Pyrimidine compounds and their use as USP1 inhibitors

Abstract

Provided herein are specific heteroaromatic compounds, such as compounds of Formula (I), as ubiquitin-specific processing protease 1 (USP1) inhibitors, pharmaceutical compositions comprising these compounds, and methods of use of these compounds or pharmaceutical compositions in the treatment of diseases or disorders.

Description

[0001] This application claims priority to International Application No. PCT / CN2023 / 107498, filed July 14, 2023, which is incorporated by reference herein in its entirety for all purposes. TECHNICAL FIELD

[0002] Provided herein are certain imidazole heteroaromatic compounds, such as compounds of Formula (I), as ubiquitin specific processing protease 1 (USP1) inhibitors, pharmaceutical compositions comprising these compounds, and methods of using these compounds or pharmaceutical compositions in the treatment of a disease or disorder.

[0003] BACKGROUND

[0004] Ubiquitin (Ub) is a highly conserved 76-amino acid peptide that is post- transcriptionally attached to target proteins. The ubiquitin-proteasome system (UPS) is the major proteolytic system that controls protein degradation and it also regulates many cellular processes in eukaryotic cells. Polyubiquitination via surface lysine-48 (K48) or lysine-11 (K11) residues of ubiquitin generally leads to protein proteolysis by the 26S proteasome. In contrast, mono-ubiquitination or polyubiquitin chains through 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 exists a family of enzymes called deubiquitinases (DUBs) that act on ubiquitinated substrates to catalyze the removal of ubiquitin moieties.

[0005] One of the most characteristic human DUBs is ubiquitin specific protease 1 (USP1), which plays an important role in cellular responses to DNA damage. USP1, together with the cofactor UAF1 (USP1-associated factor 1), acts during DNA repair processes to specifically remove mono-ubiquitin signals. The mono-ubiquitinated FANCI FANCD2 heterodimer is one such substrate and is involved in the repair of DNA interstrand crosslinks via the Fanconi anemia pathway. A second DNA repair-related process, translesion synthesis (TLS), is also regulated by USP1, further supporting the critical role of this DUB in DNA damage response. A key USP1 substrate in TLS is mono-ubiquitinated PCNA (proliferating cell nuclear antigen). By reversing PCNA mono-ubiquitination, USP1 helps prevent the

[0006] SUMMARY

[0007] In one embodiment, certain pyrimidine heteroaromatic compounds are provided herein as inhibitors of ubiquitin-specific processing protease 1 (USP1). In one embodiment, the compound has a pyrimidine core structure.

[0008] In one embodiment, compounds of formula (I) are provided herein:

[0009]

[0010] (I)

[0011] Or its stereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein X 1 X 2 X 3 , R, R 1 R 2 R 3 L and ring A are as defined herein or elsewhere.

[0012] This article also provides pharmaceutical compositions comprising the compounds provided herein and pharmaceutically acceptable excipients.

[0013] This article also provides a method for inhibiting the USP1 protein, which includes contacting the USP1 protein with a compound or pharmaceutical composition provided herein.

[0014] This article also provides methods for treating USP1 protein-mediated disorders or cancers, which include administering a therapeutically effective amount of the compound or pharmaceutical composition provided herein to a subject suffering from the disorder or cancer.

[0015] This article also provides for the use of the compounds or pharmaceutical compositions described herein in the preparation of medicaments for the prevention or treatment of USP1 protein-mediated disorders or cancers. Brief description of the attached diagram

[0016] Figure 1 The dose-dependent antitumor effects of compound 30 relative to the mediator were described at different doses and at different times.

[0017] Detailed Explanation

[0018] definition

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications, publications, and other publications are incorporated herein by reference in their entirety. Where multiple definitions exist for terms herein, the definitions provided in this section shall prevail unless otherwise stated.

[0020] As used herein, in the specification, and in the appended claims, unless the context clearly indicates otherwise, the indefinite article “a / an” and the definite article “the / said” include both plural and single indicators.

[0021] As used herein, the terms “comprising” and “including” are used interchangeably. The terms “comprising” and “including” should be interpreted as specifying the presence of the referred feature or component, but do not exclude the presence or addition of one or more features, components, or groups thereof. Furthermore, the terms “comprising” and “including” are intended to include instances covered by the term “consisting of”. Therefore, the term “consisting of” can be used in place of the terms “comprising” and “including” to provide a more specific implementation.

[0022] As used herein, the term "or" should be interpreted as inclusive "or," meaning any one / any combination. Therefore, "A, B, or C" means any of the following: "A; B; C; A and B; A and C; B and C; A, B, and C." Exceptions to this definition will only occur if the combination of elements, functions, steps, or behaviors is inherently mutually exclusive in some way.

[0023] As used herein, the phrase "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 phrase "and / or" as used in phrases such as "A, B, and / or C" is intended to cover each of 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).

[0024] It should be noted that if there is a discrepancy between the described structure and its name, the described structure shall prevail.

[0025] As used herein, and unless otherwise stated, the term "alkyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, which is saturated. In one embodiment, the alkyl group has, for example, one to twenty-four carbon atoms (C1-C2). 24 Alkyl groups, with four to twenty carbon atoms (C4-C5). 20 Alkyl groups, with six to sixteen carbon atoms (C6-C6). 16 Alkyl groups, six to nine carbon atoms (C6-C9 alkyl groups), one to fifteen carbon atoms (C1-C9 alkyl groups) 15 Alkyl groups, with one to twelve carbon atoms (C1-C2). 12Alkyl groups are alkyl groups with one to eight carbon atoms (C1-C8 alkyl) or one to six carbon atoms (C1-C6 alkyl), and are connected to the rest of the molecule by single bonds. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, etc. Unless otherwise stated, alkyl groups are optionally substituted.

[0026] As used herein, and unless otherwise stated, the term "alkenyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing one or more carbon-carbon double bonds. The term "alkenyl" also includes groups having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations as understood by those skilled in the art. In one embodiment, the alkenyl group has, for example, two to twenty-four carbon atoms (C2-C4). 24 alkenyl), four to twenty carbon atoms (C4-C) 20 alkenyl), six to sixteen carbon atoms (C6-C) 16 alkenyl), six to nine carbon atoms (C6-C9 alkenyl), two to fifteen carbon atoms (C2-C9 alkenyl) 15 alkenyl), two to twelve carbon atoms (C2-C) 12 The alkenyl group consists of two to eight carbon atoms (C2-C8 alkenyl) or two to six carbon atoms (C2-C6 alkenyl), and is connected to the rest of the molecule by a single bond. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, pent-1,4-dienyl, etc. Unless otherwise stated, the alkenyl group is optionally substituted.

[0027] As used herein, and unless otherwise stated, the term "alkynyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing one or more carbon-carbon triple bonds. In one embodiment, the alkynyl group has, for example, two to twenty-four carbon atoms (C2-C4). 24 Alkyne group), four to twenty carbon atoms (C4-C) 20 Alkyne group, six to sixteen carbon atoms (C6-C) 16 Alkyne group, six to nine carbon atoms (C6-C9 alkynyl), two to fifteen carbon atoms (C2-C9 alkynyl) 15 alkynyl group), two to twelve carbon atoms (C2-C) 12 The alkynyl group consists of two to eight carbon atoms (C2-C8 alkynyl) or two to six carbon atoms (C2-C6 alkynyl), and is attached to the rest of the molecule by a single bond. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and pentyynyl. Unless otherwise stated, the alkynyl group is optionally substituted.

[0028] As used herein, and unless otherwise stated, the terms "cycloalkyl" or "carbocyclic" refer to a non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, and which is saturated. Cycloalkyl groups can include fused ring, bridged ring, or spirocyclic systems. In one embodiment, the cycloalkyl group has, for example, 3 to 15 ring carbon atoms (C3-C4). 15 cycloalkyl groups, 3 to 10 cyclic carbon atoms (C3-C4) 10 Cycloalkyl groups (3 to 8 carbon atoms in a ring, C3-C8 cycloalkyl). The cycloalkyl group is attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl groups include, but are not limited to, adamantyl, norbornyl, naphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Unless otherwise stated, the cycloalkyl group is optionally substituted.

[0029] As used herein, “phenyl isosteres” refers to a portion or functional group that exhibits physical, biological, and / or chemical properties similar to those of a phenyl group. Exemplary phenyl isosteres 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, closed-cell -1,2-carborane, closed-cell -1,7-carborane, and closed-cell -1,12-carborane.

[0030] As used herein, and unless otherwise stated, the term "aryl" refers to a monocyclic aromatic group and / or a polycyclic aromatic group containing at least one aromatic hydrocarbon ring. In some embodiments, the aryl group has 6 to 18 ring carbon atoms (C6-C1). 18 aryl), 6 to 14 cyclic carbon atoms (C6-C) 14 (aryl) or 6 to 10 cyclic carbon atoms (C6-C) 10 Aryl. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulel, anthracene, phenanthryl, pyrene, biphenyl, and terphenyl. The term "aryl" also refers to a bicyclic, tricyclic, or other polycyclic hydrocarbon ring, wherein at least one of these rings is aromatic and the other rings may be saturated, partially unsaturated, or aromatic, such as dihydronaphthyl, indenyl, indenyl, or tetrahydronaphthyl (tetrahydronaphthyl). Unless otherwise stated, aryl groups are optionally substituted.

[0031] As used herein, and unless otherwise stated, the term "heteroaryl" refers to a monocyclic aromatic group and / or a polycyclic aromatic group containing at least one aromatic ring, wherein the at least one aromatic ring contains one or more (e.g., one, one or two, one to three, or one to four) heteroatoms independently selected from O, S, and N. The heteroaryl group may be attached to the host structure at any heteroatom or carbon atom. In some embodiments, the heteroaryl group has 5 to 20, 5 to 15, or 5 to 10 ring atoms. The term "heteroaryl" also refers to bicyclic, tricyclic, or other polycyclic rings, wherein at least one of these rings is aromatic and the other rings may be saturated, partially unsaturated, or aromatic, wherein the at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N. Examples of monocyclic heteroaryl groups include, but are not limited to, pyrroloyl, pyrazolyl, pyrazolinyl, imidazoyl, oxazolyl, isoxazolyl, thiazoyl, thiadiazoyl, isothiazolyl, furanyl, thiophene, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl. Examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, benzothiazoyl, benzooxazolyl, benzothiaphene, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolazinyl, benzofuranyl, isobenzofuranyl, crononeyl, coumarinyl, cinolinyl, quinoxolinyl, indazoleyl, purinyl, pyrrolopyridyl, furanopyridyl, thiophenopyridyl, dihydroisoindolyl, and tetrahydroquinolinyl. Examples of tricyclic heteroaryl groups include, but are not limited to, carbazolyl, benzoindolyl, phenanthrolinel, acridinel, phenanthidyl, and xanthonyl. Unless otherwise stated, heteroaryl groups are optionally substituted.

[0032] As used herein, and unless otherwise stated, the term "heterocyclic group" refers to a monocyclic and / or polycyclic non-aromatic group containing one or more (e.g., one, one or two, one to three, or one to four) heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. A heterocyclic group can be attached to the host structure at any heteroatom or carbon atom. A heterocyclic group can be a monocyclic, bicyclic, tricyclic, tetracyclic, or other polycyclic system, wherein the polycyclic system can be a fused ring, a bridged ring, or a spirocyclic system. A heterocyclic polycyclic system can include one or more heteroatoms in one or more rings. A heterocyclic group can be saturated or partially unsaturated. A saturated heterocyclic alkyl group can be referred to as a "heterocyclic alkyl group." A partially unsaturated heterocyclic alkyl group can be referred to as a "heterocyclic alkenyl group" if it contains at least one double bond, or as a "heterocyclic alkynyl group" if it contains at least one triple bond. In one embodiment, the heterocyclic group has, for example, 3 to 18 ring atoms (3- to 18-membered heterocyclic group), 4 to 18 ring atoms (4- to 18-membered heterocyclic group), 5 to 18 ring atoms (5- to 18-membered heterocyclic group), 4 to 8 ring atoms (4- to 8-membered heterocyclic group), or 5 to 8 ring atoms (5- to 8-membered heterocyclic group). Examples of heterocyclic groups include, but are not limited to, oxacyclobutane, azacyclobutane, imidazoalkyl, oxazolyl, thiazoalkyl, pyrazolyl, isoxazolyl, isothiazolyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyridyl, tetrahydropyridyl, tetrahydrothiaranyl, piperazinyl, and piperidinyl. Unless otherwise stated, the heterocyclic group is optionally substituted.

[0033] Whenever it appears in this text, numerical ranges such as "3 to 18" refer to each integer within the given range; for example, a heterocyclic group having "3 to 18 ring atoms" means that the heterocyclic group can be composed of 3, 4, 5, 6, 7, 8, 9, 10 ring atoms, and so on up to and including 18 ring atoms. Similarly, C1-C6 alkyl means that the alkyl group can be composed of 1, 2, 3, 4, 5, and 6 carbon atoms.

[0034] As used herein and unless otherwise stated, "cycloalkylalkyl" is a group of the following formula: -alkyl-cycloalkyl, wherein the alkyl and cycloalkyl are as defined above. A substituted cycloalkylalkyl group may be substituted at the alkyl, cycloalkyl, or both alkyl and cycloalkyl moieties. Representative cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cyclopentylpropyl, cyclohexylpropyl, etc.

[0035] As used herein and unless otherwise stated, "aralkyl" is a group having the formula: -alkyl-aryl, wherein the alkyl and aryl groups are as defined above. A substituted aralkyl group may be substituted at either the alkyl, aryl, or both alkyl and aryl moieties. Representative aralkyl groups include, but are not limited to, benzyl and phenethyl groups, as well as aralkyl groups in which the aryl group is fused to a cycloalkyl group, such as inden-4-ylethyl.

[0036] As used herein and unless otherwise stated, other similar compound terms reflect the above descriptions of “cycloalkylalkyl” and “arylalkyl”. For example, “heterocyclic alkyl” is a group of the following formula: -alkyl-heterocyclic, wherein the alkyl and heterocyclic groups are as defined above. “Heteroarylalkyl” is a group of the following formula: -alkyl-heteroaryl, wherein the alkyl and heteroaryl groups are as defined above. “Heterocyclic alkylalkyl” is a group of the following formula: -alkyl-heterocyclic alkyl, wherein the alkyl and heterocyclic alkyl groups are as defined above.

[0037] As used herein, and unless otherwise stated, the terms “halogen,” “halide,” or “halogenated” refer to fluorine (F), chlorine (Cl), bromine (Br), and / or iodine (I). As used herein, and unless otherwise stated, the terms “halogenated alkyl,” “halogenated alkenyl,” “halogenated alkynyl,” and “halogenated alkoxy” refer to an alkyl, alkenyl, alkynyl, or alkoxy structure substituted with one or more halogenated groups or combinations thereof.

[0038] As used herein, and unless otherwise stated, the term "alkoxy" refers to -O-(alkyl), where alkyl is as defined above. As used herein, and unless otherwise stated, the term "aryloxy" refers to -O-(aryl), where aryl is as defined above.

[0039] As used herein, and unless otherwise stated, the term "alkylsulfonyl" refers to –SO2-alkyl, where alkyl is as defined above.

[0040] As used herein, and unless otherwise stated, the term "carboxyl" refers to -COOH.

[0041] As used herein, and unless otherwise stated, the term "acyl" refers to –C(O)-R x , where R x It can be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocyclic, each of which is defined above. In some embodiments, R x It can be unsubstituted or substituted with one or more substituents.

[0042] As used herein, and unless otherwise stated, the term "amino" refers to –N(R y (R) y), where each R y It can be, independently, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocyclic, each of which is defined above. When -N(R y (R) y The group has two R groups in addition to hydrogen. y When combined with nitrogen atoms, they can form rings. 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 includes N-oxides (–N+(R y (R) y In some implementations, each R y Or by -N(R) y (R) y The ring formed can be either unsubstituted or substituted by one or more substituents.

[0043] As used herein, and unless otherwise stated, the terms “amide,” “amide group,” or “formamide group” refer to –C(O)N(R y )2 or –NR y C(O)R y , where each R y It can be, independently but not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocyclic, each of which is defined above. When –C(O)N(R) y The )2 group has two R groups in addition to hydrogen. y At this time, they can combine with nitrogen atoms to form rings. In one embodiment, the ring is a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered ring. In one embodiment, one or more ring atoms are heteroatoms independently selected from O, S, and N. In some embodiments, each R y Or by -N(R) y (R) y The ring formed can be either unsubstituted or substituted by one or more substituents.

[0044] As used herein, and unless otherwise stated, the term "aminoalkyl" means -(alkyl)-(amino), where alkyl and amino are as defined above. As used herein, and unless otherwise stated, the term "aminoalkoxy" means -O-(alkyl)-(amino), where alkyl and amino are as defined above.

[0045] As used herein, and unless otherwise stated, the term "alkylamino" means -NH(alkyl) or -N(alkyl)(alkyl), where alkyl is defined above. Examples of such alkylaminos 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, -N(CH3)(CH2CH3), etc.

[0046] As used herein, and unless otherwise stated, the terms "thioalkyl," "sulfide," or "thio" refer to -SR z , where R z It can be, but is not limited to, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocyclic groups, each of which is defined above. In some embodiments, R z It can be unsubstituted or substituted with one or more substituents.

[0047] As used herein, and unless otherwise stated, the terms “sulfonyl” or “sulfone” refer to –S(O)2-R m , where R m It can be, but is not limited to, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocyclic groups, each of which is defined above. In some embodiments, R m It can be unsubstituted or substituted with one or more substituents.

[0048] As used herein, and unless otherwise stated, the term "sulfonamide" or "sulfonamide" refers to –S(=O)2–N(R y )2 or –N(R y )–S(=O)2–R y , where each R y It can be, independently but not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocyclic, each of which is defined above. When –S(=O)2–N(R) y The )2 group has two R groups in addition to hydrogen. y At this time, they can combine with nitrogen atoms to form rings. In one embodiment, the ring is a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered ring. In one embodiment, one or more ring atoms are heteroatoms independently selected from O, S, and N. In some embodiments, each R y Or by -N(R) y (R) y The ring formed can be either unsubstituted or substituted by one or more substituents.

[0049] As used herein, and unless otherwise stated, the term "cyano" refers to the –CN group.

[0050] As used herein, and unless otherwise stated, the term "nitro" refers to the –NO2 group.

[0051] As used herein, and unless otherwise stated, the term "oxo" refers to the =O group.

[0052] As used herein, and unless otherwise stated, the term "oxygen group" refers to the -O- group.

[0053] As used herein, and unless otherwise stated, the term "hydroxyl group" refers to the -OH group.

[0054] As used herein, and unless otherwise stated, the term "carbonyl" refers to the -C(O)- group.

[0055] As used herein, and unless otherwise stated, the term "thiol" refers to the -SH group.

[0056] As used herein, and unless otherwise stated, the terms “optional” or “optionally” (e.g., optionally substituted) mean that the event described below may or may not occur, and the description includes both the case where said event or condition occurs and the case where said event or condition does not occur. For example, “optionally substituted alkyl” means that an alkyl group may or may not be substituted, and the description includes both substituted and unsubstituted alkyl groups.

[0057] When the groups described herein are referred to as “substituted,” they can be substituted by any one or more suitable substituents. Illustrative examples of substituents include, but are not limited to, those found in the exemplary compounds and embodiments disclosed herein, as well as halogens (chlorine, iodine, bromine, or fluorine); alkyl; alkenyl; alkynyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxyl; nitro; cyano; thiol; thioether; imine; imide; amidine; amide; guanidine; enamine; aminocarbonyl; acyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfonamide; ketone; aldehyde; ester; urea; ethyl carbamate; oxime; hydroxylamine; alkoxyamine; aryloxyamine, arylalkoxyamine; N-oxide; hydrazine; acylhydrazine; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxo (═O); B(OH)2, O(alkyl)aminocarbonyl; cycloalkyl, It can be a monocyclic or fused or unfused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocyclic group, which can be a monocyclic or fused or unfused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxacyclobutyl, aziridine, imidazolidinyl, or thiazinyl); a monocyclic or fused or unfused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolidinyl, indolyl, furanyl, thiophene, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridineyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophene, or benzofuranyl); spirocyclic; aryloxy; arylalkoxy; heteroaryloxy; heterocyclic oxy; and heterocyclic alkoxy.

[0058] As used herein, and unless otherwise stated, the term "isomer" refers to different compounds having the same molecular formula. "Stereoisomers" are isomers that differ only in the spatial arrangement of their atoms. "Restricted rotational isomers" are stereoisomers derived from restricted rotation around a single bond. "Enantiomers" are a pair of stereoisomers that are non-overlapping mirror images of each other. A mixture of a pair of enantiomers in any proportion may be called a "racemic" mixture. "Diadiaomers" are stereoisomers having at least two asymmetric atoms but not being mirror images of each other. Absolute stereochemistry can be specified according to the Cahn-Ingold-Prelog RS system. When the compound is an enantiomer, the stereochemistry at each chiral carbon can be specified as R or S. Resolved compounds with unknown absolute configurations can be designated (+) or (-) depending on the direction (right-handed or left-handed) of their rotational polarization plane at the wavelength of the sodium D line. However, the signs (+) and (-) for optical rotation are independent of the absolute configurations R and S of the molecule. Some of the compounds described herein contain one or more asymmetric centers and thus can produce enantiomers, diastereomers, and other stereoisomers that can be defined as (R)- or (S)- in terms of absolute stereochemistry at each asymmetric atom. The chemical entities, pharmaceutical compositions, and methods of the present invention are intended to 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 resolved using conventional techniques.

