GPR139 agonist

Abstract

The present disclosure relates to the compound represented by formula (I) or a pharmaceutically acceptable salt thereof used as a GPR139 agonist, a composition comprising the compound or pharmaceutically acceptable salt thereof, and a therapeutic use thereof.

Description

GPR139 agonists Technical Field

[0001] The present application relates to the field of medicinal chemistry, and in particular to a compound serving as a GPR139 agonist, a composition containing the compound, and its use in treating diseases associated with GPR139. Background Art

[0002] GRP139 is an orphan receptor of the GPCR family of proteins. The human GPR139 gene is a 345-amino acid orphan receptor located on chromosome 16pl2.3. The GPR139 protein (also known as hGPRgl or hGPCR12) is highly conserved across species, with over 94% homology between the human, mouse, and rat GPRL39 protein sequences. GPR139 mRNA is primarily expressed in the human central nervous system (CNS), particularly in the basal ganglia and hypothalamus, where it may be involved in motor control, regulating food intake and metabolism. The consistent expression of GPR139 mRNA in the CNS provides evidence across species that it plays a specific role in regulation, and GPR139 is considered a potential target for any drug, including diabetes, obesity, and Parkinson's disease (Wang et al, Acta Pharmacologica Sinica, 36:874-878, 2015).

[0003] In mammals, GPR139 is mainly expressed in the central nervous system, with the highest expression in the striatum, pituitary, habenula, thalamus and hypothalamus (Matsuo et al, Biochem Biophys Res Commun, 2005, 331: 363-9). The habenula consists of the medial habenula (MHb) and the lateral habenula (LHb). In mice, GPR139 is mainly expressed in the MHb and less expressed in the LHb (Wang et al, Science, 2019, 365: 1267-73). The habenula is also a brain region associated with addiction, and studies have shown that the GPR139 protein agonist JNJ-6533054 developed by Johnson & Johnson has the ability to reduce the compulsive self-administration of alcohol in rats. In addition, the use of JNJ-6533054 also alleviated withdrawal-induced hyperalgesia in alcohol-dependent rats (Kononoff et al, eNeuro, 2018, 5:ENEURO.0153-18.2018). In morphine addiction experiments, GRP139 agonists also reduced rat addiction and truncation symptoms in morphine-dependent rats. GPR139 gene mutations are also associated with inattention symptoms in schizophrenia and attention deficit hyperactivity disorder (Frank et al, Philos TR Soc B, 2007, 362:1641-54).

[0004] Because GRP139 is a potential target for neurological diseases, multiple research institutions and pharmaceutical companies have developed a series of GRP139 modulators. Among them, TAK041 is currently being used to treat anhedonia symptoms following major depression.

[0005] Based on the potential application of GRP139 modulators in neurological diseases, there is still a great demand for compounds for regulating GPR139 receptors. Summary of the Invention

[0006] The purpose of the present application is to provide new GRP139 modulators, especially modulators with GRP139 activation effect, which have potential applications in the treatment of neurological diseases.

[0007] Therefore, in the first aspect, the present application provides a compound as shown in Formula I, or a pharmaceutically acceptable salt thereof

[0008] wherein Q1 is selected from N or CR5, and Q2 is selected from N, NR5 or CR5,

[0009] wherein R1 and R5 are each independently selected from H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl; or two adjacent R5 or R5 and R1 together with the atoms to which they are attached form a C4-10 cycloalkenyl, a 4-10 membered heterocycloalkenyl, or a 5-10 membered heteroaryl; wherein the -O-C1- wherein R is selected from -OH, halogen, or C1-3 alkyl;

[0010] R2 is each independently selected from H, deuterium, halogen, C1-5 alkyl optionally substituted by one or more halogens, or -O-C1-5 alkyl optionally substituted by one or more halogens;

[0011] R3 is selected from deuterium, C1-6 alkyl, which is optionally substituted with one or more groups selected from the following: deuterium, -OH, halogen, oxo, -O-glucuronide, -NH2, or -NHCH2COOH;

[0012] R4 is selected from H, deuterium, -OH or -O-glucuronide; and

[0013] wherein m is an integer selected from 0 to 2, n is an integer selected from 0 to 5, and Indicates a double bond or a single bond.

[0014] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is substantially enantiomerically pure.

[0015] In some embodiments, R1 and R5 are each independently selected from H, deuterium, halogen, -OH, -O-C1-5 alkyl, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, phenyl, C3-6 cycloalkyl, C4-6 cycloalkenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, or 4-6 membered heterocycloalkenyl, or two adjacent R5 or R5 and R1 together with the atoms to which they are attached form a C4-6 cycloalkenyl, a 4-6 membered heterocycloalkenyl, or a 5- wherein the -O-C1-5 alkyl, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, phenyl, C3-6 cycloalkyl, C4-6 cycloalkenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, or 5-6 membered heteroaryl is optionally substituted with one or more groups selected from the group consisting of deuterium, -F, -Cl, -Br, -OH, -O-C1-3 alkyl, C1-3 alkyl, C2-4 alkenyl, or C2-4 alkynyl.

[0016] In some embodiments, R2 is independently selected from H, deuterium, -F, -Cl, -Br, perhalogen-substituted C1-3 alkyl or perhalogen-substituted -O-C1-3 alkyl, preferably perhalogen-substituted methyl or perhalogen-substituted methoxy, also preferably -CF3 or -OCF3, preferably -OCF3.

[0017] In some embodiments, R3 is selected from deuterium, C1-3 alkyl, which is optionally substituted with one or more groups selected from deuterium, -OH, halogen, oxo, or -NH2.

[0018] In some embodiments, R4 is selected from H or deuterium.

[0019] In some embodiments, m is 0 or 1. In some embodiments, n is 0, 1, or 2.

[0020] In some embodiments, R1 and R5 are each independently selected from H, deuterium, -F, -Cl, -Br, and -O-C1-3 alkyl, C1-3 alkyl, propenyl, allyl, phenyl, C3-5 cycloalkyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, cyclopentenyl, cyclohexenyl, 3,6-dihydro-2H-pyranyl, or 2,5-dihydrofuranyl; or two adjacent R5 or R5 and R1 together with the atoms to which they are attached form a C5-6 cycloalkenyl, a 5-6 membered heterocycloalkenyl, or a 5-6 membered heteroaryl optionally substituted with one or more deuterium, -F, -Cl, Br, C1-3 alkyl, C2-4 alkenyl, or -O-C1-3 alkyl.

[0021] In some embodiments, R1 and R5 are each independently selected from H, deuterium, -F, -Cl, -Br, and -O-C1-3 alkyl, C1-3 alkyl, propenyl, allyl, phenyl, Or two adjacent R5 or R5 and R1 together with the atoms to which they are respectively attached form a cyclopentenyl, cyclopentadienyl, cyclohexenyl, 1,4-cyclohexadienyl, tetrahydropyridinyl, dihydropyridinyl, pyrrolinyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2,5-dihydrofuranyl, 1H-imidazolyl, 1H-pyrrolyl group which is optionally substituted with one or more deuterium, -F, -Cl, Br, C1-3 alkyl or -O-C1-3 alkyl group.

[0022] In some embodiments, R3 is selected from methyl and R4 is selected from H.

[0023] In some embodiments, R1 and R5 are each independently selected from isopropyl, phenyl, cyclopropyl, or phenyl groups optionally substituted with one or more deuterium, -F, -Cl, Br, C1-3 alkyl, or -O-C1-3 alkyl. Or two adjacent R5 or R5 and R1 together with the atoms to which they are respectively attached form a cyclopentenyl group optionally substituted by one or more deuterium, -F, -Cl, Br, C1-3 alkyl or -O-C1-3 alkyl.

[0024] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure as shown in any one of Formula (I-1) to Formula (I-4):

[0025] wherein R1, R2, R5, Q1, Q2 and n are as defined above, and Q4 is selected from N or CR 10 , R 10 is selected from H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, or -C(O)R9, wherein R9 is selected from -OH, halogen or C1-3 alkyl, and q is an integer from 0 to 2. When q is 2, R 10 Can be the same or different.

[0026] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure as shown in Formula (I-2i):

[0027] wherein R1 is selected from H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl; wherein said -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl is optionally substituted with one or more groups selected from deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl;

[0028] R2 is selected from H, deuterium, halogen, C1-5 alkyl optionally substituted by one or more halogens, or -O-C1-5 alkyl optionally substituted by one or more halogens;

[0029] Preferably, R1 is selected from the group consisting of:

[0030] Deuterium, halogen (preferably Br), linear or branched C1-3 alkyl, -O-C1-3 alkyl, cis or trans propenyl

[0031] wherein R6 is selected from deuterium, halogen (e.g., F, Cl, Br), -OH, -C1-3 alkyl, -O-C1-3 alkyl, and o is 0, 1 or 2, and when o is 2, R6 may be the same or different;

[0032] Q3 is selected from O, S, -CH2- or -N(R7)- wherein R7 is selected from H, deuterium or C1-3 alkyl, preferably H and methyl, and

[0033] R2 is selected from H, deuterium, -F, -Cl, -Br, perhalogen-substituted C1-3 alkyl or perhalogen-substituted -O-C1-3 alkyl, preferably perhalogen-substituted methyl or perhalogen-substituted methoxy, also preferably -CF3 or -OCF3, preferably -OCF3.

[0034] In some embodiments, R1 is selected from the group consisting of:

[0035] Deuterium, Br, methyl, ethyl, propyl, isopropyl, -O-CH3, wherein each X is independently selected from F, Cl, Br or I.

[0036] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure as shown in Formula (I-2ii):

[0037] wherein Q3 is selected from O, S, -CH2- or -N(R7)- And wherein R7 is selected from H, deuterium or C1-3 alkyl, preferably H and methyl, R8 is selected from H, deuterium, halogen, oxo, -OH, -O-C1-3 alkyl or C1-3 alkyl, and wherein R2 is selected from H, deuterium, -F, -Cl, -Br, perhalogen-substituted C1-3 alkyl or perhalogen-substituted -O-C1-3 alkyl, preferably perhalogen-substituted methyl or perhalogen-substituted methoxy, also preferably -CF3 or -OCF3, preferably -OCF3.

[0038] In some embodiments, the group in formula (I-2ii) Having a structure selected from the following:

[0039] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure as shown in Formula (I-3i):

[0040] wherein R1 is selected from H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl; wherein said -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl is optionally substituted with one or more groups selected from deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C1-10 alkenyl, or C2-10 alkynyl;

[0041] R2 is selected from H, deuterium, halogen, C1-5 alkyl optionally substituted by one or more halogens, or -O-C1-5 alkyl optionally substituted by one or more halogens;

[0042] Preferably, R1 is selected from the group consisting of:

[0043] Deuterium, halogen (preferably Br), linear or branched C1-3 alkyl, -O-C1-3 alkyl, cis or trans propenyl

[0044] wherein R6 is selected from deuterium, halogen (e.g., F, Cl, Br), -OH, C1-3 alkyl, -O-C1-3 alkyl, and o is 0, 1 or 2, and when o is 2, R6 may be the same or different;

[0045] Q3 is selected from O, S, -CH2- or -N(R7)- wherein R7 is selected from H, deuterium or C1-3 alkyl, preferably H and methyl, and

[0046] R2 is selected from H, deuterium, -F, -Cl, -Br, perhalogen-substituted C1-3 alkyl or perhalogen-substituted -O-C1-3 alkyl, preferably perhalogen-substituted methyl or perhalogen-substituted methoxy, also preferably -CF3 or -OCF3, preferably -OCF3.

[0047] In some embodiments, R1 is selected from the group consisting of:

[0048] Deuterium, Br, methyl, ethyl, propyl, isopropyl, -O-CH3, wherein each X is independently selected from F, Cl, Br or I.

[0049] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure as shown in Formula (I-3ii):

[0050] wherein Q3 is selected from O, S, -CH2- or -N(R7)- And wherein R7 is selected from H, deuterium or C1-3 alkyl, preferably H and methyl, R8 is selected from H, deuterium, halogen, oxo, -OH, -O-C1-3 alkyl or C1-3 alkyl, and wherein R2 is selected from H, deuterium, -F, -Cl, -Br, perhalogen-substituted C1-3 alkyl or perhalogen-substituted -O-C1-3 alkyl, preferably perhalogen-substituted methyl or perhalogen-substituted methoxy, also preferably -CF3 or -OCF3, preferably -OCF3.

[0051] In some embodiments, the group in formula (I-3ii) Having a structure selected from the following:

[0052] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure as shown in Formula (I-4i):

[0053] wherein R1 is selected from H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl; wherein said -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl is optionally substituted with one or more groups selected from deuterium, halogen, -OH, -O-C1-10 alkyl, or C1-10 alkyl;

[0054] R2 is selected from H, deuterium, halogen, C1-5 alkyl optionally substituted by one or more halogens, or -O-C1-5 alkyl optionally substituted by one or more halogens;

[0055] Preferably, R1 is selected from the group consisting of:

[0056] Halogen (preferably Br), linear or branched C1-3 alkyl, -O-C1-3 alkyl, cis or trans propenyl

[0057] wherein R6 is selected from halogen (e.g., F, Cl, Br), -OH, C1-3 alkyl, -O-C1-3 alkyl, and o is 0, 1 or 2, and when o is 2, R6 may be the same or different;

[0058] Q3 is selected from O, S, -CH2- or -N(R7)- wherein R7 is selected from H or C1-3 alkyl, preferably H and methyl, and

[0059] R2 is selected from H, -F, -Cl, -Br, perhalogen-substituted C1-3 alkyl or perhalogen-substituted -O-C1-3 alkyl, preferably perhalogen-substituted methyl or perhalogen-substituted methoxy, also preferably -CF3 or -OCF3, preferably -OCF3.

[0060] In some embodiments, R1 is selected from the group consisting of:

[0061] Br, methyl, ethyl, propyl, isopropyl, -O-CH3, wherein each X is independently selected from F, Cl, Br or I.

[0062] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure as shown in Formula (I-5i):

[0063] where R 10 Each is independently selected from -H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-5 alkenyl, or -C(O)R9, wherein R9 is selected from -OH, halogen or C1-3 alkyl, preferably R 10 Each is independently selected from -H, C1-3 alkyl, and C2-3 alkenyl.

[0064] In some embodiments, the group in formula (I-5i) Having a structure selected from the following:

[0065] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure as shown in Formula (I-5ii):

[0066] where R 10 Each is independently selected from -H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-5 alkenyl, or -C(O)R9, wherein R9 is selected from -OH, halogen or C1-3 alkyl, preferably R 10 Each is independently selected from -H, C1-3 alkyl, and C2-3 alkenyl.

[0067] In some embodiments, the group in formula (I-5ii) It has the following structure:

[0068] In some embodiments, the compound represented by Formula I is selected from the compounds shown in Table 1.

[0069] In the first aspect, the present application also provides a compound as shown in Formula I, or a pharmaceutically acceptable salt thereof,

[0070] in represents a double bond, and

[0071] wherein Q1 and Q2 are each independently selected from N or CR5, provided that Q1 and Q2 are not N at the same time,

[0072] wherein R1 and R5 are each independently selected from H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl; or two R5 on adjacent carbons or R5 and R1 together with the carbons to which they are attached form a C4-10 cycloalkenyl or a 4-10 membered heterocycloalkenyl; wherein the -O -C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C4-10 cycloalkenyl, or 4-10 membered heterocycloalkenyl is optionally substituted with one or more groups selected from deuterium, oxo, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, or -C(O)R9, wherein R9 is selected from -OH, halogen, or C1-3 alkyl;

[0073] R2 is each independently selected from H, deuterium, halogen, C1-5 alkyl optionally substituted by one or more halogens, or -O-C1-5 alkyl optionally substituted by one or more halogens;

[0074] R3 is selected from deuterium, C1-6 alkyl, which is optionally substituted with one or more groups selected from the following: deuterium, -OH, halogen, oxo, -O-glucuronide, -NH2, or -NHCH2COOH;

[0075] R4 is selected from H, deuterium, -OH or -O-glucuronide; and

[0076] wherein m is an integer selected from 0 to 2, and n is an integer selected from 0 to 5.

[0077] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is substantially enantiomerically pure.

[0078] In some embodiments, R1 and R5 are each independently selected from H, deuterium, halogen, -OH, -O-C1-5 alkyl, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, phenyl, C3-6 cycloalkyl, C4-6 cycloalkenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, or 4-6 membered heterocycloalkenyl, or two R5 on adjacent carbons or R5 and R1 together with the carbons to which they are attached together form a C4-6 cycloalkenyl. or 4-6 membered heterocycloalkenyl; wherein the -O-C1-5 alkyl, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, phenyl, C3-6 cycloalkyl, C4-6 cycloalkenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C4-6 cycloalkenyl or 4-6 membered heterocycloalkenyl is optionally substituted by one or more groups selected from the group consisting of deuterium, -F, -Cl, -Br, -OH, -O-C1-3 alkyl, or C1-3 alkyl.

[0079] In some embodiments, R2 is independently selected from H, deuterium, -F, -Cl, -Br, perhalogen-substituted C1-3 alkyl or perhalogen-substituted -O-C1-3 alkyl, preferably perhalogen-substituted methyl or perhalogen-substituted methoxy, also preferably -CF3 or -OCF3, preferably -OCF3.

[0080] In some embodiments, R3 is selected from deuterium, C1-3 alkyl, which is optionally substituted with one or more groups selected from deuterium, -OH, halogen, oxo, or -NH2.

[0081] In some embodiments, R4 is selected from H or deuterium.

[0082] In some embodiments, m is 0 or 1. In some embodiments, n is 0, 1, or 2.

[0083] In some embodiments, R1 and R5 are each independently selected from H, deuterium, -F, -Cl, -Br, and -O-C1-3 alkyl, C1-3 alkyl, propenyl, allyl, phenyl, C3-5 cycloalkyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, cyclopentenyl, cyclohexenyl, 3,6-dihydro-2H-pyranyl, or 2,5-dihydrofuranyl; or two R5 on adjacent carbons or R5 and R1 together with the carbon to which they are each attached form a C5-6 cycloalkenyl or 5-6 membered heterocycloalkenyl optionally substituted with one or more deuterium, -F, -Cl, Br, C1-3 alkyl, or -O-C1-3 alkyl.

[0084] In some embodiments, R1 and R5 are each independently selected from H, deuterium, -F, -Cl, -Br, and -O-C1-3 alkyl, C1-3 alkyl, propenyl, allyl, phenyl, Or two R5 on adjacent carbons or R5 and R1 together with the carbon to which they are respectively attached form a cyclopentenyl, cyclopentadienyl, cyclohexenyl, 1,4-cyclohexadienyl, tetrahydropyridinyl, dihydropyridinyl, pyrrolinyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2,5-dihydrofuranyl optionally substituted with one or more deuterium, -F, -Cl, Br, C1-3 alkyl or -O-C1-3 alkyl.

[0085] In some embodiments, R3 is selected from methyl and R4 is selected from H.

[0086] In some embodiments, R1 and R5 are each independently selected from isopropyl, phenyl, cyclopropyl, or phenyl groups optionally substituted with one or more deuterium, -F, -Cl, Br, C1-3 alkyl, or -O-C1-3 alkyl. Or two R5 on adjacent carbons or R5 and R1 together with the carbons to which they are respectively attached form a cyclopentenyl group optionally substituted with one or more deuterium, -F, -Cl, Br, C1-3 alkyl or -O-C1-3 alkyl.

[0087] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure as shown in any one of Formula (I-1) to Formula (I-4):

[0088] wherein R1, R2, R5, Q1, Q2 and n are as defined above, and wherein in formula (I-1) Represents a double bond.

[0089] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure as shown in Formula (I-2i):

[0090] wherein R1 is selected from H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl; wherein said -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl is optionally substituted with one or more groups selected from deuterium, halogen, -OH, -O-C1-10 alkyl, or C1-10 alkyl;

[0091] R2 is selected from H, deuterium, halogen, C1-5 alkyl optionally substituted by one or more halogens, or -O-C1-5 alkyl optionally substituted by one or more halogens;

[0092] Preferably, R1 is selected from the group consisting of:

[0093] Deuterium, halogen (preferably Br), linear or branched C1-3 alkyl, -O-C1-3 alkyl, cis or trans propenyl

[0094] wherein R6 is selected from deuterium, halogen (e.g., F, Cl, Br), -OH, -O-C1-3 alkyl, and o is 0, 1 or 2, and when o is 2, R6 may be the same or different;

[0095] Q3 is selected from O, S, -CH2- or -N(R7)- wherein R7 is selected from H, deuterium or C1-3 alkyl, preferably H and methyl, and

[0096] R2 is selected from H, deuterium, -F, -Cl, -Br, perhalogen-substituted C1-3 alkyl or perhalogen-substituted -O-C1-3 alkyl, preferably perhalogen-substituted methyl or perhalogen-substituted methoxy, also preferably -CF3 or -OCF3, preferably -OCF3.

[0097] In some embodiments, R1 is selected from the group consisting of:

[0098] Deuterium, Br, methyl, ethyl, propyl, isopropyl, -O-CH3, wherein each X is independently selected from F, Cl, Br or I.

[0099] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure as shown in Formula (I-2ii):

[0100] wherein Q3 is selected from O, S, -CH2- or -N(R7)- And wherein R7 is selected from H, deuterium or C1-3 alkyl, preferably H and methyl, R8 is selected from H, deuterium, halogen, oxo, -OH, -O-C1-3 alkyl or C1-3 alkyl, and wherein R2 is selected from H, deuterium, -F, -Cl, -Br, perhalogen-substituted C1-3 alkyl or perhalogen-substituted -O-C1-3 alkyl, preferably perhalogen-substituted methyl or perhalogen-substituted methoxy, also preferably -CF3 or -OCF3, preferably -OCF3.

[0101] In some embodiments, the group in formula (I-2ii) Having a structure selected from the following:

[0102] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure as shown in Formula (I-3i):

[0103] wherein R1 is selected from H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl; wherein said -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl is optionally substituted with one or more groups selected from deuterium, halogen, -OH, -O-C1-10 alkyl, or C1-10 alkyl;

[0104] R2 is selected from H, deuterium, halogen, C1-5 alkyl optionally substituted by one or more halogens, or -O-C1-5 alkyl optionally substituted by one or more halogens;

[0105] Preferably, R1 is selected from the group consisting of:

[0106] Deuterium, halogen (preferably Br), linear or branched C1-3 alkyl, -O-C1-3 alkyl, cis or trans propenyl

[0107] wherein R6 is selected from deuterium, halogen (e.g., F, Cl, Br), -OH, -O-C1-3 alkyl, and o is 0, 1 or 2, and when o is 2, R6 may be the same or different;

[0108] Q3 is selected from O, S, -CH2- or -N(R7)- wherein R7 is selected from H, deuterium or C1-3 alkyl, preferably H and methyl, and

[0109] R2 is selected from H, deuterium, -F, -Cl, -Br, perhalogen-substituted C1-3 alkyl or perhalogen-substituted -O-C1-3 alkyl, preferably perhalogen-substituted methyl or perhalogen-substituted methoxy, also preferably -CF3 or -OCF3, preferably -OCF3.

[0110] In some embodiments, R1 is selected from the group consisting of:

[0111] Deuterium, Br, methyl, ethyl, propyl, isopropyl, -O-CH3, wherein each X is independently selected from F, Cl, Br or I.

[0112] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure as shown in Formula (I-3ii):

[0113] wherein Q3 is selected from O, S, -CH2- or -N(R7)- And wherein R7 is selected from H, deuterium or C1-3 alkyl, preferably H and methyl, R8 is selected from H, deuterium, halogen, oxo, -OH, -O-C1-3 alkyl or C1-3 alkyl, and wherein R2 is selected from H, deuterium, -F, -Cl, -Br, perhalogen-substituted C1-3 alkyl or perhalogen-substituted -O-C1-3 alkyl, preferably perhalogen-substituted methyl or perhalogen-substituted methoxy, also preferably -CF3 or -OCF3, preferably -OCF3.

[0114] In some embodiments, the group in formula (I-3ii) Having a structure selected from the following:

[0115] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure as shown in Formula (I-4i):

[0116] wherein R1 is selected from H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl; wherein said -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl is optionally substituted with one or more groups selected from deuterium, halogen, -OH, -O-C1-10 alkyl, or C1-10 alkyl;

[0117] R2 is selected from H, deuterium, halogen, C1-5 alkyl optionally substituted by one or more halogens, or -O-C1-5 alkyl optionally substituted by one or more halogens;

[0118] Preferably, R1 is selected from the group consisting of:

[0119] Halogen (preferably Br), linear or branched C1-3 alkyl, -O-C1-3 alkyl, cis or trans propenyl

[0120] wherein R6 is selected from halogen (e.g., F, Cl, Br), -OH, -O-C1-3 alkyl, and o is 0, 1 or 2, and when o is 2, R6 may be the same or different;

[0121] Q3 is selected from O, S, -CH2- or -N(R7)- wherein R7 is selected from H or C1-3 alkyl, preferably H and methyl, and

[0122] R2 is selected from H, -F, -Cl, -Br, perhalogen-substituted C1-3 alkyl or perhalogen-substituted -O-C1-3 alkyl, preferably perhalogen-substituted methyl or perhalogen-substituted methoxy, also preferably -CF3 or -OCF3, preferably -OCF3.

