mL) and water (10 mL). The mixture was freeze-dried to obtain compound 30 (22.26 mg, 34.94 μmol, 29.84% yield, 99.461% purity) as a white solid.

[0571] The following compounds were synthesized by a method similar to that described above for compound 30.

[0572] [Table 19]

[0573] Preparation of compound 37

[0574] [ka]

[0575] A mixture of intermediate 61 (190 mg, 321.15 μmol, 1 equivalent), 3-methylsulfonylpropanoic acid (97.7 mg, 642.30 μmol, 2 equivalents), DIEA (167 μL, 963.45 μmol, 3 equivalents), and T4P (347 mg, 481.72 μmol, 50% purity, 1.5 equivalents) in DCM (2 mL) was stirred at 0°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was then subjected to preparative HPLC (column: Phenomenex luna C18 150).* 25mm * The compound was purified using a 10 μm mobile phase (A: water (FA), B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 20% to 50%). The pure fraction was collected, and volatile matter was removed under vacuum. The residue was partitioned into acetonitrile (2 mL) and water (10 mL). The solution was freeze-dried to obtain compound 37 (66.58 mg, 90.46 μmol, yield 28.17%, purity 98.74%) as a white solid.

[0576] LCMS (Liquid Chromatography / Mass Spectrometry) General procedure High-performance liquid chromatography (HPLC) measurements were performed using the LC pump, diode array (DAD), or UV detector and column specified for each method. The flow from the column was delivered to a mass spectrometer (MS) configured with an atmospheric pressure ion source. Setting adjustment parameters (e.g., scanning range, residence time, etc.) to obtain ions that enable the identification of the nominal monoisotopic molecular weight (MW) of the compound is within the knowledge of those skilled in the art. Data acquisition was performed using appropriate software.

[0577] Compounds are described by their experimental retention time (Rt) and ion. Unless otherwise specified in the data table, reported molecular ions correspond to [M+H]+ (protonated molecule) and / or [MH]- (deprotonated molecule). All results are obtained with experimental uncertainties generally associated with the methods used.

[0578] Method 1 Mobile phase: A gradient from 30% ACN (0.018% TFA) to 90% ACN in water (0.037% TFA) is applied over 2.00 minutes, with a flow rate of 1.5 mL / min. Then, a gradient is applied from 90% ACN to 100% ACN in water over 1.70 minutes. The flow rate is set to 1.5 mL / min, and the system is returned to 30% ACN in water, held for 0.30 minutes. The flow rate is set to 2.0 mL / min. Column temperature: 50°C, detector wavelength: 210 nm~265 nm. The column is Kinetex® EVO C18 4.6 × 50 mm, 5 μm.

[0579] Method 2 Mobile phase: A gradient from 5% ACN (0.01875% TFA) to 95% ACN in water (0.0375% TFA) is applied over 2.40 minutes, with a flow rate of 2.0 mL / min. The cell is then held in 95% ACN for 0.30 minutes. The flow rate is then set to 2.0 mL / min, and the cell is returned to 5% ACN in water, held for 0.30 minutes. The flow rate is set to 2.0 mL / min, and the column temperature is 50°C. The column is a Kinetex® EVO C18 4.6 × 50 mm, 5 μm.

[0580] Method 3 Mobile phase: A gradient from 5% ACN (0.01875% TFA) to 95% ACN in water (0.0375% TFA) is applied over 3.20 minutes, with a flow rate of 1.5 mL / min, followed by holding in 95% ACN for 0.30 minutes. The flow rate is then set to 1.5 mL / min to return to 5% ACN in water and hold for 0.30 minutes. The flow rate is set to 2.0 mL / min, and the column temperature is 50°C. The column is a Kinetex® EVO C18 4.6 × 50 mm, 5 μm.

[0581] Method 4 Mobile phase: A gradient from 5% ACN to 95% CAN in water (0.025% NH3·H2O) is applied over 3.00 minutes, with a flow rate of 0.6 mL / min, followed by holding in 95% ACN for 0.70 minutes. The flow rate is then set to 0.6 mL / min, returning to 5% ACN in water and holding for 0.30 minutes. The flow rate is then set to 1.2 mL / min, the column temperature is 40°C, and the detector wavelength is 210 nm to 265 nm. The column is a Kinetex® XBridge C18 2.1 × 30 mm, 3.5 μm thick.

[0582] Method 5 Mobile phase: A gradient from 5% ACN (0.01875% TFA) to 95% ACN in water (0.0375% TFA) was applied over 4.8 minutes, with a flow rate of 0.6 mL / min. The 95% ACN was then held for 0.60 minutes. The flow rate was then set to 1.0 mL / min, returning to 5% ACN in water and held for 0.60 minutes. The flow rate was set to 1.0 mL / min, and the column temperature was 50°C. The column used was a Kinetex EVO C18 2.1.* It is 50 mm long and 1.7 μm thick.