[0059] As used herein, and unless otherwise stated, the terms "enantiomer purity" or "enantiomeric purity" refer to a qualitative or quantitative measure of a purified enantiomer. The enantiomeric purity of the compounds described herein can be described by enantiomer excess (ee), which indicates the extent to which a sample contains one enantiomer in greater quantities than another. Racemic mixtures have 0% ee, while a single, completely pure enantiomer has 100% ee. Examples of enantiomer purities 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%, and 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%, or at least about 99% of ee. Similarly, "diasteremeric purity" can be described as diastereomer excess (de), which indicates the extent to which a sample contains one diastereomer in greater quantities than another or more diastereomers.

[0060] As used herein, and unless otherwise stated, the term "substantially pure enantiomer" means a compound in which one enantiomer has been enriched relative to another enantiomer and preferably the other enantiomer accounts for less than about 20%, less than about 10%, less than about 5%, or less than about 2% of the enantiomer. In one embodiment, the substantially pure 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 pure 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.

[0061] "Stereoisomers" may also include E and Z isomers or mixtures thereof, as well as cis and trans isomers or mixtures thereof. In some embodiments, the compounds described herein are isolated as either E or Z isomers. In other embodiments, the compounds described herein are mixtures of E and Z isomers.

[0062] As used herein, and unless otherwise stated, the term "pharmaceutically acceptable salt" includes both acid addition salts and base addition salts.

[0063] Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and organic acids such as, but not limited to, 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, decanoic acid, hexanoic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexane, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactopyric acid, gentianic acid, glucoheponic acid, and glucosinolate. Glucuronic acid, glucuronic acid, glutamic acid, glutamate, 2-oxoglutamate, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucoic 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, thiocyanate, p-toluenesulfonic acid, trifluoroacetic acid, undecenoic acid, etc.

[0064] Examples of pharmaceutically acceptable base addition salts include, but are not limited to, salts prepared by adding an inorganic or organic base to a free acid compound. 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 salt is an ammonium, sodium, potassium, calcium, or magnesium salt. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines. Substituted amines include naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benzylamine, benzylethylenediamine, ethylenediamine, glucosamine, methylglucosamine, 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.

[0065] As used herein, and unless otherwise stated, the term "subject" refers to an animal, 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 to refer to, for example, a mammalian subject, such as a human subject. In one embodiment, the subject is a mammal. In another embodiment, the subject is a human.

[0066] As used herein, and unless otherwise stated, the term "treatment" means the eradication or improvement of a disease or disorder, or one or more symptoms associated with a disease or disorder. Typically, treatment occurs after the onset of a disease or disorder. In some embodiments, these terms refer to minimizing the spread or worsening of a disease or disorder caused by administering one or more preventative or therapeutic agents to a subject suffering from such a disease or disorder.

[0067] As used herein, and unless otherwise stated, the term "prevention" means the prevention of the onset, recurrence, or spread of a disease or disorder or one or more symptoms thereof. Typically, prevention occurs before the onset of a disease or disorder.

[0068] As used herein, and unless otherwise stated, the term "therapeutic effective amount" is intended to include an amount of compound, when administered, sufficient to prevent or alleviate to a certain extent the symptoms of one or more of the disorder, disease, or condition being treated. The term "therapeutic effective amount" also refers to an amount of compound sufficient to elicit a biological or medical response in a cell, tissue, system, animal, or human as sought by a researcher, veterinarian, physician, or clinician.

[0069] As used herein, and unless otherwise stated, the term "IC" is used in conjunction with other terms. 50 "" refers to the amount, concentration, or dose of compound required to suppress the maximum response by 50% in an analysis measuring such a response.

[0070] As used herein, and unless otherwise stated, the terms “pharmaceuticalally acceptable carrier,” “pharmaceuticalally acceptable excipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” refer to pharmaceutically acceptable materials, compositions, or media, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials. In one embodiment, each component is “pharmaceuticalally acceptable” in the sense of compatibility with other components of the pharmaceutical preparation and is suitable for contact with tissues or organs of humans and animals without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications commensurate with a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th ed., Rowe et al., eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd ed., Ash and Ash, eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson, ed., CRC Press LLC: Boca Raton, FL, 2004.

[0071] Unless otherwise stated, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically 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, such as, for example, […]. 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. For example, having the structure of the present invention, but with hydrogen replaced or enriched at one or more atoms in the molecule by deuterium or tritium, or with...13 C or 14 Compounds that substitute or enrich carbon with C are within the scope of this disclosure. In one embodiment, compounds are provided herein with isotopically labeled with one or more hydrogen atoms that are substituted or enriched by deuterium. In one embodiment, compounds are provided herein with isotopically labeled with one or more hydrogen atoms that are substituted or enriched by tritium. In one embodiment, compounds are provided herein with one or more isotopically labeled with one or more hydrogen atoms that are substituted or enriched by tritium. 13 Compounds labeled with isotopes of carbon atoms that are substituted or enriched by C. In one embodiment, this document provides compounds having one or more of these isotopes. 14 Compounds labeled with carbon isotopes that are substituted or enriched with C atoms.

[0072] As used herein, and unless otherwise stated, the terms “about” or “approximately” mean an acceptable error in a particular value as determined by one of ordinary skill in the art, depending in part on how the value is measured or determined.

[0073] In some implementations, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In some implementations, the term "about" or "approximately" means 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.

[0074] compound

[0075] In one embodiment, certain pyrimidine heteroaromatic compounds are provided herein as inhibitors of ubiquitin-specific processing protease 1 (USP1). In one embodiment, the compound has a pyrimidine core structure.

[0076] In one embodiment, compounds of formula (I) are provided herein:

[0077]

[0078] (I)

[0079] in:

[0080] X 1 Is it N or CR? x1 ;R x1 It is hydrogen or C1-C6 alkyl;

[0081] X 2 Is it N or CR? x2 ;R x2 It is hydrogen or C1-C6 alkyl;

[0082] X 3 Is it N or CR? x3 ;R x3It is hydrogen or C1-C6 alkyl;

[0083] The condition is X 1 X 2 and X 3 At least one of them is N;

[0084] L is NR b O or S; R b It is hydrogen or C1-C6 alkyl;

[0085] R 1 Selected from alkyl, alkoxy, halogen, cyano, NR c R d -C(=O)NHR d -NHC(=O)R c , haloalkyl, cycloalkyl, cycloalkoxy, haloalkoxy, heterocyclic, aryl, and heteroaryl; and R 1 Each alkyl, alkoxy, cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl group is optionally substituted;

[0086] R c and R d Each is independently selected from hydrogen, halogen, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl; and R c Or R d Each alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently and optionally substituted;

[0087] R 2 and R 3 Each is independently selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkoxy, cycloalkoxy, heterocyclic oxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclic alkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxylalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (formamido)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkoxy, heterocyclic alkoxy, arylalkoxy, heteroarylalkoxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxyl, amide, formamido, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, and alkylthio; and R 2 Or R 3 Each alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl moiety is independently and optionally substituted by one or more C1-C6 alkyl, halogen, or deuterium;

[0088] Ring A is selected from aryl, heteroaryl, cycloalkyl, heterocyclic and phenyl isosteres; and ring A is optionally substituted.

[0089] R is selected from hydrogen, halogen, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkoxy, cycloalkoxy, heterocyclic oxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclic alkyl, aralkyl, heteroarylalkyl, cycloalkylalkoxy, heterocyclic alkoxy, arylalkoxy, heteroarylalkoxy, and amide; and each alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl moiety in R is independently and optionally substituted.

[0090] Or its stereoisomers, mixtures of stereoisomers, solvates or pharmaceutically acceptable salts thereof.

[0091] In one implementation, R 1 It is an alkyl group. In one embodiment, R 1 It is an alkoxy group. In one embodiment, R 1 It is a halogen. In one implementation, R 1 It is cyano. In one embodiment, R 1 It is NR c R d In one implementation, R 1 It is -C(=O)NHR d In one implementation, R 1 It is -NHC(=O)R c In one implementation, R 1 It is a cycloalkyl group. In one embodiment, R 1 It is a cycloalkoxy group. In one embodiment, R 1 It is a haloalkoxy group. In one embodiment, R 1 It is a heterocyclic group. In one implementation, R 1 It is aryl. In one implementation, R 1 It is a heteroaryl group. In one implementation, R 1 It is a haloalkyl group.

[0092] In one implementation, R 1 It is a C1-C6 alkyl group. In one embodiment, R 1 It is a C1-C6 alkoxy group. In one embodiment, R 1 It is N(C1-C6 alkyl)2. In one embodiment, R 1 It is -C(=O)NH (C1-C6 alkyl). In one embodiment, R 1 It is -C(=O)NH (C3-C8 cycloalkyl). In one embodiment, R 1 It is -C(=O)N(C1-C6 alkyl)2. In one embodiment, R 1It is -NHC(=O)-(C1-C6 alkyl). In one embodiment, R 1 It is a C3-C8 cycloalkyl group. In one embodiment, R 1 It is a C3-C8 cycloalkoxy group. In one embodiment, R 1 It is a C1-C6 haloalkoxy group. In one embodiment, R 1 It is a 3- to 8-membered heterocyclic group. In one implementation, R 1 It is C6-C 10 Aryl. In one embodiment, R 1 It is a 5- to 10-membered heteroaryl group. In one implementation scheme, R 1 It is a C1-C6 haloalkyl group.

[0093] In one implementation, R 1 It is methyl. In one embodiment, R 1 It is ethyl. In one embodiment, R 1 It is propyl or isopropyl. In some embodiments, R 1 It is n-butyl, isobutyl, or tert-butyl. In one embodiment, R... 1 It is pentyl. In one implementation, R 1 It is self-based. In one implementation, R 1 It is cyclopropyl. In one embodiment, R 1 It is cyclobutyl. In one implementation, R 1 It is a methoxy group. In one embodiment, R 1 It is ethoxylated. In one embodiment, R 1 It is propoxy or isopropoxy. In one embodiment, R 1 It is cyclopropoxylated. In one embodiment, R 1 It is cyclobutoxy. In one embodiment, R 1 It is 2,2,2-trifluoroethoxy. In one embodiment, R 1 It is trifluoromethoxy. In one embodiment, R 1 It is NH2. In one implementation, R 1 It is NH(CH3). In one implementation, R 1 It is N(CH3)2. In one implementation, R 1 It is trifluoromethyl.

[0094] In one implementation, R c It is hydrogen. In one implementation, R c It is an alkyl group. In one embodiment, R c It is an alkoxy group. In one embodiment, R cIt is a cycloalkyl group. In one embodiment, R c It is a heterocyclic group. In one implementation, R c It is aryl. In one implementation, R c It is a heteroaryl group. In one implementation, R c It is halogen.

[0095] In one implementation, R c It is a C1-C6 alkyl group. In one embodiment, R c It is a C1-C6 alkoxy group. In one embodiment, R c It is a C3-C8 cycloalkyl group. In one embodiment, R c It is a 3- to 8-membered heterocyclic group. In one implementation, R c It is C6-C 10 Aryl. In one embodiment, R c It is a 5- to 10-membered heteroaryl group. In one implementation scheme, R c It is fluorine. In one implementation, R c It is chlorine. In one implementation, R c It is bromine.

[0096] In one implementation, R d It is hydrogen. In one implementation, R d It is an alkyl group. In one embodiment, R d It is an alkoxy group. In one embodiment, R d It is a cycloalkyl group. In one embodiment, R d It is a heterocyclic group. In one implementation, R d It is aryl. In one implementation, R d It is a heteroaryl group. In one implementation, R d It is halogen.

[0097] In one implementation, R d It is a C1-C6 alkyl group. In one embodiment, R d It is a C1-C6 alkoxy group. In one embodiment, R d It is a C3-C8 cycloalkyl group. In one embodiment, R d It is a 3- to 8-membered heterocyclic group. In one implementation, R d It is C6-C 10 Aryl. In one embodiment, R d It is a 5- to 10-membered heteroaryl group. In one implementation scheme, R d It is fluorine. In one implementation, R d It is chlorine. In one implementation, R d It is bromine.

[0098] In one implementation, R c and R d All are hydrogen. In one implementation, R c and R d Both are alkyl groups. In one embodiment, R... c and R d All are C1-C6 alkyl groups. In one embodiment, R c and R d They are all methyl groups.

[0099] In one embodiment, R is hydrogen. In one embodiment, R is a halogen. In one embodiment, R is an alkyl group. In one embodiment, R is a cycloalkyl group. In one embodiment, R is a heterocyclic group. In one embodiment, R is an aryl group. In one embodiment, R is a heteroaryl group. In one embodiment, R is an alkoxy group. In one embodiment, R is a cycloalkoxy group. In one embodiment, R is a heterocyclic alkyl group. In one embodiment, R is a heterocyclic alkyl group. In one embodiment, R is an aralkyl group. In one embodiment, R is a heteroarylalkyl group. In one embodiment, R is a cycloalkylalkoxy group. In one embodiment, R is a heterocyclic alkoxy group. In one embodiment, R is an arylalkoxy group. In one embodiment, R is a heteroarylalkoxy group. In one embodiment, R is an amide group.

[0100] In one embodiment, R is a C1-C6 alkyl, C3-C8 cycloalkyl, 4- to 8-membered heterocyclic group, or C6-C6 cycloalkyl. 10 aryl, 5- to 10-membered heteroaryl, C1-C6 alkoxy, C3-C8 cycloalkoxy, 4- to 8-membered heterocyclic alkoxy, C6-C 10 aryloxy, 5- to 10-membered heteroaryloxy, (C3-C8 cycloalkyl)-(C1-C2 alkyl)-, (4- to 8-membered heterocyclic)-(C1-C2 alkyl)-, (C6-C 10 aryl)-(C1-C2 alkyl)-, (5- to 10-membered heteroaryl)-(C1-C2 alkyl)-, (C3-C8 cycloalkyl)-(C1-C2 alkoxy)-, (4- to 8-membered heterocyclic)-(C1-C2 alkoxy)-, (C6-C 10 Aryl)-(C1-C2alkoxy)- or (5- to 10-membered heteroaryl)-(C1-C2alkoxy)-; wherein each alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl moiety in R is independently and optionally substituted.

[0101] In one embodiment, R is a 5- to 10-membered heteroaryl group. In one embodiment, R is a 5- or 6-membered heteroaryl group. In one embodiment, R is a 5- or 6-membered nitrogen-containing heteroaryl group. In one embodiment, R is a 5- or 6-membered nitrogen- and oxygen-containing heteroaryl group. In one embodiment, R is a 5- or 6-membered nitrogen-containing heteroaryl group, and nitrogen is the only type of heteroatom contained in the heteroaryl group. In one embodiment, R is imidazolyl. In one embodiment, R is pyrazolyl. In one embodiment, R is triazolyl. In one embodiment, R is pyridinyl. In one embodiment, R is pyrimidinyl. In one embodiment, R is triazinel. In one embodiment, R is pyridazinel. In one embodiment, R is pyrazinel. In one embodiment, R is a 5- or 6-membered nitrogen-containing heteroaryl group, and the heteroaryl group 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 one embodiment, R is isothiazolyl.

[0102] In one implementation, R is optionally defined by one or more R 4 Replace; and each R 4 Independently selected from deuterium, halogen, nitro, cyano, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted deuterated alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, haloalkyl, optionally substituted alkoxy, optionally substituted deuterated alkoxy, haloalkoxy, acyl; optionally substituted cycloalkoxy, optionally substituted heterocyclic oxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted cycloalkylalkyl, optionally substituted heterocyclic alkyl, optionally substituted spiroheterocyclic, optionally substituted spirocyclic, optionally substituted bridged heterocyclic, optionally substituted bridged carbocyclic, optionally substituted aralkyl, optionally substituted heteroaryl Alkyl, optionally substituted alkoxyalkyl, optionally substituted (alkylamino)alkyl, optionally substituted (dialkylamino)alkyl, optionally substituted cyanoalkyl, optionally substituted (formamido)alkyl, optionally substituted mercaptoalkyl, optionally substituted (cycloalkylamino)alkyl, optionally substituted cycloalkylalkoxy, optionally substituted heterocyclic alkoxy, optionally substituted arylalkoxy, optionally substituted heteroarylalkoxy, amino, optionally substituted alkylamino, optionally substituted dialkylamino, (hydroxyalkyl)amino, carboxyl, amide, formamido, optionally substituted sulfonamide, optionally substituted alkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, and optionally substituted alkylthio.

[0103] In one implementation, R is two Rs4 Replacement. In one embodiment, R is replaced by R at (i) a position adjacent to the junction of R and ring A and (ii) a position separated from the junction of R and ring A by one ring atom. 4 Replacement. In one embodiment, the two locations are on the same side of the connection point between R and ring A. In another embodiment, the two locations are on opposite sides of the connection point between R and ring A.

[0104] In one implementation, R is defined by three Rs. 4 Replacement. In one embodiment, R is replaced at (i) the position adjacent to the junction of R and ring A, (ii) the position separated from the junction of R and ring A by one ring atom, and (iii) the position separated from the junction of R and ring A by two ring atoms. 4 replace.

[0105] In one implementation scheme, R is In one implementation, R is In one implementation, R is In one implementation, R is In one implementation, R is... In one implementation, R is... In one implementation, R is... .

[0106] In one implementation, R 4 Optionally by one or more R 5 Replacement. In one implementation, R 4 It is not replaced. In one implementation, R 4 By an R 5 Replacement. In one implementation, R 4 By two R 5 replace.

[0107] In one implementation scheme, each R 5Independently selected from halogen, nitro, cyano, hydroxy, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, haloalkyl, alkoxy, acyl, cycloalkoxy, heterocyclic oxy, heterocyclic carbonyl, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclic alkyl, spiroheterocyclic, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxylalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (formamide) )alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkoxy, heterocyclic alkoxy, arylalkoxy, heteroarylalkoxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, oxo, carboxyl, amide, formamide, sulfonamide, formyl, carbamoyl, aminosulfonyl, alkylcarbonyl, haloalkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, and alkylthio, and R 5 It is optional to replace; and / or both R 5 Together with the same ring carbon atom to which they are attached, they form optionally substituted C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl, and / or two R atoms attached to different carbon atoms. 5 They are connected together to form optional replacement bridge rings.

[0108] In one implementation scheme, each R 5 Independently selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, oxo, cyclopropyl, cyclopropylcarbonyl, isopropylcarbonyl, cyclobutylcarbonyl, formyl, acetyl, trifluoroacetyl, propionyl, amino, hydroxy, mercapto, oxetane-3-carbonyl, azirne-butyl, methylsulfonyl, ethylsulfonyl, aminomethylsulfonyl, methylsulfinyl, ethylsulfinyl, carbamoyl, benzoyl, aminosulfonyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazole, pyrrole, furanyl, thiophene, piperidinyl, piperazinyl, tetrahydrothiaranyl, and R 5 It is optional to replace; and / or both R 5 Together with the same ring carbon atom to which they are attached, they form optionally substituted cyclobutyl or azircyclic butyl groups, and / or two R groups attached to different carbon atoms. 5 They are linked together to form optionally substituted azabicycloheptyl or diazabicycloheptyl.

[0109] In one implementation, R 5 Optionally by one or more R 6 Replacement. In one implementation, R 5 It is not replaced. In one implementation, R 5 By an R 6Replacement. In one implementation, R 5 By two R 6 replace.

[0110] In one implementation scheme, each R 6 Independently selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, haloalkyl, alkoxy, acyl, cycloalkoxy, heterocyclic alkyl, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclic alkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxylalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (formamido)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkoxy, heterocyclic alkoxy, arylalkoxy, heteroarylalkoxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxyl, amide, formamido, sulfonamide, alkylcarbonyl, arylcarbonyl, formyl, carbamoyl, alkylsulfonyl, arylsulfonyl, and alkylthio, and R 6 It can be arbitrarily replaced.

[0111] In one implementation scheme, each R 6 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, formamido, acetamyl, propionyl, carbamoyl, methylsulfonyl, ethylsulfonyl, morpholino, piperidinyl, piperazine, tetrahydropyranyl, oxetanebutyl, aziranebutyl, isoxazolyl, and pyrroleyl, and R 6 It can be arbitrarily replaced.

[0112] In one implementation, R 6 Optionally by one or more R 7 Replacement. In one implementation, R 6 It is not replaced. In one implementation, R 6 By an R 7 Replacement. In one implementation, R 6 By two R 7 replace.

[0113] In one implementation scheme, each R 7It is independently selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, haloalkyl, alkoxy, oxo, acyl, cycloalkoxy, heterocyclic alkyl, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, hydroxyalkoxy, carboxylalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (formamido)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkoxy, heterocyclic alkoxy, arylalkoxy, heteroarylalkoxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxyl, amide, formamido, sulfonamide, alkylcarbonyl, arylcarbonyl, formyl, carbamoyl, alkylsulfonyl, arylsulfonyl, and alkylthio.

[0114] In one implementation scheme, each R 7 It is independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, acetyl, oxo, hydroxy, mercapto, oxetane, azirone, imidazoalkyl, methanesulfonyl, methylamino, dimethylamino, methoxy, ethoxy, isopropoxy, tert-butoxy, and hydroxyethoxy.

[0115] In one implementation, X 1 X 2 and X 3 At least one of them is N.

[0116] In one implementation, X 1 It is N. In one implementation, X 1 It is CR x1 In one implementation, X 1 It is CH. In one implementation, R x1 It is a C1-C6 alkyl group. In one embodiment, R x1 It is methyl. In one embodiment, R x1 It is ethyl. In one embodiment, R x1 It is propyl (e.g., n-propyl or isopropyl). In some embodiments, R x1 It is butyl (e.g., n-butyl, isobutyl, or tert-butyl). In one embodiment, R x1 It is pentyl. In one implementation, R x1 It is self-foundation.