[0123] In some embodiments, R1 is selected from the group consisting of:

[0124] Br, methyl, ethyl, propyl, isopropyl, -O-CH3, wherein each X is independently selected from F, Cl, Br or I.

[0125] In a second aspect, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0126] In some embodiments, the pharmaceutical composition is used to treat a disease, disorder or condition associated with GPR139, including but not limited to schizophrenia, Alzheimer's disease, Parkinson's disease, autism spectrum disorder, sleep disorders, cognitive impairment, depression, obsessive-compulsive disorder, anxiety, attention deficit hyperactivity disorder, post-traumatic stress disorder, bipolar disorder, eating disorders, substance use disorders, substance abuse, drug addiction, epilepsy, pain, and fibromyalgia.

[0127] In some embodiments, the pharmaceutical composition further comprises one or more other active ingredients selected from the group consisting of antidepressants, antipsychotics, antianxiety drugs, sedatives, hypnotics, and tranquilizers.

[0128] In a third aspect, the present application provides a pharmaceutical kit comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, and optionally instructions.

[0129] In some embodiments, the kit further comprises one or more other active ingredients selected from the group consisting of antidepressants, antipsychotics, antianxiety drugs, sedatives, hypnotics, and tranquilizers.

[0130] In a fourth aspect, the present application provides a compound of formula I or a pharmaceutically acceptable salt thereof for use as a medicament.

[0131] In some embodiments, the medicament is used to treat a disease, disorder or condition associated with GPR139, including but not limited to schizophrenia, Alzheimer's disease, Parkinson's disease, autism spectrum disorder, sleep disorders, cognitive impairment, depression, obsessive-compulsive disorder, anxiety, attention deficit hyperactivity disorder, post-traumatic stress disorder, bipolar disorder, eating disorders, substance use disorders, substance abuse, drug addiction, epilepsy, pain, and fibromyalgia.

[0132] In a fifth aspect, the present application provides a method for treating a disease, disorder or condition associated with GPR139, comprising administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0133] In some embodiments, the disease, disorder or condition associated with GPR139 includes but is not limited to schizophrenia, Alzheimer's disease, Parkinson's disease, autism spectrum disorder, sleep disorder, cognitive impairment, depression, obsessive-compulsive disorder, anxiety disorder, attention deficit hyperactivity disorder, post-traumatic stress disorder, bipolar disorder, eating disorder, substance use disorder, substance abuse, drug addiction, epilepsy, pain, fibromyalgia.

[0134] In some embodiments, the method further comprises administering to a subject in need thereof, simultaneously or sequentially, one or more other active ingredients selected from the group consisting of antidepressants, antipsychotics, antianxiety drugs, sedatives, hypnotics, and tranquilizers.

[0135] In a sixth aspect, the present application provides a method for activating GPR139, comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject or a cell expressing GPR139. DETAILED DESCRIPTION

[0136] To make the objectives, technical solutions, and advantages of the present invention more clearly understood, the present invention will be further described in detail below with reference to the following examples. The specific embodiments described herein are intended only to illustrate the present invention and are not intended to limit the present invention in any way. In addition, in the following description, descriptions of known structures and technologies are omitted to avoid unnecessary confusion about the concepts of the present disclosure. Such structures and technologies are also described in many publications.

[0137] definition

[0138] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly used in the field to which the present invention belongs. For the purpose of interpreting this specification, the following definitions will apply, and where appropriate, terms used in the singular will also include the plural form, and vice versa.

[0139] As used herein, the articles "a," "an," and "an" include plural referents unless the context clearly dictates otherwise.

[0140] In this application, the term "substituted" when used to modify a specific group (e.g., phenyl) means that one or more hydrogen atoms of the specific group are replaced by one or more non-hydrogen atoms or groups, provided that the valence requirements are met and the substitution results in a chemically stable compound.

[0141] In this application, the term "substantially enantiomerically pure" means greater than 80% ee (enantiomeric excess), preferably greater than 97% enantiomeric purity, or more preferably greater than 98% or even greater than 99% enantiomeric purity. For compounds that exist as stereoisomers, such stereoisomers may be substantially enantiomerically pure at a stereocenter.

[0142] In this application, the term "subject" includes humans and non-human animals, such as mammals, such as mice, rats, guinea pigs, dogs, cats, rabbits, cows, horses, sheep, goats and pigs. The term can also include birds, fish, reptiles, amphibians, etc. Preferably, the subject is a human.

[0143] In this application, the term "alkyl" itself or as part of another substituent (e.g., alkoxy-O-alkyl) refers to a straight or branched hydrocarbon group with a specified number of carbon atoms. That is, a C1-10 alkyl group refers to a straight or branched hydrocarbon group with 1-10 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), and may include, for example, a straight-chain alkyl group with 1 to 10 carbon atoms and a branched-chain alkyl group with 3 to 10 carbon atoms. Preferably, the alkyl group generally contains 1 to 5 carbon atoms, i.e., a C1-5 alkyl group. Also preferably, the alkyl group may contain 1 to 3 carbon atoms, i.e., a C1-3 alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, 2-ethylhexyl, nonyl, decyl, 3,7-dimethyloctyl, etc.

[0144] In the present application, one or more (such as 2, 3, 4, 5) positions in the alkyl group may be optionally substituted, and the substitution may be performed at any position in the group, and the substituent is selected from: deuterium, halogen, -CN, -OH, -O-C1-10 alkyl, C1-10 alkyl, halogenated C1-10 alkyl, cycloalkyl, aryl or heteroaryl.

[0145] In the present application, the term "haloalkyl" refers to an alkyl group substituted by one or more (such as 1 to 3) identical or different halogen atoms. For example, the term "haloC1-10alkyl" refers to a haloalkyl group having 1 to 10 carbon atoms, such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl or -CH2CH2CF3, etc.

[0146] In this application, the term "alkenyl" refers to a linear or branched, non-cyclic, unsaturated hydrocarbon group having a specified number of carbon atoms, wherein at least two carbon atoms are bonded to each other via an unsaturated double bond. Alkenyl groups suitable for use in the present invention may have 2 to 10 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 2 to 5 carbon atoms. Examples of C2-5 alkenyl groups include, but are not limited to, ethenyl, 1-propen-1-yl, 1-propen-2-yl, 2-propen-1-yl, 2-methyl-1-propen-1-yl, 2-methyl-2-propen-1-yl, 1-buten-1-yl, 1-buten-2-yl, 2-buten-1-yl, 2-buten-2-yl, 3-buten-1-yl, 3-buten-2-yl, 1,3-butadien-1-yl, 1,3-butadien-2-yl, 1-penten-1-yl, 2-penten-1-yl, 2-penten-2-yl, 3-penten-1-yl, 3-penten-3-yl, 4-penten-1-yl, 4-penten-4-yl, etc. The alkenyl group preferably has one double bond. It is also preferred that the double bond in the alkenyl group is directly connected to the rest of the compound containing the alkenyl group, for example, 1-propen-1-yl is more preferred than 2-propen-1-yl. Without being limited by theory, in the present application, the term "alkenyl" also encompasses groups having a straight chain of carbon atoms and / or a straight chain with both unsaturated double bonds and unsaturated triple bonds.

[0147] In the present application, the alkenyl group may be optionally substituted by one or more substituents, each of which may be the same or different, for example, by one or more groups selected from the group consisting of deuterium, halogen, -CN, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkynyl, halo-C1-10 alkyl, cycloalkyl, aryl or heteroaryl.

[0148] In the present application, term " alkynyl " refers to a straight or branched, non-cyclic unsaturated hydrocarbon radical with a specified carbon atom, wherein at least two carbon atoms are bound to each other by an unsaturated triple bond. Alkynyl groups suitable for use in the present invention can have 2-10 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 2-5 carbon atoms. The example of C2-5 alkynyl includes but is not limited to ethynyl, 1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl, 2-butyn-1-yl, 3-butyn-1-yl, 3-butyn-2-yl, 1-pentyn-1-yl, 2-pentyn-1-yl, 3-pentyn-1-yl, 4-pentyn-1-yl etc. The alkynyl preferably has a triple bond. It is also preferred that the triple bond in the alkynyl group is directly connected to the rest of the compound containing the alkynyl group, for example, 1-propyn-1-yl is more preferred than 2-propyn-1-yl. Without being limited by theory, in the present application, the term "alkynyl" also encompasses groups having a straight chain of carbon atoms and / or a straight chain with both unsaturated double bonds and unsaturated triple bonds.

[0149] In the present application, the alkynyl group may be optionally substituted by one or more substituents, each of which may be the same or different, for example, by one or more groups selected from the group consisting of deuterium, halogen, -CN, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, haloC1-10 alkyl, cycloalkyl, aryl or heteroaryl.

[0150] In the present application, "aryl" refers to any functional group or substituent derived from an aromatic carbocyclic ring. Aryl can be a monocyclic aryl (e.g., phenyl) or a polycyclic aryl. In other words, aryl can be a monocyclic aryl, a condensed ring aryl, two or more monocyclic aryl groups connected by a carbon-carbon bond, a monocyclic aryl and a condensed ring aryl connected by a carbon-carbon bond, or two or more condensed ring aryl groups connected by a carbon-carbon bond. That is, unless otherwise indicated, two or more aromatic groups connected by a carbon-carbon bond can also be considered as aryl of the present application. Wherein, condensed ring aryl can, for example, include bicyclic condensed aryl (e.g., naphthyl), tricyclic condensed aryl (e.g., phenanthrenyl, fluorenyl, anthracenyl), etc. Aryl does not contain heteroatoms such as B, N, O, S, P, Se, and Si. For example, in the present application, biphenyl, terphenyl, etc. are aryl. Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, fluorenyl, spirobifluorenyl, anthracenyl, phenanthrenyl, biphenyl, terphenyl, benzo[9,10]phenanthrenyl, pyrenyl, Ji et al.

[0151] In the present application, aryl may be optionally substituted by one or more substituents, each of which may be the same or different, for example, by one or more groups selected from the group consisting of deuterium, halogen, -CN, -OH, -O-C1-10 alkyl, C1-10 alkyl, halo-C1-10 alkyl, cycloalkyl, aryl or heteroaryl.

[0152] In the present application, the term "cycloalkyl" refers to a cyclic alkyl group including a saturated monocyclic, bicyclic or polycyclic ring, such as a C3-10 cycloalkyl group. A C3-10 cycloalkyl group refers to a cycloalkyl group including 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms as ring atoms (i.e., not including the number of carbon atoms in the substituent). Cycloalkyl groups may also include cycloalkyl groups having structures such as spirocycles, bridged rings, and rings. Representative cycloalkyl groups of the present invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, and norbornyl. It should be understood that substituted or unsubstituted cycloalkyl groups, such as branched cycloalkyl groups (e.g., 1-methylcyclopropyl and 2-methylcyclopropyl), are all included in the definition of "cycloalkyl". A C5-12 fused bicyclic group refers to a bicycloalkyl group including 5-12 carbon atoms as ring atoms, including, but not limited to: etc. C5-12 spiro bicyclic refers to a bicyclic alkyl group comprising 5 to 12 carbon atoms as ring atoms, including but not limited to: In the present invention, the cycloalkyl group is preferably a monocyclic or bicyclic cycloalkyl group containing 3 to 6 carbon atoms (ie, C3-6), such as cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl or cyclohexyl.

[0153] In the present application, the cycloalkyl group may be optionally substituted by one or more substituents, each of which may be the same or different, for example, by one or more groups selected from the group consisting of deuterium, halogen, -CN, -OH, -O-C1-10 alkyl, C1-10 alkyl, haloC1-10 alkyl, cycloalkyl, aryl or heteroaryl.

[0154] In the present application, term " cycloalkenyl " refers to cyclic aliphatic ring structure, and it has 1 or 2 unsaturated double bonds.C4-10 cycloalkenyl refers to the cycloalkenyl (i.e. excluding the carbon atom number in the substituent) including 4-10 (such as 4,5,6,7,8,9,10) carbon atoms as ring atoms. In some embodiments, similar to cycloalkyl, cycloalkenyl includes monocycle, spirocycle, condensed ring or bridged ring. In some embodiments, cycloalkenyl is preferably a monocyclic cycloalkenyl containing 4 to 6 carbon atoms, such as cyclobutenyl, cyclopentenyl, cyclohexenyl, 1,4-cyclohexadienyl etc. Cycloalkenyl can be connected by any ring atom, and it is also preferred that the double bond in the cycloalkenyl is directly connected to the rest of the compound comprising the cycloalkenyl, for example, cyclobutene-1-yl is more preferably cyclobutene-1-yl compared with cyclobutene-3-yl.

[0155] In the present application, the cycloalkenyl group may be optionally substituted by one or more substituents, each of which may be the same or different, for example, by one or more groups selected from the group consisting of deuterium, halogen, -CN, -OH, -O-C1-10 alkyl, C1-10 alkyl, halo-C1-10 alkyl, cycloalkyl, aryl or heteroaryl.

[0156] As used herein, the term "heterocycloalkenyl" refers to a cyclic unsaturated group in which one or two carbon atoms of the cycloalkenyl group are each independently replaced by a heteroatom selected from N, O, and S. No adjacent oxygen and / or sulfur atoms are present in the ring system. Preferred heterocycloalkenyl groups contain 5 to 6 ring atoms. The prefix aza, oxa, or thia before the heterocycloalkenyl name means that at least one nitrogen, oxygen, or sulfur atom, respectively, is present as a ring atom. Non-limiting examples of suitable monocyclic azaheterocycloalkenyl groups include 1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like. Non-limiting examples of suitable oxeterocyclyl groups include 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2,5-dihydrofuranyl, fluorodihydrofuranyl, and the like. A non-limiting example of a suitable polycyclic oxeterocyclyl group is 7-oxabicyclo[2.2.1]heptenyl. Non-limiting examples of suitable monocyclic thioheterocyclyl rings include dihydrothiophenyl, dihydrothiopyranyl, and the like.

[0157] In the present application, the heterocycloalkenyl group may be optionally substituted by one or more substituents, each of which may be the same or different, for example, by one or more groups selected from the group consisting of deuterium, halogen, -CN, -OH, -O-C1-10 alkyl, C1-10 alkyl, haloC1-10 alkyl, cycloalkyl, aryl or heteroaryl.

[0158] In the present application, the term "heteroaryl" refers to a monovalent aromatic ring or a derivative thereof containing at least one heteroatom in the ring, and the heteroatom can be one or more of B, O, N, P, Si, Se and S. The heteroaryl group can be a monocyclic heteroaryl group or a polycyclic (e.g., bicyclic) heteroaryl group. In other words, the heteroaryl group can be a single aromatic ring system or a plurality of aromatic ring systems connected by conjugated carbon-carbon bonds, and any aromatic ring system can be a single aromatic ring or a condensed aromatic ring. For example, heteroaryl groups can include, but are not limited to, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, oxadiazolyl, triazolyl, pyridyl, bipyridyl, pyrimidyl, triazinyl, acridinyl, pyridazinyl, pyrazinyl, quinolyl, quinazolinyl, quinoxalinyl, phenoxazinyl, phthalazinyl, 1H-imidazolyl, 1H-pyrrolyl, pyridopyrimidinyl, pyridopyrazinyl, pyrazinopyrazinyl, isoquinolyl, indolyl, carbazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzocarbazolyl, benzothiophenyl, dibenzothiophenyl, thienothiphenyl, benzofuranyl, phenanthrolinyl, isoxazolyl, thiadiazolyl, phenothiazinyl, silafluorenyl, dibenzofuranyl, and the like.

[0159] In the present application, the substituted heteroaryl group may be a heteroaryl group in which one or more hydrogen atoms are replaced by groups such as a deuterium atom, a halogen group, -CN, -OH, -O-C1-10 alkyl, an aryl group, a heteroaryl group, a C1-10 alkyl group, a cycloalkyl group, a halogenated C1-10 alkyl group, or the like.

[0160] In the present application, the term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spirocyclic ring. Heterocycloalkyl is typically a cycloalkyl group containing 1 to 5, preferably 1 to 3, heteroatoms independently selected from N, O and S (preferably 1 or 2 heteroatoms). Examples of heterocycloalkyl groups include, but are not limited to, oxiranyl, thioranyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, tetrahydropyrazolyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, pyranyl, pyridonyl, 3-pyrrolinyl, thiopyranyl, pyroneyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, azepanyl, oxepanyl, thiepanyl. A heterocycloalkyl group can be attached to the remainder of the molecule through a ring carbon or a heteroatom.

[0161] In the present application, the heterocycloalkyl group may be optionally substituted by one or more substituents, each of which may be the same or different, for example, by one or more groups selected from the group consisting of deuterium, halogen, -CN, -OH, -O-C1-10 alkyl, C1-10 alkyl, halo-substituted C1-10 alkyl, cycloalkyl, aryl or heteroaryl.

[0162] In the present application, examples of halogen include fluorine, chlorine, bromine or iodine.

[0163] "Haloalkyl" refers to an alkyl group substituted with one or more halogen atoms, wherein alkyl is as defined above and generally has the specified number of carbon atoms. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1-chloroethyl, 1,1-dichloroethyl, 1-fluoro-1-methylethyl, 1-chloro-1-methylethyl, and the like.

[0164] As used herein, "oxo" refers to a double-bonded oxygen (=0).

[0165] Unless otherwise indicated, as used herein, the point of attachment of a substituent can be from any suitable position of the substituent.

[0166] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

[0167] In this application, the wavy line Indicates the point of attachment of a group to the rest of the molecule.

[0168] In this application, when the same symbol appears multiple times, the substituents or atoms represented by the same symbol may be the same or different. For example, In Formula I, when R1 and R2 appear multiple times, they may be the same or different. This also applies to R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, 10 , definitions of Q1, Q2, Q3 and Q4.

[0169] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. A review of suitable salts is provided in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts formed by amino groups and acids, for example, amino salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane-propionate, diphosphite, dodecylsulfate, ethanesulfonate, formate, fumarate, gluconate, heptahydrogen sulfate, heptahydrogen sulfate, heptahydrogen iodide, 2-hydroxyethanesulfonate, lactate, laurate, lauroyl sulfate, malate, maleate, propionate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, hexanoate, fruit salt, persulfate, 3-phenylpropionate, phosphate, picrate, valerate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, etc. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide anions, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl groups having 1 to 6 carbon atoms, sulfonate and arylsulfonate. Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

[0170] In the present invention, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered together with the therapeutic agent and is suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response or other problems or complications corresponding to a reasonable benefit / risk ratio within the scope of reasonable medical judgment.

[0171] The pharmaceutical compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered by suitable routes, for example, by injection (such as intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

[0172] For these routes of administration, the pharmaceutical composition of the present invention can be administered in a suitable dosage form. The dosage form can be, for example, a solid preparation, a semi-solid preparation, a liquid preparation, or a gaseous preparation. The solid preparation is, for example, a tablet, capsule, powder, granule, or suppository, and the liquid preparation is, for example, a solution, suspension, or injection. The composition can also be in the form of a liposome, microsphere, or other dosage form. In some embodiments, the pharmaceutical composition is in the form of a preparation suitable for oral administration.

[0173] When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Physiological saline and glucose and glycerol aqueous solutions can also be used as liquid carriers, particularly for injections. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, etc. The composition can also optionally include a small amount of wetting agent, emulsifier or pH buffer. Oral formulations can include standard carriers, such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, saccharin sodium, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0174] As described below, the present application provides a compound of Formula I or a pharmaceutically acceptable salt thereof. The present application also provides materials and methods for preparing the compound of Formula 1, pharmaceutical compositions containing them, and uses of the compound of Formula I for treating diseases associated with GPR139.

[0175] The compound of formula I can also be used in combination with one or more other active ingredients to provide significant therapeutic advantages, such as providing a higher therapeutic effect or reducing side effects. Other active ingredients considered herein include antidepressants, antianxiety drugs, antipsychotics, sedatives, sleeping pills, or tranquilizers.

[0176] Antidepressants that can be used in combination with the compounds of Formula I include, but are not limited to, tricyclic antidepressants (TCAs), such as amitriptyline, butriptyline, clomipramine, desipramine, dosulepin, doxepin, imipramine, iprindole, lofepramine, melitracen, nortriptyline, opipramol, protriptyline, and trimipramine; tetracyclic antidepressants such as amoxapine, maprotiline, mianserin, and mirtazapine; dopaminergic agents such as bupropion, aripiprazole, sertraline, duloxetine, venlafaxine, nefazodone, milnacipran, amphetamine salts, pramipexole, ropinirole, citalopram, dapoxetine, S-citalopram, fluoxetine, fluvoxamine, indalpine, paroxetine, and zimelidine.

[0177] Anxiolytics that can be used in combination with the compounds of Formula I include, but are not limited to, benzodiazepines, such as midazolam, triazolam, alprazolam, lorazepam, chlordiazepoxide, diazepam, clonazepam.

[0178] Antipsychotics, sedatives, hypnotics, or tranquilizers that can be used in combination with the compounds of Formula I are selected from conventional drugs used in the art, such as chlorpromazine, sulpiride, haloperidol, risperidone, quetiapine, olanzapine, diazepam, alprazolam, clonazepam, estazolam, lorazepam, nitrazepam, zolpidem, zopiclone, eszopiclone, zaleplon, etc.

[0179] In the compound of formula I,

[0180] wherein each R1 is independently selected from H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl; wherein said -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl is optionally substituted with one or more groups selected from deuterium, halogen, -OH, -O-C1-10 alkyl, or C1-10 alkyl;

[0181] R2 is each independently selected from H, deuterium, halogen, C1-5 alkyl optionally substituted by one or more halogens, or -O-C1-5 alkyl optionally substituted by one or more halogens;

[0182] R3 is selected from deuterium, C1-6 alkyl, which is optionally substituted with one or more groups selected from the following: deuterium, -OH, halogen, oxo, -O-glucuronide, -NH2, or -NHCH2COOH;

[0183] R4 is selected from H, deuterium, -OH or -O-glucuronide;

[0184] Q1 and Q2 are each independently selected from N, NR5 or CR5, provided that Q1 and Q2 are not CR5 at the same time, wherein R5 is selected from H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl, or two adjacent R5 or R5 and R1 together with the atoms to which they are attached together form C4-10 cycloalkenyl, 4-10 membered heterocycloalkenyl, or 5- wherein the -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, , 4-10 membered heterocycloalkenyl, or 5-10 membered heteroaryl is optionally substituted with one or more groups selected from deuterium, oxo, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, or -C(O)R6, wherein R6 is selected from -OH, halogen, or C1-3 alkyl; and

[0185] wherein m is an integer selected from 0 to 2, and n is an integer selected from 0 to 5.

[0186] The compound of formula I may particularly have a structure represented by formula (I-1), formula (I-2), formula (I-3), formula (I-4), or formula (I-5):

[0187] The compounds of Formula I provided herein may exist as salts, complexes, solvates, hydrates, and liquid crystals, or may exist in amorphous, crystalline, or mixed solid forms thereof. The compounds of Formula I may also be isotopically labeled, resulting from the administration of a prodrug or forming metabolites with the desired pharmacological activity after administration. The compounds of Formula (I) may be stereoisomers, tautomers, or combinations thereof.

[0188] The term "solvate" refers to a compound that exists in combination with certain solvent molecules. The combination may include a stoichiometric amount of a certain solvent, for example, when the solvent is water, a "hydrate" is formed, such as a monohydrate or a dihydrate, or may include any amount of water; for example, when the solvent is an alcohol, such as methanol or ethanol, an "alcoholate" may be formed, which may also be stoichiometric or non-stoichiometric. The term "solvate" as used herein refers to a solid form, that is, a compound in a solution of a solvent, although it may be solvated, it is not a solvate as the term is used herein. The term "isotopically labeled" refers to a compound in which any atom in the compound is replaced by an isotope atom thereof. Examples of isotopes of compounds that can be listed as of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, such as respectively 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl. The term "prodrug" refers to a derivative that can be hydrolyzed, oxidized or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound of the present invention. Prodrugs only undergo this reaction to become active compounds under biological conditions, or they have no or only low activity in their unreactive form. "Metabolite" refers to a compound formed in vivo after administration of a pharmacologically active compound. "Stereoisomers" are produced by the presence of one or more stereocenters, one or more double bonds, or both, and stereoisomers can be pure, substantially pure, or mixtures. The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom in two positions in a molecule, such as the very typical enol-keto tautomers.

[0189] The following abbreviations may be used in this specification: DIPEA (N,N-diisopropylethylamine); DCM (dichloromethane); HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate); DMF (N,N-dimethylformamide); dppf (1,1"-bis(diphenylphosphino)ferrocene); THF (tetrahydrofuran); PE (petroleum ether); EtOAc (ethyl acetate); NBS (N-bromosuccinimide); MeOH (methanol); EtOH (ethanol).

[0190] Some exemplary compounds of Formula I can be produced by one or more of the following synthetic schemes. The substituent identifiers R1, R2, and R5 in the schemes have the meanings as defined above for the compounds of Formula I.