[0583] Method 6 Mobile phase: A gradient from 5% ACN (0.01875% TFA) to 95% ACN in water (0.0375% TFA) is applied over 3.20 minutes, with a flow rate of 1.5 mL / min, followed by holding in 95% ACN for 0.30 minutes. The flow rate is then set to 1.5 mL / min to return to 5% ACN in water, and held for 0.30 minutes. The flow rate is set to 2.0 mL / min, and the column temperature is 50°C. The column is a Kinetex® EVO C18 4.6 × 50 mm, 5 μm thick.

[0584] Method 7 Mobile phase: A gradient from 5% ACN (0.01875% TFA) to 95% ACN in water (0.0375% TFA) is applied over 2.40 minutes, with a flow rate of 2.0 mL / min. The cell is then held in 95% ACN for 0.30 minutes. The flow rate is then set to 2.0 mL / min, and the cell is returned to 5% ACN in water, held for 0.30 minutes. The flow rate is set to 2.0 mL / min, and the column temperature is 50°C. The column is a Kinetex® EVO C18 4.6 × 50 mm, 5 μm thick.

[0585] Method 8 Mobile phase: A gradient from 5% ACN (0.01875% TFA) to 95% ACN in water (0.0375% TFA) is applied over 3.20 minutes, with a flow rate of 1.5 mL / min, followed by holding in 95% ACN for 0.30 minutes. The flow rate is then set to 1.5 mL / min to return to 5% ACN in water, and held for 0.30 minutes. The flow rate is set to 2.0 mL / min, and the column temperature is 50°C. The column is a Kinetex® EVO C18 4.6 × 50 mm, 5 μm thick.

[0586] Method 9 Mobile phase: A gradient from 5% ACN (0.018% TFA) to 95% ACN in water (0.037% TFA) is applied over 3.0 minutes, with a flow rate of 1.0 mL / min. The cell is then held in 95% ACN for 0.60 minutes. The flow rate is then set to 1.0 mL / min to 1.5 mL / min, returning to 5% ACN in water and held for 0.40 minutes. The flow rate is set to 1.5 mL / min. Column temperature is 50°C. The column is a Shim-pack Velox SP-C18 3.0 × 30 mm, 2.7 μm.

[0587] Method 10 Mobile phase: A gradient from 5% ACN to 95% ACN in water (0.025% NH3·H2O) was applied over 2.60 minutes, with a flow rate set to 0.6 mL / min, followed by holding in 95% ACN for 0.25 minutes. The flow rate was then set to 0.8 mL / min, returning to 5% ACN in water and holding for 0.15 minutes. The flow rate was then set to 1.2 mL / min, the column temperature was 40°C, and the detector wavelength was 210 nm to 265 nm. The column was a Kinetex® XBridge C18 2.1 × 30 mm, 3.5 μm thick.

[0588] Method 11 Mobile phase: A gradient from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water is applied over 0.60 minutes, with a flow rate of 2.0 mL / min. The 95% ACN is then held for 0.18 minutes. The flow rate is then set to 2.0 mL / min to return to 5% ACN in water and held for 0.02 minutes. The flow rate is set to 2.0 mL / min. Column temperature is 50°C. The column is a Kinetex® EVO C18 2.1 × 30 mm, 5 μm.

[0589] Method 12 Mobile phase: A gradient is applied from 5% ACN to 95% ACN in water (0.025% NH3·H2O) at 3.00 min, with a flow rate set to 0.9 mL / min, followed by holding at 95% ACN for 0.70 min. The flow rate is then set to 0.9 mL / min, returning to 5% ACN in water and holding for 0.30 min. The flow rate is then set to 1.2 mL / min. Column temperature is 40°C, and detector wavelength is 210 nm to 265 nm. The column is a Kinetex® XBridge C18 3.0 × 50 mm, 5 μm thick.

[0590] Analysis data The LCMS analysis information is shown in the table below.

[0591] [Table 20-1]

[0592] (Continuation of the table above) [Table 20-2]

[0593] NMR method: NMR experiments were performed using a Bruker Advance III 400 spectrometer at ambient temperature (298.6 K), with an internal deuterium lock and a BBO 400 MHz S1 5 mm probe head with a z-gradient. The experiment was conducted at 400 MHz for protons and 100 MHz for carbon. Chemical shifts (δ) are reported in parts per million (ppm). J values ​​are expressed in Hz.

[0594] The NMR analysis information is shown in the table below.