[0117] In one implementation, X 2 It is N. In one implementation, X 2 It is CR x2 In one implementation, X 2 It is CH. In one implementation, R x2It is a C1-C6 alkyl group. In one embodiment, R x2 It is methyl. In one embodiment, R x2 It is ethyl. In one embodiment, R x2 It is propyl (e.g., n-propyl or isopropyl). In some embodiments, R x2 It is butyl (e.g., n-butyl, isobutyl, or tert-butyl). In one embodiment, R x2 It is pentyl. In one implementation, R x2 It is self-foundation.

[0118] In one implementation, X 3 It is N. In one implementation, X 3 It is CR x3 In one implementation, X 3 It is CH. In one implementation, R x3 It is a C1-C6 alkyl group. In one embodiment, R x3 It is methyl. In one embodiment, R x3 It is ethyl. In one embodiment, R x3 It is propyl (e.g., n-propyl or isopropyl). In some embodiments, R x3 It is butyl (e.g., n-butyl, isobutyl, or tert-butyl). In one embodiment, R x3 It is pentyl. In one implementation, R x3 It is self-foundation.

[0119] In one implementation, X 1 It is CR x1 And X 2 It is CR x2 In one implementation, X 1 It is CR x1 And X 2 It is N. In one implementation, X 1 It is N, and X 2 It is CR x2 In one implementation, X 1 It is N, and X 2 It is N. In one implementation, X 1 It is CR x1 And X 3 It is CR x3 In one implementation, X 1 It is CR x1 And X 3 It is N. In one implementation, X 1 It is N, and X 3 It is CR x3 In one implementation, X1 It is N, and X 3 It is N. In one implementation, X 2 It is CR x2 And X 3 It is CR x3 In one implementation, X 2 It is CR x2 And X 3 It is N. In one implementation, X 2 It is N, and X 3 It is CR x3 In one implementation, X 2 It is N, and X 3 It is N.

[0120] In one implementation, X 1 It is N, X 2 It is N, and X 3 It is CR x3 In one implementation, X 1 It is N, X 2 It is N, and X 3 It is CH. In one implementation, X 1 It is N, X 2 It is CR x2 And X 3 It is N. In one implementation, X 1 It is N, X 2 It is CH, and X 3 It is N. In one implementation, X 1 It is CR x1 X 2 It is N, and X 3 It is N. In one implementation, X 1 It is CH, X 2 It is N, and X 3 It is N.

[0121] In one implementation, R 2 and R 3Each is independently selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkoxy, cycloalkoxy, heterocyclic oxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclic alkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxylalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (formamido)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkoxy, heterocyclic alkoxy, arylalkoxy, heteroarylalkoxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxyl, amide, formamido, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, and alkylthio; and R 2 Or R 3 Each alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl moiety is independently and optionally substituted by one or more C1-C6 alkyl, halogen, or deuterium.

[0122] In one implementation, R 2 and R 3 Each is independently selected from halogen, nitro, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, 5- to 10-membered aryl, 5- to 10-membered heteroaryl, C1-C6 alkoxy, C3-C8 cycloalkoxy, 3- to 8-membered heterocyclic oxy, 5- to 10-membered aryloxy, 5- to 10-membered heteroaryloxy, (C3-C8 cycloalkyl)(C1-C6 alkyl) and (3- to 8-membered heterocyclic)(C1-C6 alkyl).

[0123] In one implementation, R 2 Selected from cyano, 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, chlorine, fluorine, l-fluoroprop-2-yl, (S)-1-fluoroprop-2-yl, (R)-1-fluoroprop-2-yl -yl, hydroxyethyl, l-methoxy-2-methylprop-2-yl, 1-methoxyprop-2-yl, (S)-1-methoxyprop-2-yl, (R)-l-methoxyprop-2-yl, 1-(methoxymethyl)cyclopropyl, l-hydroxyprop-2-yl, oxetane-3-yl, tetrahydrofuran-3-yl, 1-methylcyclopropyl, deuterated methyl, deuterated ethyl, deuterated isopropyl, deuterated methoxy, and deuterated ethoxy.

[0124] In one implementation, R 2 It is a cycloalkyl group. In one embodiment, R 2 It is a C3-C8 cycloalkyl group. In one embodiment, R2 It is cyclopropyl. In one embodiment, R 2 It is cyclobutyl.

[0125] In one implementation, R 3 Selected from cyano, 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, chlorine, fluorine, l-fluoroprop-2-yl, (S)-1-fluoroprop-2-yl, (R)-1-fluoroprop-2-yl -yl, hydroxyethyl, l-methoxy-2-methylprop-2-yl, 1-methoxyprop-2-yl, (S)-1-methoxyprop-2-yl, (R)-l-methoxyprop-2-yl, 1-(methoxymethyl)cyclopropyl, l-hydroxyprop-2-yl, oxetane-3-yl, tetrahydrofuran-3-yl, 1-methylcyclopropyl, deuterated methyl, deuterated ethyl, deuterated isopropyl, deuterated methoxy, and deuterated ethoxy.

[0126] In one implementation, R 3 It is an alkoxy group. In one embodiment, R 3 It is a C1-C6 alkoxy group. In one embodiment, R 3 It is a methoxy group. In one embodiment, R 3 It is an ethoxy group.

[0127] In one implementation, R 2 It is a cycloalkyl group and R 3 It is an alkoxy group. In one embodiment, R 2 It is a C3-C8 cycloalkyl group and R 3 It is a C1-C6 alkoxy group. In one embodiment, R 2 It is cyclopropyl and R 3 It is a methoxy group.

[0128] In one implementation, X 1 It is N, X 2 It is CR x2 X 3 It is CR x3 R 2 It is a cycloalkyl group, and R 3 It is an alkoxy group. In one embodiment, X 2 It is N, X 1 It is CR x1 X 3 It is CR x3 R 2 It is a cycloalkyl group, and R 3 It is an alkoxy group. In one embodiment, X3 It is N, X 1 It is CR x1 X 2 It is CR x2 R 2 It is a cycloalkyl group, and R 3 It is an alkoxy group. In one embodiment, X 1 It is N, X 2 It is N, X 3 It is CR x3 R 2 It is a cycloalkyl group, and R 3 It is an alkoxy group. In one embodiment, X 1 It is N, X 2 It is N, X 3 It is CH, R 2 It is a cycloalkyl group, and R 3 It is an alkoxy group. In one embodiment, X 1 It is N, X 2 It is CR x2 X 3 It is N, R 2 It is a cycloalkyl group, and R 3 It is an alkoxy group. In one embodiment, X 1 It is N, X 2 It is CH, X 3 It is N, R 2 It is a cycloalkyl group, and R 3 It is an alkoxy group. In one embodiment, X 2 It is N, X 3 It is N, X 1 It is CR x1 R 2 It is a cycloalkyl group, and R 3 It is an alkoxy group. In one embodiment, X 2 It is N, X 3 It is N, X 1 It is CH, R 2 It is a cycloalkyl group, and R 3 It is an alkoxy group.

[0129] In one embodiment, compounds of formula (II) are provided herein:

[0130]

[0131] (II)

[0132] in:

[0133] X 4 Is it N or CR? x4 ;R x4 Selected from hydrogen, C1-C6 alkyl groups, and halogens;

[0134] X 5 Is it N or CR? x5 ;R x5 Selected from hydrogen, C1-C6 alkyl groups, and halogens;

[0135] R a1 Selected from deuterium, halogen, nitro, cyano, hydroxyl, alkyl, cycloalkyl, haloalkyl, alkoxy and haloalkoxy;

[0136] R a2 Selected from deuterium, halogen, nitro, cyano, hydroxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, acyl; cycloalkoxy, heterocyclic alkoxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclic alkyl, spiroheterocyclic, spirocyclic, bridged heterocyclic, bridged carbocyclic, aralkyl, heteroarylalkyl, alkoxyalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (formamido)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkoxy, heterocyclic alkoxy, arylalkoxy, heteroarylalkoxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxyl, amide, formamido, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, and alkylthio, and R a2 It can be arbitrarily replaced.

[0137] Rings A, L, R 1 R 2 and R 3 Each as defined above;

[0138] Or its stereoisomers, mixtures of stereoisomers, solvates or pharmaceutically acceptable salts thereof.

[0139] In one implementation, X 4 It is N. In one implementation, X 4 It is CR x4 In one implementation, X 4 It is CH. In one implementation, R x4 It is a halogen. In one implementation, R x4 It is fluorine. In one implementation, R x4 It is chlorine. In one implementation, R x4 It is bromine. In one implementation, R x4 It is iodine. In one implementation, R x4 It is a C1-C6 alkyl group. In one embodiment, R x4 It is ethyl. In one embodiment, R x4It is propyl (e.g., n-propyl or isopropyl). In some embodiments, R x4 It is butyl (e.g., n-butyl, isobutyl, or tert-butyl). In one embodiment, R x4 It is pentyl. In one implementation, R x4 It is self-foundation.

[0140] In one implementation, X 5 It is N. In one implementation, X 5 It is CR x5 In one implementation, X 5 It is CH. In one implementation, R x5 It is a halogen. In one implementation, R x5 It is fluorine. In one implementation, R x5 It is chlorine. In one implementation, R x5 It is bromine. In one implementation, R x5 It is iodine. In one implementation, R x5 It is a C1-C6 alkyl group. In one embodiment, R x5 It is ethyl. In one embodiment, R x5 It is propyl (e.g., n-propyl or isopropyl). In some embodiments, R x5 It is butyl (e.g., n-butyl, isobutyl, or tert-butyl). In one embodiment, R x5 It is pentyl. In one implementation, R x5 It is self-foundation.

[0141] In one implementation, X 4 It is N, and X 5 It is CR x5 In one implementation, X 4 It is N, and X 5 It is N. In one implementation, X 4 It is CR x4 And X 5 It is N. In one implementation, X 4 It is CR x4 And X 5 It is CR x5 .

[0142] In one implementation, X 4 It is N, and X 5 It is CH. In one implementation, X 4 It is N, and X 5 It is N. In one implementation, X 4 It is CH, and X 5 It is N. In one implementation, X 4It is CH, and X 5 It is CH.

[0143] In one implementation, R a1 Selected from cyano, nitro, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, fluoromethyl, difluoromethyl, trifluoromethyl, l-fluoropropyl-2-yl, 2-fluoroethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethoxy, and trifluoromethoxy.

[0144] In one implementation, R a2 Selected from fluorine, chlorine, bromine, 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, l-fluoroprop-2-yl, 2-fluoroethyl, formyl, acetyl, propionyl, amino, methylamino, ethylamino, dimethylamino, 2,2-difluoroethoxy, cyclopropoxy, morpholinyl, piperidinyl, piperazine, tetrahydropyranyl, oxetanebutylalkyl, aziranebutylalkyl, pyrrolealkyl, dihydropyridinyl, tetrahydropyridinyl, tetrahydrothiaranyl. Morpholinyloxy, piperidinyloxy, piperazinyloxy, tetrahydropyranyloxy, oxetaneyloxy, aziraneyloxy, pyrrolidinyloxy, dihydropyridinyloxy, tetrahydropyridinyloxy, tetrahydrothiaranyloxy, morpholinylmethyl, piperidinylmethyl, piperazinylmethyl, tetrahydropyranylmethyl, oxetaneylmethyl, aziraneylmethyl, pyrrolidinylmethyl, dihydropyridinylmethyl, tetrahydropyridinylmethyl, tetrahydrothiaranylmethyl, azispiroheptyl, azibicycloheptyl, diazibicycloheptyl, methoxymethyl, methylaminomethyl, deuterated methyl, deuterated ethyl, deuterated isopropyl, deuterated methoxy, and deuterated ethoxy, and R a2 It can be arbitrarily replaced.

[0145] In one implementation, R a2 Optionally by one or more R 5 Replacement. In one implementation, R a2 It is not replaced. In one implementation, R a2 By an R 5 Replacement. In one implementation, R a2 By two R 5 replace.

[0146] In one implementation scheme, each R 5Independently selected from halogen, nitro, cyano, hydroxy, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, haloalkyl, alkoxy, acyl, cycloalkoxy, heterocyclic oxy, heterocyclic carbonyl, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclic alkyl, spiroheterocyclic, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxylalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (formamide) )alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkoxy, heterocyclic alkoxy, arylalkoxy, heteroarylalkoxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, oxo, carboxyl, amide, formamide, sulfonamide, formyl, carbamoyl, aminosulfonyl, alkylcarbonyl, haloalkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, and alkylthio, and R 5 It is optional to replace; and / or both R 5 Together with the same ring carbon atom to which they are attached, they form optionally substituted C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl, and / or two R atoms attached to different carbon atoms. 5 They are connected together to form optional replacement bridge rings.

[0147] In one implementation scheme, each R 5 Independently selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, oxo, cyclopropyl, cyclopropylcarbonyl, isopropylcarbonyl, cyclobutylcarbonyl, formyl, acetyl, trifluoroacetyl, propionyl, amino, hydroxy, mercapto, oxetane-3-carbonyl, azirne-butyl, methylsulfonyl, ethylsulfonyl, aminomethylsulfonyl, methylsulfinyl, ethylsulfinyl, carbamoyl, benzoyl, aminosulfonyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, pyrrole, furanyl, thiophene, piperidinyl, piperazinyl, tetrahydrothiapyranyl, and tetrahydrothiopyranyl, and R 5 It is optional to replace; and / or both R 5 Together with the same ring carbon atom to which they are attached, they form optionally substituted cyclobutyl or azircyclic butyl groups, and / or two R groups attached to different carbon atoms. 5 They are linked together to form optionally substituted azabicycloheptyl or diazabicycloheptyl.

[0148] In one implementation, R 5 Optionally by one or more R 6 Replacement. In one implementation, R5 It is not replaced. In one implementation, R 5 By an R 6 Replacement. In one implementation, R 5 By two R 6 replace.

[0149] In one implementation scheme, each R 6 Independently selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, haloalkyl, alkoxy, acyl, cycloalkoxy, heterocyclic alkyl, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclic alkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxylalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (formamido)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkoxy, heterocyclic alkoxy, arylalkoxy, heteroarylalkoxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxyl, amide, formamido, sulfonamide, alkylcarbonyl, arylcarbonyl, formyl, carbamoyl, alkylsulfonyl, arylsulfonyl, and alkylthio, and R 6 It can be arbitrarily replaced.

[0150] In one implementation scheme, each R 6 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, formamido, acetamyl, propionyl, carbamoyl, methylsulfonyl, ethylsulfonyl, morpholino, piperidinyl, piperazine, tetrahydropyranyl, oxetanebutyl, aziranebutyl, isoxazolyl, and pyrroleyl, and R 6 It can be arbitrarily replaced.

[0151] In one implementation, R 6 Optionally by one or more R 7 Replacement. In one implementation, R 6 It is not replaced. In one implementation, R 6 By an R 7 Replacement. In one implementation, R 6 By two R 7 replace.

[0152] In one implementation scheme, each R 7It is independently selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, haloalkyl, alkoxy, oxo, acyl, cycloalkoxy, heterocyclic alkyl, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, hydroxyalkoxy, carboxylalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (formamido)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkoxy, heterocyclic alkoxy, arylalkoxy, heteroarylalkoxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxyl, amide, formamido, sulfonamide, alkylcarbonyl, arylcarbonyl, formyl, carbamoyl, alkylsulfonyl, arylsulfonyl, and alkylthio.

[0153] In one implementation scheme, each R 7 It is independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, acetyl, oxo, hydroxy, mercapto, oxetane, azirone, imidazoalkyl, methanesulfonyl, methylamino, dimethylamino, methoxy, ethoxy, isopropoxy, tert-butoxy, and hydroxyethoxy.

[0154] In one implementation, R a2 It is methyl. In one embodiment, R a2 It is a methoxy group. In one embodiment, R a2 It is dimethylamino. In one embodiment, R a2 It is cyclopropyl. In one embodiment, R a2 It is fluorine. In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes In one implementation, R a2 yes .

[0155] In one embodiment, ring A is an aryl group. In another embodiment, ring A is C6-C. 10 Aryl. In one embodiment, ring A is phenyl. In one embodiment, ring A is... .

[0156] In one embodiment, ring A is a heteroaryl group. In one embodiment, ring A is a 5- to 10-membered heteroaryl group. In one embodiment, ring A is a 5- or 6-membered heteroaryl group. In one embodiment, nitrogen is the only type of heteroatom contained in the heteroaryl group. In one embodiment, ring A is a pyridyl group. In one embodiment, ring A is... In one implementation, ring A is .

[0157] 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 cyclopentyl. In one embodiment, ring A is cyclohexyl.

[0158] In one embodiment, ring A is a heterocyclic group. In one embodiment, ring A is a 5- to 10-membered heterocyclic group. In one embodiment, ring A is a 5- or 6-membered heterocyclic group. In one embodiment, nitrogen is the only type of heteroatom contained in the heterocyclic group. In one embodiment, ring A is a pyrrolidinyl group. In one embodiment, ring A is... In one embodiment, ring A is piperidinyl. In one embodiment, ring A is... In one embodiment, ring A is a piperidinyl group.

[0159] In one embodiment, ring A is a phenyl isosteric isostat. In one embodiment, ring A is a cubane. In one embodiment, ring A is... .

[0160] In one implementation, ring A is optionally bounded by one or more R 8 Replace; where each R 8 The group is independently selected from halogen, cyano, alkyl, amino, alkylamino, dialkylamino, hydroxy, and alkoxy groups; and each alkyl, alkylamino, dialkylamino, or alkoxy moiety is optionally substituted independently with one or more halogen, hydroxy, or alkoxy groups. In one embodiment, ring A is unsubstituted. In one embodiment, ring A is substituted with an R 8 Replacement. In one implementation, ring A is replaced by two R... 8 Substitution. Unless otherwise stated, the substitution state of ring A as described herein does not take into account the R group.

[0161] In one implementation scheme, each R 8 It is independently selected from fluorine, chlorine, cyano, methoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy, hydroxyethoxy, and methoxyethoxy.

[0162] In one implementation, ring A is In one implementation, ring A is In one implementation, ring A is In one implementation, ring A is In one implementation, ring A is In one implementation, ring A is In one implementation, ring A is In one implementation, ring A is In one implementation, ring A is In one implementation, ring A is In one implementation, ring A is In one implementation, ring A is In one implementation, ring A is In one implementation, ring A is In one implementation, ring A is In one implementation, ring A is In one implementation, ring A is In one implementation, ring A is .

[0163] As shown in this document and unless otherwise stated, the connection point on the left side of the ring A structure is the carbon atom between L and ring A, and the connection point on the right side is the R group.

[0164] In one implementation, R a2 It is piperidinyl and R 5 It is an acyl group.

[0165] In one embodiment, compounds of formula (III) are provided herein:

[0166]

[0167] (III)

[0168] in:

[0169] R a3 Selected from halogens, haloalkyl groups, nitro groups, cyano groups, hydroxyl groups, alkyl groups, alkoxy groups, and cycloalkyl groups;

[0170] R a4Selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, haloalkyl, alkoxy, acyl, cycloalkoxy, heterocyclic alkyl, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclic alkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxylalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (formamido)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkoxy, heterocyclic alkoxy, arylalkoxy, heteroarylalkoxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxyl, amide, formamido, sulfonamide, alkylcarbonyl, arylcarbonyl, formyl, carbamoyl, alkylsulfonyl, arylsulfonyl, and alkylthio; and R a4 It is an optional replacement;

[0171] L, R 1 R 2 and R 3 Each as defined above;

[0172] Or its stereoisomers, mixtures of stereoisomers, solvates or pharmaceutically acceptable salts thereof.

[0173] In one implementation, R a3 Selected from cyano, nitro, hydroxy, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, isopropoxy, and tert-butoxy.

[0174] In one implementation, R a4 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, formamido, acetamamido, propionamido, carbamoyl, methylsulfonyl, ethylsulfonyl, morpholino, piperidinyl, piperazine, tetrahydropyranyl, oxetanebutyl, aziranebutyl, isoxazolyl, and pyrroleyl; and R a4 It can be arbitrarily replaced.

[0175] In one implementation, R a4 Optionally by one or more R 9 Replacement. In one implementation, R a4 It is not replaced. In one implementation, R a4 By an R 9 Replacement. In one implementation, R a4 By two R 9 replace.

[0176] In one implementation scheme, each R 9 It is independently selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, haloalkyl, alkoxy, oxo, acyl, cycloalkoxy, heterocyclic alkyl, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, hydroxyalkoxy, carboxylalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (formamido)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkoxy, heterocyclic alkoxy, arylalkoxy, heteroarylalkoxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxyl, amide, formamido, sulfonamide, alkylcarbonyl, arylcarbonyl, formyl, carbamoyl, alkylsulfonyl, arylsulfonyl, and alkylthio.

[0177] In one implementation scheme, each R 9 It is independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, acetyl, oxo, hydroxy, mercapto, oxetane, azirone, imidazoalkyl, methanesulfonyl, methylamino, dimethylamino, methoxy, ethoxy, isopropoxy, tert-butoxy, and hydroxyethoxy.

[0178] In one implementation, R a4 It is methyl. In one embodiment, R a4 It is ethyl. In one embodiment, R a4 It is isopropyl. In one embodiment, R a4 It is cyclopropyl. In one embodiment, R a4 It is an amino group. In one embodiment, R a4 It is a methylamino group. In one embodiment, R a4 It is hydroxymethyl. In one embodiment, R a4 It is trifluoromethyl. In one embodiment, R a4 It is methylsulfonyl ethyl. In one embodiment, R a4 yes In one implementation, R a4 yes In one implementation, R a4 yes In one implementation, R a4 yes In one implementation, R a4 yes In one implementation, R a4 yes In one implementation, Ra4 yes In one implementation, R a4 yes In one implementation, R a4 yes In one implementation, R a4 yes In one implementation, R a4 yes In one implementation, R a4 yes In one implementation, R a4 yes In one implementation, R a4 yes In one implementation, R a4 yes In one implementation, R a4 yes In one implementation, R a4 yes In one implementation, R a4 yes In one implementation, R a4 yes .

[0179] In one implementation, 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.