[0191] Synthesis Scheme A

[0192] Synthesis Scheme B

[0193] Synthesis Scheme C

[0194] The compounds whose synthesis methods are not mentioned in this application are all raw materials obtained through commercial channels.

[0195] Example

[0196] The following examples are provided to facilitate understanding of the present invention. However, it should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the present invention in any way. The actual scope of the present invention is set forth in the claims. It should be understood that any modifications and variations may be made without departing from the spirit of the present invention.

[0197] The following Table 1 lists the specific compounds in the Examples, and Table 2 lists the preferred compounds.

[0198] Table 1.

[0199] Table 2. List of preferred compounds

[0200] Example 1: Synthesis of compound BR-028723

[0201] Step 1: To a solution of 5-bromopyrimidin-4(3H)-one (1 g, 5.71 mmol) and phenylboronic acid (1.05 g, 8.57 mmol) in dioxane / H2O (15 mL, 7:1) was added Pd(dppf)Cl2 (414.4 mg, 1.79 mmol) and Na2CO3 (1.51 g, 14.27 mmol) at room temperature. The reaction mixture was stirred at 100°C for 12 hours. The mixture was extracted with ethyl acetate (40 mL×3), and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to provide a residue, which was purified by silica gel column chromatography (PE:EtOAc=1:1) to give 5-phenylpyrimidin-4(3H)-one (980 mg, 5.69 mmol, yield=99.6%) as a gray solid. LCMS (ESI) m / z: [m+H] +173.0

[0202] Step 2: To a solution of 5-phenylpyrimidin-4(3H)-one (980 mg, 5.69 mmol) and methyl 2-bromoacetate (1.04 g, 6.83 mmol) in DMSO (10 mL) was added KCO (1570 mg, 11.38 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was extracted with ethyl acetate (40 mL×3), and the combined organic layers were washed with brine, dried over NaSO, filtered and concentrated to give crude methyl 2-(6-oxo-5-phenylpyrimidin-1(6H)-yl)acetate (800 mg, 3.28 mmol, yield = 57.55%) as a gray solid. LCMS (ESI) m / z: [m+H] + 245.0

[0203] Step 3: To a solution of methyl 2-(6-oxo-5-phenylpyrimidin-1(6H)-yl)acetate (800 mg, 3.28 mmol) in THF / H2O (14 mL, 5:1) was added LiOH (392 mg, 16.4 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The pH of the reaction mixture was adjusted to 1 and extracted with ethyl acetate (30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 2-(6-oxo-5-phenylpyrimidin-1(6H)-yl)acetic acid (600 mg, 2.61 mmol, yield = 79.57%) as a gray solid. LCMS (ESI) m / z: [m+H] + 231.0

[0204] Step 4: To a solution of 2-(6-oxo-5-phenylpyrimidin-1(6H)-yl)acetic acid (600 mg, 2.61 mmol) in DMF (10 mL) was added (S)-1-phenylethane-1-amine (379 mg, 3.13 mmol), HATU (1985 mg, 5.22 mmol), and DIPEA (1349 mg, 10.44 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was extracted with ethyl acetate (30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by Perp-HPLC to give (S)-2-(6-oxo-5-phenylpyrimidin-1(6H)-yl)-N-(1-phenylethyl)acetamide (56.4 mg, 0.169 mmol, yield = 6.5%) as a white solid.

[0205] 1H-NMR (400MHz, DMSO-d6) δ8.78 (d, J=7.9Hz, 1H), 8.37 (s, 1H), 8.12 (s, 1H), 7.66-7.60 (m, 2H), 7.41-7. 26(m,7H),7.20(ddt,J=8.6,5.6,2.7Hz,1H),4.90(p,J=7.0Hz,1H),4.66(s,2H),1.35(d,J=7.0Hz,3H).

[0206] LCMS (ESI) m / z: [M+H] + 334.1; purity = 97.59% (254 nm); retention time = 1.30 min.

[0207] Example 2: Synthesis of compound BR-028724

[0208] Step 1: To a solution of 3-oxo-3-phenyl-propionic acid ethyl ester (2000 mg, 10.41 mmol, 1.80 mL) in MeOH (15 mL) was added formamidine hydrochloride (458.41 mg, 10.41 mmol) and sodium methoxide (1.75 grams, 15.61 mmol). The mixture was heated to 80 ° C and stirred for 12 hours. LCMS showed that the reaction was complete. Water was added and filtered to obtain a crude product. The crude product was washed with MeOH to obtain 4-phenyl-1H-pyrimidin-6-one (310 mg, 1.80 mmol, 17.30% yield). LCMS (ESI) m / z: [m + H] + 173.1

[0209] Step 2: To a solution of 4-phenyl-1H-pyrimidin-6-one (310 mg, 1.80 mmol) in DMF (5 mL) was added methyl 2-bromoacetate (330.50 mg, 2.16 mmol, 199.70 μL) and potassium carbonate (497.65 mg, 3.60 mmol, 217.32 μL). The mixture was stirred at room temperature for 12 hours. Lcms indicated the reaction was complete. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel chromatography (gradient: ethyl acetate in PE from 0% to 50%) to give methyl 2-(6-oxo-4-phenyl-pyrimidin-1-yl)acetate (230 mg, 941.68 μmol, 52.30% yield). LCMS (ESI) m / z: [m+H] + 245.3

[0210] Step 3: To a solution of methyl 2-(6-oxo-4-phenyl-pyrimidin-1-yl)acetate (230 mg, 941.68 μmol) in MeOH (10 mL) and water (2 mL) was added lithium hydroxide (225.52 mg, 9.42 mmol). The mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The pH of the mixture was then adjusted to 7 with 2M HCl. The solvent was removed under reduced pressure to give 2-(6-oxo-4-phenyl-pyrimidin-1-yl)acetic acid (200 mg, 868.74 μmol, 92.25% yield). LCMS (ESI) m / z: [m+H] + 231.3

[0211] Step 4: To a solution of 2-(6-oxo-4-phenyl-pyrimidin-1-yl)acetic acid (200 mg, 868.74 μmol) in DMF (5 mL) was added (S)-1-phenylethane-1-amine (157.91 mg, 1.30 mmol, 166.57 μL), HATU (498.11 mg, 498.11 mg, 1.30 mmol) and DIPEA (224.56 mg, 1.74 mmol, 302.64 μL). The mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The residue was diluted with water (50 milliliters) and extracted with ethyl acetate (3 x 50 milliliters). The combined organic layers were washed with saturated sodium chloride aqueous solution (50 mL), dried over sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by preparative HPLC to give 2-(6-oxo-4-phenyl-pyrimidin-1-yl)-N-[(1S)-1-phenylethyl]acetamide (92 mg, 275.96 μmol, 31.77% yield).

[0212] 1 H-NMR (400MHz, DMSO-d6) δ8.77(t,J=6.6Hz,1H),8.44(s,1H),8.06-7.98(m,2H),7.50-7.42(m,3H),7. 34-7.26(m,4H),7.24-7.16(m,1H),6.93(s,1H),4.96-4.84(m,1H),4.62(s,2H),1.35(d,J=5.7Hz,3H).

[0213] LCMS (ESI) m / z: [M+H] + 334.1; purity = 100% (254 nm); retention time = 1.50 min.

[0214] Example 3: Synthesis of compound BR-028725

[0215] The same method as in Example 2: Synthesis of Compound BR-028724 was used, except that the starting material 3-oxo-3-phenyl-propionic acid ethyl ester was replaced with 3-oxohexanoic acid ethyl ester (2000 mg, 12.64 mmol).

[0216] Step 1: Obtain 4-propyl-1H-pyrimidin-6-one (1 g, 7.24 mmol, 57.25% yield). LCMS (ESI) m / z: [m+H] + 139.0

[0217] Step 2: Obtain 2-(6-oxo-4-propyl-pyrimidin-1-yl)acetic acid methyl ester (600 mg, 2.85 mmol, 39.43% yield). LCMS (ESI) m / z: [m+H] + 214.3

[0218] Step 3: 2-(6-Oxo-4-propyl-pyrimidin-1-yl)acetic acid (500 mg, 2.55 mmol, 89.29% yield). LCMS (ESI) m / z: [m+H] + 197.3

[0219] Step 4: 2-(6-oxo-4-propylpyrimidin-1-yl)-N-[(1S)-1-phenylethyl]acetamide (6 mg, 20.04 μmol, 3.93% yield) was obtained.

[0220] 1 H NMR(400MHz, DMSO-d6)δ8.71(d,J=7.9Hz,1H),8.23(s,1H),7.42–7.13(m,5H),6.16(s,1H),4.86(q,J=7 .1Hz,1H),4.53(s,2H),2.37(s,2H),1.57(d,J=7.5Hz,2H),1.34(d,J=7.0Hz,3H),0.85(t,J=7.4Hz,3H).

[0221] LCMS (ESI) m / z: [M+H] + 300.3; purity = 100% (254 nm); retention time = 1.55 min.

[0222] Example 4: Synthesis of compound BR-028811

[0223] Step 1: To a solution of 5-bromo-1H-pyrimidin-6-one (500 mg, 2.86 mmol) in 1,4-dioxane (9.77 mL) was added potassium (E)-trifluoro(prop-1-en-1-yl)borate (634.22 mg, 4.29 mmol) and Na2CO3. The reaction mixture was stirred at 150°C for 12 hours. Water (30 mL) was added, the combined aqueous layers were extracted with ethyl acetate (3×50 mL), the combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification by silica gel column chromatography (DCM:MeOH=10:1) gave compound 5-[(E)-prop-1-enyl]-1H-pyrimidin-6-one (271 mg, 1.99 mmol, 69.66% yield) as a white solid.

[0224] LCMS (ESI) m / z: [m+H] + 137.0.

[0225] Step 2: To a solution of 5-[(E)-propyl-1-enyl]-1H-pyrimidin-6-one (100 mg, 734.48 μmol) in DMF (10 mL) was added (S)-2-bromo-N(1-phenylethyl)acetamide (177.83 mg, 734.4 μmol) and potassium carbonate (203.02 mg, 1.47 mmol, 88.65 μL). The reaction mixture was stirred at 25° C. for 12 hours. Water (30 mL) was added and the combined aqueous layers were extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel column chromatography (DCM:MeOH=10:1) to give the target compound 2-[6-oxo-5-[(Z)-propyl-1-enyl]pyrimidin-1-yl]-N-[(1S)-1-phenylethyl]acetamide (27.9 mg, 93.83 μmol, 12.77% yield) as a white solid.

[0226] 1 H NMR(400MHz, DMSO-d6)δ8.73(d,J=8.0Hz,1H),8.22(s,1H),7.93(s,1H),7.33-7.17(m,5H),6.80-6.60( m,1H),6.30-6.15(m,1H),4.96-4.85(m,1H),4.60(s,2H),1.78(d,J=4.5Hz,3H),1.35(d,J=4.0Hz,3H).

[0227] LCMS (ESI) m / z: [M+H] + 298.0; purity = 97.99% (254nm); retention time = 7.964

[0228] Example 5: Synthesis of Compound BR-028812

[0229] Step 1: To a solution of 5-[(E)-propyl-1-enyl]-1H-pyrimidin-6-one (130 mg, 954.82 μmol) in methanol (10 mL) was added Pd / C (10%, 30.84 mg) at room temperature under a nitrogen atmosphere. The mixture was hydrogenated at room temperature for 10 hours using a hydrogen balloon, filtered through a celite pad, and concentrated under reduced pressure to give the crude product 5-propyl-1H-pyrimidin-6-one (100 mg, 723.76 μmol, 75.80% yield) as a white solid.

[0230] LCMS (ESI) m / z: [m+H] + 139.0

[0231] Step 2: To a solution of 5-propyl-1H-pyrimidin-6-one (100 mg, 723.76 μmol) in DMF (9.96 mL) were added (S)-2-bromo-N-(1-phenylethyl)acetamide (175.23 mg, 723.75 μmol) and potassium carbonate (200.06 mg, 1.45 mmol, 87.36 μL). After completion of the reaction, water (30 mL) was added, and the combined aqueous layers were extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel column chromatography (DCM:MeOH = 10:1) to afford the target compound, 2-(6-oxo-5-propylpyrimidin-1-yl)-N-[(1S)-1-phenylethyl]acetamide (15.7 mg, 52.44 μmol, 7.25% yield), as a white solid.

[0232] 1 H NMR(400MHz, DMSO-d6)δ8.72(d,J=7.9Hz,1H),8.19(s,1H),7.73(s,1H),7.40-7.15(m,5H),4.95-4.80(m ,1H),4.57(s,2H),2.28(t,J=8.0Hz,2H),1.55-1.40(m,2H),1.34(d,J=7.0Hz,3H),0.83(t,J=7.4Hz,3H).

[0233] LCMS (ESI) m / z: [M+H] + 300.0; purity = 100.00% (254 nm); retention time = 7.846 min.

[0234] Example 6: Synthesis of Compound BR-029039

[0235] To a solution of 2-(7-hydroxy-4-oxo-6,7-dihydro-5H-cyclopentyl[d]pyrimidin-3-yl)-N-[(1S)-1-phenylethyl]acetamide (50 mg, 159.57 μmol) in DCM (10 mL) was added (1,1-diacetoxy-3-oxo-1,2-benzyliodineoxy-1-yl)acetate (81,21 mg, 191.48 μmol). The mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The solvent was removed under reduced pressure to give a crude product. The residue was diluted with water (50 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered and concentrated to give a crude product, which was purified by preparative HPLC to give 2-(4,7-dioxy-5,6-dihydrocyclopenta[d]pyrimidin-3-yl)-N-[(1S)-1-phenylethyl]acetamide (10 mg, 32.12 μmol, 20.13% yield).

[0236] 1 H NMR(400MHz, DMSO-d6)δ8.81(d,J=7.9Hz,1H),8.45(s,1H),7.42–7.30(m,4H),7.30–7.22(m,1H) ),5.06–4.86(m,1H),4.71(s,2H),2.92–2.72(m,2H),2.71–2.59(m,2H),1.39(d,J=7.0Hz,3H).

[0237] LCMS (ESI) m / z: [M+H] + 312.3; purity = 95.90% (254 nm); retention time = 2.27 min.

[0238] Example 7: Synthesis of Compound BR-029131

[0239] Step 1: To a solution of trifluoromethanesulfonic anhydride (8.30 g, 29.41 mmol) in THF (40 mL) was added NaH (60% dispersion in oil) (705.66 mg, 29.41 mol) at 0°C. The mixture was stirred at rt for 30 minutes, then 2-oxocyclopentane-1-methyl carboxylate (3800 mg, 26.73 mmol) was added and stirred for 4 hours. Lcms indicated the reaction was complete. The residue was diluted with water (50 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with saturated aqueous sodium chloride (50 ml), dried over sodium sulfate, filtered and concentrated to give the crude product which was purified by silica gel chromatography (Gradient: 0% to 20% MeOH in DCM) to give methyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-1-ene-1-carboxylate (7000 mg, 25.53 mmol, 95.49% yield). LCMS (ESI) m / z: [m+H]+ 275.3

[0240] Step 2: Under N2 atmosphere, to a solution of methyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclopentane-1-carboxylate (6500 mg, 23.70 mmol) in DMF (50 mL) were added CuI (451.45 mg, 2.37 mmol, 80.33 μL), ethynyltrimethylsilane (2.56 g, 26.07 mmol) and Pd(PPh3)2Cl2 (831.89 mg, 1.19 mmol). The mixture was heated to 60°C and stirred under N2 atmosphere for 12 hours. Lcms showed that the reaction was complete. The residue was diluted with water (50 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with saturated sodium chloride aqueous solution (50 ml), dried over sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel chromatography (Gradient: 0% to 20% ethyl acetate in PE) to give methyl 2-((trimethylsilyl)ethynyl)cyclopent-1-ene-1-carboxylate (4000 mg, 17.99 mmol, 75.89% yield). LCMS (ESI) m / z: [m+H]+ 222.3

[0241] Step 3: To a solution of methyl 2-(2-trimethylsilylethynyl)cyclopentene-1-carboxylate (3500 mg, 15.74 mmol) in MeOH (20 mL) and water (3 mL) was added LiOH.HO (6.61 g, 157.41 mmol). The mixture was heated to 60°C and stirred under N2 atmosphere for 12 hours. Lcms showed that the reaction was complete. The solvent was removed under reduced pressure to give the crude product. The residue was diluted with water (50 mL), the pH was adjusted to 7, and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated to give the crude product, which was used directly in the next step without further purification. 2-ethynylcyclopentene-1-carboxylic acid (2000 mg, 14.69 mmol, 93.33% yield) LCMS (ESI) m / z: [m+H]+137.3.

[0242] Step 4: To a solution of 2-ethynylcyclopentene-1-carboxylic acid (500 mg, 3.67 mmol) in DMF (10 mL) were added HATU (2.09 g, 5.51 mmol), ammonia; hydrochloric acid (589.34 mg, 11.02 mmol), and DIPEA (1.42 g, 11.02 mol, 1.92 mL). The mixture was stirred at room temperature for 4 h. Lcms indicated the reaction was complete. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated to give the crude product, which was purified by silica gel chromatography (gradient: 0% to 50% ethyl acetate in PE) to give 2-ethynylcyclopentene-1-carboxamide (200 mg, 1.48 mmol, 40.29% yield).

[0243] LCMS (ESI) m / z: [m+H] + 136.3

[0244] Step 5: To a solution of 2-ethynylcyclopentene-1-carboxamide (200 mg, 1.48 mmol) in MeOH (10 mL) was added morpholine (257.82 mg, 2.96 mmol, 258.86 μL). The mixture was heated to 100 ° C and stirred for 4 hours. Lcms showed that the reaction was complete. The solvent was removed under reduced pressure to give the crude product. The residue was diluted with water (50 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by silica gel chromatography (gradient: 0% to 100% ethyl acetate in PE) to give 2,5,6,7-tetrahydrocyclopenta [c] pyridin-1-one (100 mg, 739.85 μmol, 50.00% yield)

[0245] LCMS (ESI) m / z: [m+H] + 126.3

[0246] Step 6: To a solution of (S)-1-(4-(trifluoromethoxy)phenyl)ethan-1-amine (48.25 mg, 147.97 μmol) in DMF (3 mL) were added KCO (40.84 mg, 295.94 μmol), 2,5,6,7-tetrahydrocyclopenta[c]pyridin-1-one (20 mg, 147.907 μmol). The mixture was stirred at room temperature for 2 hours. Lcms showed that the reaction was complete. The residue was diluted with water (50 mL) and washed with ethyl acetate (3x The combined organic layers were washed with saturated aqueous sodium chloride (50 ml), dried over sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel chromatography (gradient: 0% to 50% ethyl acetate in PE) to give 2-(1-oxo-6,7-dihydro-5H-cyclopenta[c]pyridin-2-yl)-N-[(1S)-1-[4-(trifluoromethoxy)phenyl]ethyl]acetamide (40 mg, 105.16 μmol, 71.07% yield).

[0247] 1 H NMR (400MHz, DMSO-d6) δ8.65(d,J=7.4Hz,1H),7.48–7.33(m,3H),7.28(d,J=9.8Hz,2H),6.14(d,J=5.0Hz,1H),4.90(d ,J=9.6Hz,1H),4.53(s,2H),2.74(t,J=7.5Hz,2H),2.57(t,J=7.3Hz,2H),1.93(d,J=8.3Hz,2H),1.34(d,J=7.0Hz,3H).

[0248] LCMS (ESI) m / z: [M+H] + 431.3; purity = 98.85% (254 nm); retention time = 1.40 min.

[0249] Example 8: Synthesis of Compound BR-029218

[0250] To a solution of 5,7-dihydro-3H-furo[3,4-d]pyrimidin-4-one (80 mg, 579.19 μmol) in DMF (3 mL) were added K2CO3 (159.86 mg, 1.16 mmol), 2-bromo-N-[(1S)-1-phenylethyl]acetamide (140.23 mg, 579.19 μmol). The mixture was stirred at room temperature for 2 hours. Lcms showed that the reaction was complete. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL),

[0251] The residue was dried over sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by preparative HPLC (TFA) to give 2-(4-oxo-5,7-dihydrofuro[3,4-d]pyrimidin-3-yl)-N-[(1S)-1-phenylethyl]acetamide (20 mg, 66.82 μmol, 11.54% yield).

[0252] 1 H NMR(400MHz, DMSO-d6)δ8.74(d,J=5.3Hz,1H),8.37(s,1H),7.37–7.26(m,4H),7. 26–7.14(m,1H),4.94–4.84(m,3H),4.84–4.78(m,2H),4.63(s,2H),1.35(d,3H).

[0253] LCMS (ESI) m / z: [M+H] + 300.20; purity = 98.13% (254 nm); retention time = 1.38 min.

[0254] Example 9: Synthesis of Compound BR-032121

[0255] Step 1: To a solution of 3,5,6,7-tetrahydrocyclopenta[d]pyrimidin-4-one (800 mg, 5.88 mmol) in AcOH (20 mL) was added NBS (1.25 g, 7.05 mmol, 598.17 μL) and the mixture was stirred at 110 ° C for 12 hours. LCMS showed that the reaction was complete. The crude product was purified by preparative HPLC to give 7-bromo-3,5,6,7-tetrahydrocyclopenta[d]pyrimidin-4-one (400 mg, 1.86 mmol, 31.66% yield). LCMS (ESI) m / z: [M+H] + 251.3

[0256] Step 2: To a solution of 7-bromo-3,5,6,7-tetrahydrocyclopentanepyrimidin-4-one (10 mg, 46.50 μmol) in acetic acid (5 mL) was added AcONa (11.44 mg, 139.50 μmol, 7.49 μL). The mixture was heated to 120 ° C and stirred under a nitrogen atmosphere for 12 hours. LCMS showed that the reaction was complete. The solvent was removed under reduced pressure to obtain a crude product. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered and concentrated to give the crude product, which was purified by silica gel chromatography (Gradient: 0% to 20% MeOH in DCM) to give (4-oxo-3,5,6,7-tetrahydrocyclopentanepyrimidin-7-yl)acetate (8 mg, 41.20 μmol, 88.59% yield). LCMS (ESI) m / z: [M+H] + 195.3

[0257] Step 3: To a solution of (4-oxo-3,5,6,7-tetrahydrocyclopenta[d]pyrimidin-7-yl)acetate (300 mg, 1.54 mmol) in MeOH (30 mL) and water (5 mL) was added LiOH.HO (648.30 mg, 15.45 mmol). The mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. LCMS showed that the reaction was complete. The pH was adjusted to 7 with HCl aqueous solution, and the solvent was removed under reduced pressure to obtain a crude product. The residue was diluted with water (50 mL), extracted with ethyl acetate (3 x 80 mL), and the combined organic layers were washed with saturated sodium chloride aqueous solution (50 mL), dried over sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel chromatography (Gradient: 0% to 20% MeOH in DCM) to give 7-hydroxy-3,5,6,7-tetrahydrocyclopenta[d]pyrimidin-4-one (200 mg, 1.31 mmol, 85.09% yield). LCMS (ESI) m / z: [M+H] + 256.3.

[0258] Step 4: To a solution of 7-hydroxy-3,5,5,6,7-tetrahydrocyclopentadien[d]pyrimidin-4-one (300 mg, 1.97 mmol) in dry DMF (15 mL) was added KCO (545.01 mg, 3.94 mmol) at 0°C. The mixture was stirred at room temperature for 15 minutes, followed by the addition of 2-bromo-N-[(1S)-1-phenylethyl]acetamide (477.38 mg, 1.97% mmol) and stirred for 4 hours. LCMS indicated completion. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered and concentrated to give the crude product, which was purified by silica gel chromatography (Gradient: 0% to 20% MeOH in DCM) to give 2-(7-hydroxy-4-oxo-6,7-dihydro-5H-cyclopentyl[d]pyrimidin-3-yl)-N-[(1S)-1-phenylethyl]acetamide (300 mg, 957.39 μmol, 48.56% yield).

[0259] 1 H NMR (400MHz, DMSO-d6) δ8.75(d,J=7.9Hz,1H),8.29(s,1H),7.42–7.28(m,4H),7.29–7.16(m,1H),5.52–5.41(m,1H),4.99–4.87(m,1H) ),4.86–4.77(m,1H),4.62(s,2H),2.75–2.57(m,1H),2.49–2.39(m,1H),2.38–2.23(m,1H),1.80–1.66(m,1H),1.38(d,J=7.0Hz,3H).

[0260] LCMS (ESI) m / z: [M+H] + 314.3; purity = 100% (254 nm); retention time = 2.17 min.

[0261] Example 10: Synthesis of Compound BR-032122

[0262] To a solution of 2-(7-hydroxy-4-oxo-6,7-dihydro-5H-cyclopentadien[d]pyrimidin-3-yl)-N-[(1S)-1-phenylethyl]acetamide (50 mg, 159.57 μmol) in DCM (15 mL) was added DAST (77.16 mg, 478.70 μmol, 63.25 μL) at 0° C. The mixture was stirred at 25° C. for 2 hours. Lcms indicated the reaction was complete. The residue was quenched with ice water (10 mL), diluted with water (50 mL), extracted with ethyl acetate (3×50 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL). The crude product was purified by preparative HPLC to give 2-(7-fluoro-4-oxo-6,7-dihydro-5H-cyclopentyl[d]pyrimidin-3-yl)-N-[(1S)-1-phenylethyl]acetamide (32 mg, 101.48 μmol, 63.60% yield).