[0595] [Table 21-1] [Table 21-2]

[0596] (Continuation of the table above) [Table 21-3] [Table 21-4]

[0597] (Continuation of the table above) [Table 21-5] [Table 21-6]

[0598] (Continuation of the table above) [Table 21-7] [Table 21-8]

[0599] (Continuation of the table above) [Table 21-9]

[0600] USP1-UAF1 Deubiquitination Assay The specific compounds provided herein were evaluated by the USP1-UAF1 deubiquitination assay. The deubiquitinating enzyme was measured by detecting the fluorescence signal produced when the amide bond between rhodamine and the C-terminal glycine of ubiquitin was hydrolyzed by USP1, using ubiquitin-rhodamine 110 (catalog U-555-050, R&D Systems) as the active substrate. The assay was performed in a total reaction volume of 15 μl containing 0.05 nM USP1-UAF1 enzyme and assay buffer (50 mM HEPES, pH 7.8, 0.5 mM EDTA, 100 mM NaCl, 0.1 mg / mL bovine serum albumin, 1 mM DTT, and 0.01% Tween-20), and was initiated by adding ubiquitin-rhodamine 110 substrate to a final concentration of 150 nM.

[0601] Deubiquitinating enzyme inhibition assays were performed using compounds dissolved in DMSO at a starting concentration of 10 μM. The dissolved compounds were added to a 384-well microplate and pre-mixed with the USP1-UAF1 enzyme for a 20-minute incubation. The intrinsic fluorescence provided by the compounds was measured as a control before the addition of ubiquitin-rhodamine 110. The enzymatic reaction was initiated by adding ubiquitin-rhodamine 110 to the mixture, and each well was read at 30 minutes using a microplate reader (Spark® TECAN), with fluorescence intensity detected at 480 nm excitation / 530 nm emission.

[0602] All measurement data is subtracted from the values ​​in the control well, IC 50 The values ​​were calculated using a four-parameter dose-response inhibition model in GraphPad Prism 8.0.2 (La Jolla, California, USA, www.graphpad.com).

[0603] Cell proliferation assay For USP1 sensitivity, exponentially growing cells were seeded at very low densities (typically 0.3k–1.2k cells / well) in 96-well or 384-well plates, aiming to prevent division for at least 7 days. Cells were seeded on day -1 and treated with DMSO or an increasing dose of a USP1 inhibitor on day 0. At the end of the experiment, cell viability was estimated using Cell-TiterGlo (Promega).

[0604] Biological data [Table 22-1]

[0605] (Continuation of the table above) [Table 22-2] I C 50(nM):0 <A<50;50<B<1000;1000<C<10000

[0606] Liver microsome stability assay The liver microsome stability assay of the compound of the present invention was performed as follows.

[0607] Composition of the experimental incubation system

[0608] [Table 23]

[0609] Experimental procedure: (1) Remove liver microsomes from the refrigerator and place them on a 37°C water bath shaker for preheating. Incubate for 5 minutes until thawed and leave until ready to use. (2) Weigh a certain amount of NADPH and dissolve it in an appropriate amount of magnesium chloride solution to prepare a 2 mM solution, which is left to stand until ready to use. (3) Prepare the incubation system according to the above proportions (excluding NADPH) and dispense 165 μL per tube (75 μL per tube for the negative control group, 120 μL per tube for the positive control group). (4) 0 min sample: Add 200 μL of internal standard working precipitate (acetonitrile solution of carbamazepine, glibenclamide, propranolol, and tolbutamide, concentration 20 ng / mL), then add 30 μL of NADPH solution (30 μL of magnesium chloride solution was added to the negative control group). (5) Other samples: The reaction was started by adding 135 μL of NADPH solution (45 μL of magnesium chloride solution was added for the negative control group), incubated at 37°C for 5, 15, 30, and 60 minutes, and then 200 μL of internal standard working precipitate was added to these samples. (6) Positive control group: The reaction was started by adding 90 μL of NADPH solution, incubated at 37°C for 5 and 15 minutes, and then 200 μL of internal standard working precipitate was added to these samples. (7) All samples were vortexed and centrifuged. (8) 150 μL of supernatant was taken and added to 150 μL of water, the system was vortexed and thoroughly mixed, and analyzed by LC-MS / MS.

[0610] Data analysis: The half-life (t1 / 2) and clearance (CL) are calculated using the following first-order reaction rate equation.

[0611] Ct=C0 * e -kt t1 / 2 = ln2 / k = 0.693 / k CL=Vd * k Vd = 1 / Protein content in liver microsomes

[0612] The metabolic stability of compound 30 in mouse, rat, dog, and human liver microsomes is shown in the table below.

[0613] [Table 24]

[0614] The experimental data show that compound 30 exhibits good stability in liver microsomes and minimal species differences.