[0180] In one implementation, R b It is methyl. In one embodiment, R b It is ethyl. In one embodiment, R b It is propyl (e.g., n-propyl or isopropyl). In some embodiments, R b It is butyl (e.g., n-butyl, isobutyl, or tert-butyl). In one embodiment, R b It is pentyl. In one implementation, R b It is self-foundation.

[0181] In one embodiment of formula (II) or (III), R 1 It is an alkoxy group. In one embodiment of formula (II) or (III), R 2 It is a cycloalkyl group. In one embodiment of formula (II) or (III), R 3 It is a methoxy group.

[0182] In one embodiment, the compound provided herein is a single enantiomer. In one embodiment, the compound provided herein is a single diastereomer. In one embodiment, the compound provided herein is a mixture of enantiomers. In one embodiment, the compound provided herein is a mixture of diastereomers. In one embodiment, the compound provided herein is a racemic compound.

[0183] In one embodiment, the compound provided herein has 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 pure enantiomer. In one embodiment, the compound is a substantially pure S-configuration enantiomer. In one embodiment, the compound is a substantially pure R-configuration enantiomer.

[0184] In one embodiment, the compound has an excess of at least about 80% of the S-configuration enantiomers. In one embodiment, the compound has an excess of at least about 90% of the S-configuration enantiomers. In one embodiment, the compound has an excess of at least about 92% of the S-configuration enantiomers. In one embodiment, the compound has an excess of at least about 94% of the S-configuration enantiomers. In one embodiment, the compound has an excess of at least about 96% of the S-configuration enantiomers. In one embodiment, the compound has an excess of at least about 98% of the S-configuration enantiomers. In one embodiment, the compound has an excess of at least about 99% of the S-configuration enantiomers. In one embodiment, the compound has an excess of at least about 99.5% of the S-configuration enantiomers. In one embodiment, the compound has an excess of at least about 99.9% of the S-configuration enantiomers.

[0185] In one embodiment, the compound has an excess of at least about 80% of the R-configuration enantiomers. In one embodiment, the compound has an excess of at least about 90% of the R-configuration enantiomers. In one embodiment, the compound has an excess of at least about 92% of the R-configuration enantiomers. In one embodiment, the compound has an excess of at least about 94% of the R-configuration enantiomers. In one embodiment, the compound has an excess of at least about 96% of the R-configuration enantiomers. In one embodiment, the compound has an excess of at least about 98% of the R-configuration enantiomers. In one embodiment, the compound has an excess of at least about 99% of the R-configuration enantiomers. In one embodiment, the compound has an excess of at least about 99.5% of the R-configuration enantiomers. In one embodiment, the compound has an excess of at least about 99.9% of the R-configuration enantiomers.

[0186] In one embodiment, the compound is a compound in Table 1 or a pharmaceutically acceptable salt thereof.

[0187] Table 1

[0188]

[0189] As used herein and unless otherwise stated, when the stereochemical configuration of the chiral center in the compounds provided herein is specifically stereographed (e.g., with wedge and / or dashed bonds), it is either not specified otherwise or is designated as “R” (or “(R)”) or “S” (or “(S)”), which implies that the absolute stereochemistry is known. For some compounds where the absolute stereochemistry is undetermined (even if the bonds are specifically stereographed), although the compound itself has been isolated into a single stereoisomer and is enantiomerically pure, the stereochemical configuration indicating the center has been designated as “*R” (if the column conditions for isolation are described in the synthetic protocol and the first elution from the column is when only one stereocenter is present or indicates it) or “*S” (if the column conditions for isolation are described in the synthetic protocol and the second elution from the column is when only one stereocenter is present or indicates it). If a compound designated as “*R” is converted into another compound, the “*R” indication of the resulting compound is derived from its starting material.

[0190] 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 USP1 protein.

[0191] In one embodiment, the compound provided herein specifically binds to the USP1 protein. In one embodiment, the compound provided herein specifically binds to the USP1 protein in the USP1-UAF1 complex. In one embodiment, the compound provided herein specifically binds to USP1 mRNA. In one embodiment, the compound provided herein specifically binds to the USP1 protein (alone or in the USP1-UAF1 complex) or USP1 mRNA. In one embodiment, the compound provided herein specifically binds to UAF1 (alone or in the USP1-UAF1 complex) and inhibits or reduces the formation or activity of the USP1-UAF1 complex.

[0192] In one embodiment, without being bound by any particular theory, the S enantiomer of the compound provided herein has a higher binding affinity for the USP1 protein than the R enantiomer. In one embodiment, the S enantiomer has a binding affinity for the USP1 protein that is at least 1.5, 2, 3, 4, 5, 6, 8, 10, 20, 30, 50, or 100 times higher than that of the R enantiomer.

[0193] In one embodiment, without being bound by any particular theory, the R enantiomer of the compound provided herein has a higher binding affinity for the USP1 protein than the S enantiomer. In one embodiment, the R enantiomer has a binding affinity for the USP1 protein that is at least 1.5, 2, 3, 4, 5, 6, 8, 10, 20, 30, 50, or 100 times higher than that of the S enantiomer.

[0194] 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 monoubiquitination of PCNA. In one embodiment, the compounds provided herein increase monoubiquitination of FANCD2.

[0195] In one embodiment, the compounds provided herein increase monoubiquitinated FANCI.

[0196] 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-fold, at least about 10-fold, at least about 20-fold, or at least about 100-fold lower than that for USP1 (i.e., the KD of the compounds provided herein for other deubiquitinating enzymes, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1) is at least about 5-fold, at least about 10-fold, at least about 20-fold, or at least about 100-fold higher than that for USP1).

[0197] In one embodiment, the compounds provided herein are used in IC50 solutions 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 (For example, as measured using the analytical method described in U.S. Patent Application Publication No. 2017 / 0145012) or ICs of 50 nM to 1000 nM. 50 (For example, as measured using the analytical method disclosed in Liang et al., Nat ChemBiol 10:289-304 (2014)) inhibits USP1 deubiquitinase activity. In one embodiment, the compounds provided herein inhibit USP1 deubiquitinase activity with an IC50 as measured using the analytical method disclosed in Chen et al., Chem Biol., 18(11):1390-1400 (2011). 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 inhibit the activity of USP1 deubiquitinase activity with an IC50 as measured using the analytical method disclosed in Chen et al., Chem Biol., 18(11):1390-1400 (2011). 50 Compared to IC, which is at least about 5 times, at least about 10 times, at least about 20 times, or at least about 100 times higher. 50 Inhibits the activity of other deubiquitinating enzymes, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1).

[0198] In one embodiment, the compounds provided herein bind to the USP1 protein with an affinity 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 an affinity 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. In some embodiments, the compounds provided herein are expressed in quantities 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, about 200 nM to about 1 μM, about 300 nM to about 1 μM, about 400 nM to about 1 μM, about 500 nM to about 1 μM, about 600 nM to about 1 μM, about 700 nM to about 1 μM, about 800 nM to about 1 μM, about 900 nM to about 1 μM, about 100 nM, about 200 nM, about 300 nM, about 400 nM, about 500 nM, etc. It binds to the USP1 protein with an affinity of nM, approximately 600 nM, approximately 700 nM, approximately 800 nM, or approximately 900 nM.In some embodiments, the compounds provided herein are expressed in the form of about 1 nM to about 100 nM, about 1 nM to about 90 nM, about 1 nM to about 80 nM, about 1 nM to about 70 nM, about 1 nM to about 60 nM, about 1 nM to about 50 nM, about 1 nM to about 40 nM, about 1 nM to about 30 nM, about 1 nM to about 20 nM, about 1 nM to about 10 nM, about 10 nM to about 100 nM, about 20 nM to about 100 nM, about 30 nM to about 100 nM, about 40 nM to about 100 nM, about 50 nM to about 100 nM, about 60 nM to about 100 nM, about 70 nM to about 100 nM, about 80 nM to about 100 nM, about 90 nM to about 100 nM, about 1 nM, about 2 nM, about 3 nM, about 4 nM, about 5 nM, about 6 ... The compounds provided herein bind to the USP1 protein with an affinity of about 1 μM, about 7 nM, about 8 nM, about 9 nM, about 10 nM, about 20 nM, about 30 nM, about 40 nM, about 50 nM, about 60 nM, about 70 nM, about 80 nM, about 90 nM, or about 100 nM. In some embodiments, the compounds provided herein bind to the USP1 protein with an affinity of less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. In one embodiment, the compounds provided herein bind to the USP1 protein with an affinity of less than 1 nM.

[0199] In one embodiment, the compounds provided herein are expressed in IC50 at 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 Inhibits USP1 activity. In one embodiment, the compounds provided herein are used at IC50 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. 50Inhibits USP1 activity. In some embodiments, the compounds provided herein are expressed in quantities 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, about 200 nM to about 1 μM, about 300 nM to about 1 μM, about 400 nM to about 1 μM, about 500 nM to about 1 μM, about 600 nM to about 1 μM, about 700 nM to about 1 μM, about 800 nM to about 1 μM, about 900 nM to about 1 μM, about 100 nM, about 200 nM, about 300 nM, about 400 nM, about 500 nM, etc. ICs of approximately nM, 600 nM, 700 nM, 800 nM, or 900 nM 50 Inhibits USP1 activity. In some embodiments, the compounds provided herein are expressed in the form of about 1 nM to about 100 nM, about 1 nM to about 90 nM, about 1 nM to about 80 nM, about 1 nM to about 70 nM, about 1 nM to about 60 nM, about 1 nM to about 50 nM, about 1 nM to about 40 nM, about 1 nM to about 30 nM, about 1 nM to about 20 nM, about 1 nM to about 10 nM, about 10 nM to about 100 nM, about 20 nM to about 100 nM, about 30 nM to about 100 nM, about 40 nM to about 100 nM, about 50 nM to about 100 nM, about 60 nM to about 100 nM, about 70 nM to about 100 nM, about 80 nM to about 100 nM, about 90 nM to about 100 nM, about 1 nM, about 2 nM, about 3 nM, about 4 nM, about 5 nM, about 6 ... ICs of approximately 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 50 Inhibits USP1 activity. In some embodiments, the compounds provided herein are used at 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 Inhibits USP1 activity. In one embodiment, the compounds provided herein have an IC50 concentration of less than 1 nM. 50 Inhibits USP1 activity.

[0200] In one implementation, without being bound by any particular theory, the S enantiomer of the compound presented herein is effective for inhibiting USP1 activity via IC50. 50 IC below R enantiomer 50 In one implementation, the R enantiomer is effective for inhibiting USP1 activity in IC. 50 IC of S enantiomer 50 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.

[0201] In one implementation, without being bound by any particular theory, the R enantiomer of the compound provided herein is effective for inhibiting USP1 activity via IC50. 50 IC lower than that of the S enantiomer 50 In one implementation, the S enantiomer is effective for inhibiting USP1 activity in IC. 50 IC of R enantiomer 50 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.

[0202] How to use

[0203] 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. Contact can occur in vitro or in vivo. In one embodiment, contact occurs in a subject suffering from a USP1 protein-mediated disorder.

[0204] In one embodiment, the compounds provided herein can be used to treat USP1 protein-mediated disorders. In one embodiment, a method of treating USP1 protein-mediated disorders or cancer is provided herein, comprising administering a therapeutically effective amount of the compounds or pharmaceutical compositions provided herein to a subject suffering from 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 disease, such as cancer.

[0205] In one embodiment, this document provides a method for treating diseases and disorders using the compounds provided herein. Example diseases and disorders that can be treated with the compounds provided herein include, but are not limited to, cancer.

[0206] In one embodiment, this document provides a method of treating cancer, comprising administering to a subject suffering from cancer a therapeutically effective amount of a compound or pharmaceutical composition provided herein.

[0207] In one embodiment, the cancer is a hematologic cancer, lymphoma, cancer with a defective DNA damage repair pathway, cancer with a defective homologous recombination pathway, cancer containing cancer cells with a gene mutation encoding p53, or cancer containing cancer cells with a loss-of-function mutation in a gene encoding p53. In one embodiment, the cancer is a cancer containing cancer cells with a gene mutation encoding p53. In one embodiment, the cancer is a cancer containing cancer cells with a loss-of-function mutation in a gene encoding p53. In one embodiment, the cancer is a cancer containing cancer cells with a gene mutation encoding BRCA1. In one embodiment, the cancer is a cancer containing cancer cells with a gene mutation encoding BRCA2. In one embodiment, the cancer is a cancer containing cancer cells with a loss-of-function mutation in a gene encoding ATM.

[0208] In one implementation, the cancer is a solid tumor. In one implementation, 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 implementation, the cancer is non-small cell lung cancer (NSCLC), osteosarcoma, ovarian cancer, or breast cancer. In one implementation, the cancer is ovarian cancer. In one implementation, the cancer is breast cancer. In one implementation, the cancer is triple-negative breast cancer.

[0209] In one embodiment, the cancer to be treated with the compounds provided herein is selected from the group consisting of: bone cancer, including osteosarcoma and chondrosarcoma; brain cancer, including glioma, glioblastoma, astrocytoma, myeloma, and meningioma; soft tissue cancer, including rhabdomyosarcoma and sarcoma; kidney cancer; bladder cancer; skin cancer, including melanoma; and lung cancer, including non-small cell lung cancer; colon cancer; uterine cancer; nervous system cancer; head and neck cancer; pancreatic cancer; and cervical cancer.

[0210] In one embodiment, this document provides a method of treating cancer, comprising administering to a subject suffering from cancer a therapeutically effective amount of a compound or pharmaceutical composition provided herein, wherein the cancer comprises cancer cells having elevated RAD18 levels. In one embodiment, the elevated RAD18 level is an elevated RAD18 protein level. In one embodiment, the elevated RAD18 level is an elevated RAD18 mRNA level. In one embodiment, the elevated RAD18 level (e.g., RAD18 protein and / or RAD18 mRNA) has been detected prior to administration (e.g., in a cancer sample obtained from the subject). That is, in one embodiment, the RAD18 protein or mRNA in the cancer of the subject has been tested before initiating treatment with a USP1 inhibitor such as a compound provided herein.

[0211] In one implementation, such a method includes (a) confirming that the cancer in the subject is a USP1 inhibitor-sensitive cancer, and then (b) administering to the subject a therapeutically effective amount of the compound provided herein.

[0212] In one implementation, such a method includes (a) detecting the level of RAD 18 (e.g., RAD 18 protein and / or RAD 18 mRNA) in cancer cells (e.g., cancer samples obtained from a subject), and then (b) administering a therapeutically effective amount of the compound provided herein to a subject suffering from cancer containing cancer cells with elevated RAD 18 levels.

[0213] In one implementation, such a method includes administering a therapeutically effective amount of the compound provided herein to a subject suffering from triple-negative breast cancer.

[0214] In one embodiment, the compounds provided herein are used to treat cancer, wherein the cancer is a homologous recombination-deficient cancer. In one embodiment, the compounds provided herein are used to treat cancer, wherein the cancer comprises cancer cells with mutations in a gene encoding p53. In one embodiment, the compounds provided herein are used to treat cancer, wherein the cancer comprises cancer cells with loss-of-function mutations in a gene encoding p53. In one embodiment, the compounds provided herein are used to treat cancers without defects in the homologous recombination pathway.

[0215] In one embodiment, the compounds provided herein are used to treat cancer, wherein the cancer is a BRCA1-mutant cancer. In one embodiment, the compounds provided herein are used to treat cancer, wherein the cancer is a BRCA2-mutant cancer. In one embodiment, the compounds provided herein are used to treat cancer, wherein the cancer is both 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 both a BRCA1-deficient cancer and a BRCA2-deficient cancer.

[0216] In one embodiment, the compounds provided herein are used to treat cancer, wherein the cancer is an ATM-mutant cancer. In one embodiment, the cancer is not an ATM-mutant cancer. In one embodiment, the cancer is an ATM-deficient cancer.

[0217] In one embodiment, the compounds provided herein are used to treat cancer, wherein the cancer is PARP inhibitor-resistant or refractory cancer. In one embodiment, the cancer is PARP inhibitor-resistant or refractory BRCA1-mutated cancer. In one embodiment, the cancer is PARP inhibitor-resistant or refractory BRCA1-deficient cancer. In one embodiment, the cancer is PARP inhibitor-resistant or refractory BRCA2-mutated cancer. In one embodiment, the cancer is PARP inhibitor-resistant or refractory BRCA2-deficient cancer.

[0218] In one embodiment, the cancer is a BRCA1 and / or BRCA2 mutated cancer, wherein the cancer comprises cells with elevated RAD18 levels. In one embodiment, the elevated RAD18 level is at least as high as the RAD18 protein and / or mRNA levels in ES2 cells. In one embodiment, the elevated RAD18 level is higher than the RAD18 protein and / or mRNA levels in HEP3B217 cells. In one embodiment, triple-negative breast cancer is a BRCA1 and / or BRCA2 mutated cancer.

[0219] In one embodiment, the cancer is a solid cancer. In one embodiment, the cancer is a hematologic / lymphoma. In one embodiment, the cancer is a cancer with a defective DNA damage repair pathway. In one embodiment, the cancer is a cancer with a defective homologous recombination pathway. In one embodiment, the cancer comprises cancer cells with a mutation in a gene encoding p53. In one embodiment, the cancer comprises cancer cells with a loss-of-function mutation in a 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.

[0220] In one embodiment, the compounds provided herein are used in combination with one or more other therapeutic agents to treat cancer. It has been reported that p53 status determines the sensitization of PARP inhibitors (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-mutant cancers and BRCA-mutant cancers exhibit increased sensitivity to USP1 inhibitors. Therefore, in one embodiment, the compounds provided herein are used in combination with PARP inhibitors to treat cancer.

[0221] In one embodiment, the compounds provided herein are provided for use as a medicine or for use in the preparation of a medicine, for example, for treating cancer. In one embodiment, the compounds provided herein are provided for use in a method of treating cancer.

[0222] Pharmaceutical Composition

[0223] This article also provides pharmaceutical compositions comprising the compounds provided herein and pharmaceutically acceptable excipients.

[0224] In one embodiment, the compounds provided herein are administered to a mammal as a raw material chemical without any other components. In another embodiment, the compounds provided herein are administered to a mammal as part of a pharmaceutical composition comprising the compounds in combination 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 edition (2003); Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition, Lippencott Williams and Wilkins (2004); Kibbe et al., Handbook of Pharmaceutical Excipients, 3rd edition, Pharmaceutical Press (2000)). Such carriers may be selected from pharmaceutically acceptable excipients and adjuvants.

[0225] In one embodiment, the pharmaceutical compositions provided herein can be prepared as liquid suspensions or solutions using liquids such as oils, water, alcohols, and combinations thereof.

[0226] In one embodiment, the pharmaceutical compositions provided herein can be prepared as sterile injectable preparations, which can be aqueous or oil-based suspensions. These suspensions can be formulated according to techniques known in the art.

[0227] In one embodiment, the pharmaceutical composition provided herein can be administered orally in any orally acceptable dosage form, including capsules, tablets, aqueous suspensions, or solutions.

[0228] In one embodiment, the pharmaceutical composition provided herein can be administered in the form of a suppository for rectal administration.

[0229] In one embodiment, the pharmaceutical compositions provided herein can also be administered topically, particularly when the therapeutic target includes areas or organs easily accessible by topical application, including diseases of the eyes, skin, or lower intestine. Topical application to the lower intestine can be achieved as a rectal suppository formulation (see above) or as a suitable enema formulation. Topical transdermal patches may also be used. For topical application, the pharmaceutical compositions can be formulated as suitable ointments, lotions, or creams containing an active ingredient suspended or dissolved in one or more carriers.

[0230] In one embodiment, the pharmaceutical composition provided herein may also be administered ocularly and formulated as a micronized suspension in isotonic, pH-adjusted sterile saline or as a solution in isotonic, pH-adjusted sterile saline, with or without a preservative such as benzalkonium chloride. In one embodiment, for ophthalmic use, the pharmaceutical composition may be formulated as an ointment, such as petrolatum.

[0231] In one embodiment, the pharmaceutical composition provided herein can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the field of pharmaceutical formulation and can be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, bioavailability enhancers, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0232] In one embodiment, the pharmaceutical composition intended for in vivo administration may be sterile. In one embodiment, this is achieved, for example, by filtration through a sterile filter membrane.

[0233] In one embodiment, the pharmaceutical compositions provided herein comprise all compositions in which the compounds provided herein are combined with one or more pharmaceutically acceptable carriers. In one embodiment, the compounds provided herein are present in the composition in an amount that effectively achieves their intended therapeutic purpose.

[0234] In one embodiment, the pharmaceutical composition provided herein can be given 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.

[0235] In one embodiment, a kit comprising the compounds provided herein (or compositions comprising the compounds provided herein) is also provided, packaged in a manner that facilitates their use in practicing 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 resealable vial or container, having a label affixed to the container or included in the kit describing the use of the compound or composition in practicing the methods provided herein. In one embodiment, the compound or composition is packaged in a unit dosage form. In one embodiment, the kit further comprises means suitable for administering the compound or composition according to the intended route of administration. In one embodiment, the kit comprises the compounds provided herein and instructions for administering the compound to a patient with cancer. Example

[0236] Some embodiments of the claimed subject matter are illustrated by the following non-limiting examples.

[0237] The disclosed compounds can generally be synthesized by the following general procedure or by a suitable combination of commonly known synthetic methods. Based on this disclosure, the techniques available for synthesizing these compounds will be obvious and readily available to those skilled in the art. Many optionally substituted starting compounds and other reactants are commercially available or can be readily prepared by those skilled in the art using commonly used synthetic methods.

[0238] The following examples illustrate certain methods for preparing the disclosed compounds and are not intended to limit the range of reactions or reaction sequences that may be used to prepare the compounds provided herein.