[0263] 1 H NMR (400MHz, DMSO-d6) δ8.78(d,J=7.9Hz,1H),8.38(s,1H),7.46–7.18(m,5H),5.97–5.66(m,1H),5.04–4.85(m,1H ),4.66(s,2H),2.87–2.72(m,1H),2.70–2.55(m,1H),2.50–2.36(m,1H),2.22–1.98(m,1H),1.39(d,J=7.0Hz,3H).

[0264] LCMS (ESI) m / z: [M+H] + 316.3; purity = 100% (254 nm); retention time = 2.39 min.

[0265] Example 11 Synthesis of Compound BR-032146

[0266] Step 1: A mixture of 5-bromo-1H-pyrimidin-6-one (4.5 g, 25.72 mmol), phenylboronic acid (4.86 g, 39.86 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.87 g, 2.57 mmol) and sodium carbonate (8.18 g, 77.15 mmol, 3.23 mL) in dioxane (100 mL) and water (20 mL) was stirred at 100° C. under N2 overnight. Concentration and purification by column chromatography (DCM:MeOH=20:1) gave 5-phenyl-1H-pyrimidin-6-one (953 mg, 5.26 mmol, 20.45% yield, 95% purity) as a light grey solid.

[0267] LCMS (ESI) m / z: [m+H] + 173.0

[0268] Step 2: A mixture of 5-phenyl-1H-pyrimidin-6-one (966 mg, 5.61 mmol), methyl 2-bromoacetate (1.03 g, 6.73 mmol, 622.28 μL) and potassium carbonate (1.55 g, 11.22 mmol, 677.18 μL) in DMF (15 mL) was stirred at room temperature overnight. Water (100 mL) was added to the mixture and extracted with EA (50 mL x 2). The organic layer was washed with brine (100 mL) and concentrated. The crude product was purified by flash column chromatography (PE: EA = 1: 1) to give methyl 2-(6-oxo-5-phenyl-pyrimidin-1-yl)acetate (952 mg, 3.51 mmol, 62.53% yield, 90% purity) as a light grey solid. LCMS (ESI) m / z: [M+H] + 245.0

[0269] Step 3: A mixture of methyl 2-(6-oxo-5-phenyl-pyrimidin-1-yl)acetate (875 mg, 3.58 mmol) and lithium hydroxide monohydrate (902.00 mg, 21.49 mmol) in MeOH (20 mL), THF (10 mL) and water (4 mL) was stirred at room temperature overnight. The mixture was concentrated and the pH was adjusted to pH=5 with HCl (1 N), then extracted with EA (50 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated to give the title product 2-(6-oxo-5-phenyl-pyrimidin-1-yl)acetic acid (712 mg, 2.94 mmol, 82.01% yield, 95% purity) as a white solid.

[0270] LCMS (ESI) m / z: [M+H] + 231.0

[0271] Step 4: A mixture of 2-(6-oxo-5-phenyl-pyrimidin-1-yl)acetic acid (100 mg, 434.37 μmol) and (1S)-1-(p-tolyl)ethylamine (76.35 mg, 564.68 μmol) in DMF (3 mL) was added EDCI (124.90 mg, 651.55 μmol), HOBT (88.04 mg, 651.5 μmol) and DIPEA (168.42 mg, 1.30 mmol, 226.98 μL). The reaction was stirred at room temperature for 16 hours. The mixture was added to water (20 mL) and extracted with EA (20 mL×2). The organic layer was washed with brine and concentrated. The crude product was purified by preparative TLC (DCM:MeOH=15:1) to give 2-(6-oxo-5-phenyl-pyrimidin-1-yl)-N-[(1S)-1-(p-tolyl)ethyl]acetamide (49.2 mg, 139.50 μmol, 32.11% yield, 98.5% purity) as a white solid.

[0272] 1 H NMR (400MHz, DMSO-d6) δ8.74(d,J=7.9Hz,1H),8.39(s,1H),8.14(s,1H),7.69–7.64(m,2H),7.44–7.33(m,3H),7. 22(d,J=8.1Hz,2H),7.12(d,J=7.9Hz,2H),4.89(p,J=7.0Hz,1H),4.68(s,2H),2.27(s,3H),1.36(d,J=7.0Hz,3H).

[0273] LCMS (ESI) m / z: [M+H] + 348.2; purity = 100.0% (214 nm); retention time = 2.72 min.

[0274] Example 12 Synthesis of Compound BR-032148

[0275] To a mixture of (S)-1-(3,4-difluorophenyl)ethane-1-amine (69.57 mg, 359.29 μmol, HCl) and 2-(6-oxo-5-phenyl-pyrimidin-1-yl)acetic acid (80 mg, 347.50 μmol) in DMF (3 mL) was added EDCI (99.92 mg, 521.24 μmol), 1-hydroxybenzotriazole (70.43 mg, 5210.24 μmol) and DIPEA (134.73 mg, 1.04 mmol, 181.58 μL). The reaction was stirred at room temperature for 16 hours. Water (20 mL) was added and the mixture was extracted with EA (20 mL x 2). Washed with brine. Concentration and purification by preparative TLC (DCM:MeOH=15:1) gave (S)-N-(1-(3,4-difluorophenyl)ethyl)-2-(6-oxo-5-phenylpyrimidin-1(6H)-yl)acetamide (38.1 mg, 101.09 μmol, 29.09% yield, 98% purity) as a white solid.

[0276] 1 H NMR(400MHz, DMSO-d6)δ8.84(d,J=7.7Hz,1H),8.40(s,1H),8.16(s,1H),7.71–7.64(m,2H),7. 47–7.33(m,5H),7.22–7.14(m,1H),4.92(p,J=7.0Hz,1H),4.69(s,2H),1.38(d,J=7.0Hz,3H).

[0277] LCMS (ESI) m / z: [M+H] + 370.2; purity = 100.0% (214 nm); retention time = 2.70 min.

[0278] Example 13 Synthesis of Compound BR-032183

[0279] To a mixture of (1S)-1-[4-(trifluoromethoxy)phenyl]ethanamine (65.50 mg, 319.26 μmol) and 2-(6-oxo-5-phenyl-pyrimidin-1-yl)acetic acid (70 mg, 304.06 μmol) in DMF (3 mL) was added EDCI (87.43 mg, 456.09 μmol). The reactants were stirred at room temperature for 16 hours. After the reaction was completed, water (20 mL) was added to the mixture and extracted with EA (20 mL×2). The organic layer was washed with brine and concentrated. The crude product was purified by preparative TLC (DCM:MeOH=15:1) to give BR-032183 (64.1 mg, 152.04 μmol, 50.00% yield, 99% purity) as a white solid.

[0280] 1 H NMR(400MHz,DMSO-d6)δ8.86(d,J=7.7Hz,1H),8.40(s,1H),8.15(s,1H),7.70–7.64(m,2H),7.4 9–7.29(m,7H),4.96(p,J=7.0Hz,1H),4.69(s,2H),1.39(d,J=7.0Hz,3H).LCMS(ESI)m / z:[M+H] + 418.2; purity = 98.45% (214 nm); retention time = 2.85 min.

[0281] Example 14 Synthesis of Compound BR-032184

[0282] To a solution of 2-(6-oxo-5-phenyl-pyrimidin-1-yl)acetic acid (80 mg, 347.50 μmol) and DIPEA (134.73 mg, 1.04 mmol, 181.58 μL) in DMF (4.84 mL) was added EDCI (99.92 mg, 521.24 μmol) and HOBT (79.82 mg, 5210.24 μmol). After 15 minutes, (S)-1-(4-(trifluoromethyl)phenyl)ethan-1-amine (78.89 mg, 416.99 μmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was then purified by preparative HPLC to afford BR-032184 (6 mg, 14.95 μmol, 4.30% yield) as a white solid.

[0283] 1 H NMR(400MHz, DMSO-d6)δ8.93(d,J=7.4Hz,1H),8.39(s,1H),8.15(s,1H),7.68(t,J=8.6Hz,4H), 7.56(d,J=8.1Hz,2H),7.45–7.34(m,3H),5.04–4.95(m,1H),4.71(s,2H),1.41(d,J=7.0Hz,3H).

[0284] LCMS (ESI) m / z: [M+H] + 402.0; purity = 99.19% (254 nm); retention time = 7.433 min.

[0285] Example 15 Synthesis of Compound BR-032185

[0286] To a solution of 2-(6-oxo-5-phenyl-pyrimidin-1-yl)acetic acid (80 mg, 347.50 μmol) and DIPEA (134.73 mg, 1.04 mmol, 181.58 μL) in DMF (5 mL) was added EDCI (99.92 mg, 521.24 μmol) and HOBT (79.82 mg, 5210.24 μmol). After 15 minutes, (1S)-1-(4-chlorophenyl)ethanamine (64.89 mg, 416.99 μmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The mixture was purified by preparative HPLC to give BR-032185 (29 mg, 78.84 μmol, 22.69% yield) as a white solid.

[0287] 1 H NMR(400MHz,DMSO-d6)δ8.85(d,J=7.8Hz,1H),8.40(s,1H),8.16(s,1H),7.73–7.65(m,2H),7 .51–7.34(m,7H),4.97–4.89(m,1H),4.70(s,2H),1.38(d,J=7.0Hz,3H).LCMS(ESI)m / z:[M+H] + 368.0; purity = 97.24% (254nm);

[0288] Example 16 Synthesis of Compound BR-032186

[0289] To a mixture of (1S)-1-(2,4-difluorophenyl)ethylamine (69.57 mg, 359.29 μmol, HCl) and 2-(6-oxo-5-phenyl-pyrimidin-1-yl)acetic acid (80 mg, 347.50 μmol) in DMF (3 mL) was added EDCI (99.92 mg, 521.24 μmol), HOBT (70.43 mg, 5210.24 μmol) and DIPEA (134.73 mg, 1.04 mmol, 181.58 μL). The reactants were stirred at room temperature for 16 hours. The mixture was added to water (20 mL) and extracted with EA (20 mL × 2). The organic layer was washed with brine and concentrated. The crude product was purified by preparative TLC (DCM:MeOH=15:1) to give BR-032186 (38.1 mg, 101.09 μmol, 29.09% yield, 98% purity) as a white solid.

[0290] 1H NMR(400MHz, DMSO-d6)δ8.84(d,J=7.7Hz,1H),8.40(s,1H),8.16(s,1H),7.71–7.64(m,2H),7. 47–7.33(m,5H),7.22–7.14(m,1H),4.92(p,J=7.0Hz,1H),4.69(s,2H),1.38(d,J=7.0Hz,3H).

[0291] LCMS (ESI) m / z: [M+H] + 370.2; purity = 100.0% (214 nm); retention time = 2.70 min.

[0292] Example 17 Synthesis of Compound BR-032280

[0293] To a solution of 2-(6-oxo-5-phenyl-pyrimidin-1-yl)acetic acid (80 mg, 347.50 μmol), (1S)-1-(4-fluorophenyl)ethanamine (58.03 mg, 416.99 μmol) and DIPEA (53.89 mg, 416.9 μmol, 72.63 μL) in DMF (5 mL) was added EDCI (66.62 mg, 347.50 mol) and HOBT (53.21 mg, 3470.50 μmol). The reaction mixture was stirred at 25 ° C for 12 hours. The mixture was then purified by preparative HPLC to give BR-032280 (18.2 mg, 51.80 μmol, 14.91% yield) as a white solid. LCMS (ESI)

[0294] m / z:[M+H] + 352.38

[0295] 1 H NMR(400MHz, DMSO-d6)δ8.80(d,J=7.8Hz,1H),8.39(s,1H),8.15(s,1H),7.75–7.62(m,2H),7.57–7.28 (m,5H),7.24–7.06(m,2H),5.04–4.84(m,1H),4.68(s,2H),1.38(d,J=7.0Hz,3H).LCMS(ESI)m / z:[M+H] + 352.38; purity = 100% (254 nm); retention time = 6.639 min.

[0296] Example 18 Synthesis of Compound BR-032281

[0297] To a solution of 3-phenyl-1H-pyrazin-2-one (80 mg, 464.62 μmol) in DMF (3 mL) was added 2-bromo-N-[(1S)-1-phenylethyl]acetamide (112.49 mg, 4646.62 μmol) and potassium carbonate (128.43 mg, 929.24 μmol). The mixture was stirred at 25°C for 12 hours. The mixture was purified by preparative HPLC to give the target compound BR-032281 (22.9 mg, 68.69 μmol, 14.78% yield) as a white solid (22.9 mg, 68.69 μmol, 14.88% yield).

[0298] 1 H NMR (400MHz, DMSO-d6) δ8.77(d,J=7.9Hz,1H),8.28–8.19(m,2H),7.65(d,J=4.2Hz,1H),7.48(d,1H),7.46 –7.41(m,3H),7.37–7.28(m,4H),7.27–7.18(m,1H),4.99–4.87(m,1H),4.69(s,2H),1.39(d,J=7.0Hz,3H)

[0299] LCMS (ESI) m / z: [M+H] + 334.0; purity = 100% (254 nm); retention time = 6.645 min.

[0300] Example 19 Synthesis of Compound BR-032282

[0301] To a solution of 3-phenyl-1H-pyrazin-2-one (80 mg, 464.62 μmol) in DMF (5 mL) was added 2-bromo-N-[(1S)-1-[4-(trifluoromethoxy)phenyl]ethyl]acetamide (151.52 mg, 4646.62 μmol) and potassium carbonate (64.21 mg, 4646.42 μmol). The reaction mixture was stirred at 25° C. for 12 hours. The mixture was purified by preparative HPLC to afford BR-032282 (8.1 mg, 19.41 μmol, 4.18% yield) as a white solid.

[0302] 1H NMR(400MHz, DMSO-d6)δ8.82(d,J=7.7Hz,1H),8.27–8.20(m,2H),7.65(d,J=4.2Hz,1H),7.5 1–7.40(m,6H),7.32(d,J=8.1Hz,2H),5.00–4.92(m,1H),4.69(s,2H),1.40(d,J=7.0Hz,3H)

[0303] LCMS (ESI) m / z: [M+H] + 418.0; purity = 95.31% (254 nm); retention time = 10.540 min.

[0304] Example 20 Synthesis of Compound BR-032338

[0305] Step 1: A mixture of 5-[(E)-propyl-1-enyl]-1H-pyrimidin-6-one (301 mg, 2.21 mmol) and Pd / C (60 mg, 56.38 μmol, 10% purity) in methanol (10 mL) was stirred at room temperature under H2 for 1 hr. The mixture was then filtered and concentrated to give 5-propyl-1H-pyrimidin-6-one (153 mg, 1.05 mmol, 47.58% yield, 95% purity) as a yellow solid. LCMS (ESI) m / z: [M+H] + 139.05

[0306] Step 2: A mixture of 5-propyl-1H-pyrimidin-6-one (43 mg, 311.22 μmol), 2-bromo-N-[(1S)-1-[4-(trifluoromethoxy)phenyl]ethyl]acetamide (101.49 mg, 3110.22 μmol) and potassium carbonate (86.02 mg, 622.44 μmol) in DMF (3 mL) was stirred at room temperature overnight. After the reaction was complete, water (30 mL) was added to the mixture and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography (3% MeOH in DCM) to give BR-032338 (48.1 mg, 120.45 μmol, 38.70% yield, 96% purity) as a colorless oil.

[0307] 1H NMR (400MHz, DMSO-d6) δ8.81(d,J=7.7Hz,1H),8.23(s,1H),7.77(s,1H),7.45(d,J=8.6Hz,2H),7.32(d,J=8.0Hz,2H), 4.94(p,J=7.0Hz,1H),4.60(s,2H),2.35–2.25(m,2H),1.55–1.44(m,2H),1.38(d,J=7.0Hz,3H),0.87(t,J=7.4Hz,3H).

[0308] LCMS (ESI) m / z: [M+H] + 384.30

[0309] Example 21 Synthesis of Compound BR-032370

[0310] Step 1: To a solution of 2,4-dichloro-5,7-dihydrofuro[3,4-d]pyrimidine (200 mg, 1.05 mmol) in THF (5 mL) was added NaOH (2000 mg, 50.00 mmol, 938.97 mL, 1 M). The mixture was stirred at 25°C for 12 hours. After the reaction was complete, water (20 mL) was added to the mixture and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography to give 2-chloro-5,7-dihydro-3H-furo[3,4-d]pyrimidin-4-one (197 mg, 1.14 mmol, 109.03% yield) as a white solid. LCMS (ESI) m / z: [M+H]+ 173.0.

[0311] Step 2: To a solution of 2-chloro-5,7-dihydro-3H-furo[3,4-d]pyrimidin-4-one (200 mg, 1.16 mmol) in MeOH (5 mL) was added Pd / C (123,34 mg, 1.16 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 25° C. under H 2 for 1 hour. The mixture was filtered to give 2-bromo-N-[(1S)-1-[4-(trifluoromethoxy)phenyl]ethyl]acetamide (230 mg) as a yellow solid.

[0312] LCMS (ESI) m / z: [m+H] + 139.0

[0313] Step 3: To a solution of 2-bromo-N-[(1S)-1-[4-(trifluoromethoxy)phenyl]ethyl]acetamide (80 mg, 245.32 μmol) and K2CO3 (67.81 mg, 490.63 μmol) in DMF (3 mL) was added 5,7-dihydrofuro[3,4-d]pyrimidin-4-ol (33.88 mg, 2450.32 μmol). The reaction mixture was stirred at 25°C for 12 h. The mixture was purified by preparative HPLC to afford BR-032370 (5 mg, 13.04 μmol, 5.32% yield) as a white solid.

[0314] 1 H NMR (400MHz, DMSO-d6) δ8.84(d,J=7.7Hz,1H),8.41(s,1H),7.45(d,J=8.7Hz,2H),7.32(d,J=8.0Hz,2H ),4.97–4.93(m,1H),4.91–4.88(m,2H),4.85–4.83(m,2H),4.66(d,J=1.3Hz,2H),1.38(d,J=7.0Hz,3H)

[0315] LCMS (ESI) m / z: [M+H] + 384.0; purity = 100% (254 nm); retention time = 9.516 min.

[0316] Example 22 Synthesis of Compound BR-032414

[0317] To a solution of 2-(7-hydroxy-4-oxo-6,7-dihydro-5H-cyclopentyl[d]pyrimidin-3-yl)-N-[(1S)-1-[4-(trifluoromethoxy)phenyl]ethyl]acetamide (50 mg, 125.83 μmol) in DCM (10 mL) was added (1,1-diacetoxy-3-oxo-1,2-benzyliodineoxy-1-yl)acetate (64.05 mg, 151.00 μmol). The mixture was stirred at RT for 2 hours. Lcms showed that the reaction was complete. The solvent was removed under reduced pressure to give a crude product. The residue was diluted with water (50 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 ml), dried over sodium sulfate, filtered, and concentrated to give a crude product, which was purified by preparative HPLC to give 2-(4,7-dioxy-5,6-dihydrocyclopentadien[d]pyrimidin-3-yl)-N-[(1S)-1-[4-(trifluoromethoxy)phenyl]ethyl]acetamide (28.2 mg, 71.33 μmol, 56.69% yield).

[0318] 1 H NMR(400MHz, DMSO-d6)δ8.86(d,J=7.7Hz,1H),8.44(s,1H),7.52–7.41(m,2H),7.39–7.29(m,2H ),5.03–4.91(m,1H),4.71(s,2H),2.89–2.75(m,2H),2.69–2.57(m,2H),1.39(d,J=7.0Hz,3H).

[0319] LCMS (ESI) m / z: [M+H] + 396.3; purity = 100% (254 nm); retention time = 1.82 min.

[0320] Example 23 Synthesis of Compound BR-032415

[0321] To a solution of 2-(1-oxo-1,5,6,7-tetrahydro-2H-cyclopenta[c]pyridin-2-yl)acetic acid (80 mg, 414.08 μmol) in DMF (5 mL) was added EDCI (119.07 mg, 621.12 μmol), HOBT (95.12 mg, 704 μmol) and DIEA (160.55 mg, 1.24 mmol, 216.38 μL) at 0° C. The mixture was stirred at rt for 15 minutes, then (1S)-1-(3,4-difluorophenyl)ethanamine (97.62 mg, 621.15 μmol) was added and stirred for 4 hours. Lcms showed that the reaction was complete. The residue was diluted with water (50 ml), extracted with ethyl acetate (3 x 50 ml) and the combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered and concentrated to give the crude product, which was purified by silica gel chromatography (Gradient: 0% to 20% MeOH in DCM) to give N-[(1S)-1-(3,4-difluorophenyl)ethyl]-2-(1-oxo-6,7-dihydro-5H-cyclopenta[c]pyridin-2-yl)acetamide (28.7 mg, 86.36 μmol, 20.85% yield).

[0322] 1H NMR(400MHz, DMSO-d6)δ8.66(d,J=7.8Hz,1H),7.48–7.28(m,3H),7.27–7.06(m,1H),6.18(d,J=6.8Hz,1H),5.02– 4.82(m,1H),4.56(s,2H),2.78(t,J=7.6Hz,2H),2.61(t,J=7.5Hz,2H),2.03–1.89(m,2H),1.36(d,J=7.0Hz,3H).

[0323] LCMS (ESI) m / z: [M+H] + 333.3; purity = 100% (254 nm); retention time = 1.78 min.

[0324] Example 24 Synthesis of Compound BR-032435

[0325] To a solution of 2-(1-oxo-1,5,6,7-tetrahydro-2H-cyclopenta[c]pyridin-2-yl)acetic acid (80 mg, 414.08 μmol) in DMF (6 mL) was added EDCI (119.07 mg, 621.12 μmol), HOBT (95.12 mg, 704 μmol), and DIEA (160.55 mg, 1.24 mmol, 216.38 μL) at 0°C. The mixture was stirred at room temperature for 15 minutes, then (1S)-1-(p-tolyl)ethylamine (83.98 mg, 621.12 μmol) was added and stirred for 4 hours. Lcms indicated the reaction was complete. The residue was diluted with water (50 mL), extracted with ethyl acetate (3 x 50 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated to give the crude product, which was purified by silica gel chromatography (Gradient: 0% to 20% MeOH in DCM) to give BR-032435 (3.8 mg, 12.24 μmol, 2.96% yield).

[0326] 1H NMR (400MHz, DMSO-d6) δ8.57(d,J=7.9Hz,1H),7.41(d,J=6.8Hz,1H),7.21(d,J=8.0Hz,2H),7.13(d,J=7.9Hz,2H),6.18(d,J=6.8Hz,1H ),4.92–4.83(m,1H),4.55(s,2H),2.78(t,J=7.5Hz,2H),2.61(t,J=7.4Hz,2H),2.28(s,3H),2.03–1.92(m,2H),1.35(d,J=7.0Hz,3H).

[0327] LCMS (ESI) m / z: [M+H] + 311.3; purity = 100% (254 nm); retention time = 1.79 min.

[0328] Example 25 Synthesis of Compound BR-032436

[0329] Step 1: To a solution of 3-bromo-2-methoxy-pyridine (2000 mg, 10.64 mmol, 1.26 mL) and cyclopropylboronic acid (1.83 g, 21.27 mmol) in dioxane (20 mL) and water (5 mL) were added CsCO (6.93 g, 21.27 mmol) and Pd(dppf)Cl (7.78 g, 10.64 mol). After deoxygenating the flask with three alternating vacuum and purge cycles, the reaction mixture was stirred at 110°C for 12 hours. LCMS analysis indicated the reaction was complete. The mixture was filtered and water (150 mL) was added to the filtrate. The combined aqueous layers were extracted with ethyl acetate (3 x 100 mL) and the combined organic layers were washed with water (3 x 100 mL), brine (2 x 100 mL), dried over sodium sulfate (150 g), and concentrated in vacuo. The crude product was purified by column chromatography containing 200 g of silica gel (EA:PE = 10:1) to obtain the target compound 3-cyclopropyl-2-methoxypyridine (1400 mg, 9.38 mmol, 88.22% yield) as a yellow liquid. LCMS (ESI) m / z: [m+H] + 150.3

[0330] Step 2: To a solution of 3-cyclopropyl-2-methoxypyridine (1400 mg, 9.38 mmol) in MeCN (20 mL) was added TMSCl (5.10 g, 46.92 mmol, 5.96 mL). The mixture was heated to 80 ° C and stirred for 4 hours. LCMS showed that the reaction was complete. The solvent was removed by distillation under reduced pressure, and the residue was diluted with water (50 mL) and extracted with ethyl acetate (3x 50 mL). The combined organic layer was washed with saturated sodium chloride aqueous solution (50 mL), dried over sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel chromatography (gradient: 0% to 50% ethyl acetate in PE) to give 3-cyclopropyl-1H-pyridin-2-one (700 mg, 5.18 mmol, 55.19% yield). LCMS (ESI) m / z: [m+H] + 136.3

[0331] Step 3: To a solution of 2-bromo-N-[(1S)-1-[4-(trifluoromethoxy)phenyl]ethyl]acetamide (70 mg, 214.65 μmol) and 3-cyclopropyl-1H-pyridin-2-one (26.38 mg, 195.14 μmol) in DMF (5 mL) was added KCO (53.94 mg, 390.28 μmol). The reaction mixture was stirred at 25°C for 2 hours. LCMS analysis indicated total consumption of the starting material. The mixture was filtered and water (50 mL) was added to the filtrate. The combined aqueous layers were extracted with ethyl acetate (3 x 100 mL) and the combined organic layers were washed with water (3 x 100 mL), brine (2 x 100 mL), dried over sodium sulfate (10 g), and concentrated in vacuo. The resulting crude material was purified by preparative HPLC to afford the target compound BR-032436 (37.5 mg, 98.59 μmol, 50.52% yield) as a white solid.