[0615] Pharmacokinetic studies in mice Pharmacokinetic studies were conducted in ICR mice, to which the compounds of this application were administered intravenously and via oral gastric tube feeding. Blood samples were collected at different time points, and drug concentrations in the plasma were measured. The purpose of this study was to investigate and evaluate the pharmacokinetic profile of the compounds in mice.

[0616] Each group consists of nine healthy male ICR mice.

[0617] Intravenous administration: 1) A fixed amount of the test compound was weighed into a glass vial. 2) 5% DMSO was added and mixed by vortexing, then 10% Solutol HS-15 was added and mixed. Finally, 85% physiological saline was added to obtain a clear, transparent solution with a concentration of the test compound of 0.2 mg / mL.

[0618] Oral gastric tube nutrition administration: 1) A fixed amount of the test compound was weighed into a glass vial. 2) 5% DMSO was added and mixed by vortexing, then 10% Solutol HS-15 was added and mixed. Finally, 85% physiological saline was added to obtain a clear, transparent solution with a concentration of 5 mg / mL of the test compound.

[0619] For intravenous administration of the compound of the present invention to mice, 0.1 mL blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The blood samples were placed in labeled EDTA-2K anticoagulant tubes. The tubes were gently inverted to ensure complete mixing of the blood and anticoagulant (EDTA-2K), and immediately placed on moist ice. Within one hour of blood collection, the tubes were centrifuged at 6800 g for 6 minutes at 4°C to separate the plasma. The obtained plasma was transferred to labeled EP tubes and stored in a cryogenic freezer until sample analysis.

[0620] For oral gastric tube feeding of the compound of this application to mice, 0.1 mL blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The blood samples were placed in labeled EDTA-2K anticoagulant tubes. The tubes were gently inverted to ensure complete mixing of the blood and anticoagulant (EDTA-2K), and immediately placed on moist ice. Within one hour of blood collection, the tubes were centrifuged at 6800 g for 6 minutes at 4°C to separate the plasma. The obtained plasma was transferred to labeled EP tubes and stored in a cryogenic freezer until sample analysis.

[0621] The sample preparation procedure was as follows under yellow light conditions in an ice bath: 1) Except for the blank sample, 200 μL of acetonitrile solution containing an internal standard (glibenclamide) was added to the wells of a 96-well plate containing 20 μL of all other samples. For the blank sample, 200 μL of acetonitrile was added. 2) The system was thoroughly mixed by vortexing. 3) The samples were centrifuged. 4) 150 μL of the supernatant was transferred to a new 96-well plate and mixed with 150 μL of ultrapure water. 5) Sample analysis was performed by injection.

[0622] The pharmacokinetic parameters of compound 30 in mice are shown in the table below.

[0623] [Table 25]

[0624] The experimental data show that compound 30 has low clearance and high oral bioavailability in mice.

[0625] Pharmacokinetic studies in dogs Pharmacokinetic studies were conducted in beagle dogs, with the compound of this application administered to the dogs via intravenous injection and oral gastric tube feeding. Blood samples were collected at different time points, and drug concentrations in the plasma were measured. The purpose of this study was to investigate and evaluate the pharmacokinetic profile of the compound in dogs.

[0626] Each group consists of three healthy male beagle dogs.

[0627] Intravenous administration: 1) A fixed amount of the test compound was weighed into a glass vial. 2) 5% DMSO was added and mixed by vortexing, then 10% PG was added and mixed. Finally, 85% physiological saline was added to obtain a clear, transparent solution with a concentration of the test compound of 0.385 mg / mL.

[0628] Oral gastric tube nutrition administration: 1) A fixed amount of the test compound was weighed into a glass vial. 2) 5% DMSO was added and mixed by vortexing, then 10% PG was added and mixed. Finally, 85% physiological saline was added to obtain a clear, transparent solution with a concentration of the test compound of 4.878 mg / mL.

[0629] For intravenous administration of the compounds referred to in this application to dogs, 1.0 mL blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The blood samples were placed in labeled EDTA-2K anticoagulant tubes. The tubes were gently inverted to ensure complete mixing of the blood and anticoagulant (EDTA-2K), and immediately placed on moist ice. Within one hour of blood collection, the tubes were centrifuged at 2200 g for 6 minutes at 4°C to separate the plasma. The obtained plasma was transferred to labeled EP tubes and stored in a cryogenic freezer until sample analysis.

[0630] For oral gastric tube feeding of the compound of this application to dogs, 1.0 mL blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The blood samples were placed in labeled EDTA-2K anticoagulant tubes. The tubes were gently inverted to ensure complete mixing of the blood and anticoagulant (EDTA-2K), and immediately placed on moist ice. Within one hour of blood collection, the tubes were centrifuged at 2200 g for 6 minutes at 4°C to separate the plasma. The obtained plasma was transferred to labeled EP tubes and stored in a cryogenic freezer until sample analysis.