[0239] Synthesis method

[0240] In one embodiment, this document provides a method (method 1) for preparing the compound provided herein, which includes the following steps:

[0241]

[0242] X is a halogen, such as Br, Cl, or I.

[0243] Step 1: At a suitable temperature, such as approximately -10°C o C to approximately 120 o The process is carried out at C, 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.

[0244] Step 2 at a suitable temperature, such as approximately 40°C o C to approximately 120 o Under C conditions, 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, for example, CATA CXIUMI A PdG3 or Pd(dppf)Cl2, and in a suitable solvent combination such as dimethoxyethane / water or dioxane / water.

[0245] Several methods for preparing the compounds provided herein are illustrated in the following examples. Unless otherwise stated, all starting materials were obtained from commercial suppliers and used without further purification, or alternatively, could be synthesized by a person skilled in the art using well-known methods.

[0246] Preparation of intermediates

[0247] For intermediates used as crude products or as partially purified intermediates in the next reaction step, in some cases, the molar amount of such intermediates is not mentioned in the next reaction step, or the estimated or theoretical molar amount of such intermediates in the next reaction step is indicated in the reaction scheme described below.

[0248] Preparation of Intermediate 1

[0249]

[0250] 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-pyridin-4-yl)boronic acid (600 mg, 2.64 mmol, 1.1 equivalent), Cs₂CO₃ (1.57 g, 4.80 mmol, 2 equivalent), and Pd(dppf)Cl₂ (175.7 mg, 240.22 μmol, 0.1 equivalent) in dioxane (12 mL) and H₂O (3 mL) was degassed and purged three times with N₂. The mixture was then stirred at 90°C for 16 hours under N₂ atmosphere. The reaction mixture was cooled to room temperature, diluted with 100 mL of H₂O, and extracted with EA 200 mL (100 mL × 2). 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 rapid 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 = 0.3) Purification to give intermediate 1 (612.7 mg, 1.55 mmol, 64.53% yield, 91.784% purity) as a yellow oil.

[0251] Preparation of intermediate 2

[0252]

[0253] Intermediate 1 (612.7 mg, 1.69 mmol, 1 equivalent), [4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]methanol (474.4 mg, 2.03 mmol, 1.2 equivalent), Cs₂CO₃ (1.10 g, 3.38 mmol, 2 equivalent), and di-tert-butyl(cyclopentyl)phosphine dichloropalladium iron (110.1 mg, 168.89 μmol, 0.1 equivalent) were degassed in a mixture of dioxane (12 mL) and H₂O (3 mL) and purged three times with N₂. The mixture was then stirred at 100°C for 16 hours under N₂ atmosphere. The reaction mixture was cooled to room temperature, diluted with 100 mL of H₂O, and extracted with EA 200 mL (100 mL × 2). 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 purified by rapid 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 give intermediate 2 as a yellow solid (616.1 mg, 1.38 mmol, 81.98% yield, 97.632% purity).

[0254] Preparation of intermediate 3

[0255]

[0256] 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 to a solution of intermediate 2 (500 mg, 1.15 mmol, 1 equivalent) in MeOH (10 mL). 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 purified by prep-HPLC (alkaline conditions: Waters Xbridge BEH C18 150*25mm*5um column; mobile phase: [water (NH4HCO3)-ACN]; gradient: 44%-64% B, for 10 min) to give intermediate 3 as a white solid (231 mg, 495.43 μmol, 43.05% yield, 93.610% purity).

[0257] Preparation of intermediate 4

[0258]

[0259] Under N2 at 0°C, NaH (42.3 mg, 1.06 mmol, 60% purity, 2 equivalents) was added to a mixture of intermediate 3 (231 mg, 529.25 μmol, 1 equivalent) in THF (5 mL), and the mixture was stirred at 0°C for 0.5 h. 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 h. The reaction mixture was quenched by adding 10 mL of saturated NH4Cl, diluted with 40 mL of H2O, and extracted with 120 mL of EA (40 mL × 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 rapid 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 give intermediate 4 as a colorless oil (306.7 mg, 521.15 μmol, 98.47% yield, 98.386% purity).

[0260] The following intermediates are synthesized using a method similar to that described above for intermediate 4.

[0261] Preparation of intermediate 5

[0262]

[0263] Intermediate 4 (306.7 mg, 529.70 μmol, 1 equivalent), 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-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 equivalents) were degassed in a mixture of DME (8 mL) and H2O (2 mL) and purged three times with N2. The mixture was then stirred at 90°C for 2 hours under N2 atmosphere. The reaction mixture was cooled to room temperature, diluted with 40 mL of H2O, and extracted with 60 mL of EA (20 mL × 3). 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 prep-HPLC (alkaline conditions; column: Waters Xbridge C18 150*50mm*10um; mobile phase: [water (NH4+)] 3. [H2O)-ACN]; gradient: 70%-100% B, purified for 11 min to give intermediate 5 as a white solid (171.1 mg, 247.00 μmol, 46.63% yield, 100% purity).

[0264] The following intermediates are synthesized using a method similar to that described above for intermediate 5.

[0265] Preparation of intermediate 6

[0266]

[0267] TFA (0.5 mL, 6.73 mmol, 27.25 equivalents) was added to a solution of intermediate 5 (171.1 mg, 247.00 μmol, 1 equivalent) in DCM (1 mL). The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to give intermediate 6 (200 mg, crude, TFA), which was used in the next step without further purification.

[0268] The following intermediates are synthesized using a method similar to that described above for intermediate 6.

[0269] Preparation of intermediate 10

[0270]

[0271] To a solution of intermediate 6 (150 mg, crude, 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 fractionally. 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 rapid silica gel chromatography (ISCO®; 4 g SepaFlash® silica gel rapid separation column, eluent 0 / 1 to 80 / 20 ethyl acetate / petroleum ether gradient, 35 mL / min) to give intermediate 10 (55 mg, 66.39 μmol, 62.55% yield, 92.2% purity) as a white solid.

[0272] The following intermediates are synthesized using a method similar to that described above for intermediate 10.

[0273] Preparation of intermediate 11

[0274]

[0275] 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 and purged three times with N2. Then, Pd(dppf)Cl2 (561.9 mg, 767.93 μmol, 0.1 equivalent) and Na2CO3 (1.63 g, 15.36 mmol, 2 equivalent) were added, and the mixture was stirred at 90°C for 12 hours under N2 atmosphere. The reaction mixture was cooled to room temperature, poured into H2O (50 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic layers were 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 give intermediate 11 as a brown solid (1.4 g, 4.80 mmol, 62.53% yield, 99% purity).

[0276] Preparation of intermediate 12

[0277]

[0278] The mixture of intermediate 11 (250 mg, 866.09 μmol, 1 equivalent) and [4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]methanol (202.7 mg, 866.09 μmol, 1 equivalent) in DME (2 mL) and H2O (0.5 mL) was degassed and purged three times with N2. Cs2CO3 (564.3 mg, 1.73 mmol, 2 equivalents) and di-tert-butyl(cyclopentyl)phosphine dichloropalladium iron (56.4 mg, 86.61 μmol, 0.1 equivalents) were added, and the mixture was again degassed and purged three times with N2. The mixture was stirred at 95°C for 12 h under N2 atmosphere. The reaction mixture was cooled to room temperature and diluted with H2O (40 mL) and extracted with ethyl acetate (20 mL × 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 give intermediate 12 as a brown solid (260 mg, 707.13 μmol, 81.65% yield, 98% purity).

[0279] Preparation of intermediate 14

[0280]

[0281] A mixture of 3-bromo-2-chloro-6-(trifluoromethyl)pyridine (940 mg, 3.61 mmol, 1 equivalent), 2-(3,6-dihydro-2H-thiaran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane (979.4 mg, 4.33 mmol, 1.2 equivalent) and an aqueous solution of Na₂CO₃ (2 M, 2.71 mL, 1.5 equivalent) in n-BuOH (8.4 mL) was degassed and purged three times with N₂. Then, Pd(PPh₃)₄ (417 mg, 360.93 μmol, 0.1 equivalent) was added, and the mixture was stirred at 130°C for 15 min under N₂ atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by FCC (ISCO®; 12g SepaFlash® silica rapid separation column, EA 3%, PE / EA, 40mL / min; PE / EA = 5:1, Rf = 0.8) to obtain the crude product, which was then purified by FCC (ISCO®; 4g SepaFlash® silica rapid separation column, EA 0-7%, PE / EA, 20mL / min; PE / EA = 7:1, Rf = 0.6) to obtain intermediate 14 (550 mg, 1.70 mmol, 47.07% yield, 86.4% purity) as a yellow oil.

[0282] Preparation of intermediate 15

[0283]

[0284] Intermediate 14 (550 mg, 1.97 mmol, 1 equivalent), (4-methoxycarbonylphenyl)boronic acid (424.6 mg, 2.36 mmol, 1.2 equivalent), and Cs₂CO₃ (1.28 g, 3.93 mmol, 2 equivalent) were degassed in a mixture of dioxane (4 mL) and H₂O (1 mL) and purged three times with N₂. Then, Pd(dppf)Cl₂ (128.1 mg, 196.63 μmol, 0.1 equivalent) was added and the mixture was stirred at 100°C for 4 hours under N₂ atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by FCC (ISCO®; 12g SepaFlash® silica gel rapid separation column, EA 7% PE / EA, 40mL / min; PE / EA=3:1, Rf=0.5) to obtain intermediate 15 (602 mg, 1.55 mmol, 78.79% yield, 97.64% purity) as a white oil.

[0285] Preparation of intermediate 16

[0286]

[0287] m-CPBA (684.5 mg, 3.17 mmol, 80% purity, 2 equivalents) was added to a solution of methyl intermediate 15 (602 mg, 1.59 mmol, 1 equivalent) in DCM (10 mL). 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 × 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by FCC (ISCO®; 12 g SepaFlash® silica gel rapid separation column, EA 30%, PE / EA, 40 mL / min; PE / EA = 1:1, Rf = 0.5) to give intermediate 16 (588 mg, 1.37 mmol, 86.61% yield, 96.156% purity) as a white solid.

[0288] Preparation of intermediate 17

[0289]

[0290] The mixture of intermediate 16 (288 mg, 700.06 μmol, 1 equivalent) in MeOH (3 mL) was degassed and purged three times with H2, and then Pd / C (372.5 mg, 350.03 μmol, 10% purity, 0.5 equivalent) was added and stirred at 25°C for 2 hours under H2 (15 psi) atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give intermediate 17 (260 mg, 574.83 μmol, 82.11% yield, 91.4% purity) as a white solid.

[0291] Preparation of intermediate 18

[0292]

[0293] The mixture of intermediate 17 (210 mg, 507.97 μmol, 1 equivalent) in THF (3 mL) was degassed and purged three times with N2, and then LiBH4 (2 M, 761 μL, 3.00 equivalent) was added dropwise and stirred at 40°C for 4 hours under N2 atmosphere. The mixture was quenched under N2 atmosphere by dropwise addition of HCl (10%, 100 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give intermediate 18 (220 mg, crude) as a white solid, which was used in the next step without further purification.

[0294] Preparation of intermediate 20

[0295]

[0296] At 0°C, t-BuONO (3.88 g, 37.63 mmol, 4.48 mL, 1.4 equivalents) was added dropwise to a suspension of CuBr2 (6.90 g, 30.91 mmol, 1.45 mL, 1.15 equivalents) in MeCN (120 mL). 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 h, and then slowly heated to 20°C and stirred for 12 h. 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 × 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. This crude product was then subjected to rapid column chromatography on 80 g 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 = 0.35) Purification to give intermediate 20 (8.36 g, 24.67 mmol, 91.77% yield, 98% purity) in brown oil.

[0297] Preparation of intermediate 21

[0298]

[0299] Intermediate 20 (100 mg, 301.10 μmol, 1 equivalent), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydro-2H-pyridin-1-yl]acetone (90.7 mg, 361.32 μmol, 1.2 equivalent), and K3PO4 (127.8 mg, 602.20 μmol, 2 equivalent) were degassed in a mixture of H2O (0.5 mL) and dioxane (2 mL) and purged three times with N2. 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 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 × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was then purified by FCC (ISCO®; 4 g SepaFlash® silica gel rapid separation column, 0-20% MeOH, DCM / MeOH, 30 mL / min; DCM / MeOH = 5:1, Rf = 0.4) to give intermediate 21 (94 mg, 249.75 μmol, 82.95% yield) as a white solid.

[0300] Preparation of intermediate 23

[0301]

[0302] Intermediate 20 (500 mg, 1.51 mmol, 1 equivalent), 3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,5-dihydropyrrole-1-carboxylic acid tert-butyl ester (500 mg, 1.69 mmol, 1.13 equivalent), Cs₂CO₃ (981 mg, 3.01 mmol, 2 equivalent), and cyclopentyl(diphenyl)phosphine dichloropalladium iron (110.1 mg, 150.55 μmol, 0.1 equivalent) and H₂O (2.5 mL) in dioxane (10 mL) were degassed and purged three times with N₂. The mixture was then stirred at 90°C for 16 hours under N₂ atmosphere. The reaction mixture was cooled to room temperature, diluted with 50 mL of H₂O, and extracted with EA 100 mL (50 mL × 2). The combined organic layers were washed with 50 mL of NaCl aqueous solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by rapid 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 give intermediate 23 (609.5 mg, 1.39 mmol, 92.35% yield, 95.901% purity) as a yellow oil.

[0303] Preparation of intermediate 24

[0304]

[0305] 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 to a solution of intermediate 23 (500 mg, 1.19 mmol, 1 equivalent) in MeOH (25 mL). 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 give 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.

[0306] Preparation of intermediate 28

[0307]

[0308] A stir bar, 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 flask under a nitrogen atmosphere. The suspension was degassed under vacuum and purged three times with an Ar atmosphere, followed by three purgings with hydrogen. The resulting mixture was stirred at 25°C for 24 hours under H2 (40 Psi). The mixture was filtered through a diatomaceous earth mat, and the filter cake was washed with methanol (30 mL × 3). The combined filtrates were concentrated under reduced pressure to give intermediate 28 (215 mg, 590.07 μmol, 64.43% yield) as a yellow solid, which was used in the next step without further purification.

[0309] Preparation of intermediate 30

[0310]

[0311] A mixture of 2-chloro-6-(trifluoromethyl)pyridine-3-carboxaldehyde (500 mg, 2.39 mmol, 1 equivalent), 1-piperazin-1-ylethyl ketone (458.7 mg, 3.58 mmol, 1.5 equivalent), and AcOH (136 μL, 2.39 mmol, 1 equivalent) in MeOH (3 mL) was stirred for 30 min, and then NaBH3CN (299.8 mg, 4.77 mmol, 2 equivalent) was added and the mixture was stirred at 25°C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by rapid silica gel chromatography (ISCO®; 4 g SepaFlash® silica gel rapid separation column, eluent 0 / 1 to 1 / 1 ethyl acetate / petroleum ether gradient, 30 mL / min) to give intermediate 30 (600 mg, 1.86 mmol, 78.16% yield) as a white solid.

[0312] Preparation of intermediate 31

[0313]

[0314] Intermediate 30 (580 mg, 1.80 mmol, 1 equivalent), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]methanol (633 mg, 2.70 mmol, 1.5 equivalent), K3PO4 (1.15 g, 5.41 mmol, 3 equivalent), [2-(2-aminophenyl)phenyl]palladium (1+); bis(1-adamantyl)-butylphosphine; methanesulfonate (131.2 mg, 180.28 μmol, 0.1 equivalent) in H2O (2 mL) and dioxane (6 mL) were stirred at 95°C under N2 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 × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by rapid silica gel chromatography (ISCO®; 4 g SepaFlash® silica gel rapid separation column, eluent 0 / 1~90 / 10 ethyl acetate / petroleum ether gradient, 30 mL / min) to give intermediate 31 as a white solid (280 mg, 711.74 μmol, 39.48% yield).

[0315] Preparation of intermediate 33

[0316]

[0317] Under N2, Pd(OAc)2 (33.8 mg, 150.55 μmol, 0.1 equivalent) and tri-o-tolylphosphine (91.6 mg, 301.10 μmol, 0.2 equivalent) were added to a mixture of intermediate 20 (500 mg, 1.51 mmol, 1 equivalent), 3-methyleneazacyclobutane-1-carboxylic acid tert-butyl ester (509.5 mg, 3.01 mmol, 2 equivalent), TEA (628 μL, 4.52 mmol, 3 equivalent) in MeCN (4 mL), and 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 rapid silica gel chromatography (ISCO®; 4 g SepaFlash® silica gel rapid separation column, eluent 0 / 1 to 50 / 50 ethyl acetate / petroleum ether gradient, 30 mL / min) to give intermediate 33 as a colorless gel (530 mg, 1.26 mmol, 83.74% yield).

[0318] Preparation of intermediate 34

[0319]

[0320] Under N2, Pd(OAc)2 (33.8 mg, 150.55 μmol, 0.1 equivalent) and tri-o-tolylphosphine (91.6 mg, 301.10 μmol, 0.2 equivalent) were added to a mixture of intermediate 33 (500 mg, 1.51 mmol, 1 equivalent), 3-methyleneazacyclobutane-1-carboxylic acid tert-butyl ester (509.5 mg, 3.01 mmol, 2 equivalent), TEA (628 μL, 4.52 mmol, 3 equivalent) in MeCN (4 mL), and 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 rapid silica gel chromatography (ISCO®; 4 g SepaFlash® silica gel rapid separation column, eluent 0 / 1 to 50 / 50 ethyl acetate / petroleum ether gradient, 30 mL / min) to give intermediate 34 as a colorless gel (530 mg, 1.26 mmol, 83.74% yield).

[0321] Preparation of intermediate 36

[0322]

[0323] Intermediate 35 (150 mg, 265.49 μmol, 1 equivalent), 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-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 equivalents) were stirred at 100°C under N2 for 0.5 h in H2O (0.5 mL) and dioxane (1.5 mL). The reaction mixture was cooled to room temperature, H2O (40 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by rapid silica gel chromatography (ISCO®; 4 g SepaFlash® silica gel rapid separation column, eluent 0 / 1~40 / 60 ethyl acetate / petroleum ether gradient, 30 mL / min) to give intermediate 36 as a colorless gel (140 mg, 206.28 μmol, 77.70% yield).

[0324] The following intermediates are synthesized using a method similar to that described above for intermediate 36.

[0325] Preparation of intermediate 38

[0326]

[0327] Phenyl chloroformate (343 μL, 2.74 mmol, 1 equivalent) was added dropwise to a solution of oxetane-3-amine (200 mg, 2.74 mmol, 1 equivalent) and DIEA (953 μL, 5.47 mmol, 2 equivalent) in THF (3 mL). 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 rapid silica gel chromatography (ISCO®; 12 g SepaFlash® silica gel rapid separation column, eluent gradient of 0 / 1 to 50 / 50 ethyl acetate / petroleum ether, 40 mL / min) to give intermediate 38 as a white solid (410 mg, 2.12 mmol, 77.56% yield, 100% purity).

[0328] Preparation of intermediate 39

[0329]

[0330] To a solution of intermediate 20 (2.4 g, 7.23 mmol, 1 equivalent) in THF (20 mL), tert-butyldimethylchlorosilane (1.33 mL, 10.84 mmol, 1.5 equivalent) and TEA (2.01 mL, 14.45 mmol, 2 equivalent) 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 × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to give intermediate 39 (3.17 g, 7.09 mmol, 81.71% yield, 99.78% purity) as a white solid.

[0331] Preparation of intermediate 40

[0332]

[0333] t-BuONa (344.4 mg, 3.58 mmol, 4 equivalents) was added to a solution of intermediate 39 (400 mg, 896.11 μmol, 1 equivalent) and 4-methylpiperidin-4-ol (206.4 mg, 1.79 mmol, 2 equivalents) in toluene (5 mL). The suspension was degassed under vacuum and purged three times with N2 atmosphere, followed by the addition of BINAP (55.8 mg, 89.61 μmol, 0.1 equivalent) and Pd2(dba)3 (82 mg, 89.61 μmol, 0.1 equivalent). The mixture was degassed under vacuum and purged three times with 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 of ethyl acetate (20 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by rapid column chromatography on 4 g 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 give intermediate 40 (460 mg, 890.07 μmol, 99.33% yield, 93% purity) as a yellow oil.

[0334] Preparation of intermediate 41

[0335]

[0336] Intermediate 40 (460 mg, 957.06 μmol, 1 equivalent) and TBAF (1 M, 1.44 mL, 1.5 equivalent) were dissolved in THF (5 mL), and the reaction mixture was stirred at 25°C for 1 h. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with H2O (30 mL × 3) and saturated NaCl aqueous solution (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give intermediate 41 (460 mg, crude) as a yellow oil, which was used in the next step without further purification.

[0337] The following intermediates are synthesized using a method similar to that described above for intermediate 41.

[0338] Preparation of intermediate 43

[0339]

[0340] 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]chloro-palladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphine (64.3 mg, 81.77 μmol, 0.1 equivalents) were added to a vial, which was then degassed under vacuum and purged three times with N₂ atmosphere. Dioxane (8 mL) was added to the vial and purged again with N₂ atmosphere. The mixture was stirred at 90°C for 12 h. After cooling to room temperature, the reaction mixture was diluted with H₂O (30 mL) and extracted with EA (20 mL * 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was subjected to rapid column chromatography on 4 g 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 =0.4) Purification yielded intermediate 43 (277 mg, 427.50 μmol, 52.28% yield, 87% purity) as a yellow solid.