[0332] 1 H NMR (400MHz, DMSO-d6) δ8.72(d,J=7.7Hz,1H),7.55–7.43(m,2H),7.39(dd,J=6.8,2.0Hz,1H),7.32(d,J=8.0Hz,2H),6.94(dd,J=6.9,1.7Hz,1H) ,6.09(t,J=6.8Hz,1H),5.04–4.89(m,1H),4.58(d,J=2.0Hz,2H),2.04–1 .94(m,1H),1.39(d,J=7.0Hz,3H),0.90–0.76(m,2H),0.67–0.51(m,2H).

[0333] Example 26 Synthesis of Compound BR-032437

[0334] To a solution of 2-bromo-N-[(1S)-1-phenylethyl]acetamide (51.96 mg, 214.65 μmol) and 3-cyclopropyl-1H-pyridin-2-one (26.38 mg, 195.14 μmol) in DMF (5 mL) was added K2CO3 (53.94 mg, 390.28 μmol). The reaction mixture was stirred at 25°C for 2 hours. LCMS analysis showed the disappearance of the starting material. The reaction mixture was filtered and water (50 mL) was added to the filtrate. The combined aqueous layers were extracted with ethyl acetate (3×100 mL), and the combined organic layers were washed with water (3×100 mL) and brine (2×100 mL), dried over sodium sulfate (10 g), and concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC to give the target compound BR-032437 (33.7 mg, 113.71 μmol, 58.3% yield) as a white solid.

[0335] 1 H NMR(400MHz, DMSO-d6)δ8.64(d,J=7.9Hz,1H),7.39(dd,J=6.8,2.0Hz,1H),7.37–7.29(m,4H),7.29–7.16(m,1H),6.93(dd,J=6.9,1.9Hz,1H),6 .09(t,J=6.8Hz,1H),5.03–4.85(m,1H),4.58(d,J=1.6Hz,2H),2.05–1. 93(m,1H),1.39(d,J=7.0Hz,3H),0.92–0.78(m,2H),0.69–0.51(m,2H).

[0336] LCMS (ESI) m / z: [M+H] + 297.3; purity = 100% (254 nm); retention time = 1.73 min.

[0337] Example 27 Synthesis of Compound BR-032438

[0338] To a solution of 2-(1-oxo-1,5,6,7-tetrahydro-2H-cyclopenta[c]pyridin-2-yl)acetic acid (80 mg, 414.08 μmol), (1S)-1-[4-(trifluoromethyl)phenyl]acetamide]acetamide (117.50 mg, 621.12 μmol) and DIEA (160.55 mg, 1.24 mmol, 216.38 μL) in DMF (5 mL) was added EDCI (119.07 mg, 621.12 μmol) and HOBT (95.12 mg, 621.621.621212 μmol). After completion of the reaction, the mixture was purified by preparative HPLC to afford BR-032438 (17.8 mg, 48.85 μmol, 11.80% yield).

[0339] 1 H NMR (400MHz, DMSO-d6) δ8.74(d,J=7.6Hz,1H),7.69(d,J=8.2Hz,2H),7.56(d,J=8.2Hz,2H),7.41(d,J=6.8Hz,1H),6.23–6.1 5(m,1H),5.01–4.93(m,1H),4.58(s,2H),2.78(t,J=7.5Hz,2H),2.69–2.59(m,2H),2.02–1.91(m,2H),1.40(d,J=7.0Hz,3H)

[0340] LCMS (ESI) m / z: [M+H]+ 365.0; purity = 100% (254 nm); retention time = 10.317 min.

[0341] Example 28 Synthesis of Compound BR-032439

[0342] To a solution of 2-(1-oxo-1,5,6,7-tetrahydro-2H-cyclopenta[c]pyridin-2-yl)acetic acid (80 mg, 414.08 μmol), (1S)-1-(2,4-difluorophenyl)ethanamine (97.62 mg, 621.12 μmol) and DIEA (160.55 mg, 1.24 mmol, 216.38 μL) in DMF (5 mL) was added EDCI (119.07 mg, 621.12 μmol) and HOBT (95.12 mg, 704 μmol) at 0° C. After completion of the reaction, the mixture was purified by preparative HPLC to afford BR-032439 (12.2 mg, 36.71 μmol, 8.87% yield) as a white solid.

[0343] 1H NMR(400MHz, DMSO-d6)δ8.73(d,J=7.6Hz,1H),7.50–7.38(m,2H),7.23–7.06(m,2H),6.18(d,J=6.8Hz,1H),5.13 –5.05(m,1H),4.54(s,2H),2.78(t,J=7.5Hz,2H),2.61(t,J=7.4Hz,2H),2.01–1.92(m,2H),1.36(d,J=7.0Hz,3H)

[0344] LCMS (ESI) m / z: [M+H]+ 333.0; purity = 95.26% (254 nm); retention time = 9.453 min.

[0345] Example 29 Synthesis of Compound BR-032479

[0346] Step 1: 2H-2,7-naphthyridin-1-one (100 mg, 684.25 μmol) was dissolved in MeCN (3.0 mL), followed by the addition of tert-butyl 2-bromoacetate (160.16 mg, 821.10 μmol, 120.42 μL) and CsCO (445.88 mg, 1.37 mmol). The reaction was stirred at room temperature for 2 hours. Purification with a PE / EA gradient from 1:1 to 1:2 afforded tert-butyl 2-(1-oxo-2,7-naphthyridin-2-yl)acetate (166 mg, 93% yield).

[0347] Step 2: Under N2 atmosphere, tert-butyl 2-(1-oxo-2,7-naphthyridin-2-yl)acetate (50 mg, 192.10 μmol) and PtO2 (10 mg, 44.04 μmol, 0.98 μL) were dissolved in AcOH (1.0 mL). N2 was then replaced with H2 and stirred at room temperature for 2 h. After complete conversion of the starting material, the solution was filtered through a celite pad and washed with EA. The organic solvent was removed to give 40 mg of crude product tert-butyl 2-(1-oxo-5,6,7,8-tetrahydro-2,7-naphthyridin-2-yl)acetate.

[0348] Step 3: Dissolve tert-butyl 2-(1-oxo-5,6,7,8-tetrahydro-2,7-naphthyridin-2-yl)acetate (40 mg, 151.33 μmol) in formic acid (595.80 μL) and add 37% aqueous formaldehyde (4.54 mg, 151.33 μmol, 4.20 μL). Heat the reaction to 85°C and stir overnight under a N2 atmosphere. After the starting material reacts completely, filter through a pad of Celite and concentrate under vacuum. This gives 30 mg of crude 2-(7-methyl-1-oxo-6,8-dihydro-5H-2,7-naphthyridin-2-yl)acetic acid.

[0349] Step 4: 2-(7-Methyl-1-oxo-6,8-dihydro-5H-2,7-naphthyridin-2-yl)acetic acid (15 mg, 67.49 μmol), (1S)-1-[4-(trifluoromethyl)phenyl]ethanamine (22.84 mg, 101.24 μmol), and HATU (51.33 mg, 134.99 μmol) were added to DCM, and then DIPEA (26.17 mg, 202.48 μmol, 35.27 μL) was added to the stirred reaction. TLC confirmed the complete consumption of the starting material, and the product was extracted with EA. The organic layer was collected and concentrated in vacuo, and the residue was purified by HPLC. The product BR-032479 (4.5 mg, 15.6% yield) was obtained.

[0350] 1 H NMR (400MHz, MeOD) δ7.62(d,J=8.3Hz,2H),7.56–7.49(m,3H),6.29(d,J=7.0Hz,1H),5.05(q,J=6.9Hz,1H),4.69( t,J=10.6Hz,2H),4.09(s,2H),3.48(d,J=4.4Hz,2H),3.06–2.98(m,4H),1.50(d,J=7.1Hz,3H).MS(ESI)m / z:[M+H] + 394.4.

[0351] Example 30 Synthesis of Compound BR-032480

[0352] To a solution of 2-(1-oxo-1,5,6,7-tetrahydro-2H-cyclopenta[c]pyridin-2-yl)acetic acid (80 mg, 414.08 μmol), (1S)-1-(4-chlorophenyl)acetamide (96.66 mg, 621.12 μmol) and DIEA (160.55 mg, 1.24 mmol, 216.38 μL) in DMF (5 mL) was added HOBT (95.12 mg, 704 μmol) and EDCI (119.07 mg, 621.12 μmol). Under N2 atmosphere, the reaction was complete as determined by LCMS and the mixture was purified by preparative HPLC to afford BR-032480 (15.2 mg, 45.95 μmol, 11.10% yield) as a white solid.

[0353] 1 H NMR(400MHz, DMSO-d6)δ8.67(d,J=7.8Hz,1H),7.42–7.34(m,5H),6.18(d,J=6.8Hz,1H),4.93–4.86(m, 1H),4.56(s,2H),2.78(t,J=7.5Hz,2H),2.61(t,J=7.4Hz,2H),2.00–1.93(m,2H),1.36(d,J=7.0Hz,3H)

[0354] LCMS (ESI) m / z: [M+H]+331.0; purity = 89.90% (254 nm); retention time = 9.860 min.

[0355] Example 31 Synthesis of Compound BR-032481

[0356] To a solution of 2-(1-oxo-1,5,6,7-tetrahydro-2H-cyclopenta[c]pyridin-2-yl)acetic acid (80 mg, 414.08 μmol), (1S)-1-(4-fluorophenyl)ethanamine (86.44 mg, 621.12 μmol, 83.92 μL) and DIEA (160.55 mg, 1.24 mmol, 216.38 μL) in DMF (5.0 mL) was added HOBT (95.12 mg, 704 μmol) and EDCI (119.07 mg, 621.12 μmol). After completion of the reaction as detected by LCMS, the mixture was purified by preparative HPLC to afford BR-032481 (18.5 mg, 58.85 μmol, 14.21% yield) as a white solid.

[0357] 1H NMR(400MHz, DMSO-d6)δ8.64(d,J=7.9Hz,1H),7.43–7.35(m,3H),7.18–7.11(m,2H),6.18(d,J=6.8Hz,1H),4.94 –4.87(m,1H),4.56(s,2H),2.78(t,J=7.5Hz,2H),2.61(t,J=7.4Hz,2H),2.01–1.93(m,2H),1.36(d,J=7.0Hz,3H)

[0358] LCMS (ESI) m / z: [M+H]+ 315.0; purity = 99.13% (254 nm); retention time = 9.265 min.

[0359] Example 32 Synthesis of Compound BR-032482

[0360] To a solution of 2-(1-oxo-1,5,6,7-tetrahydro-2H-cyclopenta[c]pyridin-2-yl)acetic acid (90 mg, 465.84 μmol) in DMF (1.70 mL) were added EDCI (133.95 mg, 698.76 μmol), HOBT (107.01 mg, 698.75 μmol) and DIEA (180.62 mg, 1.40 mmol, 243.42 μL). The mixture was stirred at room temperature for 15 minutes, then (1S)-1-phenylethylamine (84.68 mg, 698.76 μmol, 89.32 μL) was added and stirred for 4 hours.

[0361] LCMS showed the reaction was complete. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride (50 mL), dried over sodium sulfate, filtered, and concentrated to give the crude product, which was purified by silica gel chromatography (Gradient: 0% to 20% MeOH in DCM) to give BR-032482 (35.3 mg, 119.11 μmol, 25.57% yield).

[0362] 1H NMR (400MHz, DMSO-d6) δ8.59(d,J=7.9Hz,1H),7.41(d,J=6.7Hz,1H),7.38–7.28(m,4H),7.27–7.19(m,1H),6.18(d,J=6.7Hz ,1H),4.96–4.88(m,1H),4.57(s,2H),2.78(t,J=7.5Hz,2H),2.62(t,J=7.5Hz,2H),2.02–1.91(m,2H),1.38(d,J=7.0Hz,3H).

[0363] LCMS (ESI) m / z: [M+H] + 297.3; purity = 100% (254 nm); retention time = 1.67 min.

[0364] Example 33 Synthesis of Compound BR-032483

[0365] Step 1: Under N2, a mixture of 3-bromo-1H-pyridin-2-one (308.07 mg, 1.77 mmol), potassium trans-1-propenyltrifluoroborate (262.00 mg, 1.77 mmol) and Na2CO3 (469.15 mg, 4.43 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added Pd(dppf)Cl2 (129.55 mg, 177.06 μmol). The mixture was then stirred at 120°C for 16 hours. Water (10 mL) was added to the mixture and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine and concentrated. The crude product was then purified by flash column chromatography (3% MeOH in DCM) to afford the target compound 3-[(E)-prop-1-enyl]-1H-pyridin-2-one (115.5 mg, 854.53 μmol, 48.26% yield) as a yellow solid.

[0366] LCMS (ESI) m / z: [M+H] + 172.19

[0367] Step 2: To a solution of 3-[(E)-propyl-1-enyl]-1H-pyridin-2-one (50 mg, 369.92 μmol) and 2-bromo-N-[(1S)-1-[4-(trifluoromethoxy)phenyl]ethyl]acetamide (120.64 mg, 36.92 μmol) in DMF (6 mL) was added KCO (102.25 mg, 739.85 μmol). The mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the mixture was added with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated. The crude product was purified by preparative TLC and preparative HPLC to give BR-032483 (30 mg, 78.87 μmol, 21.32% yield) as a white solid.

[0368] 1 H NMR (400MHz, DMSO-d6) δ8.76(d,J=7.7Hz,1H),7.68–7.61(m,4H),7.47(d,J=8.7Hz,2H),7.37(dd,J=8.1,6.7H z,2H),7.34–7.27(m,3H),6.32(t,J=6.8Hz,1H),4.99–4.91(m,1H),4.70–4.62(m,2H),1.39(d,J=7.0Hz,3H).

[0369] LCMS (ESI) m / z: [M+H] + 397.37

[0370] Example 34 Synthesis of Compound BR-032484

[0371] To a solution of 3-[(E)-propyl-1-enyl]-1H-pyridin-2-one (50 mg, 369.92 μmol) and 2-bromo-N-[(1S)-1-phenylethyl]acetamide (107.48 mg, 443.91 μmol) in DMF (2 mL) was added KCO (102.25 mg, 739.85 μmol). The reaction mixture was stirred at room temperature for 30 minutes. The crude product was purified by preparative HPLC to afford BR-032484 (52 mg, 175.46 μmol, 47.43% yield) as a white solid.

[0372] 1H NMR(400MHz,DMSO-d6)δ8.64(d,J=8.0Hz,1H),7.46(ddd,J=14.3,7.0,1.9Hz, 2H),7.35–7.28(m,4H),7.23(dd,J=5.9,2.8Hz,1H),6.56(dt,J=19.9,6.6Hz, 1H),6.37(dd,J=15.9,1.5Hz,1H),6.19(dt,J=9.3,6.9Hz,1H),4.94–4.87(m, 1H), 4.59 (d, J = 2.2Hz, 2H), 1.81 (dd, J = 6.7, 1.4Hz, 3H), 1.37 (d, J = 7.0Hz, 3H).

[0373] LCMS (ESI) m / z: [M+H] + 397.37

[0374] Example 35 Synthesis of Compound BR-032491

[0375] Step 1: A mixture of 3-bromo-1H-pyridin-2-one (1 g, 5.75 mmol), phenylboronic acid (1.40 g, 11.49 mmol), Pd(dppf)Cl2 (150 mg, 205.00 μmol) and Na2CO3 (1.83 g, 17.24 mmol, 721.74 μL) in 1,4-dioxane (12 mL) and water (2 mL) was stirred at 98°C under argon for 16 hours. LCMS showed the reaction was complete. The mixture was added with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was then purified by flash column chromatography (3% MeOH in DCM) to give the target compound 3-phenyl-1H-pyridin-2-one (517 mg) as a yellow solid. Finally, the target compound 3-phenyl-1H-pyridin-2-one (112 mg, 654.23 μmol, 11.38% yield) was obtained by preparative HPLC purification as a pink solid. LCMS (ESI) m / z: [M+H] + 172.19

[0376] Step 2: To a solution of 3-phenyl-1H-pyridin-2-one (60 mg, 350.48 μmol) and 2-bromo-N-[(1S)-1-[4-(trifluoromethoxy)phenyl]ethyl]acetamide (91.15 mg, 279.51 μmol) in DMF (5 mL) was added KCO (80.72 mg, 584.06 μmol). The reaction mixture was stirred at 35° C. for 2 hours. LCMS showed that the starting material was consumed and the desired product was observed. The mixture was purified by preparative HPLC to give BR-032491 (100 mg, 240.16 μmol, 68.52% yield) as a white solid.

[0377] 1 H NMR (400MHz, DMSO-d6) δ8.76(d,J=7.7Hz,1H),7.68–7.61(m,4H),7.47(d,J=8.7Hz,2H),7.37(dd,J=8.1,6.7Hz,2H),7.3 4–7.27(m,3H),6.32(t,J=6.8Hz,1H),4.99–4.91(m,1H),4.70–4.62(m,2H),1.39(d,J=7.0Hz,3H).LCMS(ESI)m / z:[M+H] + 417.40

[0378] Example 36 Synthesis of Compound BR-032492

[0379] To a solution of 3-phenyl-1H-pyridin-2-one (50 mg, 292.06 μmol) and 2-bromo-N-[(1S)-1-phenylethyl]acetamide (84.85 mg, 350.48 μmol) in DMF (2 mL) was added KCO (80.73 mg, 584.13 μmol). The reaction mixture was stirred at 35° C. for 2 hours. The residue was purified by preparative HPLC to afford BR-032492 (80 mg, 240.68 μmol, 82.41% yield) as a white solid.

[0380] 1 H NMR(400MHz, DMSO-d6)δ8.68(d,J=7.9Hz,1H),7.69–7.60(m,4H),7.41–7.28(m,7H),7.25–7.20(m,1H ),6.32(t,J=6.8Hz,1H),4.97–4.88(m,1H),4.66(s,2H),1.38(d,J=7.0Hz,3H).LCMS(ESI)m / z:[M+H] + 333.39

[0381] Example 37 Synthesis of Compound BR-032493

[0382] Step 1: To a solution of methyl 4-oxotetrahydrofuran-3-carboxylate (1 g, 6.94 mmol) in DCM (20 mL) was added Tf2O (2.15 g, 7.63 mmol, 1.28 mL) and DIEA (986.41 mg, 7.63 mol, 1.33 mL) at -78°C under N2 atmosphere. The mixture was then heated to room temperature and stirred for 12 hours. The mixture was added to water (20 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography to give 2 (1.9 g, 6.88 mmol, 99.15% yield).

[0383] LCMS (ESI) m / z: [M+H] + 277.0

[0384] Step 2: To a solution of 2 (1.8 g, 6.52 mmol), ethynyl(trimethyl)silane (960.18 mg, 9.78 mmol, 1.38 mL) and TEA (1.98 g, 19.55 mmol, 2.73 mL) in DMF (30 mL) were added CuI (62.06 mg, 325.87 μmol) and Pd(dppf)Cl (238.44 mg, 3250.87 μmol) under N2 atmosphere. The mixture was stirred at 60°C for 3 h. The reaction mixture was diluted with water (5 mL) and extracted with dichloromethane (5 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 3 (1 g, 4.46 mmol, 68.40% yield) as a brown oil.

[0385] LCMS (ESI) m / z: [M+H] + 225.00

[0386] Step 3: To a solution of 3 (1 g, 4.46 mmol) in methanol (20 mL) and water (5 mL) was added lithium hydroxide (213.51 mg, 8.92 mmol). The mixture was stirred at 60°C for 3 hours. The mixture was concentrated and the pH was adjusted to 3 with HCl (1 M). The mixture was then filtered to give 4 (336 mg, 2.43 mmol, 54.57% yield) as a white solid. LCMS (ESI) m / z: [M+H] + 139.0

[0387] Step 4: Under N2 atmosphere, HATU (1.34 g, 3.53 mol) was added to a solution of 4 (325 mg, 2.35 mmol) and ammonium bicarbonate (1.86 g, 23.53 mmol) and DIEA (912.33 mg, 7.06 mmol, 1.23 mL) in DCM (30 mL). The reaction mixture was stirred at 25 ° C for 12 hours. The mixture was added to water (30 mL) and extracted with DCM (40 mL×2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography to give 5 (224 mg, 1.63 mmol, 69.42% yield) as a white solid. LCMS (ESI) m / z: [M+H] + 138.0

[0388] Step 5: To a solution of 5 (175 mg, 1.28 mmol) in methanol (10 mL) was added morpholine (222.35 mg, 2.55 mmol, 223.24 μL). The reaction mixture was stirred at 100 ° C for 2 h in a microwave reactor. The mixture was concentrated and purified by flash column chromatography to give 6 (56 mg, 408.35 μmol, 32.00% yield) as a white solid.

[0389] LCMS (ESI) m / z: [m+H] + 138.0

[0390] Step 6: To a solution of 2-bromo-N-[(1S)-1-phenylethyl]acetamide (20 mg, 82.61 μmol) and 3,5-dihydro-1H-furo[3,4-c]pyridin-4-one (11.33 mg, 82.6 μmol) in DMF (5 mL) was added potassium carbonate (22.83 mg, 165.21 μmol). The reaction mixture was stirred at 25° C. for 16 hours. The mixture was purified by preparative HPLC to afford BR-032493 (7.5 mg, 25.14 μmol, 30.43% yield) as a white solid.

[0391] LCMS (ESI) m / z: [M+H] + 299.0

[0392] 1 H NMR (400MHz, DMSO-d6) δ8.67(d,J=7.9Hz,1H),7.58(d,J=6.8Hz,1H),7.39–7.23(m,5H),6.28(d,J =6.8Hz,1H),5.00–4.90(m,3H),4.81(t,J=3.2Hz,2H),4.61(t,J=8.3Hz,2H),1.38(t,J=7.4Hz,3H)

[0393] LCMS (ESI) m / z: [M+H] + 299.0; purity = 100% (254 nm); retention time = 8.056 min.

[0394] Example 38 Synthesis of Compound BR-032524

[0395] Step 1: A solution of methyl 4-oxotetrahydrothiophene-3-carboxylate (2.42 g, 15.11 mmol) in DCM (48.80 mL) was maintained at -78 ° C for 10 minutes under N2 to maintain the internal temperature at -78 ° C under N2, and a solution of Tf2O (5.11 g, 18.13 mmol, 3.05 mL) was added. The reaction was slowly warmed to 25 ° C and stirred for 16 hours. TLC analysis showed that the reaction was complete. Water (10 mL) was added and extracted with DCM (10 mL x 2), and the combined organic layers were washed with water (10 mL × 2) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product methyl 4-(trifluoromethylsulfonyloxy)-2,5-dihydrothiophene-3-carboxylate (4.76 g, 16.29 mmol, 107.81% yield).

[0396] Step 2: A mixture of methyl 4-(trifluoromethylsulfonylsulfonyloxy)-2,5-dihydrothiophene-3-carboxylate (4.76 g, 16.29 mmol), ethynyl(trimethyl)silane (2.40 g, 24.43 mmol, 3.45 mL), CuI (155.10 mg, 814.36 μmol, 27.60 μL), and TEA (4.94 g, 48.86 mmol, 6.81 mL) in DMF (12.95 mL) was stirred at 60°C under N2 for 3 h. TLC analysis showed complete conversion of the starting material. Water (30 mL) was added, and the combined aqueous layers were extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate (1 g), and concentrated in vacuo. The crude material was purified by flash column chromatography (EA / PE 3:97) to give the target compound methyl 4-(2-trimethylsilylethynyl)-2,5-dihydrothiophene-3-carboxylate (1.14 g, 4.74 mmol, 29.12% yield).