[0631] The sample preparation procedure was as follows under yellow light conditions in an ice bath: 1) Except for the blank sample, 200 μL of acetonitrile solution containing an internal standard (carbamazepine) was added to the wells of a 96-well plate containing 20 μL of all other samples. For the blank sample, 200 μL of acetonitrile was added. 2) The system was thoroughly mixed by vortexing. 3) The samples were centrifuged. 4) 150 μL of the supernatant was transferred to a new 96-well plate and mixed with 150 μL of ultrapure water. 5) Sample analysis was performed by injection.

[0632] The pharmacokinetic parameters of compound 30 in dogs are shown in the table below.

[0633] [Table 26]

[0634] Experimental data show that compound 30 has low clearance and high oral bioavailability in dogs.

[0635] Efficacy trials in preclinical tumor models MDA-MB-436 cells were cultured in DMEM medium supplemented with 10% thermo-inactivated fetal bovine serum. 1 × 10 7 One MDA-MB-436 cell was subcutaneously transplanted into the right flank of female NOD-SCID mice (body weight 18-22g, 6-8 weeks old, supplied by Shanghai Jihui Laboratory Animal Breeding Co., Ltd). The tumor was approximately 80-120 mm. 3 When this was reached, mice were randomly assigned to treatment groups as shown in Table 2 below. Tumor volume (TV) was measured twice weekly in two dimensions using a caliper, and the volume was expressed using the formula: V = 0.5a × b 2 Using mm 3 This is expressed as follows, where a and b are the long and short diameters of the tumor, respectively.

[0636] Compound 30 monotherapy demonstrated a dose-dependent antitumor effect compared to the control vehicle treatment group (shown in Figure 1). Tumor growth inhibition (TGI) is summarized in Table 2. Treatment with compound 30 was well tolerated at all administered doses, as evidenced by the minimal change in body weight. TGI is given by the following formula: %TGI=((TV vehicle / last -TV vehicle / day0 )-(TV treated / last -TV treated / day0 )) / (TV vehicle / last -TV vehicle / day0 The formula was defined based on the mean values ​​of the treatment group on day 0 and the last day of measurement, calculated by multiplying by 100.

[0637] [Table 27]

[0638] The embodiments described above are intended to be illustrative only, and those skilled in the art can identify or confirm numerous equivalents of particular compounds, substances, and procedures using only routine experiments. All such equivalents are considered to fall within the scope of the present invention and are encompassed within the appended claims.

Claims

1. A compound of formula (I), 【Chemistry 1】 During the ceremony X 1 is N or CR x1 And R x1 is hydrogen or C 1 ~C 6 It is alkyl, X 2 is N or CR x2 where R x2 is hydrogen or C 1 to C 6 alkyl X 3 is N or CR x3 And R x3 is hydrogen or C 1 ~C 6 It is alkyl, X 1 , X 2 , and X 3 Under the condition that at least one of them is N; L stands for NR b , O, or S, R b is hydrogen or C 1 ~C 6 It is alkyl, R 1 Alkyl, alkoxy, halogen, cyano, NR c R d , -C(=O)NHR d , -NHC(=O)R c , haloalkyl, cycloalkyl, cycloalkyloxy, haloalkyloxy, heterocyclyl, aryl, and heteroaryl, R 1 Each alkyl, alkoxy, cycloalkyl, cycloalkyloxy, heterocyclyl, aryl, and heteroaryl in the compound may be optionally substituted. R c and R d Each of these is independently selected from hydrogen, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, R c or R d Each alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl group within can be independently and optionally substituted. R 2 and R 3 Each of these is independently selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (carboxamide)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxy, amide, carboxamide, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, and alkylthio, R 2 or R 3 Each alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl moiety in the compound is one or more C 1 ~C 6 They are independently and optionally substituted with alkyl, halogen, or deuterium. Ring A is selected from aryl, heteroaryl, cycloalkyl, heterocyclyl, and phenyl equivalents, and ring A is optionally substituted. R is selected from hydrogen, halogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, and amide, and each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl moiety in R is independently and arbitrarily substituted, in the compound. Or stereoisomers, mixtures thereof, solvates, or pharmaceutically acceptable salts thereof.