[0341] Preparation of intermediate 48

[0342]

[0343] Intermediate 39 (893 mg, 2 mmol, 1 equivalent), tert-butyl 3-bromozacyclobutane-1-carboxylate (614 mg, 2.60 mmol, 1.3 equivalent), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (22.4 mg, 20 μmol, 0.01 equivalent), NiCl2.dtbbpy (11.9 mg, 30 μmol, 0.015 equivalent), TTMSS (49.7 mg, 0.2 mmol, 1.00 equivalent), and Na2CO3 (42.4 mg, 0.4 mmol, 2 equivalent) were added to a 15 mL vial equipped with a stir bar. The vial was sealed and placed under nitrogen. The reaction was stirred and 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 × 3). The combined organic layers were washed with saturated aqueous NaCl solution (20 mL × 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 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 give intermediate 48 as a colorless oil (640 mg, 1.05 mmol, 52.42% yield, 86% purity).

[0344] Preparation of intermediate 53

[0345]

[0346] t-BuONa (1.11 g, 11.52 mmol, 1.5 equivalent) was added to a solution of 3-bromo-2-chloro-6-(trifluoromethyl)pyridine (2 g, 7.68 mmol, 1 equivalent) and methyl piperidinium-4-carboxylate (989.6 mg, 6.91 mmol, 0.9 equivalent) in toluene (20 mL). The suspension was degassed under vacuum and purged three times with N2 atmosphere, and then Pd2(dba)3 (703.2 mg, 767.93 μmol, 0.1 equivalent) and xanthones (444.3 mg, 767.93 μmol, 0.1 equivalent) were added. The mixture was degassed under vacuum and purged three times with 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 × 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 rapid column chromatography on 12 g 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 give intermediate 53 (270 mg, 711.16 μmol, 9.26% yield, 85% purity) as a yellow oil.

[0347] Preparation of intermediate 54

[0348]

[0349] Cs₂CO₃ (545.2 mg, 1.67 mmol, 2 equivalents) was added to a solution of intermediate 53 (270 mg, 836.66 μmol, 1 equivalent) and [4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)phenyl]methanol (293.7 mg, 1.25 mmol, 1.5 equivalents) in dioxane (2 mL) and H₂O (0.5 mL). The suspension was degassed under vacuum and purged three times with N₂ atmosphere, and then di-tert-butyl(cyclopentyl)phosphine; palladium dichloro; iron (54.5 mg, 83.67 μmol, 0.1 equivalents) was added. The mixture was degassed under vacuum and purged three times with 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 × 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 rapid column chromatography on 4 g 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 give intermediate 54 (218 mg, 528.99 μmol, 63.23% yield, 95.7% purity) as a yellow solid.

[0350] Preparation of intermediate 56

[0351]

[0352] DIEA (84 μL, 487.66 μmol, 3 equivalents) was added to a stirred solution of intermediate 55 (85 mg, 162.55 μmol, 1 equivalent) and methylamine hydrochloride (16.4 mg, 243.83 μmol, 1.5 equivalents) in DMF (2 mL). Then HATU (92.7 mg, 243.83 μmol, 1.5 equivalents) was added at 0°C. The reaction mixture was heated to 25°C and stirred at 25°C for 8 h. 20 mL of H2O was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give intermediate 56 (41 mg, crude) as a pale yellow oil, which was used in the next step without further purification.

[0353] Preparation of intermediate 57

[0354]

[0355] Intermediate 1 (1.13 g, 3.11 mmol, 1 equivalent), (4-cyanophenyl)boronic acid (549.2 mg, 3.74 mmol, 1.2 equivalent), Cs₂CO₃ (2.03 g, 6.23 mmol, 2 equivalent), and di-tert-butyl(cyclopentyl)phosphine; dichloropalladium; iron (203 mg, 311.49 μmol, 0.1 equivalent) were degassed in a mixture of dioxane (20 mL) and H₂O (5 mL) and purged three times with N₂. The mixture was then stirred at 100°C for 16 hours under N₂ atmosphere. The reaction mixture was cooled to room temperature, diluted with 100 mL of H₂O, and extracted with EA 240 mL (80 mL × 3). The combined organic layers were washed with 200 mL of NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by rapid 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 give intermediate 57 (1.37 g, 3.04 mmol, 89.73% yield, 95.366% purity) as a yellow solid.

[0356] The following intermediates are synthesized using a method similar to that described above for intermediate 57.

[0357] Preparation of intermediate 58

[0358]

[0359] Under N2, Pd / C (49.5 mg, 46.57 μmol, 10% purity, 0.1 equivalent) was added to a solution of intermediate 57 (0.2 g, 465.73 μmol, 1 equivalent) in MeOH (5 mL). The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 35°C for 2 hours under H2 (15 psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give intermediate 58 (300 mg, crude) as a colorless oil, which was used in the next step without further purification.

[0360] Preparation of intermediate 59

[0361]

[0362] TEA (194 μL, 1.40 mmol, 3 equivalents) and 2,4-dichloro-5-methoxypyrimidine (83.3 mg, 465.73 μmol, 1 equivalent) were added to a solution of intermediate 58 (202.8 mg, 465.73 μmol, 1 equivalent) in THF (5 mL). The mixture was stirred at 60°C for 16 hours. The reaction mixture was diluted with 50 mL of H2O and extracted with EA 100 mL (50 mL × 2). The combined organic layers were 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 rapid 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 give intermediate 59 as a colorless oil (77.2 mg, 102.34 μmol, 21.97% yield, 76.626% purity).

[0363] The following intermediates are synthesized using a method similar to that described above for intermediate 59.

[0364] Preparation of intermediate 60

[0365]

[0366] Intermediate 59 (77.2 mg, 133.56 μmol, 1 equivalent), 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrimidine (73.7 mg, 267.12 μmol, 2 equivalent), Na2CO3 (28.3 mg, 267.12 μmol, 2 equivalent), and CATACXIUM(R) A Pd G3 (9.7 mg, 13.36 μmol, 0.1 equivalent) were degassed in a mixture of DME (2 mL) and H2O (0.5 mL) and purged three times with N2. The mixture was then stirred at 90°C for 2 h under N2 atmosphere. The reaction mixture was cooled to room temperature, diluted with 60 mL of H2O, and extracted with EA 100 mL (50 mL × 2). 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 purified by prep-HPLC (alkaline conditions: column: Waters Xbridge C18 150*50mm*10um; mobile phase: [water (NH3H2O)-ACN]; gradient: 63%-93% B, for 10 min) to give intermediate 60 as a white solid (81 mg, 111.62 μmol, 83.57% yield, 95.320% purity).

[0367] The following intermediates are synthesized using a method similar to that described above for intermediate 60.

[0368] Preparation of intermediate 61

[0369]

[0370] TFA (3.07 g, 26.92 mmol, 2 mL, 229.93 equivalents) was added to a solution of intermediate 60 (81 mg, 117.10 μmol, 1 equivalent) in DCM (2 mL). The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to give intermediate 61 (100 mg, crude, TFA) as a yellow oil, which was used in the next step without further purification.

[0371] The following intermediates are synthesized using a method similar to that described above for intermediate 61.

[0372] Preparation of intermediate 62

[0373]

[0374] A mixture of 1-piperazin-1-ylethyl ketone (320 mg, 2.50 mmol, 1 equivalent), 3-bromo-2-chloro-6-(trifluoromethyl)pyridine (845.2 mg, 3.25 mmol, 1.3 equivalent), t-BuONa (359.9 mg, 3.74 mmol, 1.5 equivalent), and xanthones (86.6 mg, 149.80 μmol, 0.06 equivalent) in toluene (15 mL) was degassed under vacuum and purged three times with N2 atmosphere, and then Pd2(dba)3 (45.7 mg, 49.93 μmol, 0.02 equivalent) was added. The mixture was degassed under vacuum and purged three times with N2 atmosphere and stirred at 100°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (ISCO®; 12 g SepaFlash® silica gel rapid separation column, eluent 0-100% ethyl acetate / petroleum ether gradient, 40 mL / min) to give intermediate 62 (820 mg, 1.82 mmol, 72.90% yield, 68.3% purity) as a yellow oil.

[0375] Preparation of intermediate 63

[0376]

[0377] K₂CO₃ (1.10 g, 7.99 mmol, 3 equivalents) was added to a solution of intermediate 62 (820 mg, 2.66 mmol, 1 equivalent) and N-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)phenyl]methyl]carbamate tert-butyl (1.07 g, 3.20 mmol, 1.2 equivalents) in dioxane (15 mL) and H₂O (5 mL). The suspension was degassed under vacuum and purged three times with N₂ atmosphere, and then Pd(dppf)Cl₂•CH₂Cl₂ (217.6 mg, 266.49 μmol, 0.1 equivalents) was added. The mixture was degassed under vacuum and purged three times with N₂ atmosphere and stirred at 100°C for 12 h. The reaction mixture was cooled to room temperature, H₂O (80 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by rapid silica gel chromatography (ISCO®; 12 g SepaFlash® silica gel rapid separation column, eluent gradient of 0 / 100 to 90 / 10 ethyl acetate / petroleum ether, 40 mL / min) to give intermediate 63 (1.04 g, 2.16 mmol, 81.15% yield, 99.5% purity) as a pale yellow solid.

[0378] Preparation of intermediate 64

[0379]

[0380] HCl / dioxane (4 M, 3.13 mL, 20 equivalents) was added to a solution of intermediate 63 (300 mg, 626.95 μmol, 1 equivalent) in DCM (3 mL). The mixture was stirred at 25°C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give intermediate 64 (300 mg, crude, HCl) as a yellow solid, which was used in the next step without further purification.

[0381] Preparation of intermediate 66

[0382]

[0383] Under N2 at 0°C, NaH (298.7 mg, 7.47 mmol, 60% purity, 3 equivalents) was added to a mixture of 2-bromo-6-(trifluoromethyl)pyridine-3-amine (600 mg, 2.49 mmol, 1 equivalent) in DMF (12 mL), and the mixture was stirred at 25°C for 15 min. 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 min. The reaction mixture was quenched by adding 10 mL of saturated NH4Cl, and water (50 mL) was added. The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with a saturated solution of lithium chloride (50 mL × 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain intermediate 66 (1.35 g, crude product), which was a yellow oil and used in the next step without further purification.

[0384] Preparation of intermediate 67

[0385]

[0386] Intermediate 66 (1.35 g, 4.34 mmol, 1 equivalent), N-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]methyl]carbamate tert-butyl ester (1.59 g, 4.77 mmol, 1.1 equivalent), Cs₂CO₃ (2.83 g, 8.68 mmol, 2 equivalent), and di-tert-butyl(cyclopentyl)phosphine dichloropalladium iron (282.8 mg, 433.95 μmol, 0.1 equivalent) were degassed in a mixture of dioxane (20 mL) and H₂O (5 mL) and purged three times with N₂. The mixture was then stirred at 100°C for 16 hours under a N₂ atmosphere. The reaction mixture was cooled to room temperature, diluted with 100 mL of H₂O, and extracted with EA 200 mL (100 mL × 2). The combined organic layers were washed with 100 mL of NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by rapid 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 give intermediate 67 as a yellow solid (1.40 g, 3.19 mmol, 73.52% yield, 100% purity).

[0387] The following intermediates are synthesized using a method similar to that described above for intermediate 67.

[0388] Preparation of intermediate 68

[0389]

[0390] TFA (7.68 g, 67.31 mmol, 5 mL, 21.03 equivalents) was added to a solution of intermediate 67 (1.4 g, 3.20 mmol, 1 equivalent) in DCM (10 mL). The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to give intermediate 68 (1.6 g, crude, TFA) as a yellow oil, which was used in the next step without further purification.

[0391] The following intermediates are synthesized using a method similar to that described above for intermediate 68.

[0392] Preparation of intermediate 70

[0393]

[0394] At 0°C, m-CPBA (4.61 g, 22.72 mmol, 1 equivalent) was added fractionally to a solution of 5-bromo-2-cyclopropylpyridine (4.5 g, 22.72 mmol, 1 equivalent) in DCM (90 mL), and the solution was stirred at 25°C for 12 h. The mixture was diluted with H2O (100 mL) and acidified to pH = 11 with 10% NaOH aqueous solution. The mixture was extracted with DCM (80 mL × 3). The combined organic layers were washed with saturated Na2S2O3 aqueous solution (150 mL × 2) and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was subjected to rapid column chromatography on 80 g 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 =0.2) Purification to give intermediate 70 (3.68 g, 17.16 mmol, 75.53% yield, 99.82% purity) as a pale yellow oil.

[0395] Preparation of intermediate 71

[0396]

[0397] The mixture of intermediate 70 (3.6 g, 16.82 mmol, 1 equivalent) in POCl3 (12 mL) was stirred at 90°C for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was added dropwise to a saturated aqueous solution of NaHCO3 to adjust the pH to 7. The mixture was extracted with EA (80 mL × 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 rapid column chromatography on 40 g 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 = 0.6) Purification to give intermediate 71 as a colorless oil (2.41 g, 10.18 mmol, 60.51% yield, 98.17% purity).

[0398] Preparation of intermediate 72

[0399]

[0400] Cs₂CO₃ (6.73 g, 20.64 mmol, 2 equivalents) was added to a solution of intermediate 71 (2.4 g, 10.32 mmol, 1 equivalent) and (1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)boronic acid (2.70 g, 11.87 mmol, 1.15 equivalents) in dioxane (60 mL) and H₂O (15 mL). The suspension was degassed under vacuum and purged three times with N₂ atmosphere, and then cyclopentyl(diphenyl)phosphine; palladium dichloro; iron (755.2 mg, 1.03 mmol, 0.1 equivalents) was added. The mixture was degassed under vacuum and purged three times with N₂ atmosphere and stirred at 100°C for 12 h. After cooling to room temperature, the reaction mixture was diluted with H₂O (100 mL) and extracted with EA (80 mL × 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 rapid column chromatography on 40 g 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 =0.5) Purification to give intermediate 72 (2.89 g, 7.95 mmol, 77.06% yield, 92.16% purity) as a pale yellow oil.

[0401] Preparation of intermediates 74 and 75

[0402]

[0403] Pd / C (150 mg, 140.95 μmol, 10% purity, 1.41e-1 equivalent) and NH3·H2O (76 μL, 498.13 μmol, 25% purity, 0.5 equivalent) were added to a solution of intermediate 73 (400 mg, 996.26 μmol, 1 equivalent) in MeOH (10 mL). The suspension was degassed under vacuum and purged several times with H2 (15 psi), and the mixture was stirred at 30°C for 8 h under H2. The reaction mixture was filtered and the filter cake was washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure to give 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.

[0404] Preparation of intermediates 76 and 77

[0405]

[0406] Add 2,4-dichloro-5-methoxypyrimidine (287.9 ​​mg, 1.61 mmol, 1.5 equivalents) to a mixture of intermediates 74 and 75 (437 mg, crude) and TEA (298 μL, 2.14 mmol, 2 equivalents) in THF (10 mL). Allow the mixture to be stirred at 50°C for 12 h. After cooling to room temperature, dilute the reaction mixture with H2O (50 mL) and extract with EA (40 mL × 3). Dry the combined organic layers over anhydrous Na2SO4, filter, and concentrate under reduced pressure to obtain the residue. Perform rapid column chromatography on 20 g 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 = 0.2) Purification to obtain crude product. The crude product was separated by SFC (separation conditions: DAICEL CHIRALCEL OJ (250 mm * 30 mm, 10 μm)); mobile phase: A: supercritical CO2, B: 0.1% NH3H2O ​​MEOH, A: B = 70: 30, at 100 mL / min. The pure fraction was collected and the solvent was evaporated under vacuum to give intermediate 76 (R t : 1.617 min) and 77 (R t 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.

[0407] Preparation of intermediate 82

[0408]

[0409] At 0°C, 1-(4-hydroxy-1-piperidinyl)acetone (942.2 mg, 6.58 mmol, 1.3 equivalent), PPh3 (1.73 g, 6.58 mmol, 1.3 equivalent), and DBAD (1.52 g, 6.58 mmol, 1.3 equivalent) were added to a solution of 2-chloro-6-(trifluoromethyl)pyridin-3-ol (1 g, 5.06 mmol, 1.3 equivalent) in THF (10 mL). The mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with 100 mL of H2O and extracted with EA 200 mL (100 mL × 2). The combined organic layers were washed with 100 mL of aqueous NaCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid 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 give intermediate 82 as a colorless oil (1.28 g, 3.91 mmol, 77.34% yield, 99.066% purity).

[0410] Preparation of intermediate 86

[0411]

[0412] A mixture of 3-bromo-2-chloro-6-fluoropyridine (300 mg, 1.43 mmol, 1 equivalent), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (528.9 mg, 1.71 mmol, 1.2 equivalent), and K3PO4 (907.8 mg, 4.28 mmol, 3 equivalent) in dioxane (3 mL) and H2O (0.75 mL) was degassed and purged three times with N2. Then, Pd(dppf)Cl2 (52.1 mg, 71.28 μmol, 0.05 equivalent) was added and the mixture was stirred at 100°C for 1 hour under N2 atmosphere. The mixture was cooled to room temperature, H2O (40 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by FCC (ISCO®; 4g SepaFlash® silica gel rapid separation column, EA 0-100%, PE / EA, 30mL / min; PE / EA=3:1, Rf=0.5) to obtain intermediate 86 (392 mg, 1.25 mmol, 87.91% yield) as a white solid.

[0413] Preparation of intermediate 87

[0414]

[0415] The mixture of intermediate 86 (392 mg, 1.25 mmol, 1 equivalent), (4-cyanophenyl)boronic acid (221 mg, 1.50 mmol, 1.2 equivalent), and Cs₂CO₃ (816.7 mg, 2.51 mmol, 2 equivalent) in dioxane (3 mL) and H₂O (0.75 mL) was degassed and purged three times with N₂. Pd(dppf)Cl₂ (81.6 mg, 125.33 μmol, 0.1 equivalent) was then added, and the mixture was stirred at 100°C for 1 hour under N₂ atmosphere. The mixture was cooled to room temperature, H₂O (40 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by FCC (ISCO®; 4g SepaFlash® silica gel rapid separation column, EA 0-15%, PE / EA, 30mL / min; PE / EA=3:1, Rf=0.5) to give intermediate 87 (415 mg, 1.09 mmol, 87.27% yield) as a white solid.

[0416] Preparation of intermediate 88

[0417]

[0418] The 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 equivalent) in MeOH (5 mL) was degassed and purged three times with H2. The mixture was then 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 give intermediate 88 (160 mg, crude product) as a colorless gel, which was used in the next step without further purification.

[0419] Preparation of intermediate 89

[0420]

[0421] At 25°C, 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 to a solution of intermediate 88 (310 mg, 804.20 μmol, 1 equivalent) in THF (5 mL). The mixture was stirred at 50°C for 12 hours. The reaction mixture was concentrated under reduced pressure to give the crude product. The residue was purified by rapid silica gel chromatography (ISCO®; 12 g SepaFlash® silica gel rapid separation column, eluent gradient of 0 / 1 to 45 / 55 ethyl acetate / petroleum ether, 40 mL / min) to give intermediate 89 (130 mg, 211.98 μmol, 26.36% yield, 86.1% purity) as a yellow solid.

[0422] Preparation of Compound 1

[0423]

[0424] TEA (1 mL, 7.18 mmol, 29.09 equivalents) and Ac₂O (23 μL, 247.00 μmol, 1 equivalent) were added to a solution of intermediate 6 (174.5 mg, 247.00 μmol, 1 equivalent) in DCM (1 mL). The mixture was stirred at 25°C for one hour. The reaction mixture was quenched by adding 10 mL of aqueous NH₄Cl solution at 25°C, and then diluted with 30 mL of H₂O and extracted with 30 mL of DCM (10 mL × 3). The combined organic layers were 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 prep-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 between CH₃CN (2 mL) and water (10 mL). The mixture was freeze-dried to dryness to give compound 1 as a white solid (104.7 mg, 158.97 μmol, 64.36% yield, 96.360% purity).

[0425] The following compounds were synthesized by a method similar to that described above for compound 1.

[0426] Preparation of compound 3

[0427]

[0428] At 0°C, TEA (1 mL, 7.18 mmol, 23.97 equivalents) and 2-methoxyacetyl chloride (27 μL, 299.69 μmol, 1 equivalent) were added to a solution of intermediate 6 (211.7 mg, 299.69 μmol, 1 equivalent) in DCM (2 mL). The mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched by adding 10 mL of aqueous NH4Cl solution at 25°C, and then diluted with 30 mL of H2O and extracted with 60 mL of DCM (20 mL × 3). The combined organic layers were 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 prep-HPLC (alkaline conditions; column: Waters Xbridge C18 150*50mm*10um; mobile phase: [water (NH3H2O)-ACN]; gradient: 47%-77% B, for 11 min) to give intermediate 3 as a white solid (37.12 mg, 53.75 μmol, 17.93% yield, 96.241% purity).

[0429] Preparation of compound 4

[0430]

[0431] At 25°C, AcOH (16 μL, 288.72 μmol, 2 equivalents) and formaldehyde (107 μL, 1.44 mmol, 10 equivalents) were added to a solution of intermediate 6 (85.5 mg, 144.36 μmol, 1 equivalent) in MeOH (2 mL). After addition, the mixture was stirred at 45°C for 0.5 h, 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 h. The reaction mixture was diluted with dichloromethane (40 mL), alkalized to pH = 8 with a saturated solution of sodium bicarbonate (30 mL), and then extracted with dichloromethane (20 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by prep-HPLC (FA conditions; column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; gradient: 20%-50% B, for 10 min) to give intermediate 4 as a white solid (56.49 mg, 90.70 μmol, 62.83% yield, 99.623% purity, 0.3FA).