[0397] Step 3: A mixture of 4-(2-trimethylsilylethynyl)-2,5-dihydrothiophene-3-carboxylate (1.14 g, 4.74 mmol) and LiOH.H2O (97.65 mg, 9.48 mmol) in MeOH (4 mL), THF (4 mL) and water (2 mL) was stirred at 60 ° C for 3 hours. Concentrate and adjust the pH to 3 with HCl (1.0 M). Water (10 mL) was added, the combined aqueous layer was extracted with EA (3×10 mL), and the combined organic layer was dried with brine (2×10 mL), sodium sulfate (10 g) and concentrated in vacuo. It was then filtered and dried to give 4-ethynyl-2,5-dihydrothiophene-3-carboxylic acid (529 mg, 3.43 mmol, 72.41% yield) as a yellow solid. LCMS (ESI) m / z: [M+H] + 152.82

[0398] Step 4: A mixture of 4-ethynyl-2,5-dihydrothiophene-3-carboxylic acid (529 mg, 3.43 mmol), HATU (1.96 g, 5.15 mmol), NH4HCO3 (1.36 g, 17.15 mmol) and DIEA (1.33 g, 10.29 mmol, 1.79 mL) in DCM (35 mL) was stirred at room temperature for 16 hours. Water (10 mL) was added and extracted with EA (10 mL x 3). Concentration and purification by flash column chromatography (eluent: 17% MeOH in DCM) gave the target product 4-ethynyl-2,5-dihydrothiophene-3-carboxamide (207 mg, 1.35 mmol, 39.38% yield). LCMS (ESI) m / z: [M+H] + 154.1

[0399] Step 5: A solution of 4-ethynyl-2,5-dihydrothiophene-3-carboxamide (100 mg, 652.74 μmol) and morpholine (113.73 mg, 1.31 mmol, 114.19 μL) was stirred at 100°C under N₂ for 4 h. LCMS confirmed complete conversion of the starting material. The pH was then adjusted to 5.0 with citric acid, and the organic solvent was removed in vacuo. Water (10 mL) was added, and the combined aqueous layers were extracted with DCM (3 × 10 mL), washed with brine (2 × 10 mL), dried over sodium sulfate (10 g), and concentrated in vacuo. The crude product was purified by preparative TLC (DCM:MeOH = 10:1) to afford the target compound, 3,5-dihydro-1H-thieno[3,4-c]pyridin-4-one (24 mg, 156.66 μmol, 24% yield). LCMS (ESI) m / z: [M+H] + 154.1

[0400] Step 6: To a solution of 3,5-dihydro-1H-thieno[3,4-c]pyridin-4-one (24 mg, 156.66 μmol) and 2-bromo-N-[(1R)-1-phenylethyl]acetamide (49.31 mg, 203.65 μmol) in DMF (1.5 mL) was added K2CO3 (43.30 mg, 313.31 μmol) and the reaction mixture was stirred at room temperature for 16 hours. LCMS analysis indicated the total consumption of the starting material. The reaction solutions were combined and filtered. The residue was purified by preparative HPLC (water) to give the target compound 2-(4-oxo-1,3-dihydrothieno[3,4-c]pyridin-5-yl)-N-[(1R)-1-phenylethyl]acetamide (2 mg, 6.36 μmol, 4.06% yield) as a white solid.

[0401] 1 H NMR(400MHz, DMSO-d6)δ8.72(d,J=7.9Hz,1H),7.55(d,J=6.9Hz,1H),7.40–7.32(m,4H),7.31–7.22(m, 1H),6.25(d,J=6.9Hz,1H),4.94(p,J=7.0Hz,1H),4.63(s,1H),4.25–3.97(m,4H),1.41(d,J=7.0Hz,3H)

[0402] LCMS (ESI) m / z: [M+H] + 315.35; purity = 100.00% (254 nm); retention time = 4.040 min.

[0403] Example 39 Synthesis of Compound BR-032525

[0404] Step 1: To a solution of 5-bromo-1H-pyrimidin-6-one (200 mg, 1.14 mmol) and 1-methyl-3-(4.4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (237.81 mg, 1.14 mmol) in dioxane (10 mL) and water (1 mL) was added Pd(dppf)Cl2 (41.82 mg, 57.15 μmol) and Na2CO3 (363.42 mg, 3.43 mmol, 143.53 μL). After deoxygenating the flask with three alternating vacuum and purge cycles, the reaction mixture was stirred at 110°C for 12 hours. LCMS analysis indicated complete consumption of the starting material. The reaction mixture was filtered through a glass frit funnel and water was added to the filtrate. The combined aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with water, brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography (eluent: DCM / MeOH = 10:) to give the target compound 5-(1-methylpyrazol-3-yl)-1H-pyrimidin-6-one (15 mg, 85.14 μmol, 7.45% yield). LCMS (ESI) m / z: [M+H] + 177.3.

[0405] Step 2: To a solution of 5-(1-methylpyrazol-3-yl)-1H-pyrimidin-6-one (14.20 mg, 80.62 μmol) and 2-bromo-N-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]acetamide (25 mg, 80.63 μmol) in DMF (5 mL) was added K2CO3 (22.28 mg, 161.23 μmol). The reaction mixture was stirred at 25°C for 2 hours. LCMS analysis indicated the reaction was complete. The reaction mixture was filtered through a glass frit funnel and water was added to the filtrate. The combined aqueous layers were extracted with ethyl acetate and the combined organic layers were washed sequentially with water, brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude material obtained as a residue was purified by preparative HPLC to give the target compound BR-032525 (6.3 mg, 15.54 μmol, 19.28% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.95(d,J=7.6Hz,1H),8.47(s,1H),8.37(s,1H),7.77–7.66(m,3H),7.57(d,J=8.1Hz,2H),6.8 9(d,J=2.2Hz,1H),5.04–4.96(m,1H),4.70(d,J=2.2Hz,2H),3.88(s,3H),1.41(d,J=7.0Hz,3H).LCMS(ESI)m / z:[M+H] +406.3; purity = 100% (254 nm); retention time = 1.79 min.

[0406] Example 40 Synthesis of Compound BR-032530

[0407] Step 1: Under N2 atmosphere, to a solution of 5-bromo-1H-pyrimidin-6-one (200 mg, 1.14 mmol), sodium carbonate (242.28 mg, 2.29 mmol, 95.69 μL) and (2-fluorophenyl)-4.4.5.5-tetramethyl-1.3.2-dioxaborolane (279.19 mg, 1.26 mmol) in dioxane (5 mL) and water (1 mL) was added Pd(dppf)Cl2 (41.82 mg, 41.82 mg, 57.15 μmol). The mixture was stirred at 110 ° C for 12 hours. The reaction mixture was diluted with water (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain a brown oily substance, 5-(2-fluorophenyl)pyrimidin-4(3H)-one (70 mg, 368.08 μmol, 32.20% yield). LCMS (ESI) m / z: [M+H] + 191.0

[0408] Step 2: To a solution of 2-bromo-N-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]acetamide (25 mg, 80.62 μmol) and 5-(2-fluorophenyl)pyrimidin-4(3H)-one (16.86 mg, 88.68 μmol) in DMF (5 mL) was added potassium carbonate (22.28 mg, 161.23 μmol). The reaction mixture was stirred at 25° C. for 16 hours. The mixture was purified by preparative HPLC to afford BR-032530 (2.2 mg, 5.25 μmol, 6.51% yield) as a white solid.

[0409] 1 H NMR (400MHz, DMSO-d6) δ8.98(d,J=7.5Hz,1H),8.27(d,J=2.5Hz,1H),7.86(d,J=2.5Hz,1H),7.69(d,J=8.2Hz,2H), 7.57(d,J=8.1Hz,2H),7.42–7.35(m,2H),7.26–7.19(m,2H),5.03–4.98(m,1H),4.74(s,2H),1.41(d,J=7.0Hz,3H)

[0410] LCMS (ESI) m / z: [M+H] +420.3; purity = 100% (254 nm); retention time = 9.918 min.

[0411] Example 41 Synthesis of Compound BR-032531

[0412] Step 1: Under N2 atmosphere, a mixture of 3-bromo-1H-pyridin-2-one (200 mg, 1.15 mmol), 1-methyl-3-(4,4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (239.16 mg, 1.15 mol) and Na2CO3 (365.49 mg, 3.45 mmol, 144.35 μL) in dioxane (8 mL) and water (2 mL) was added Pd(dppf)Cl2 (67.28 mg, 91.96 μmol). The mixture was then stirred at 98°C for 16 hours. Water (10 mL) was added to the mixture and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine and concentrated. The crude product was then purified by pre-HPLC to give 3-(1-methylpyrazol-3-yl)-1H-pyridin-2-one (30 mg, 171.25 μmol, 14.90% yield). LCMS (ESI) m / z: [M+H] + 176.2

[0413] Step 2: To a solution of 3-(1-methylpyrazol-3-yl)-1H-pyridin-2-one (20 mg, 114.16 μmol) and 2-bromo-N-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]acetamide (35.40 mg, 114.16 μmol) in DMF (4 mL) was added KCO (31.56 mg, 228.33 μmol). The reaction mixture was stirred at room temperature for 16 hours. The residue was purified by preparative HPLC to afford BR-032531 (14 mg, 34.62 μmol, 30.33% yield) as a white solid.

[0414] 1 H NMR (400MHz, DMSO-d6) δ8.83(d,J=7.7Hz,1H),8.04(dd,J=7.1,2.0Hz,1H),7.64(ddd,J=16.4,13.7,8.1Hz,7H),6.98(d,J=2.2H z,1H),6.29(t,J=6.9Hz,1H),5.01–4.96(m,1H),4.67(d,J=2.4Hz,2H),3.87(s,3H),1.41(d,J=7.0Hz,3H).LCMS(ESI)m / z:[M+H] + 405.66

[0415] Example 42 Synthesis of Compound BR-032532

[0416] Step 1: Under N2 atmosphere, a mixture of 3-bromo-1H-pyridin-2-one (200 mg, 1.15 mmol), 1-methyl-4-(4,4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (239.16 mg, 1.15 mol) and Na2CO3 (365.49 mg, 3.45 mmol, 144.35 μL) in dioxane (8 mL) and water (2 mL) was added Pd(dppf)Cl2 (67.28 mg, 91.96 μmol). The mixture was then stirred at 98°C for 16 hours. Water (10 mL) was added to the mixture and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine and concentrated. The crude product was then purified by preparative TLC (DCM:MeOH=10:1) to give the target product 3-(1-methylpyrazol-3-yl)-1H-pyridin-2-one (60 mg, 342.49 μmol, 29.80% yield). LCMS (ESI) m / z: [M+H] + 176.2

[0417] Step 2: To a solution of 3-(1-methylpyrazol-4-yl)-1H-pyridin-2-one (38.92 mg, 222.16 μmol) and 2-bromo-N-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]acetamide (53.00 mg, 170.89 μmol) in DMF (2 mL) was added KCO (47.24 mg, 341.79 μmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was purified by preparative HPLC to afford BR-032532 (11 mg, 27.20 μmol, 15.92% yield) as a white solid.

[0418] 1 H NMR (400MHz, DMSO-d6) δ8.83(d,J=7.6Hz,1H),8.30(s,1H),7.97(s,1H),7.77(dd,J=7.1,1.9Hz,1H),7.69(d,J=8.2Hz,2H),7.58(d,J=8.1Hz ,2H),7.50(dd,J=6.7,1.9Hz,1H),6.26(t,J=6.9Hz,1H),5.00–4.95(m,1H),4.67(d,J=2.5Hz,2H),3.84(d,J=5.7Hz,3H),1.43–1.39(m,3H)..

[0419] LCMS (ESI) m / z: [M+H] + 405.6

[0420] Example 43 Synthesis of Compound BR-032533

[0421] Step 1: Under N2 atmosphere, Pd(dppf)Cl2 (83.63 mg, 114.30 μmol) and K2CO3 (473.89 mg, 3.43 mmol) were added to a solution of 5-bromo-1H-pyrimidin-6-one (200 mg, 1.14 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (285.37 mg, 1.37 mmol) in dioxane (6 mL) and water (1 mL) - what? After deoxygenating the flask with three alternating vacuum and purge cycles, the reaction mixture was stirred at 110 [UNK] for 12 hours. LCMS analysis indicated that the reaction was complete. The mixture was filtered through a glass frit funnel and water was added to the filtrate. The combined aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with water, then brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by column chromatography (elution, DCM: MeOH 10: 1) gave the target compound 5-(1-methylpyrazol-4-yl)-1H-pyrimidin-6-one (23 mg, 130.55 μmol, 11.42% yield) as crude material. LCMS (ESI) m / z: [M+H] + 177.3

[0422] Step 2: To a solution of 5-(1-methylpyrazol-4-yl)-1H-pyrimidin-6-one (14.20 mg, 80.62 μmol) and 2-bromo-N-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]acetamide (25 mg, 80.63 μmol) in DMF (5 mL) was added K2CO3 (22.28 mg, 161.23 μmol). The reaction mixture was stirred at 25°C for 2 hours. LCMS analysis indicated that the reaction was complete. The mixture was filtered and water was added to the filtrate. The combined aqueous layers were extracted with ethyl acetate, and the combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude material was purified by preparative HPLC to give the target compound BR-032533 (14.2 mg, 35.03 μmol, 43.45% yield) as a white solid.

[0423] 1H NMR (400MHz, DMSO-d6) δ8.94(d,J=7.7Hz,1H),8.36(s,1H),8.30(s,1H),8.27(s,1H),8.01(s,1H),7.70(d,J=8. 1Hz,2H),7.57(d,J=8.0Hz,2H),5.00(q,J=7.1Hz,1H),4.70(d,J=2.0Hz,2H),3.86(s,3H),1.41(d,J=7.0Hz,3H).

[0424] LCMS (ESI) m / z: [M+H] + 406.3; purity = 100% (254 nm); retention time = 1.76 min.

[0425] Example 44 Synthesis of Compound BR-032540

[0426] Step 1: To a DCM solution of 1 (7000 mg, 27.21 mmol) was added DIEA (3.87 g, 29.93 mmol, 5.21 mL) and Tf2O (8.44 g, 29.93% mmol, 5.04 mL) at -78 ° C, then slowly warmed to room temperature and stirred for 15 hours. The mixture was diluted with DCM, washed with saturated NaHCO3 and brine, and the organic phases were combined, dried and concentrated to give the crude product 2 (8500 mg, 21.83 mmol, 80.24% yield), which was used directly in the next step without purification. LCMS (ESI) m / z: [M+H] + 390.3

[0427] Step 2: Under N2 atmosphere, CuI (415.78 mg, 2.18 mmol, 73.98 μL), ethynyltrimethylsilane (2.36 g, 24.01 mmol), and Pd(PPh3)Cl2 (766.18 mg, 1.09 mmol) were added to a solution of 2 (8500 mg, 21.83 mmol) in DMF (4.93 mL). The mixture was heated to 60°C and stirred under N2 atmosphere for 12 hours. LCMS showed the reaction was complete. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by silica gel chromatography (gradient: 0% to 20% ethyl acetate in PE) to give 3 (5800 mg, 17.19 mmol, 78.72% yield). LCMS (ESI) m / z: [M+H] + 338.3

[0428] Step 3: To a solution of 3 (5800 mg, 17.93 mmol) in MeOH (5 mL) and water (1 mL) was added LiOH.H2O (2.26 g, 53.79 mmol). The mixture was heated to 60 ° C and stirred under N2 atmosphere for 12 hours. LCMS showed that the reaction was complete. The solvent was removed under reduced pressure to give a crude product. The residue was diluted with water (50 mL), and the pH was adjusted to 7 and extracted with ethyl acetate (3x 80 mL). The combined organic layers were washed with saturated sodium chloride aqueous solution (50 mL), dried over sodium sulfate, filtered, and concentrated to give a crude product 4 (4000 mg, 16.86 mmol, 94.02% yield). The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: [M+H] + 238.3.

[0429] Step 4: To a solution of 4 (100 mg, 421.49 μmol) in DCM (5 mL) were added HATU (240.40 mg, 632.24 μmol), NH4HCO3 (166.61 mg, 2.11 mmol), DIEA (163.42 mg, 1.26 mmol, 220.25 μL). The mixture was stirred at room temperature for 4 hours. LCMS showed that the reaction was complete. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by silica gel chromatography (gradient: 0% to 50% ethyl acetate in PE) to give 5 (65 mg, 275.11 μmol, 65.27% yield). LCMS (ESI)

[0430] m / z:[M+H] + 237.3

[0431] Step 5: To a solution of 5 (500 mg, 2.12 mmol) in MeOH (10 mL) was added morpholine (368.74 mg, 4.23 mmol, 370.22 μL). The mixture was heated to 100 ° C and stirred for 4 h. LCMS showed that the reaction was complete. The solvent was removed under reduced pressure to give a crude product. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel chromatography (gradient: 0% to 100% ethyl acetate in PE), 6 (250 mg, 1.06 mmol, 50.00% yield). LCMS (ESI) m / z: [M + H] + 237.3

[0432] Step 6: To a solution of 6 (700 mg, 2.96 mmol) and 2-bromo-N-[(1S)-1-phenylethyl]acetamide (7) (789.05 mg, 3.26 mmol) in DMF was added K2CO3 (22.28 mg, 161.23 μmol). The reaction mixture was stirred at 25°C for 2 hours. LCMS analysis indicated the total consumption of the starting material. The mixture was filtered through a funnel and water (50 mL) was added to the filtrate. The combined aqueous layers were extracted with ethyl acetate (3×100 mL) and the combined organic layers were washed with water (3×100 mL) and brine (2×100 mL), dried over anhydrous sodium sulfate (10 g) and concentrated in vacuo. The crude product obtained was purified by silica gel column eluting the column with a mixture of petroleum ether and ethyl acetate (10:1) to afford the title compound 7 (700 mg, 1.76 mmol, 59.44% yield) as a white solid. LCMS (ESI) m / z: [m+H] + 398.3

[0433] Step 7: To a solution of 7 (60 mg, 150.96 μmol) and DCM (3 mL) was added HCl (4.0 M in dioxane) (16.51 mg, 452.87 μmol) and the reaction mixture was stirred at 25° C. for 2 hours. LCMS analysis indicated the reaction was complete. The mixture was concentrated under reduced pressure to give a crude product, which was purified by preparative HPLC to afford the target compound BR-032540 (11.1 mg, 37.33 μmol, 24.73% yield) as a white solid.

[0434] 1 H NMR (400MHz, DMSO-d6) δ8.66(d,J=8.0Hz,1H),7.56(d,J=6.9Hz,1H),7.44–7.05(m,5H),6.25(d,J=6 .9Hz,2H),4.97–4.87(m,1H),4.60(d,J=2.4Hz,2H),4.47(s,2H),4.28(s,2H),1.37(d,J=7.0Hz,3H).

[0435] LCMS (ESI) m / z: [M+H] + 298.2; purity = 100% (254 nm); retention time = 1.07 min.

[0436] Example 45 Synthesis of Compound BR-032541

[0437] To a solution of 2-(4-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-5-yl)-N-[(1S)-1-phenylethyl]acetamide (50 mg, 168.15 μmol) in MeOH (5 mL) at 0°C was added hexachlorocyclohexane (28.63 mg, 840.76 μmol). The mixture was stirred at room temperature for 15 minutes, then NaBH3CN (21.13 mg, 336.30 μmol) was added and stirred for 4 hours. LCMS showed that the reaction was complete. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL, dried over sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC to give BR-032541 (18.9 mg, 60.70 μmol, 36.10% yield).

[0438] 1 H NMR (400MHz, DMSO-d6) δ8.65(d,J=7.9Hz,1H),7.50(d,J=6.8Hz,1H),7.43–7.11(m,5H),6.21(d,J=6.7Hz,1H),5.01– 4.87(m,1H),4.59(d,J=1.4Hz,2H),3.78(t,J=3.1Hz,2H),3.65(d,J=3.1Hz,2H),2.43(s,3H),1.38(d,J=7.0Hz,3H).

[0439] LCMS (ESI) m / z: [M+H] + 312.2; purity = 100% (254 nm); retention time = 1.09 min.

[0440] Example 46 Synthesis of Compound BR-032542

[0441] To a solution of 2-(4-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-5-yl)-N-[(1S)-1-phenylethyl]acetamide (60 mg, 201.78 μmol) in DCM (8 mL) was added DIEA (104.32 mg, 807.13 μmol, 140.59 μL) at 0°C. The mixture was stirred at room temperature for 15 minutes, then acetyl chloride (19.01 mg, 242.14 μmol, 14.69 μL) was added and stirring continued for 4 hours. LCMS showed that the reaction was complete. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by preparative HPLC to afford BR-032542 (24.8 mg, 73.07 μmol, 36.21% yield).

[0442] 1 H NMR(400MHz, DMSO-d6)δ8.69(dd,J=8.0,2.0Hz,1H),7.61(d,J=6.8Hz,1H),7.44–7.13(m,5H),6.30(t,J=6.9Hz,1H),4.97–4.88(m,1H),4.7 6(s,1H),4.63(d,J=3.0Hz,2H),4.58–4.50(m,2H),4.33(d,J=3.0Hz,1H),2.03(d,J=5.6Hz,3H),1.38(d,J=7.0Hz,3H).LCMS(ESI)m / z:[M+H] + 340.2; purity = 100% (254nm); retention time = 1.42min

[0443] Example 47 Synthesis of Compound BR-032543

[0444] Step 1: Under N2 atmosphere, a mixture of 3-bromo-1H-pyridin-2-one (200 mg, 1.15 mmol), tert-butyl 3-(4,4,5,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate (339.30 mg, 1.15 mol) and Na2CO3 (365.49 mg, 3.45 mmol, 144.35 μL) in dioxane (8 mL) and water (2 mL) was added Pd(dppf)Cl2(67) (91.96 μmol). The mixture was then stirred at 98°C for 16 hours. Water (10 mL) was added to the mixture and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine and concentrated. The product was then purified by flash column chromatography (10 g, 3% in DCM) The crude product was purified by filtration with 4% MeOH to obtain the target compound 3 (215 mg, 819.66 μmol, 71.31% yield). LCMS (ESI) m / z: [M+H] + 261.2

[0445] Step 2: To a solution of 4 (30 mg, 96.74 μmol) and 3 (30.45 mg, 116.09 μmol) in DMF (1.5 mL) was added KCO (26.74 mg, 193.48 μmol). The reaction mixture was stirred at room temperature for 16 hours. The crude product was purified by preparative HPLC to afford 5 (18 mg, 36.62 μmol, 37.86% yield). LCMS (ESI) m / z: [M+H] + 490.3

[0446] Step 3: To 5 (18 mg, 36.62 μmol) was added 2 mL of a 4 M HCl solution in dioxane. The reaction mixture was stirred at room temperature for 2 hours. The mixture was purified by preparative HPLC to afford the title compound BR-032543 (1 mg, 2.56 μmol, 6.98% yield) as a white solid.

[0447] 1 H NMR (400MHz, DMSO-d6) δ8.86(d,J=7.6Hz,1H),8.34(s,1H),7.69(d,J=8.2Hz,2H),7.62(d,J=5.3Hz,1H),7.57(d,J=8.1Hz,2H),7.35(d,J= 7.0Hz,1H),6.96(s,1H),6.27(t,J=6.9Hz,1H),5.01–4.93(m,1H),4.66(d,J=2.0Hz,2H),4.08(s,2H),3.96(s,2H),1.40(d,J=7.0Hz,3H).

[0448] LCMS (ESI) m / z: [M+H] + 392.2

[0449] Example 48 Synthesis of Compound BR-032580

[0450] Step 1: Under N2 atmosphere, to a solution of 2 (200 mg, 900.65 μmol), 5-bromo-1H-pyrimidin-6-one (173.36 mg, 990.71 μmol) and Na2CO3 (286.37 mg, 2.70 mmol) in dioxane (8 mL) and water (2 mL) was added Pd(dppf)Cl2 (52.72 mg, 72.05 μmol). The mixture was then stirred at 98°C for 16 hours. The mixture was added with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine and concentrated. The crude product was then purified by flash column chromatography (10% MeOH in DCM) and preparative HPLC to give the target compound 3 (98 mg, 515.32 μmol, 57.22% yield). LCMS (ESI) m / z: [M+H] + 192.04

[0451] Step 2: To a solution of 4 (146.30 mg, 448.63 μmol) and 3 (32 mg, 168.27 μmol) in DMF (1.5 mL) was added KCO (38.76 mg, 280.45 μmol). The reaction mixture was stirred at 60°C for 16 hours. The crude product was purified by preparative HPLC to afford BR-032580 (30.05 mg, 69.02 μmol, 49.22% yield) as a white solid.

[0452] 1 H NMR (400MHz, DMSO-d6) δ8.87(d,J=7.7Hz,1H),8.40(s,1H),8.17(s,1H),7.76–7.71(m,2H),7.46(d,J=8. 7Hz,2H),7.32(d,J=8.2Hz,2H),7.28–7.22(m,2H),4.99–4.92(m,1H),4.69(s,2H),1.39(d,J=7.0Hz,3H).