2. R stands for hydrogen, halogen, C 1 ~C 6 Alkyl, C 3 ~C 8 Cycloalkyl, 4-8 membered heterocyclyl, C 6 ~C 10 Aryl, 5-10 member heteroaryl, C 1 ~C 6 Alkoxy, C 3 ~C 8 Cycloalkyloxy, 4-8 member heterocyclyloxy, C 6 ~C 10 Aryloxy, 5-10 member heteroaryloxy, (C 3 ~C 8 (Cycloalkyl)-(C 1 ~C 2 (alkyl)-, (4-8 member heterocyclyl)-(C 1 ~C 2 (Alkyl)-, (C 6 ~C 10 Ariel) - (C 1 ~C 2 (alkyl)-, (5-10 member heteroaryl)-(C 1 ~C 2 (Alkyl), (C 3 ~C 8 (Cycloalkyl)-(C 1 ~C 2 (alkyloxy)-, (4-8 member heterocyclyl)-(C 1 ~C 2 (alkyloxy)-, (C 6 ~C 10 Ariel) - (C 1 ~C 2 (alkyloxy)-, and (5-10 member heteroaryl)-(C 1 ~C 2 The compound according to claim 1, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl moieties in the formula are independently and optionally substituted.

3. R is a 5- or 6-membered heteroaryl compound. Preferably, R is a 5- or 6-membered nitrogen-containing heteroaryl compound or a nitrogen and oxygen-containing heteroaryl compound according to claim 1 or 2.

4. R is one or more R 4 Replaced by each R 4 This includes deuterium, halogens, nitro, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted deuterated alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, haloalkyl, optionally substituted alkoxy, optionally substituted deuterated alkoxy, haloalkyloxy, acyl, optionally substituted cycloalkyloxy, optionally substituted heterocyclyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl, optionally substituted spiroheterocyclyl, optionally substituted spirocyclyl, optionally substituted cross-linked heterocyclyl, optionally substituted cross-linked carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted alkoxy A compound according to any one of claims 1 to 3, independently selected from xyalkyl, optionally substituted (alkylamino)alkyl, optionally substituted (dialkylamino)alkyl, optionally substituted cyanoalkyl, optionally substituted (carboxamide)alkyl, optionally substituted mercaptoalkyl, optionally substituted (cycloalkylamino)alkyl, optionally substituted cycloalkylalkyloxy, optionally substituted heterocyclylalkyloxy, optionally substituted aralkyloxy, optionally substituted heteroarylalkyloxy, amino, optionally substituted alkylamino, optionally substituted dialkylamino, (hydroxyalkyl)amino, carboxy, amide, carboxamide, optionally substituted sulfonamide, optionally substituted alkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, and optionally substituted alkylthio.

5. R is, 【Chemistry 2】 A compound selected from any one of claims 1 to 4.

6. X 1 The compound according to any one of claims 1 to 5, wherein is N.

7. X 2 is N or CR x2 And R x2 is hydrogen or C 1 ~C 6 A compound according to any one of claims 1 to 6, wherein it is alkyl.

8. X 3 The compound according to any one of claims 1 to 7, wherein is N.

9. The compound according to any one of claims 1 to 8, wherein the compound is a compound of formula (II), 【Transformation 3】 During the ceremony X 4 is N or CR x4 And R x4 is hydrogen, C 1 ~C 6 Alkyl or halogen, X 5 is N or CR x5 where R x5 is hydrogen, C 1 to C 6 alkyl, or halogen, R a1 is selected from deuterium, halogen, nitro, cyano, hydroxy, alkyl, cycloalkyl, haloalkyl, alkoxy, and haloalkyloxy, preferably R a1 These are selected from cyano, nitro, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoropropan-2-yl, 2-fluoroethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethoxy, and trifluoromethoxy. R a2 is selected from deuterium, halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, deuterated alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkyl, alkoxy, deuterated alkoxy, haloalkyloxy, acyl, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, spiroheterocyclyl, spirocyclicryl, bridged heterocyclyl, bridged carbocyclicryl, aralkyl, heteroarylalkyl, alkoxyalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (carboxamide)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxy, amide, carboxamide, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, and alkylthio, and preferably, R a2 Fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, 1-fluoropropan-2-yl, 2-fluoroethyl, formyl, acetyl, propionyl, amino, methylamino, ethylamino, dimethylamino, 2,2-difluoroethoxy, cyclopropoxy, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranil, oxetanyl, azetidinyl, pyrrolidinyl, dihydropyridinyl, tetrahydropyridinyl, tetrahydrothiapyranil, tetrahydro Selected from dorothiopyranyl, and selected from morpholinyloxy, piperidinyloxy, piperazinyloxy, tetrahydropyranyloxy, oxetanyloxy, azetidinyloxy, pyrrolidinyloxy, dihydropyridinyloxy, tetrahydropyridinyloxy, tetrahydrothiapyranyloxy, morpholinylmethyl, piperidinylmethyl, piperazinylmethyl, tetrahydropyranylmethyl, oxetanylmethyl, azetidinylmethyl, pyrrolidinylmethyl, dihydropyridinylmethyl, tetrahydropyridinylmethyl, tetrahydrothiapyranylmethyl, azaspiroheptyl, azabicycloheptyl, diazabicycloheptyl, methoxymethyl, methylaminomethyl, deuterium methyl, deuterium ethyl, deuterium isopropyl, deuterium methoxy, and deuterium ethoxy, R a2 It can be arbitrarily replaced, Ring A, L, R 1 , R 2 , and R 3 Each of the compounds is as defined in claim 1, Or stereoisomers, mixtures thereof, solvates, or pharmaceutically acceptable salts thereof.