[0432] Preparation of compound 5

[0433]

[0434] Intermediate 13 (325 mg, 646.29 μmol, 1 equivalent) and 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrimidine (321.2 mg, 1.16 mmol, 1.8 equivalent) in DME (4 mL) and H2O (1 mL) were degassed and purged three times with N2. CATACXIUM(R) A Pd G3 (47 mg, 64.63 μmol, 0.1 equivalent) and Na2CO3 (137 mg, 1.29 mmol, 2 equivalent) were added to the mixture, and the mixture was then degassed again and purged three times with N2. The mixture was stirred at 95°C for 2 h under N2 atmosphere. The mixture was cooled to room temperature and diluted with H2O (40 mL), and extracted with ethyl acetate (20 mL × 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 prep-HPLC (column: Waters Xbridge BEH C18 150*25mm*5um; mobile phase: [water (ammonia hydroxide v / v)-ACN]; gradient: 40%-70% B, for 10 min) to obtain a crude product. The crude product was purified by prep-TLC (SiO₂, petroleum ether / ethyl acetate = 0 / 1; TLC: EA:MeOH = 10:1, Rf = 0.5) to give compound 5 as a white solid (98.16 mg, 159.20 μmol, 24.63% yield, 100% purity).

[0435] The following compounds were synthesized by a method similar to that described above for compound 5.

[0436] Preparation of compound 6

[0437]

[0438] Intermediate 19 (156 mg, 295.49 μmol, 1 equivalent), 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyrimidine (163.1 mg, 590.97 μmol, 2 equivalent), and K3PO4 (125.4 mg, 590.97 μmol, 2 equivalent) were degassed in a mixture of dioxane (3 mL) and H2O (0.75 mL) and purged three times with N2. Then, CATACXIUM(R) 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 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 × 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to the residue, which was then purified by FCC (ISCO®; 4 g SepaFlash® silica gel rapid separation column, 0-70% EA, PE / EA, 25 mL / min; PE / EA = 0:1, Rf = 0.4) to obtain the product. The product was further purified by prep-HPLC (column: Waters xbridge 150*25 mm 5 μm, mobile phase A: [water (NH₄HCO₃)-ACN], mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 45% B to 75%). The pure fraction was collected and volatiles were removed under vacuum. The residue was partitioned between ACN (2 mL) and water (10 mL). The solution was lyophilized to dryness to give compound 6 as a white solid (112.8 mg, 175.79 μmol, 59.49% yield, 100% purity).

[0439] The following compounds were synthesized by a method similar to that described above for compound 6.

[0440] Preparation of compound 7

[0441]

[0442] At 0°C, TEA (1 mL, 7.18 mmol, 62.21 equivalents) and N-methylcarbamoyl chloride (10.8 mg, 115.49 μmol, 1 equivalent) were added to a solution of intermediate 6 (81.6 mg, 115.49 μmol, 1 equivalent) in DCM (2 mL). The mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched by adding 10 mL of aqueous NH4Cl solution at 25°C, and then diluted with 30 mL of H2O and extracted with 60 mL of DCM (20 mL × 3). The combined organic layers were washed with 50 mL of aqueous NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by prep-HPLC (alkaline conditions: column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH3H2O)-ACN]; gradient: 38%-68% B, for 10 min) to give compound 7 as a white solid (32.15 mg, 49.02 μmol, 42.44% yield, 99.053% purity).

[0443] Preparation of compounds 9 and 10

[0444]

[0445] TEA (2 mL, 14.37 mmol, 60.95 equivalents) and Ac₂O (22 μL, 235.75 μmol, 1 equivalent) were added to a solution of intermediate 27 (163.2 mg, 235.75 μmol, 1 equivalent) in DCM (2 mL). The mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched by adding 10 mL of aqueous NH₄Cl solution at 25°C, and then diluted with 30 mL of H₂O and extracted with 60 mL of DCM (20 mL × 3). The combined organic layers were washed with 40 mL of NaCl aqueous solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by prep-TLC (SiO2, dichloromethane:methanol = 10:1, Rf = 0.4) to give a mixture of compounds 9 and 10 as white solids (69.71 mg, 109.80 μmol, 46.58% yield, 97.755% purity).

[0446]

[0447] The mixture was separated by supercritical fluid chromatography (column: REGIS (R,R)WHELK-O1 (250mm*25mm, 10um); mobile phase: [CO2-ACN / MeOH (0.1% NH3H2O)]; B%: 30%, isocratic elution mode).

[0448] Compound 9 was given as a white solid (18.10 mg, 28.40 μmol, 26.11% yield, 97.394% purity).

[0449] Compound 10 was given as a white solid (19.29 mg, 29.78 μmol, 27.37% yield, 95.818% purity).

[0450] Preparation of compound 11

[0451]

[0452] 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-dioxacyclopentaborane-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 with N2 atmosphere, and then CATACXIUM(R) A Pd G3 (40.2 mg, 55.24 μmol, 0.1 equivalents) was added. The mixture was degassed under vacuum and purged three times with N2 atmosphere and stirred at 100°C for 16 h. The reaction mixture was cooled to room temperature, H2O (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; gradient: 44%-64% B, for 10 min) to obtain the crude product, which was then purified by prep-TLC (SiO2, PE:EA = 0:1) to obtain compound 11 as a white solid (18.63 mg, 30.02 μmol, 5.43% yield, 100% purity).

[0453] Preparation of compound 12

[0454]

[0455] DIEA (88 μL, 509.46 μmol, 3 equivalents) was added to a solution of intermediate 6 (120 mg, crude TFA) and 2-(oxecyclobutan-3-yl)acetic acid (29.5 mg, 254.73 μmol, 1.5 equivalents) in DCM (1 mL). 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 purified by prep-HPLC (column: Waters xbridge 150*25mm 5μm, mobile phase A: [water (NH4HCO3)-ACN], mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 43% B to 73%). The pure fraction was collected and volatiles were removed under vacuum. The residue was partitioned between ACN (2 mL) and water (10 mL). The solution was freeze-dried to dryness to give compound 12 as a white solid (10 mg, 13.81 μmol, 8.13% yield, 95.389% purity).

[0456] Preparation of compound 13

[0457]

[0458] Intermediate 6 (100 mg, crude, TFA), 1-bromo-2-methoxy-ethane (39.3 mg, 283.03 μmol, 26.60 μL, 2 equivalents), and K₂CO₃ (39.1 mg, 283.03 μmol, 2 equivalents) were mixed in MeCN (9 mL), and then KI (23.4 mg, 141.52 μmol, 1 equivalent) was added and the mixture was stirred at 80°C for 12 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude product, which was purified by prep.HPLC (column: Waters Xbridge 150*25 mm 5 μm, mobile phase A: [water (NH₄HCO₃)-ACN], mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 52% B to 82%). The pure fraction was collected and volatiles were removed under vacuum. The residue was partitioned between ACN (2 mL) and water (10 mL). The solution was freeze-dried to dryness to give compound 13 as a white solid (13.54 mg, 20.71 μmol, 14.63% yield, 99.517% purity).

[0459] Preparation of compound 15

[0460]

[0461] TEA (105 μL, 759.35 μmol, 3 equivalents) was added to a solution of intermediate 6 (150 mg, crude, 1 equivalent) in DCM (2 mL). 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 prep-HPLC (column: Phenomenex luna C18 150*25mm*10μm, 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 volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to give compound 15 as a white solid (15.88 mg, 23.64 μmol, 9.34% yield, 99.83% purity).

[0462] Preparation of compound 17

[0463]

[0464] HCl / dioxane (4 M, 3 mL, 166.65 equivalents) was added to a solution of intermediate 10 (55 mg, 72.01 μmol, 1 equivalent) in DCM (3 mL). The mixture was stirred at 25°C for 0.5 h. 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 × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep. HPLC (column: Phenomenex C18 150*25 mm*10 μm, 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 volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (8 mL). The solution was freeze-dried to dryness to give compound 17 as a white solid (10.58 mg, 15.63 μmol, 21.70% yield, 98.04% purity).

[0465] Preparation of compound 18

[0466]

[0467] A mixture of intermediate 6 (200 mg, crude), 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 purified by prep-HPLC (column: Waters Xbridge 150*25mm*5μm, mobile phase A: water (NH₃•H₂O), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 41% B to 71%). The pure fraction was collected and volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was freeze-dried to dryness to give compound 18 as a white solid (17.97 mg, 26.73 μmol, 98.72% yield, 98.72% purity).

[0468] Preparation of compound 19

[0469]

[0470] DIEA (54 μL, 310.56 μmol, 3 equivalents) and intermediate 6 (146.3 mg, 103.52 μmol, 1 equivalent, TFA) were added to a solution of intermediate 38 (20 mg, 103.52 μmol, 1 equivalent) in MeCN (1 mL). The mixture was stirred at 60°C for 10 h. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by prep-HPLC (column: WatersXbridge BEH C18 150*25mm*5μm, 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 volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (8 mL). The solution was freeze-dried to dryness to give compound 19 as a yellow solid (26.79 mg, 36.62 μmol, 35.37% yield, 94.54% purity).

[0471] Preparation of compound 22

[0472]

[0473] Intermediate 6 (150 mg, crude, 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) were stirred in DCM (2 mL) at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by prep-HPLC (column: Waters Xbridge 150*25mm*5μm, 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 volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was freeze-dried to dryness to give compound 22 as a white solid (24.13 mg, 34.11 μmol, 13.48% yield, 95.65% purity).

[0474] The following compounds were synthesized by a method similar to that described above for compound 22.

[0475] Preparation of compound 28

[0476]

[0477] TFA (2 mL, 26.92 mmol, 349.04 equivalents) was added to a solution of intermediate 53 (60 mg, 77.14 μmol, 1 equivalent) in DCM (2 mL). The mixture was stirred at 25°C for 0.5 h. 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 × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-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 19% B to 49%). The pure fraction was collected and volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (8 mL). The solution was freeze-dried to dryness to give compound 28 as a white solid (21.96 mg, 29.73 μmol, 38.54% yield, 97.97% purity, FA).

[0478] Preparation of compound 30

[0479]

[0480] TEA (1 mL, 7.18 mmol, 61.35 equivalents) and Ac₂O (11 μL, 117.10 μmol, 1 equivalent) were added to a solution of intermediate 61 (82.6 mg, 117.10 μmol, 1 equivalent) in DCM (2 mL). The mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched by adding 10 mL of aqueous NH₄Cl solution at 25°C, then diluted with 10 mL of H₂O and extracted with 30 mL of DCM (10 mL × 3). The combined organic layers were washed with 10 mL of aqueous NaCl solution, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by prep-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 between MeCN (2 mL) and water (10 mL). The mixture was freeze-dried to dryness to give compound 30 as a white solid (22.26 mg, 34.94 μmol, 29.84% yield, 99.461% purity).

[0481] The following compounds were synthesized by a method similar to that described above for compound 30.

[0482] Preparation of compound 37

[0483]

[0484] A mixture of intermediate 61 (190 mg, 321.15 μmol, 1 equivalent), 3-methylsulfonylpropionic 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 h. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10um, mobile phase A: water (FA), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 20% B to 50%). The pure fraction was collected and volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was freeze-dried to dryness to give compound 37 as a white solid (66.58 mg, 90.46 μmol, 28.17% yield, 98.74% purity).

[0485] LCMS (Liquid Chromatography / Mass Spectrometry)

[0486] General Procedure

[0487] High-performance liquid chromatography (HPLC) measurements are performed using an LC pump, diode array (DAD) or UV detector, and a column as specified in the corresponding method. The liquid stream from the column is introduced into a mass spectrometer (MS) equipped with an atmospheric pressure ion source. Adjusted parameters (e.g., scan range, residence time, etc.) are set to obtain ions that allow determination of the nominal monoisotope molecular weight (MW) of the compound within the knowledge of a technician. Data acquisition is performed using appropriate software.

[0488] Compounds are described by their experimental retention time (Rt) and ion. Unless otherwise specified in the data table, the reported molecular ion corresponds to [M+H]+ (protonated molecule) and / or [MH]- (deprotonated molecule). All results are obtained with experimental uncertainty typically associated with the methods used.

[0489] Method 1

[0490] Mobile phase: The flow rate was increased from 30% ACN (0.018% TFA) in water (0.037% TFA) to 90% ACN over 2.00 min at a flow rate of 1.5 mL / min; then increased from 90% ACN in water to 100% ACN over 1.70 min at a flow rate of 1.5 mL / min; finally, the flow rate was reduced back to 30% ACN in water and held for 0.30 min at a flow rate of 2.0 mL / min. The column temperature was 50 °C. oC and the detector wavelengths range from 210 nm to 265 nm. The column is a Kinetex® EVO C18 4.6 x 50 mm, 5 μm.

[0491] Method 2

[0492] Mobile phase: The flow rate was increased from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN over 2.40 min at a flow rate of 2.0 mL / min; then maintained at 95% ACN for 0.30 min at a flow rate of 2.0 mL / min; finally, the flow rate was reduced back to 5% ACN in water and maintained for 0.30 min at a flow rate of 2.0 mL / min. The column temperature was 50 °C. o C. The column is a Kinetex® EVO C18 4.6x50mm, 5 μm.

[0493] Method 3

[0494] Mobile phase: The flow rate was increased from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN over 3.20 min at a flow rate of 1.5 mL / min; then maintained at 95% ACN for 0.30 min at a flow rate of 1.5 mL / min; finally, the flow rate was reduced back to 5% ACN in water and maintained for 0.30 min at a flow rate of 2.0 mL / min. The column temperature was 50 °C. o C. The column is a Kinetex® EVO C18 4.6 x 50 mm, 5 μm.

[0495] Method 4

[0496] Mobile phase: The flow rate was increased from 5% ACN in water (0.025% NH3•H2O) to 95% ACN over 3.00 min at a rate of 0.6 mL / min; then maintained at 95% ACN for 0.70 min at a rate of 0.6 mL / min; finally, the flow rate was reduced back to 5% ACN in water and maintained for 0.30 min at a rate of 1.2 mL / min. Column temperature was maintained at 40 °C. o The detector wavelength ranges from 210 nm to 265 nm. The column is a Kinetex® XBridge C18 2.1 x 30 mm, 3.5 μm.

[0497] Method 5

[0498] Mobile phase: The flow rate was increased from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN over 4.8 min at a flow rate of 0.6 mL / min; then maintained at 95% ACN for 0.60 min at a flow rate of 1.0 mL / min; finally, the flow rate was reduced back to 5% ACN in water and maintained for 0.60 min at a flow rate of 1.0 mL / min. The column temperature was 50 °C. o C. The column is a Kinetex EVO C18 2.1*50mm, 1.7 μm.

[0499] Method 6

[0500] Mobile phase: The flow rate was increased from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN over 3.20 min at a flow rate of 1.5 mL / min; then maintained at 95% ACN for 0.30 min at a flow rate of 1.5 mL / min; finally, the flow rate was reduced back to 5% ACN in water and maintained for 0.30 min at a flow rate of 2.0 mL / min. The column temperature was 50 °C. o C. The column is a Kinetex® EVO C18 4.6 x 50 mm, 5 μm.

[0501] Method 7

[0502] Mobile phase: The flow rate was increased from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN over 2.40 min at a flow rate of 2.0 mL / min; then maintained at 95% ACN for 0.30 min at a flow rate of 2.0 mL / min; finally, the flow rate was reduced back to 5% ACN in water and maintained for 0.30 min at a flow rate of 2.0 mL / min. The column temperature was 50 °C. o C. The column is a Kinetex® EVO C18 4.6 x 50 mm, 5 μm.

[0503] Method 8

[0504] Mobile phase: The flow rate was increased from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN over 3.20 min at a flow rate of 1.5 mL / min; then maintained at 95% ACN for 0.30 min at a flow rate of 1.5 mL / min; finally, the flow rate was reduced back to 5% ACN in water and maintained for 0.30 min at a flow rate of 2.0 mL / min. The column temperature was 50 °C. oC. The column is a Kinetex® EVO C18 4.6 x 50 mm, 5 μm.

[0505] Method 9

[0506] Mobile phase: A rapid rise from 5% ACN (0.018% TFA) in water (0.037% TFA) to 95% ACN over 3.0 min at a flow rate of 1.0 mL / min; then maintain at 95% ACN for 0.60 min at a flow rate increasing from 1.0 mL / min to 1.5 mL / min; return to 5% ACN in water and maintain for 0.40 min at a flow rate of 1.5 mL / min. Column temperature: 50 °C. o C. The column is a Shim-pack Velox SP-C18 3.0 x 30 mm, 2.7 μm.

[0507] Method 10

[0508] Mobile phase: The flow rate was increased from 5% ACN in water (0.025% NH3•H2O) to 95% ACN over 2.60 min at a rate of 0.6 mL / min; then maintained at 95% ACN for 0.25 min at a rate of 0.8 mL / min; finally, the flow rate was reduced back to 5% ACN in water and maintained for 0.15 min at a rate of 1.2 mL / min. Column temperature was maintained at 40 °C. o The detector wavelength ranges from 210 nm to 265 nm. The column is a Kinetex® XBridge C18 2.1 x 30 mm, 3.5 μm.

[0509] Method 11

[0510] Mobile phase: The flow rate was increased from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 min at a flow rate of 2.0 mL / min; then maintained at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; finally, the flow rate was reduced back to 5% ACN in water and maintained for 0.02 min at a flow rate of 2.0 mL / min. The column temperature was 50 °C. o C. The column is a Kinetex® EVO C18 2.1 x 30 mm, 5 μm.

[0511] Method 12

[0512] Mobile phase: The flow rate was increased from 5% ACN in water (0.025% NH3•H2O) to 95% ACN over 3.00 min at a rate of 0.9 mL / min; then maintained at 95% ACN for 0.70 min at a rate of 0.9 mL / min; finally, the flow rate was reduced back to 5% ACN in water and maintained for 0.30 min at a rate of 1.2 mL / min. Column temperature was maintained at 40 °C. o C and the detector wavelengths range from 210 nm to 265 nm. The column is a Kinetex® XBridge C18 3.0 x 50 mm, 5 μm.

[0513] Analyze data

[0514] The following table contains LCMS analysis information.

[0515] NMR method:

[0516] NMR experiments were performed as follows: A Bruker Advance III 400 spectrometer with internal deuterium lock-in was used at ambient temperature (298.6 K) and equipped with a BBO 400 MHz S1 5 mm probe with z-gradient, operating 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.

[0517] The NMR analysis information is shown in the table below.

[0518] USP1-UAF1 Deubiquitination Analysis

[0519] Some of the compounds described herein were evaluated using a USP1-UAF1 deubiquitination assay. The deubiquitination enzyme was measured by the fluorescence signal generated when the USP1 hydrolyzes the amide bond between the C-terminal glycine of rhodamine and ubiquitin 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, comprising 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 started with the addition of a final concentration of 150 nM ubiquitin-rhodamine 110 substrate.

[0520] Deubiquitination enzyme inhibition assays were performed using a compound dissolved in DMSO at an initial concentration of 10 μM. The dissolved compound was added to 384-well microplates and premixed with USP1-UAF1 enzyme, then incubated for 20 min. Intrinsic fluorescence provided by the compound 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 min using a microplate reader (Spark®, TECAN) to detect fluorescence intensity at 480 nm excitation / 530 nm emission.

[0521] All measurements were subtracted from the control wells, and the IC was calculated using a four-parameter dose-response inhibition model in GraphPad Prism 8.0.2 (La Jolla, California, USA, www.graphpad.com). 50 value.

[0522] Cell proliferation analysis

[0523] For USP1 sensitivity, exponentially growing cells were seeded at very low densities in 96 or 384-well plates, aiming for at least 7 days without division (typically 0.3k–1.2k cells / well). Cells were seeded on day -1 and treated with DMSO or an escalating concentration of a USP1 inhibitor on day 0. At the end of the experiment, cell viability was estimated using Cell-Titer Glo (Promega).

[0524] Biological data

[0525] IC 50(nM): 0 <A<50;50<B<1000;1000<C<10000

[0526] Liver microsomal stability analysis

[0527] The liver microsomal stability analysis of the compounds in this application was performed as follows.

[0528] Composition of the experimental incubation system

[0529] 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 allow to stand until used. (2) Weigh a certain amount of NADPH and dissolve it in an appropriate amount of magnesium chloride solution to prepare a 2 mM solution, then allow it to stand until used. (3) Prepare the incubation system (excluding NADPH) according to the proportions mentioned above and dispense at 165 μL / tube (75 μL for the negative control group and 120 μL for the positive control group). (4) 0-minute sample: Add 200 μL of internal standard working precipitant (a solution of carbamazepine, glibenclamide, propranolol, and tolbutamide in acetonitrile, concentration 20 ng / mL), then add 30 μL of NADPH solution (30 μL of magnesium chloride solution for the negative control group). (5) Other samples: Add 135 μL of NADPH solution to initiate the reaction (45 μL of magnesium chloride solution for the negative control group), incubate at 37°C for 5, 15, 30, and 60 minutes, and then add 200 μL of internal standard working precipitant to these samples. (6) Positive control group: Add 90 μL of NADPH solution to initiate the reaction, incubate at 37°C for 5 and 15 minutes, and then add 200 μL of internal standard working precipitant to these samples. (7) Vortex and centrifuge all samples. (8) Take 150 μL of the supernatant and add it to 150 μL of water, vortex and mix the system thoroughly, and analyze by LC-MS / MS.

[0530] Data analysis: The half-life (t1 / 2) and clearance rate (CL) were calculated using the following first-order kinetic equations.

[0531] Ct = C0 * e -kt

[0532] t1 / 2 = ln2 / k = 0.693 / k

[0533] CL = Vd * k

[0534] Vd = 1 / protein content in liver microsomes

[0535] The metabolic stability of compound 30 in mouse, rat, dog and human liver microsomes is shown in the table below.

[0536] Experimental data show that compound 30 exhibits good stability in liver microsomes and shows minimal species variability.

[0537] Pharmacokinetic studies in mice

[0538] Pharmacokinetic studies were conducted in ICR mice, where the compound of this application was administered to the mice via intravenous injection and oral tube feeding. Blood samples were collected at different time points to measure plasma drug concentrations. The aim of this study was to investigate and evaluate the pharmacokinetic properties of the compound in mice.