[0453] LCMS (ESI) m / z: [M+H] + 436.2

[0454] Example 49 Synthesis of Compound BR-032582

[0455] Step 1: To a solution of 2-(2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200 mg, 900.65 μmol), 5-bromo-1H-pyrimidin-6-one (173.36 mg, 990.71 μmol) and NaCO (286.37 mg, 2.70 mmol) in dioxane (8 mL) and water (2 mL) was added Pd(dppf)Cl (52.72 mg, 72.05 μmol) under N2 atmosphere. The mixture was then stirred at 120°C for 12 hours. Water (10 mL) was added to the mixture and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude product was then purified by flash column chromatography (10% MeOH in DCM) and preparative HPLC to afford the target compound 5-(2-fluorophenyl)-1H-pyrimidin-6-one (35 mg, 184.04 μmol, 20.43% yield). LCMS (ESI) m / z: [M+H] + 191.97

[0456] Step 2: To a solution of 4 (50.01 mg, 153.37 μmol) in DMF (2 mL) was added KCO (42.39 mg, 306.74 μmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was stirred at elevated temperature for 30 minutes. The crude product was purified by preparative HPLC to afford BR-032582 (22.1 mg, 50.76 μmol, 33.10% yield).

[0457] 1 H NMR(400MHz,DMSO-d6)δ8.88(d,J=7.7Hz,1H),8.44(s,1H),8.04(s,1H),7.50–7.39(m,4H), 7.36–7.21(m,4H),5.00–4.90(m,1H),4.92–5.01(m,1H),4.69(s,2H),1.38(d,J=7.0Hz,3H)

[0458] LCMS (ESI) m / z: [M+H] + 436.07

[0459] Example 50 Synthesis of Compound BR-032622

[0460] To a solution of 2-bromo-N-[(1S)-1-[4-(trifluoromethoxy)phenyl]ethyl]acetamide (53 mg, 162.52 μmol) and 3,5-dihydro-1H-furo[3,4-c]pyridin-4-one (26.75 mg, 195.03 μmol) in DMF (5 mL) was added potassium carbonate (44.92 mg, 325.04 μmol). The reaction mixture was stirred at 25 °C for 16 h. The mixture was then purified by preparative HPLC to give BR-032622 (9.1 mg, 23.80 μmol, 14.64% yield).

[0461] 1 H NMR (400MHz, DMSO-d6) δ8.76(d,J=7.7Hz,1H),7.64-7.24(m,5H),6.29(d,J=6.8Hz,1H),5.07-4.76(m,5H),4.63(s,2H),1.39(d,J=7.0Hz,3H).

[0462] LCMS (ESI) m / z: [M+H] + 383.0; purity = 100% (254 nm); retention time = 2.767 min.

[0463] Example 51 Synthesis of Compound BR-032708

[0464] Step 1: 5-bromopyrimidin-4-one (100 mg, 571.48 μmol), 3-fluorophenylboronic acid (119.94 mg, 857.22 μmol), Pd(dppf)Cl2 (41.82 mg, 57.15 μmol), and sodium carbonate (181.71 mg, 1.71 mmol) were added to a Schlenk reaction tube, replaced with a nitrogen atmosphere, and dioxane (1.5 mL) and H2O (0.5 mL) were added. The reaction was then allowed to react overnight at 100 ° C. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with DCM. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The crude product was separated by column to obtain 5-(3-fluorophenyl)-1H-pyrimidin-6-one (80 mg).

[0465] Step 2: 5-(3-Fluorophenyl)-1H-pyrimidin-6-one (20 mg, 105.17 μmol), 2-bromo-N-[(1S)-1-[4-(trifluoromethoxy)phenyl]ethyl]acetamide (34.30 mg, 105.17 μmol), potassium carbonate (29.07 mg, 210.33 μmol), and DMF (1 mL) were added to a reaction flask and reacted at room temperature for 2 h. After the reaction, water was added and the mixture was extracted with DCM. The solvent was removed by concentration under reduced pressure and separated by reverse phase chromatography to obtain BR-032708 (23 mg, 49% yield).

[0466] 1 H NMR (600MHz, DMSO-d6) δ8.89(d,J=7.7Hz,1H),8.44(s,1H),8.26(s,1H),7.62–7.54(m,2H),7.47(d,J=8.6Hz,3H ), 7.33 (d, J = 8.2Hz, 2H), 7.21 (td, J = 8.6, 2.6Hz, 1H), 4.97 (p, J = 7.1Hz, 1H), 4.71 (s, 2H), 1.40 (d, J = 7.0Hz, 3H). LC-MS:m / z[M+H] + 436.10

[0467] Example 52 Synthesis of Compound BR-032709

[0468] The same method as Example 51: Synthesis of Compound BR-032708 was used, except that the starting material 3-fluoroboric acid was replaced with 2-(cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (83.18 mg, 428.61 μmol).

[0469] Step 1: 5-(Cyclopent-1-en-1-yl)pyrimidin-4(3H)-one (34 mg, 73% yield) was obtained.

[0470] Step 2: BR-032709 was obtained (36 mg, 45% yield).

[0471] 1H NMR (600MHz, DMSO-d6) δ8.84(d,J=7.7Hz,1H),8.29(s,1H),7.87(s,1H),7.47(d,J=8.2Hz,2H),7.33(d,J=8.1Hz,2H),7.01–6.94(m,1H),4.95( p,J=7.1Hz,1H),4.66(d,J=4.1Hz,2H),2.60(t,J=7.4Hz,2H),2.49(s,2H),1.87(p,J=7.5Hz,2H),1.40(d,J=7.0Hz,3H).LC-MS(ESI):m / z[M+H] + 408.20.

[0472] Example 53 Synthesis of Compound BR-032832

[0473] 5-Bromopyrimidin-4-one (100 mg, 571.48 μmol), 2-bromo-N-[(1S)-1-[4-(trifluoromethoxy)phenyl]ethyl]acetamide (186.37 mg, 571.48 μmol), potassium carbonate (78.98 mg, 571.48 μmol), and DMF (1 mL) were added to a reaction flask and reacted at room temperature for 2 h. After the reaction, water was added and the mixture was extracted with DCM. The solvent was removed by concentration under reduced pressure, and (S)-2-(5-bromo-6-oxopyrimidin-1(6H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide (23 mg, 49% yield) was obtained by preparative separation using reverse phase chromatography.

[0474] 1 H NMR (400MHz, DMSO-d6) δ8.88(d,J=7.7Hz,1H),8.42(s,1H),8.36(s,1H),7.52–7.41(m,2H),7.33(d,J= 8.3Hz,2H),4.95(p,J=7.1Hz,1H),4.68(d,J=2.0Hz,2H),1.39(d,J=7.0Hz,3H).LC-MS(ESI):m / z[M+H] + 420.10.

[0475] Example 54 Synthesis of Compound BR-032710

[0476] (S)-2-(5-bromo-6-oxopyrimidin-1(6H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide (50 mg, 119.00 μmol), 2-(2,5-dihydrofuran-3-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborolane (34.99 mg, 178.49 μmol), PdCl2(dppf) (8.71 mg, 11.90 μmol), sodium carbonate (37.84 mg, 356.99 μmol) mol) was added to a Schlenk reaction tube, the atmosphere was replaced with nitrogen, Dioxane (1.5 mL) and H2O (0.5 mL) were added, and the mixture was reacted at 100°C overnight. After the reaction, water was added, the mixture was extracted with DCM, and the solvent was removed by concentration under reduced pressure. Reverse phase chromatography was used to obtain (S)-2-(5-(2,5-dihydrofuran-3-yl)-6-oxopyrimidin-1(6H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide (28 mg, yield 52%).

[0477] 1 H NMR (600MHz, DMSO-d6) δ8.87(d,J=7.7Hz,1H),8.36(s,1H),7.80(s,1H),7.47(d,J=8.7Hz,2H),7.33(d,J=8.2Hz,2H),7.05–6.95(m,1H),4.96(t,J =7.2Hz, 1H), 4.83 (td, J = 4.8, 2.0Hz, 2H), 4.71 (q, J = 4.8, 3.6Hz, 2H), 4.68 (d, J = 4.5Hz, 2H), 1.40 (d, J = 7.0Hz, 3H). LC-MS (ESI): m / z [M+H] + 410.20.

[0478] Example 55 Synthesis of Compound BR-032711

[0479] The same method as in Example 54: Synthesis of Compound BR-032710 was used, except that the starting material, 2-(2,5-dihydrofuran-3-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborolane, was replaced with (4-chloro-3-fluorophenyl)boronic acid (18.67 mg, 107.10 μmol). This afforded (S)-2-(5-(4-chloro-3-fluorophenyl)-6-oxopyrimidin-1(6H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide (18 mg, 51% yield).

[0480] 1H NMR(600MHz, Methanol-d4)δ8.37(s,1H),8.18(s,1H),7.64(dt,J=10.7,1.5Hz,1H),7.53–7.42(m,4H),7.22 (d,J=8.2Hz,2H),5.05(q,J=7.0Hz,1H),4.76(d,J=2.9Hz,2H),1.49(d,J=7.1Hz,3H).LC-MS(ESI):m / z[M+H] + 470.10.

[0481] Example 56 Synthesis of Compound BR-032712

[0482] The same method as in Example 54: Synthesis of Compound BR-032710 was used, except that the starting material, 2-(2,5-dihydrofuran-3-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborolane, was replaced with (3-chlorophenyl)boronic acid (16.75 mg, 107.10 μmol). This afforded (S)-2-(5-(3-chlorophenyl)-6-oxopyrimidin-1(6H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide (22 mg, 67% yield).

[0483] 1 H NMR(400MHz, Methanol-d4)δ8.40(s,1H),8.14(s,1H),7.78–7.69(m,1H),7.54(s,1H),7.46(d,J=8.7Hz,2H),7.44–7 .35(m,2H),7.28–7.19(m,2H),5.05(td,J=7.3,5.0Hz,1H),4.77(s,2H),1.50(d,J=7.0Hz,3H).LC-MS(ESI):m / z[M+H] + 452.10.

[0484] Example 57 Synthesis of Compound BR-032713

[0485] The same method as in Example 54: Synthesis of Compound BR-032710 was used, except that the starting material, 2-(2,5-dihydrofuran-3-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborolane, was replaced with pyridin-4-ylboronic acid (13.16 mg, 107.10 μmol). This afforded (S)-2-(6-oxo-5-(pyridin-4-yl)pyrimidin-1(6H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide (23 mg, 74% yield).

[0486] 1 H NMR(600MHz,Methanol-d4)δ8.62–8.53(m,2H),8.42(s,1H),8.31(s,1H),7.82–7.75(m,2H),7.45(d,J=8.3Hz,2H) ,7.22(d,J=8.2Hz,2H),5.05(q,J=7.0Hz,1H),4.78(d,J=2.7Hz,2H),1.50(d,J=7.0Hz,3H).LC-MS(ESI):m / z[M+H] + 419.10.

[0487] Example 58 Synthesis of Compound BR-032714

[0488] The same method as in Example 54: Synthesis of Compound BR-032710 was used, except that the starting material, 2-(2,5-dihydrofuran-3-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborolane, was replaced with pyridin-3-ylboronic acid (13.16 mg, 107.10 μmol). This afforded (S)-2-(6-oxo-5-(pyridin-3-yl)pyrimidin-1(6H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide (20 mg, 64% yield).

[0489] 1 H NMR (600MHz, Methanol-d4) δ8.84(d,J=2.2Hz,1H),8.52(dd,J=4.9,1.5Hz,1H),8.39(s,1H),8.21(s,1H),8.13(dd,J=7.9,1.8Hz,1H) ,7.54–7.38(m,3H),7.22(d,J=8.2Hz,2H),5.05(q,J=7.0Hz,1H),4.78(d,J=1.8Hz,2H),1.50(d,J=7.0Hz,3H).LC-MS(ESI):m / z[M+H] + 419.20.

[0490] Example 59 Synthesis of Compound BR-032758

[0491] The same method as in Example 54: Synthesis of Compound BR-032710 was used, except that the starting material, 2-(2,5-dihydrofuran-3-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborolane, was replaced with (3-chloro-4-methoxyphenyl)boronic acid (19.96 mg, 107.10 μmol). This afforded (S)-2-(5-(3-chloro-4-methoxyphenyl)-6-oxopyrimidin-1(6H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide (11 mg, 31% yield).

[0492] 1 H NMR (400MHz, Methanol-d4) δ8.37(s,1H),8.10(s,1H),7.75(d,J=2.2Hz,1H),7.56(dd,J=8.6,2.2Hz,1H),7.51–7.40(m,2H),7.27–7. 20(m,2H),7.11(d,J=8.6Hz,1H),5.05(tt,J=7.1,3.5Hz,1H),4.75(s,2H),3.91(s,3H),1.50(d,J=7.0Hz,3H).LC-MS(ESI):m / z[M+H] + 482.20.

[0493] Example 60 Synthesis of Compound BR-032759

[0494] The same method as in Example 54: Synthesis of Compound BR-032710 was used, except that the starting material, 2-(2,5-dihydrofuran-3-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborolane, was replaced with 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborolane (22.50 mg, 107.10 μmol). ((S)-2-(5-(3,6-dihydro-2H-pyran-4-yl)-6-oxopyrimidin-1(6H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide (16 mg, 52% yield) was obtained.

[0495] 1H NMR (400MHz, Methanol-d4) δ8.40(s,1H),7.92(s,1H),7.50–7.40(m,2H),7.27–7.17(m,2H),6.74–6.66(m,1H),5.04(q,J=7.1Hz,1H) ,4.71(d,J=1.4Hz,2H),4.27(t,J=2.8Hz,2H),3.87(t,J=5.4Hz,2H),2.50–2.39(m,2H),1.49(d,J=7.0Hz,3H).LC-MS(ESI):m / z[M+H] + 424.30.

[0496] Example 61 Synthesis of Compound BR-032833

[0497] Synthesis of BR-032833: Same as Example 1, purified by silica gel column to obtain 390 mg of product (yield 77%).

[0498] 1 H NMR (400MHz, DMSO-d6) δ8.79(d,J=7.7Hz,1H),7.92(dd,J=7.3,1.8Hz,1H),7.68(dd,J=6.7,1.9Hz,1H),7.53–7.41(m,2H),7.33(d, J=8.3Hz,2H),6.18(t,J=7.0Hz,1H),4.94(t,J=7.2Hz,1H),4.66(d,J=3.0Hz,2H),1.39(d,J=7.0Hz,3H).LC-MS: m / z[M+H]+419.10.

[0499] Example 62 Synthesis of Compound BR-032828

[0500] Synthesis of BR-032828: Same as Example 54, thick preparative plating to give 20 mg of product (yield 64%).

[0501] 1H NMR(400MHz,Chloroform-d)δ7.41(d,J=7.8Hz,1H),7.37(dd,J=6.7,1.9Hz,1H),7.33–7.21(m,3H),7.17–7.07(m,4H),6 .29(t,J=6.9Hz,1H),5.03(p,J=7.1Hz,1H),4.97–4.83(m,4H),4.69–4.55(m,2H),1.43(d,J=6.9Hz,3H).LC-MS:m / z[M+H] + 409.10.

[0502] Example 63 Synthesis of Compound BR-032847

[0503] BR-032709 (15 mg, 36.82 μmol), Pd / C (10%, 2 mg), MeOH (0.75 mL), and EA (0.25 mL) were added to a reaction flask, connected to a hydrogen balloon, and replaced with a hydrogen atmosphere. The reaction was allowed to proceed at room temperature for 1 h. After the reaction was completed, the mixture was filtered and the solvent was removed by concentration under reduced pressure. Reverse phase chromatography was used to obtain 8 mg of the product BR-032847 (yield 52%).

[0504] 1 H NMR (600MHz, Methanol-d4) δ8.89(d,J=7.6Hz,1H),8.37(s,1H),7.82(s,1H),7.45(d,J=8.7Hz,2H),7.30–7.15(m,2H),5.10–4.99(m,1H),4.69(s,2H) ,3.08–2.97(m,1H),2.03–1.95(m,2H),1.80(ddt,J=9.2,7.3,2.9Hz,2H),1 .75–1.64(m,2H),1.64–1.55(m,2H),1.49(d,J=6.9Hz,3H).LC-MS:m / z[M+H] + 410.20.

[0505] Example 64 Synthesis of Compound BR-032848

[0506] As in Example 1, 26 mg of the product was purified by thick preparative plating (yield 86%).

[0507] 1H NMR (600MHz, Methanol-d4) δ7.48–7.41(m,2H),7.25–7.19(m,2H),7.13(dd,J=6.9,1.6Hz,1H),6.91(dd,J=7.6,1.6Hz,1H ),6.28(t,J=7.2Hz,1H),5.03(q,J=7.0Hz,1H),4.67(d,J=0.9Hz,2H),3.80(s,3H),1.48(d,J=7.0Hz,3H).LC-MS:m / z[M+H] + 371.10.

[0508] Example 65 Synthesis of Compound BR-032849

[0509] As in Example 1, 24 mg of the product was purified by thick preparative plating (yield 80%).

[0510] 1 H NMR (600MHz, Methanol-d4) δ7.43(dd,J=12.1,8.1Hz,3H),7.21(dt,J=7.8,1.1Hz,2H),6.07(dd,J=7.6,2.7Hz,1H),5. 90(d,J=2.7Hz,1H),5.03(q,J=7.0Hz,1H),4.59(s,2H),3.80(s,3H),1.48(d,J=7.0Hz,3H).LC-MS:m / z[M+H]+371.10.

[0511] Example 66 Synthesis of Compound BR-032850

[0512] Step 1: 2,3-Dihydroxypyridine (1 g, 9.00 mmol), sodium tert-butoxide (865.00 mg, 9.00 mmol), and MeOH (5 mL) were added to a microwave reaction tube, and then iodoethane (1.54 g, 9.90 mmol, 795.99 μL) was added. The mixture was reacted at 100°C in a microwave for 20 min. After the reaction was completed, water was added, and the mixture was extracted with DCM. The solvent was removed by concentration under reduced pressure, and 400 mg of product 2 was obtained by separation on a silica gel column.

[0513] Step 1: As in Example 1, thick preparative plating was performed to obtain 20 mg of the product (yield 74%).

[0514] 1H NMR (600MHz, Methanol-d4) δ7.48–7.40(m,2H),7.25–7.18(m,2H),7.11(dd,J=6.9,1.6Hz,1H),6.87(dd,J=7.6,1.6Hz,1H),6.25(t,J =7.2Hz,1H),5.03(q,J=7.0Hz,1H),4.67(s,2H),3.99(q,J=7.0Hz,2H),1.47(d,J=7.1Hz,3H),1.40(t,J=7.0Hz,3H).LC-MS:m / z[M+H] + 385.20.

[0515] Example 67 Synthesis of Compound BR-032876

[0516] Step 1: 4,5-Dihydro-4-oxofurano[3,2]pyridine (200 mg, 1.48 mmol), Pd / C (10%, 20 mg), and EtOH (4 mL) were added to a reaction flask, connected to a hydrogen balloon, replaced with a hydrogen atmosphere, and reacted at 70°C overnight. After the reaction was completed, the mixture was filtered, concentrated under reduced pressure to remove the solvent, and separated by column to obtain 105 mg of product 2 (yield 52%).

[0517] Step 2: As in Example 1, thick preparative plate purification gave 11 mg of product (yield 39%).

[0518] 1 H NMR (600MHz, Methanol-d4) δ7.52–7.40(m,3H),7.26–7.18(m,2H),6.13(d,J=7.3Hz,1H),5.03(q,J=7.0H z,1H),4.68(t,J=9.2Hz,2H),4.64(s,2H),3.04(t,J=9.2Hz,2H),1.48(d,J=7.0Hz,3H).LC-MS:m / z[M+H] + 383.30.

[0519] Example 68 Synthesis of Compound BR-032882

[0520] As in Example 1, 30 mg of the product was purified by thick preparative plating (yield 81%).

[0521] 1H NMR (600MHz, Methanol-d4) δ7.59–7.50(m,2H),7.49–7.42(m,2H),7.22(d,J=8.3Hz,2H),6.53(dd,J=9.1,1.3H z,1H),6.36(td,J=6.8,1.4Hz,1H),5.03(q,J=7.0Hz,1H),4.67(s,2H),1.48(d,J=7.0Hz,3H).LC-MS:m / z[M+H] + 341.10.

[0522] Example 69 Synthesis of Compound BR-032921

[0523] As in Example 2, 11 mg of the product was purified by thick preparative plating (yield 39%).

[0524] 1 H NMR (400MHz, Methanol-d4) δ8.19(s,1H),7.62(s,1H),7.45(d,J=8.6Hz,2H),7.23(d,J=8.3Hz,2H),5.04(q,J=7.0Hz,1H),4. 68(s,2H),1.84(tt,J=8.5,5.3Hz,1H),1.49(d,J=7.0Hz,3H),0.94–0.85(m,2H),0.72(dd,J=5.4,2.0Hz,2H).LC-MS:m / z[M+H] + 382.10.

[0525] Example 70 Synthesis of Compound BR-033019

[0526] As in Example 1, 13 mg of product BR-033019 was obtained through thick preparative plate purification (yield 51%).

[0527] 1 H NMR (400MHz, DMSO-d6) δ8.89(d,J=7.7Hz,1H),8.03(d,J=4.1Hz,1H),7.54(d,J=4.0Hz,1H),7.45(d,J=8.4Hz,2 H),7.33(d,J=8.3Hz,2H),4.95(p,J=7.2Hz,1H),4.73(d,J=3.9Hz,2H),1.39(d,J=7.0Hz,3H).LC-MS:m / z[M+H] + 410.20.

[0528] Example 71 Synthesis of Compound BR-033084

[0529] BR-033019 (35 mg, 83.30 μmol), cyclopropylboronic acid (10.73 mg, 124.95 μmol), PdCl2(dppf) (6.09 mg, 8.33 μmol), and sodium carbonate (26.49 mg, 249.89 μmol) were added to a Schlenk reaction tube, which was replaced with a nitrogen atmosphere. Dioxane (1.5 mL) and H2O (0.5 mL) were added, and the mixture was reacted at 100°C overnight. After the reaction, water was added, and the mixture was extracted with DCM. The solvent was removed by concentration under reduced pressure, and the product was purified by reverse phase chromatography to obtain 8 mg of BR-033084.

[0530] 1 H NMR (600MHz, Methanol-d4) δ7.45(d,J=8.2Hz,2H),7.22(dd,J=9.7,6.3Hz,3H),7.17(d,J=4.4Hz,1H),5.05(d,J=7. 1Hz, 1H), 4.64 (d, J = 5.0Hz, 2H), 2.55 (p, J = 6.8Hz, 1H), 1.49 (d, J = 7.0Hz, 3H), 0.99 (d, J = 4.4Hz, 4H). LC-MS: m / z [M+H] + 382.20.

[0531] Example 72 Synthesis of Compound BR-033552

[0532] Step 1: Bicyclo[1.1.1]pentane-1-carboxylic acid (250.00 mg, 2.23 mmol) and DCM (8 mL) were added to a reaction flask, and oxalyl chloride (566.01 mg, 4.46 mmol, 389.01 μL) and DMF (32.59 mg, 445.93 μmol, 34.53 μL) were added dropwise at 0°C. After the bubbles disappeared, the mixture was reacted at room temperature for 2.5 h. After the reaction was completed, the solvent was removed by concentration under reduced pressure.

[0533] The product, bicyclo[1.1.1]pentane-1-carbonyl chloride, was used directly in the next step.

[0534] Step 2: Bicyclo[1.1.1]pentane-1-carbonyl chloride (290.00 mg, 2.22 mmol) and ACN (8 mL) were added to the reaction flask and stirred at 0°C for 5 min. Trimethylsilylated diazomethane (2 M in n-hexane, 1.01 g, 8.88 mmol) was then added dropwise and reacted at room temperature for 5.5 h. After the reaction was completed, 10% aqueous citric acid solution was added to quench the reaction. Most of the solvent was dried and ethyl acetate was added. The mixture was extracted with 10% aqueous citric acid solution, water, saturated NaHCO3, and saturated brine, respectively. The solvent was removed by concentration under reduced pressure and column chromatography to give 200 mg of the product 1-(bicyclo[1.1.1]pentan-1-yl)-2-diazacycloethane-1-one. Gradient: PE:EA=100:0 to 94:6, TLC:PE:EA=10:1 Rf=0.5, LC-Ms m / z[M+H] + 137.2

[0535] Step 3: 1-(Bicyclo[1.1.1]pentan-1-yl)-2-diazacycloethane-1-one (200 mg, 1.47 mmol), THF (30 mL), and H2O (5.00 mL) were added to a reaction flask. Silver benzoate (67.27 mg, 293.79 μmol) and TEA (594.58 mg, 5.88 mmol, 818.97 μL) were dissolved in THF (10 mL) and added dropwise to the above solution. The solution gradually turned black and was ultrasonically reacted at room temperature for 0.5 h. After the reaction, most of the solvent was dried and the solution was acidified with 1 M HCl. Water was added and the solution was extracted with ethyl acetate. The solution was concentrated under reduced pressure to remove the solvent. The product, bicyclo[1.1.1]pentane-1-acetic acid, was used directly in the next step. MS m / z [M+H] + 125.2

[0536] Step 4: Bicyclo[1.1.1]pentane-1-acetic acid (160 mg, 1.27 mmol) and EtOH (2 mL) were added to a reaction flask, and 3 drops of sulfuric acid (24.88 mg, 253.66 μmol) were added dropwise. The reaction was allowed to proceed at 80°C overnight. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate. The solvent was removed by concentration under reduced pressure to obtain the product, bicyclo[1.1.1]pentane-1-acetic acid ethyl ester. LC-Ms m / z [M+H] + 155.2

[0537] Step 5: Ethyl bicyclo[1.1.1]pentane-1-acetate (180 mg, 1.17 mmol) was added to the reaction flask, replaced with nitrogen atmosphere, THF (2 mL), and 2M LDA (0.76 mL, 162.55 mg, 1.52 mmol) was added dropwise at -50 ° C. After stirring for 20 min, ethyl formate (129.71 mg, 1.75 mmol, 140.83 μL) was added and the reaction was allowed to react overnight at room temperature. After the reaction was completed, water was added, and the mixture was extracted with DCM. The solvent was removed by concentration under reduced pressure to give the crude product ethyl 2-(bicyclo[1.1.1]pentan-1-yl)-3-oxopropanoate, which was directly processed into the next step without purification.