10. R a2 is one or more R 5 Replaced by each R 5 These include halogen, nitro, cyano, hydroxy, sulfhydryl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkyl, alkoxy, acyl, cycloalkyloxy, heterocyclyloxy, heterocyclylcarbonyl, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, spiroheterocyclyl, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (carboxamyl) A molecule independently selected from (d)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, oxo, carboxy, amide, carboxamide, sulfonamide, formyl, carbamoyl, sulfamoyl, alkylcarbonyl, haloalkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, and alkylthio, R 5 is optionally substituted and / or two R 5 These, together with the same ring carbon atoms to which they are bonded, form optionally substituted C 3 ~C 7 Two R atoms bonded to different carbon atoms form a cycloalkyl or 3- to 7-membered heterocycloalkyl group. 5 They come together to form an arbitrarily substituted bridging ring, Preferably, each R 5 R is independently selected from fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, oxo, cyclopropyl, cyclopropylcarbonyl, isopropylcarbonyl, cyclobutylcarbonyl, formyl, acetyl, trifluoroacetyl, propionyl, amino, hydroxy, sulfhydryl, oxetanyl, oxetan-3-carbonyl, azetidinyl, methylsulfonyl, ethylsulfonyl, aminomethylsulfonyl, methylsulfinyl, ethylsulfinyl, carbamoyl, benzoyl, sulfamoyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, pyrrolyl, furanyl, thiophenyl, piperidinyl, piperazinyl, tetrahydrothiapyranil, and tetrahydrothiopyranil. 5 is optionally substituted and / or two R 5 These, together with the same ring carbon atom to which they are bonded, form optionally substituted cyclobutyl or azetidinyl, and / or two R atoms bonded to different carbon atoms. 5 The compound according to claim 9, wherein the compounds combine to form optionally substituted azabicycloheptyl or diazabicycloheptyl.

11. R 5 is one or more R 6 Replaced by each R 6 is independently selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkyl, alkoxy, acyl; cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (carboxamide)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxy, amide, carboxamide, sulfonamide, alkylcarbonyl, arylcarbonyl, formyl, carbamoyl, alkylsulfonyl, arylsulfonyl, and alkylthio, R 6 It can be arbitrarily replaced, Preferably, each R 6 R is independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, carbamoyl, methylsulfonyl, ethylsulfonyl, formyl, acetyl, propionyl, methoxy, ethoxy, isopropoxy, tert-butoxy, amino, methylamino, ethylamino, dimethylamino, hydroxy, carboxamide, acetamide, propionamide, carbamoyl, methylsulfonyl, ethylsulfonyl, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranil, oxetanyl, azetidinyl, isoxazolidinyl, or pyrrolidinyl. 6 The compound according to claim 10, wherein is optionally substituted.

12. R 6 is one or more R 7 Replaced by each R 7 These are independently selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkyl, alkoxy, oxo, acyl, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, hydroxyalkyloxy, carboxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (carboxamide)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxy, amide, carboxamide, sulfonamide, alkylcarbonyl, arylcarbonyl, formyl, carbamoyl, alkylsulfonyl, arylsulfonyl, and alkylthio. Preferably, each R 7 The compound according to claim 11, wherein is independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, acetyl, oxo, hydroxy, sulfhydryl, oxetanyl, azetidinyl, imidazolidinyl, methylsulfonyl, methylamino, dimethylamino, methoxy, ethoxy, isopropoxy, tert-butoxy, and hydroxyethoxy.

13. R a2 The compound is selected from the group consisting of methyl, methoxy, dimethylamino, cyclopropyl, and fluoro, as described in any one of claims 9 to 12. 【Chemistry 4】 【Transformation 5】

14. Ring A is C 6 ~C 10 These are aryl, 5-6 member heteroaryl, 5-6 member cycloalkyl, 5-6 member heterocyclyl, or phenyl equivalents. Preferably, ring A is phenyl, more preferably, ring A is 【Transformation 6】 And, Preferably, ring A is cubane, more preferably, ring A is 【Transformation 7】 And, Preferably, ring A is a 6-membered nitrogen-containing heteroaryl, more preferably ring A is pyridyl, and most preferably ring A is 【Transformation 8】 The compound according to any one of claims 1 to 13.