[0539] Each group consisted of 9 healthy male ICR mice.

[0540] Intravenous administration: 1) Weigh an appropriate amount of the test compound into a glass vial. 2) Add 5% DMSO and vortex to mix, then add 10% Solutol HS-15 and mix. Finally, add 85% physiological saline to obtain a clear and transparent solution with a test compound concentration of 0.2 mg / mL.

[0541] Oral administration via tube feeding: 1) Weigh a measured amount of the test compound into a glass vial. 2) Add 5% DMSO and vortex to mix, then add 10% Solutol HS-15 and mix. Finally, add 85% physiological saline to obtain a clear and transparent solution with a test compound concentration of 5 mg / mL.

[0542] For intravenous administration of the compound of this application to mice, 0.1 mL blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours post-administration. The blood samples were placed in labeled EDTA-2K anticoagulant tubes. The tubes were gently inverted to ensure thorough mixing of the anticoagulant (EDTA-2K) with the blood and immediately placed on wet ice. Within 1 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 an ultra-low temperature freezer until sample analysis.

[0543] For mice administered the compound of this application orally via tube feeding, 0.1 mL blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-administration. The blood samples were placed in labeled EDTA-2K anticoagulant tubes. The tubes were gently inverted to ensure thorough mixing of the anticoagulant (EDTA-2K) with the blood and immediately placed on wet ice. Within 1 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 an ultra-low temperature freezer until sample analysis.

[0544] The sample preparation steps are as follows, under ice-water bath and yellow light conditions: 1) Add 200 μL of acetonitrile solution containing the internal standard (glibenclamide) to the wells of a 96-well plate containing 20 μL of all other samples, except for the blank sample. For the blank sample, add 200 μL of acetonitrile. 2) Mix the system thoroughly by vortexing. 3) Centrifuge the sample. 4) Transfer 150 μL of the supernatant to a new 96-well plate and mix with 150 μL of ultrapure water. 5) Perform sample analysis by injection.

[0545] The pharmacokinetic parameters of compound 30 in mice are shown in the table below.

[0546] Experimental data show that compound 30 has low clearance and high oral bioavailability in mice.

[0547] Pharmacokinetic studies in dogs

[0548] Pharmacokinetic studies were conducted in beagle dogs, where the compound of this application was administered via intravenous injection and oral tube feeding. Blood samples were collected at different time points to measure plasma drug concentrations. The aim of this study was to investigate and evaluate the pharmacokinetic properties of the compound in dogs.

[0549] Each group consists of 3 healthy male beagles.

[0550] Intravenous administration: 1) Weigh an appropriate amount of the test compound into a glass vial. 2) Add 5% DMSO and vortex to mix, then add 10% PG and mix. Finally, add 85% physiological saline to obtain a clear and transparent solution with a test compound concentration of 0.385 mg / mL.

[0551] Oral administration via tube feeding: 1) Weigh a measured amount of the test compound into a glass vial. 2) Add 5% DMSO and vortex to mix, then add 10% PG and mix. Finally, add 85% physiological saline to obtain a clear and transparent solution with a test compound concentration of 4.878 mg / mL.

[0552] For intravenous administration of the compounds mentioned 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 post-administration. The blood samples were placed in labeled EDTA-2K anticoagulant tubes. The tubes were gently inverted to ensure thorough mixing of the anticoagulant (EDTA-2K) with the blood and immediately placed on wet ice. Within 1 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 an ultra-low temperature freezer until sample analysis.

[0553] For oral administration of the compound of this application to dogs via tube feeding, 1.0 mL blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-administration. The blood samples were placed in labeled EDTA-2K anticoagulant tubes. The tubes were gently inverted to ensure thorough mixing of the anticoagulant (EDTA-2K) with the blood and immediately placed on wet ice. Within 1 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 an ultra-low temperature freezer until sample analysis.

[0554] The sample preparation steps are as follows, under ice-water bath and yellow light conditions: 1) Add 200 μL of acetonitrile solution containing the internal standard (carbamazepine) to the wells of a 96-well plate containing 20 μL of all other samples, except for the blank sample. For the blank sample, add 200 μL of acetonitrile. 2) Mix the system thoroughly by vortexing. 3) Centrifuge the samples. 4) Transfer 150 μL of the supernatant to a new 96-well plate and mix with 150 μL of ultrapure water. 5) Perform sample analysis by injection.

[0555] The pharmacokinetic parameters of compound 30 in dogs are shown in the table below.

[0556] Experimental data show that compound 30 has low clearance and high oral bioavailability in dogs.

[0557] Efficacy studies of preclinical tumor models

[0558] MDA-MB-436 cells were cultured in DMEM medium supplemented with 10% heat-inactivated fetal bovine serum. 1×10⁶ cells were cultured... 7 One MDA-MB-436 cell was subcutaneously implanted into the right flank of female NOD-SCID mice (weighing 18-22 g, 6-8 weeks old, provided by Shanghai Jihui Experimental Animal Breeding Co., Ltd.). When the tumor reached approximately 80-120 mm... 3Mice were randomly assigned to the treatment group as shown in Table 2 below. Tumor volume (TV) was measured twice weekly in two dimensions using calipers and expressed in mm using the following formula. 3 Volume: V = 0.5 a×b 2 , where a and b are the long and short diameters of the tumor, respectively.

[0559] Compound 30 monotherapy showed dose-dependent antitumor effects relative to the control mediator treatment group (e.g. Figure 1 (As shown in the table). Tumor growth inhibition (TGI) is summarized in Table 2. Treatment with compound 30 was well tolerable at all administered doses, as demonstrated by minimal change in body weight. TGI is defined by the following formula: TGI% = ((TV...) 媒介物 / 最后一天 TV 媒介物 / 第0天 ) − (TV 治疗 / 最后一天 TV 治疗 / 第0天 )) / (TV 媒介物 / 最后一天 TV 媒介物 / 第0天 () × 100, based on the mean of the treatment group measured on day 0 and the last day.

[0560] Table 2: Dosage and TGI of Compound 30

[0561] The embodiments described above are intended to be exemplary only, and those skilled in the art will recognize or be able to determine many equivalents of a particular compound, material, and procedure using only conventional experiments. All such equivalents are considered to be within the scope of the invention and are covered by the appended claims.

Claims

1. A compound of formula (I): (I) in: X 1 Is it N or CR? x1 ;R x1 It is hydrogen or C1-C6 alkyl; X 2 Is it N or CR? x2 ;R x2 It is hydrogen or C1-C6 alkyl; X 3 Is it N or CR? x3 ;R x3 It is hydrogen or C1-C6 alkyl; The condition is X 1 X 2 and X 3 At least one of them is N; L is NR b O or S; R b It is hydrogen or C1-C6 alkyl; R 1 Selected from alkyl, alkoxy, halogen, cyano, NR c R d -C(=O)NHR d -NHC(=O)R c , haloalkyl, cycloalkyl, cycloalkoxy, haloalkoxy, heterocyclic, aryl, and heteroaryl; and R 1 Each alkyl, alkoxy, cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl group is optionally substituted; R c and R d Each is independently selected from hydrogen, halogen, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl; and R c or R d Each alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently and optionally substituted; R 2 and R 3 Each is independently selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkoxy, cycloalkoxy, heterocyclic oxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclic alkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxylalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (formamido)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkoxy, heterocyclic alkoxy, arylalkoxy, heteroarylalkoxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxyl, amide, formamido, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, and alkylthio; and R 2 or R 3 Each alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl moiety is independently and optionally substituted by one or more C1-C6 alkyl, halogen, or deuterium moiety; Ring A is selected from aryl, heteroaryl, cycloalkyl, heterocyclic and phenyl isosteres; and ring A is optionally substituted. R is selected from hydrogen, halogen, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkoxy, cycloalkoxy, heterocyclic oxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclic alkyl, aralkyl, heteroarylalkyl, cycloalkylalkoxy, heterocyclic alkoxy, arylalkoxy, heteroarylalkoxy, and amide; and each alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl moiety in R is independently and optionally substituted. Or its stereoisomers, mixtures of stereoisomers, solvates or pharmaceutically acceptable salts thereof.

2. The compound according to claim 1, wherein R is selected from hydrogen, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, 4- to 8-membered heterocyclic group, C6-C6 cycloalkyl, halogenated alkyl group, cyclo ... 10 aryl, 5- to 10-membered heteroaryl, C1-C6 alkoxy, C3-C8 cycloalkoxy, 4- to 8-membered heterocyclic alkoxy, C6-C 10 aryloxy, 5- to 10-membered heteroaryloxy, (C3-C8 cycloalkyl)-(C1-C2 alkyl)-, (4- to 8-membered heterocyclic)-(C1-C2 alkyl)-, (C6-C 10 aryl)-(C1-C2 alkyl)-, (5- to 10-membered heteroaryl)-(C1-C2 alkyl)-, (C3-C8 cycloalkyl)-(C1-C2 alkoxy)-, (4- to 8-membered heterocyclic)-(C1-C2 alkoxy)-, (C6-C 10 (aryl)-(C1-C2 alkoxy)- and (5- to 10-membered heteroaryl)-(C1-C2 alkoxy)-; wherein each alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl moiety in R is independently and optionally substituted.

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

4. The compound according to any one of claims 1-3, wherein R is reacted with one or more R 4 Replace; and each R 4 Independently selected from deuterium, halogen, nitro, cyano, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted deuterated alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, haloalkyl, optionally substituted alkoxy, optionally substituted deuterated alkoxy, haloalkoxy, acyl, optionally substituted cycloalkoxy, optionally substituted heterocyclic oxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted cycloalkylalkyl, optionally substituted heterocyclic alkyl, optionally substituted spiroheterocyclic, optionally substituted spirocyclic, optionally substituted bridged heterocyclic, optionally substituted bridged carbocyclic, optionally substituted aralkyl, optionally substituted heteroaryl Alkyl, optionally substituted alkoxyalkyl, optionally substituted (alkylamino)alkyl, optionally substituted (dialkylamino)alkyl, optionally substituted cyanoalkyl, optionally substituted (formamido)alkyl, optionally substituted mercaptoalkyl, optionally substituted (cycloalkylamino)alkyl, optionally substituted cycloalkylalkoxy, optionally substituted heterocyclic alkoxy, optionally substituted arylalkoxy, optionally substituted heteroarylalkoxy, amino, optionally substituted alkylamino, optionally substituted dialkylamino, (hydroxyalkyl)amino, carboxyl, amide, formamido, optionally substituted sulfonamide, optionally substituted alkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, and optionally substituted alkylthio.

5. The compound according to any one of claims 1-4, wherein R is selected from... , , , , , and .

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

7. The compound according to any one of claims 1-6, wherein X 2 Is it N or CR? x2 ;R x2 It is hydrogen or C1-C6 alkyl.

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

9. The compound according to any one of claims 1-8, wherein the compound is a compound of formula (II): (II) in: X 4 Is it N or CR? x4 ;R x4 Selected from hydrogen, C1-C6 alkyl groups, and halogens; X 5 Is it N or CR? x5 ;R x5 Selected from hydrogen, C1-C6 alkyl groups, and halogens; R a1 Selected from deuterium, halogen, nitro, cyano, hydroxyl, alkyl, cycloalkyl, haloalkyl, alkoxy, and haloalkoxy; preferably, R a1 Selected from cyano, nitro, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, fluoromethyl, difluoromethyl, trifluoromethyl, l-fluoropropyl-2-yl, 2-fluoroethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethoxy, and trifluoromethoxy; R a2 Selected from deuterium, halogen, nitro, cyano, hydroxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, acyl, cycloalkoxy, heterocyclic alkoxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclic alkyl, spiroheterocyclic, spirocyclic, bridged heterocyclic, bridged carbocyclic, aralkyl, heteroarylalkyl, alkoxyalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (formamido)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkoxy, heterocyclic alkoxy, arylalkoxy, heteroarylalkoxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxyl, amide, formamido, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, and alkylthio; preferably, R a2 Selected from fluorine, chlorine, bromine, 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, l-fluoroprop-2-yl, 2-fluoroethyl, formyl, acetyl, propionyl, amino, methylamino, ethylamino, dimethylamino, 2,2-difluoroethoxy, cyclopropoxy, morpholinyl, piperidinyl, piperazine, tetrahydropyranyl, oxetanebutyl, aziranebutyl, pyrroleyl, dihydropyridyl, tetrahydropyridyl, tetrahydrothiapyranyl, tetrahydrothiapyranyl The following are listed: tetrahydrothiopyranyl, morpholinyloxy, piperidinyloxy, piperazinyloxy, tetrahydropyranyloxy, oxetaneyloxy, aziraneyloxy, pyrrolidinyloxy, dihydropyridinyloxy, tetrahydropyridinyloxy, tetrahydrothiaranyloxy, morpholinylmethyl, piperidinylmethyl, piperazinylmethyl, tetrahydropyranylmethyl, oxetaneylmethyl, aziraneylmethyl, pyrrolidinylmethyl, dihydropyridinylmethyl, tetrahydropyridinylmethyl, tetrahydrothiaranylmethyl, azispiroheptyl, azibicycloheptyl, diazibicycloheptyl, methoxymethyl, methylaminomethyl, deuterated methyl, deuterated ethyl, deuterated isopropyl, deuterated methoxy, and deuterated ethoxy; and R a2 It is an optional replacement; Rings A, L, R 1 R 2 and R 3 Each as defined in claim 1; Or its stereoisomers, mixtures of stereoisomers, solvates or pharmaceutically acceptable salts thereof.

10. The compound according to claim 9, wherein R a2 by one or more R 5 Replace; each R 5 Independently selected from halogen, nitro, cyano, hydroxy, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, haloalkyl, alkoxy, acyl, cycloalkoxy, heterocyclic oxy, heterocyclic carbonyl, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclic alkyl, spiroheterocyclic, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxylalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (formamide) )alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkoxy, heterocyclic alkoxy, arylalkoxy, heteroarylalkoxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, oxo, carboxyl, amide, formamide, sulfonamide, formyl, carbamoyl, aminosulfonyl, alkylcarbonyl, haloalkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, and alkylthio, and R 5 It is optional to replace; and / or both R 5 Together with the same ring carbon atom to which they are attached, they form optionally substituted C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl, and / or two R atoms attached to different carbon atoms. 5 Connected together to form optional replacement bridge rings; Preferably, each R 5 Independently selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, oxo, cyclopropyl, cyclopropylcarbonyl, isopropylcarbonyl, cyclobutylcarbonyl, formyl, acetyl, trifluoroacetyl, propionyl, amino, hydroxy, mercapto, oxetane-3-carbonyl, azirne-butyl, methylsulfonyl, ethylsulfonyl, aminomethylsulfonyl, methylsulfinyl, ethylsulfinyl, carbamoyl, benzoyl, aminosulfonyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, pyrrole, furanyl, thiophene, piperidinyl, piperazinyl, tetrahydrothiapyranyl, and tetrahydrothiopyranyl, and R 5 It is optional to replace; and / or both R 5 Together with the same ring carbon atom to which they are attached, they form optionally substituted cyclobutyl or azircyclic butyl groups, and / or two R groups attached to different carbon atoms. 5 They are linked together to form optionally substituted azabicycloheptyl or diazabicycloheptyl.

11. The compound according to claim 10, wherein R 5 by one or more R 6 Replace; each R 6 Independently selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, haloalkyl, alkoxy, acyl; cycloalkoxy, heterocyclic alkyl, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, carboxylalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (formamido)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkoxy, heterocyclic alkoxy, arylalkoxy, heteroarylalkoxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxyl, amide, formamido, sulfonamide, alkylcarbonyl, arylcarbonyl, formyl, carbamoyl, alkylsulfonyl, arylsulfonyl, and alkylthio; and R 6 It is an optional replacement; Preferably, each R 6 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, formamido, acetamyl, propionyl, carbamoyl, methylsulfonyl, ethylsulfonyl, morpholino, piperidinyl, piperazine, tetrahydropyranyl, oxetanebutyl, aziranebutyl, isoxazolyl, or pyrroleyl; and R 6 It can be arbitrarily replaced.

12. The compound according to claim 11, wherein R 6 by one or more R 7 Replace; each R 7 Independently selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, haloalkyl, alkoxy, oxo, acyl, cycloalkoxy, heterocyclic oxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclic alkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, hydroxyalkoxy, carboxylalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (formamido)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkoxy, heterocyclic alkoxy, arylalkoxy, heteroarylalkoxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxyl, amide, formamido, sulfonamide, alkylcarbonyl, arylcarbonyl, formyl, carbamoyl, alkylsulfonyl, arylsulfonyl, and alkylthio; Preferably, each R 7 It is independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, acetyl, oxo, hydroxy, mercapto, oxetane, azirone, imidazoalkyl, methanesulfonyl, methylamino, dimethylamino, methoxy, ethoxy, isopropoxy, tert-butoxy, and hydroxyethoxy.

13. The compound according to any one of claims 9-12, wherein R a2 Choose from the group consisting of: methyl, methoxy, dimethylamino, cyclopropyl, fluorine, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

14. The compound according to any one of claims 1-13, wherein ring A is selected from C6-C. 10 Aryl, 5- to 6-membered heteroaryl, 5- to 6-membered cycloalkyl, 5- to 6-membered heterocyclic and phenyl isosteres; Preferably, ring A is phenyl; more preferably, ring A is... ; Preferably, ring A is cubane; more preferably, ring A is... ; Preferably, ring A is a 6-membered nitrogen-containing heteroaryl group; more preferably, ring A is pyridyl; most preferably, ring A is... or .

15. The compound according to any one of claims 1-14, wherein ring A is optionally separated by one or more R 8 Replace; where each R 8 Independently selected from halogen, cyano, alkyl, amino, alkylamino, dialkylamino, hydroxy, or alkoxy; and wherein each alkyl, alkylamino, dialkylamino, or alkoxy moiety is optionally substituted independently by one or more halogen, hydroxy, or alkoxy groups; preferably, each R 8 It is independently selected from fluorine, chlorine, cyano, methoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy, hydroxyethoxy, and methoxyethoxy.

16. The compound according to any one of claims 1-15, wherein ring A is selected from: , , , , , , , , , , , , , , , , and .

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

18. The compound according to any one of claims 1-17, wherein the compound is a compound of formula (III): (III) in: R a3 Selected from halogens, haloalkyl groups, nitro groups, cyano groups, hydroxyl groups, alkyl groups, alkoxy groups, and cycloalkyl groups; preferably, R a3 Selected from cyano, nitro, hydroxy, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, isopropoxy, and tert-butoxy; R a4 Selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, haloalkyl, alkoxy, acyl, cycloalkoxy, heterocyclic alkyl, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclic alkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, carboxylalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (formamido)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkoxy, heterocyclic alkoxy, arylalkoxy, heteroarylalkoxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxyl, amide, formamido, sulfonamide, alkylcarbonyl, arylcarbonyl, formyl, carbamoyl, alkylsulfonyl, arylsulfonyl, and alkylthio; preferably, R a4 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, formamido, acetamamido, propionamido, carbamoyl, methylsulfonyl, ethylsulfonyl, morpholino, piperidinyl, piperazine, tetrahydropyranyl, oxetanebutyl, aziranebutyl, isoxazolyl, and pyrroleyl; and R a4 It is an optional replacement; L, R 1 R 2 and R 3 Each as defined in claim 1; Or its stereoisomers, mixtures of stereoisomers, solvates or pharmaceutically acceptable salts thereof.

19. The compound according to claim 18, wherein R a4 by one or more R 9 Replace; each R 9 Independently selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, haloalkyl, alkoxy, oxo, acyl, cycloalkoxy, heterocyclic oxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclic alkyl, aralkyl, heteroarylalkyl, hydroxyalkyl, hydroxyalkoxy, carboxylalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, cyanoalkyl, (formamido)alkyl, mercaptoalkyl, (cycloalkylamino)alkyl, cycloalkylalkoxy, heterocyclic alkoxy, arylalkoxy, heteroarylalkoxy, amino, alkylamino, dialkylamino, (hydroxyalkyl)amino, carboxyl, amide, formamido, sulfonamide, alkylcarbonyl, arylcarbonyl, formyl, carbamoyl, alkylsulfonyl, arylsulfonyl, and alkylthio; Preferably, each R 9 It is independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, acetyl, oxo, hydroxy, mercapto, oxetane, azirone, imidazoalkyl, methanesulfonyl, methylamino, dimethylamino, methoxy, ethoxy, isopropoxy, tert-butoxy, and hydroxyethoxy.

20. The compound according to claim 18 or 19, wherein R a4 Selected from methyl, ethyl, isopropyl, cyclopropyl, amino, methylamino, hydroxymethyl, trifluoromethyl, methylsulfonylethyl, , , , , , , , , , , , , , , , , , and .

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

22. The compound according to any one of claims 1-21, wherein the compound is selected from the group consisting of: 。 23. A pharmaceutical composition comprising the compound as described in any one of claims 1-22 and a pharmaceutically acceptable excipient.

24. A method of treating a disease or condition in a subject in need, wherein the method comprises administering to the subject a therapeutically effective amount of a compound as described in any one of claims 1-22, a stereoisomer thereof, a mixture of stereoisomers thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 23, wherein the disease or condition is a USP1 protein-mediated barrier; preferably, the USP1 protein-mediated barrier is cancer; more preferably, the cancer is a hematologic cancer, lymphoma, 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 any one of the compounds of claims 1-22, or stereoisomers thereof, mixtures thereof, solvates thereof, or pharmaceutically acceptable salts thereof, or the use of the pharmaceutical composition of claim 23 in the preparation of a medicament for the prevention or treatment of a disease or condition, wherein the disease or condition is a USP1 protein-mediated barrier; preferably, the USP1 protein-mediated barrier is cancer; more preferably, the cancer is a hematologic cancer, lymphoma, or solid tumor, such as lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, or breast cancer.

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