15. Ring A contains one or more R 8 It is arbitrarily replaced by each R 8 R is independently selected from halogen, cyano, alkyl, amino, alkylamino, dialkylamino, hydroxy, or alkoxy, and each alkyl, alkylamino, dialkylamino, or alkoxy moiety is independently and optionally substituted with one or more halogens, hydroxy, or alkoxy, preferably each R 8 The compound according to any one of claims 1 to 14, wherein is independently selected from fluoro, chloro, cyano, methoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy, hydroxyethoxy, and methoxyethoxy.

16. Ring A is selected from the group consisting of the following, and is a compound according to any one of claims 1 to 15. 【Chemistry 9】

17. R a2 It is piperidinyl, and R 5 The compound according to any one of claims 9 to 16, wherein is an acyl.

18. A compound according to any one of claims 1 to 17, which is a compound of formula (III), 【Chemistry 10】 During the ceremony R a3 is selected from halogens, haloalkyls, nitros, cyanos, hydroxys, alkyls, alkoxys, and cycloalkyls, preferably R a3 These are selected from cyano, nitro, hydroxy, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, isopropoxy, and tert-butoxy. R a4 The is selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkyl, alkoxy, acyl, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (carboxamide)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxy, amide, carboxamide, sulfonamide, alkylcarbonyl, arylcarbonyl, formyl, carbamoyl, alkylsulfonyl, arylsulfonyl, and alkylthio, preferably R a4 R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, trifluoromethyl, carbamoyl, methylsulfonyl, ethylsulfonyl, formyl, acetyl, propionyl, methoxy, ethoxy, isopropoxy, tert-butoxy, amino, methylamino, ethylamino, dimethylamino, hydroxy, carboxamide, acetamide, propionamide, carbamoyl, methylsulfonyl, ethylsulfonyl, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranil, oxetanyl, azetidinyl, isoxazolidinyl, and pyrrolidinyl. a4 It can be arbitrarily replaced, L, R 1 , R 2 , and R 3 Each of the compounds is as defined in claim 1, Or stereoisomers, mixtures thereof, solvates, or pharmaceutically acceptable salts thereof.

19. R a4 is one or more R 9 Replaced by each R 9 These are independently selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkyl, alkoxy, oxo, acyl, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, hydroxyalkyloxy, carboxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (carboxamide)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkyloxy, heterocyclylalkyloxy, aralkyloxy, heteroarylalkyloxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxy, amide, carboxamide, sulfonamide, alkylcarbonyl, arylcarbonyl, formyl, carbamoyl, alkylsulfonyl, arylsulfonyl, and alkylthio. Preferably, each R 9 The compound according to claim 18, wherein is independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, acetyl, oxo, hydroxy, sulfhydryl, oxetanyl, azetidinyl, imidazolidinyl, methylsulfonyl, methylamino, dimethylamino, methoxy, ethoxy, isopropoxy, tert-butoxy, and hydroxyethoxy.

20. R a4 These include methyl, ethyl, isopropyl, cyclopropyl, amino, methylamino, hydroxymethyl, trifluoromethyl, methylsulfonylethyl, 【Chemistry 11】 【Chemistry 12】 A compound according to claim 18 or 19, selected from the above.

21. The compound according to any one of claims 1 to 20, wherein L is NH or O.

22. The aforementioned compound is selected from the group consisting of the following: Table 1-1 (Continuation of the table above) Table 1-2 (Continuation of the table above) Table 1-3 (Continuation of the table above) Table 1-4 The compound according to any one of claims 1 to 21.

23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22 and a pharmaceutically acceptable excipient.

24. A method for treating a disease or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 22, or a stereoisomer thereof, a mixture of stereoisomers thereof, a solvate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23, wherein the disease or condition is a USP1 protein-mediated disorder, preferably the USP1 protein-mediated disorder is cancer, more preferably the cancer is a hematological cancer, a lymphoid cancer, or a solid tumor, such as lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, or breast cancer.

25. The use of a compound according to any one of claims 1 to 22, or a stereoisomer thereof, a mixture of stereoisomers, a solvate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23, in the manufacture of a medicament for the prevention or treatment of a disease or condition, wherein the disease or condition is a USP1 protein-mediated disorder, preferably the USP1 protein-mediated disorder is cancer, and more preferably the cancer is a hematological cancer, a lymphoid cancer, or a solid tumor, such as lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer or breast cancer, according to any one of claims 1 to 22, or a compound according to any one of claims 1 to 22, or a stereoisomer thereof, a mixture of stereoisomers, a solvate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23.

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