[0538] Step 6: Ethyl 2-(bicyclo[1.1.1]pentan-1-yl)-3-oxopropanoate (150 mg, 823.20 μmol), thiourea (62.66 mg, 823.20 μmol, 44.60 μL), and MeOH (2 mL) were added to a reaction flask and reacted at 70°C for 4 h. After the reaction, 56 mg of the product 5-(bicyclo[1.1.1]pentan-1-yl)-2-mercaptopyrimidin-6-one was obtained by column separation. Gradient: DCM:MeOH = 100:0 to 96:4, TLC:DCM:MeOH = 20:1, Rf = 0.5, MS m / z [M+H] + 195.2.

[0539] Step 7: 5-(Bicyclo[1.1.1]pentan-1-yl)-2-mercaptopyrimidin-6-one (56 mg, 288.28 μmol), Raney nickel (10%, 6 mg), and MeOH (2 mL) were added to the reaction flask, connected to a hydrogen balloon, replaced with a hydrogen atmosphere, and reacted at 70°C overnight. After the reaction was completed, the mixture was filtered, concentrated under reduced pressure to remove the solvent, and used directly in the next step. MS m / z [M+H] + 163.2.

[0540] Step 8: As in Example 1, reverse phase chromatography was used to purify the product to give 14.6 mg (yield 28%).

[0541] 1 H NMR(400MHz,Chloroform-d)δ8.56(s,1H),7.63(s,1H),7.29(d,J=8.3Hz,2H),7.14(s,2H),6.93(d, J=7.5Hz,1H),5.04(p,J=7.1Hz,1H),4.60(s,2H),2.61(s,1H),2.12(s,6H),1.48(d,J=6.9Hz,3H).MS m / z[M+H] + 408.20.

[0542] Example 73 Synthesis of Compound BR-033588

[0543] The same method as in Example 2 was used for purification by reverse phase chromatography to obtain 1.3 mg of product BR-033588 (yield 4.4%).

[0544] 1 H NMR (600MHz, Chloroform-d) δ8.35(s,1H),7.87(s,1H),7.30(d,J=8.3Hz,2H),7.16(d,J=8.2Hz,2H),6.85(d,J=7.8Hz,1H),5.06(p,J=7. 1Hz,1H),4.58(d,J=14.2Hz,1H),4.52(d,J=14.2Hz,1H),3.50(s,1H),1.50(d,J=6.9Hz,3H),1.31(s,3H),0.77–0.70(m,4H).MS:m / z[M+H] + 396.20.

[0545] Example 74 Synthesis of Compound BR-033601

[0546] The same method as in Example 2 was used for purification by reverse phase chromatography to obtain 15 mg of the product (yield 54%).

[0547] 1 H NMR(400MHz,Chloroform-d)δ8.27(s,1H),7.95(s,1H),7.29(d,J=8.4Hz,2H),7.15(d,J=8.2Hz,2H),6.91(d,J=7.7Hz,1H),5 .79(s,1H),5.31(d,J=2.0Hz,1H),5.06(p,J=7.1Hz,1H),4.62–4.49(m,2H),2.08(s,3H),1.48(d,J=6.9Hz,3H).MS:m / z[M+H] + 382.20.

[0548] Example 75 Synthesis of Compound BR-033602

[0549] BR-033601 (8 mg, 20.98 μmol), Pd / C (10%, 2 mg), and MeOH (1 mL) were added to the reaction flask, connected to a hydrogen balloon, and replaced with a hydrogen atmosphere. The reaction was allowed to proceed at room temperature for 1 h. After the reaction was completed, the mixture was filtered, concentrated under reduced pressure to remove the solvent, and purified by reverse phase chromatography to obtain 7 mg of the product.

[0550] 1 H NMR(400MHz,Chloroform-d)δ8.50(s,1H),7.76(s,1H),7.30(d,J=8.4Hz,2H),7.15(d,J=8.2Hz,2H),6.87(d,J=11.6Hz,1H), 5.06(p,J=7.1Hz,1H),4.60(d,J=3.9Hz,2H),3.04(p,J=6.9Hz,1H),1.49(d,J=6.9Hz,3H),1.21(t,J=6.9Hz,6H).MS:m / z[M+H] + 384.20.

[0551] Example 76 Synthesis of Compound BR-033680

[0552] Step 1: As in Step 5 of Example 72, ethyl cyclobutyl-1-acetate (180 mg, 1.17 mmol) was added to the reaction flask, which was replaced with a nitrogen atmosphere. THF (2 mL) was added, and 2M LDA (0.76 mL, 162.55 mg, 1.52 mmol) was added dropwise at -50°C. The reaction was stirred for 20 min, and ethyl formate (129.71 mg, 1.75 mmol, 140.83 μL) was added. The mixture was allowed to react overnight at room temperature. After the reaction was completed, water was added, and the mixture was extracted with DCM. The solvent was removed by concentration under reduced pressure to give the crude product, ethyl 2-cyclobutyl-3-oxo-propionate, which was directly processed into the next step without purification.

[0553] Step 2: As in Step 6 of Example 72, ethyl 2-cyclobutyl-3-oxopropionate (220 mg, 1290 μmol), thiourea (110 mg, 1450 μmol, 78.29 μL), and MeOH (3.5 mL) were added to a reaction flask and reacted at 70°C for 3 h. After the reaction, 20 mg of the product 5-cyclobutyl-2-mercapto-1H-pyrimidin-6-one was obtained by column separation. MS m / z [M+H] + 195.2.

[0554] Step 3: As in Step 7 of Example 72, 5-cyclobutyl-2-mercapto-1H-pyrimidin-6-one (6 mg, 32.92 μmol), Nickel (10%, 2 mg), and MeOH were added to the reaction flask, and a hydrogen balloon was connected to replace the atmosphere with hydrogen. The reaction was carried out at 70°C overnight. After the reaction was completed, the mixture was filtered, concentrated under reduced pressure to remove the solvent, and used directly in the next step. MS: m / z [M+H] + 151.2.

[0555] Step 4: As in Example 1, the product BR-033680 was purified by reverse phase chromatography.

[0556] 1 H NMR(400MHz,Chloroform-d)δ8.37(s,1H),7.78(s,1H),7.29(d,J=8.7Hz,2H),7.16(d,J=8.8Hz,2H),6.80(d,J=7.7Hz,1H), 5.09–5.01(m,1H),4.55(s,2H),2.38–2.24(m,2H),2.15–1.96(m,4H),1.92–1.82(m,1H),1.49(d,J=6.9Hz,3H).MS:m / z[M+H] + 396.10.

[0557] Example 77 Synthesis of Compound BR-033831

[0558] Step 1: Same as Example 3, column purification was performed to obtain 90 mg of 5-cyclopropyl-4,6-dimethoxypyrimidine (yield 54%). MS: m / z [M+H] + 181.20.

[0559] Step 2: 5-Cyclopropyl-4,6-dimethoxypyrimidine (30 mg, 166.48 μmol) and DCM (0.5 mL) were added to a 10 mL reaction bottle, and boron tribromide (150 μL, 2 mol / L in DCM solution) was added at 0°C. The mixture was stirred overnight at room temperature. If there was any residual raw material, methanol was added at 0°C to quench the mixture. The solvent was removed by concentration without purification and the next step was directly performed.

[0560] Step 3: As in Example 1, the product was purified by reverse phase chromatography to give 14 mg (yield 55%).

[0561] 1 H NMR(600MHz,Chloroform-d)δ7.68(d,J=7.8Hz,1H),7.29(d,J=8.4Hz,2H),7.14(d,J=8.1Hz,2H),5.03(p,J=7.2Hz,1H),4.58(dd,J=14.4,1.4Hz ,1H),4.47(dd,J=14.5,1.4Hz,1H),3.95(s,3H),1.79–1.75(m,1H),1.45 (d,J=7.0Hz,3H),1.08–1.02(m,2H),0.79(d,J=8.8Hz,2H).MS:m / z[M+H] + 412.20.

[0562] Example 78 Synthesis of Compound BR-033833

[0563] The same method as in Example 1 was used for purification by reverse phase chromatography to obtain 25 mg of the product (yield 75%).

[0564] 1 H NMR(600MHz,Chloroform-d)δ8.08(s,1H),7.82(s,1H),7.28(d,J=8.6Hz,2H),7.19(d,J=7.8Hz,1H),7.14(d,J=8.2Hz,2H ),5.05(t,J=7.2Hz,1H),4.60(d,J=14.5Hz,1H),4.47(d,J=14.5Hz,1H),2.05(s,3H),1.46(d,J=7.0Hz,3H).MS:m / z[M+H] + 356.20.

[0565] Example 79 Synthesis of Compound BR-033834

[0566] The same method as in Example 1 was used for purification by reverse phase chromatography to obtain 24 mg of the product (yield 79%).

[0567] 1 H NMR(600MHz,Chloroform-d)δ8.03(s,1H),7.32(d,J=7.8Hz,1H),7.28(d,J=8.6Hz,2H),7.13(d,J=8.2Hz,2H),5.04(p,J= 7.1Hz,1H),4.58(d,J=14.6Hz,1H),4.46(d,J=14.5Hz,1H),2.31(s,3H),2.04(s,3H),1.45(d,J=7.0Hz,3H).MS:m / z[M+H] + 370.20.

[0568] Example 80 Synthesis of Compound BR-033875

[0569] The same method as in Example 1 was used for column purification to obtain 130 mg of the product (yield 88%).

[0570] 1H NMR (400MHz, DMSO-d6) δ8.84(d,J=7.7Hz,1H),8.28(s,1H),7.48–7.40(m,2H),7.36–7.27(m,2H ),4.94(p,J=6.9Hz,1H),4.61(d,J=1.5Hz,2H),2.03(s,3H),1.38(d,J=7.0Hz,3H).MS:m / z[M+H] + 390.20.

[0571] Example 81 Synthesis of Compound BR-033878

[0572] The same method as in Example 3 was used for purification by reverse phase chromatography to obtain 5.5 mg of the product (yield 17%).

[0573] 1 H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.33(d,J=7.7Hz,1H),7.28(d,J=8.7Hz,2H),7.13(d,J=8.2Hz,2H),5.03(p,J=7.1Hz,1H),4.57– 4.35(m,2H),1.95(dq,J=8.4,4.7,4.2Hz,1H),1.45(d,J=7.0Hz,3H),1.10(dd,J=4.6,2.8Hz,2H),0.97(dd,J=7.9,3.2Hz,2H).MS:m / z[M+H] + 396.20.

[0574] Example 82 Synthesis of Compound BR-009267

[0575] Synthesis of BR-009267: 1,5,6,7-tetrahydrocyclopenta[d]pyrimidin-4-one (5 mg, 36.72 μmol), intermediate-2 (11.98 mg, 36.72 μmol), potassium carbonate (7.61 mg, 55.09 μmol), and DMF (1 mL) were added to a reaction flask and reacted at room temperature for 2 h. After the reaction, water was added and the mixture was extracted with DCM. The solvent was removed by concentration under reduced pressure and 6 mg of the product was obtained by preparative separation using reverse phase chromatography (yield: 38%). 1H NMR(500MHz,MeOD)δ8.25(s,1H),7.45(d,J=8.5Hz,2H),7.23(d,J=8.0Hz,2H),5.04(q,J=7.0Hz,1H),4.70(s,2H), 2.88(t,J=7.8Hz,2H),2.78(t,J=7.3Hz,2H),2.10(dd,J=15.3,7.6Hz,2H),1.49(d,J=7.0Hz,3H).LC-MS:m / z[M+H] + 382.10

[0576] Example 83 Synthesis of Compound BR-034294

[0577] Step 1: Same as Example 77, column purification was performed to obtain 70 mg of 5-cyclopropyl-4-methoxy-6-methylpyrimidine (yield 86%). MS: m / z [M+H] + 164.20.

[0578] Step 2: Add 5-cyclopropyl-4-methoxy-6-methylpyrimidine (20 mg, 121.80 μmol) and DCM (0.5 mL) to a 10 mL reaction bottle, add boron tribromide (200 μL, 2 mol / L in DCM solution) at 0°C, stir at 50°C overnight, detect the residual raw material, add methanol at 0°C to quench, concentrate to remove the solvent, and proceed directly to the next step without purification.

[0579] Step 3: As in Example 77, purification by reverse phase chromatography gave 34 mg of product (yield 85%).

[0580] 1H NMR(400MHz,Chloroform-d)δ8.61(s,1H),7.33–7.21(m,3H),7.14(d,J=8.2Hz,2H),5.03(p,J=7.1Hz,1H),4.71–4.51(m ,2H),2.48(s,3H),1.52(dd,J=9.8,4.4Hz,1H),1.46(d,J=6.9Hz,3H),1.01–0.94(m,2H),0.85–0.77(m,2H).MS:m / z[M+H] + 395.20.

[0581] Example 84 Synthesis of Compound BR-034295

[0582] Step 1: Same as Example 77, column purification was performed to obtain 130 mg of 4-chloro-5-cyclopropyl-6-methoxypyrimidine (yield 71%). MS: m / z [M+H]+ 185.20.

[0583] Step 2: Add 4-chloro-5-cyclopropyl-6-methoxypyrimidine (20 mg, 108.33 μmol) and DCM (0.5 mL) to a 10 mL reaction bottle, add boron tribromide (200 μL, 2 mol / L in DCM solution) at 0°C, stir at 50°C overnight, detect the residual raw material, add methanol at 0°C to quench, concentrate to remove the solvent, and proceed directly to the next step without purification.

[0584] Step 3: As in Example 77, reverse phase chromatography was used to purify the product to give 19.5 mg (yield 76%).

[0585] 1 H NMR(400MHz,Chloroform-d)δ7.95(s,1H),7.32–7.27(m,2H),6.85(d,J=7.7Hz,1H),5.04(p,J=7.1Hz,1H),4.51–4.35(m,2H ),1.83(ddd,J=8.7,7.1,4.4Hz,1H),1.47(d,J=7.0Hz,3H),1.16(td,J=5.0,4.5,2.5Hz,2H),0.96–0.88(m,2H).MS:m / z[M+H] + 416.20.

[0586] Example 85 Synthesis of Compound BR-034594

[0587] BR-034295 (5 mg, 12.03 μmol), Pd / C (10%, 0.5 mg), and FORMIC ACID-D2 (1.16 mg, 24.05 μmol) were dissolved in deuterated methanol (0.25 mL). TEA (2.43 mg, 24.05 μmol, 3.35 μL) was added and the mixture was reacted at 50°C overnight. After completion of the reaction, filtration was performed using an Agilent preparative separation to obtain 2.7 mg of the product (57% yield).

[0588] 1H NMR(400MHz,Chloroform-d)δ7.30(d,J=8.4Hz,2H),7.16(d,J=8.3Hz,2H),6.97(d,J=7.9Hz,1H),5.06(p,J=7.1Hz ,1H),4.53(s,2H),1.92–1.87(m,1H),1.48(d,J=6.9Hz,3H),1.01–0.90(m,2H),0.71(t,J=6.4Hz,2H).MS:m / z[M+H] +384.20.

[0589] Example 86 Synthesis of Compound BR-034716

[0590] Step 1: Same as Example 77, column purification was performed to obtain 503 mg of 5-cyclopropyl-4-methoxypyrimidine (yield 63%). MS: m / z [M+H] + 164.20.

[0591] Step 2: 5-Cyclopropyl-4-methoxypyrimidine (200 mg, 1.33 mmol) and DCM (3 mL) were added to a 10 mL reaction bottle, and boron tribromide (3.3 mL, 2 mol / L in DCM solution) was added at 0°C. The mixture was stirred at 50°C overnight. If there was any residual raw material, methanol was added at 0°C to quench the mixture. The solvent was removed by concentration without purification and the next step was directly performed.

[0592] Step 3: 5-Cyclopropylpyrimidin-4-ol (120 mg, 881.38 μmol), (2S)-2-aminopropionic acid tert-butyl ester hydrochloride (192.13 mg, 1.06 mmol), and HATU (435.66 mg, 1.15 mmol) were dissolved in MeCN (3 mL), followed by the addition of DBU (201.27 mg, 1.32 mmol, 197.71 μL). The mixture was reacted at 75°C for 24 h. Saturated ammonium chloride solution was added, and the mixture was extracted with DCM. The solvent was removed by concentration under reduced pressure, and 20 mg of the product was obtained by HPLC. LC-Ms m / z [M+H] + 265.2.

[0593] Step 4: Tert-butyl (2S)-2-(5-cyclopropyl-6-oxopyrimidin-1-yl)propanoate (10 mg, 37.83 μmol) was dissolved in DCM (0.5 mL), and TFA (0.25 mL) was added dropwise to the above solution. The reaction was carried out at room temperature for 4 h. After the reaction was completed, the solvent was dried and used directly in the next step without purification.

[0594] Step 5: (2S)-2-(5-cyclopropyl-6-oxopyrimidin-1-yl)propanoic acid (6 mg, 28.82 μmol),

[0595] (1S)-1-[4-(Trifluoromethoxy)phenyl]ethanamine (5.91 mg, 28.82 μmol), HATU (21.91 mg, 57.63 μmol), DIPEA (14.90 mg, 115.27 μmol, 20.08 μL), and DCM (1 mL) were reacted at room temperature for 2 h. After the reaction, water was added, and the mixture was extracted with DCM. The solvent was removed by concentration under reduced pressure, and 3.3 mg of the product was obtained by Agilent preparative separation. 1H NMR(400MHz,Chloroform-d)δ9.65–9.48(m,1H),9.04(s,1H),7.73(s,1H),7.44(d,J=8.3Hz,2H),7.18(d,J=8.2Hz,2H),5.80(q,J=6.9Hz,1H),4.97 (p,J=7.1Hz,1H),1.87(dq,J=8.8,5.5,4.4Hz,1H),1.61(d,J=6.7Hz,3H), 1.41(d,J=7.0Hz,3H),0.93(d,J=8.3Hz,2H),0.73(d,J=5.7Hz,2H).LC-Ms m / z[M+H]+396.2

[0596] Example 87 Synthesis of Compound BR-034717

[0597] The same method as in Example 54: Synthesis of Compound BR-032710 was used, except that the starting material, 2-(2,5-dihydrofuran-3-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborolane, was replaced with 4,4,5,5-tetramethyl-2-(2-methylprop-1-enyl)-1,3,2-dioxaborolane (26.00 mg, 142.80 μmol). 23 mg of the product was obtained with a yield of 60%. 1H NMR(400MHz,Chloroform-d)δ8.43(s,1H),7.84(s,1H),7.28(d,J=8.3Hz,2H),7.14(d,J=8.2Hz,2H),7.00(d,J=7.6Hz,1H),6.05(s, 1H),5.05(p,J=7.1Hz,1H),4.62(q,J=14.7Hz,2H),1.94(s,3H),1.84(s,3H),1.46(d,J=6.9Hz,3H)..LC-MS(ESI):m / z[M+H]+396.20.

[0598] Example 88 Synthesis of Compound BR-034891

[0599] Step 1: Li-HMDS (26.2 mL, 1 M in THF) was added dropwise to a solution of compound 1 (3.00 g, 23.8 mmol) in DMF (120 mL) at -10°C under a nitrogen atmosphere. The reaction was stirred at -10°C for 2 hours. Compound 2 (6.66 g, 28.5 mmol) was added to the reaction mixture in five portions at -10°C. The resulting white mixture was diluted with DMF (30 mL) and stirred at 20°C for 12 hours. Product formation was detected by LCMS and TLC. The reaction was quenched with water (500 mL) and extracted with ethyl acetate (300 mL x 6). The organic phases were combined and concentrated under reduced pressure. The crude product was purified by normal phase column chromatography (silica, methanol:dichloromethane = 0-3%) to afford compound 3 (1.41 g, 10.0 mmol, 42.0% yield).

[0600] 1 H NMR: 400MHz, CDCl3δ7.68(s,1H),7.63(s,1H),5.31(s,2H),3.86(s,3H).

[0601] Step 2: A solution of compound 3 (200 mg, 1.42 mmol) in formamide (2 mL) was stirred at 180°C for 2 hours. LCMS indicated complete reaction of the starting material with product formation. The reaction mixture was cooled to room temperature and filtered. The filter cake was collected to afford crude compound 4 (193 mg). The product was a yellow solid and was used directly in the next reaction.

[0602] 1 H NMR: ENBJ240001-060-P1A1, 400MHz, DMSO-d6δ8.44(d,J=0.8Hz,1H),7.91(s,1H),7.75(d,J=0.8Hz,1H),7.53–7.06(m,1H).

[0603] Step 3: Compound 4 (193 mg, 1.42 mmol), compound 5 (332 mg, 1.70 mmol), and potassium carbonate (392 mg, 2.84 mmol) were dissolved in DMF (3 mL). The reaction was stirred at 20°C for 2 hours. LCMS and TLC (petroleum ether:ethyl acetate = 10:1) indicated complete reaction. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was isolated and purified by column chromatography (silica, ethyl acetate:petroleum ether = 0-50%) to afford compound 6 (587 mg, 50% purity, 1.17 mmol, 82.7% yield). 1H NMR: DMSO-d6δ8.54(s,1H),8.18(s,1H),7.87(s,1H),4.60(s,2H),1.43(s,9H).

[0604] Step 4: To a solution of compound 6 (50.0 mg, 0.200 mmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.5 mL) at 0°C. The reaction was stirred at 20°C for 12 hours. LCMS (ENBJ240001-068-P1M1) indicated complete reaction of the starting material with ~60% product detected. The reaction solution was concentrated under reduced pressure to afford crude compound 7 (40.0 mg). The product was a yellow oil and used directly in the next reaction.

[0605] Step 5: Compound 7 (40.0 mg, 0.206 mmol), DIEA (79.8 mg, 0.618 mmol), and compound 8 (42.3 mg, 0.206 mmol) were dissolved in tetrahydrofuran (2 mL). T4P (397 mg, 0.412 mmol) was added at 0°C, and the reaction was stirred at 20°C for 12 hours. LCMS indicated complete reaction of the starting materials, and product formation was observed. The mixture was concentrated under reduced pressure and purified by prep-HPLC (Gemini column, mobile phase: acetonitrile / water (0.1% TFA), gradient: 30-70%) to afford compound BR-034891 (33.6 mg, 99.9% purity, 0.0880 mmol, 42.7% yield).

[0606] 1 H NMR: ENBJ240001-069-P1A1, 400MHz, DMSO-d6δ8.81(d,J=7.6Hz,1H),8.56(s,1H),8.13(s,1H),7.86(s,1H),7.45(d,J=8. 8Hz,2H),7.33(d,J=8.4Hz,2H),4.96(p,J=7.2Hz,1H),4.64–4.52(m,2H),1.38(d,J=7.2Hz,3H).MS(ESI)m / z=382.1[M+H] +

[0607] Example 89 Synthesis of Compound BR-034892

[0608] Following the synthetic procedure of Example 88, BR-034892 (80.4 mg, 0.203 mmol, 60.4% yield) was obtained as a white solid.

[0609] 1H NMR: DMSO-d6δ8.79(d,J=7.6Hz,1H),8.33(s,1H),7.99(s,1H),7.45(d,J=8.8Hz,2H),7.33(d,J=8.0Hz,2H ),4.96(p,J=7.2Hz,1H),4.58–4.47(m,2H),2.46(s,3H),1.39(d,J=6.8Hz,3H).MS(ESI)m / z=396.15[M+H] +

[0610] Example 90 Synthesis of Compound BR-034942

[0611] The synthetic steps of Example 88 were followed to obtain BR-034942 (60.5 mg, 0.152 mmol, 50.4% yield) as a white solid.

[0612] 1 H NMR: DMSO-d6δ8.80(d,J=8.0Hz,1H),8.09(s,1H),7.72(s,1H),7.45(d,J=8.8Hz,2H),7.33(d,J=8.4Hz,2H ),4.96(p,J=7.2Hz,1H),4.62–4.50(m,2H),2.52(s,3H),1.38(d,J=6.8Hz,3H).MS(ESI)m / z=395.75[M+H] +

[0613] Example 91 Synthesis of Compound BR-040742

[0614] Step 1: To a solution of compound 6 (1.09 g, 0.0044 mol) from Example 88 in DMF (9 mL) was added dropwise a solution of NBS (390 mg, 0.0022 mmol) in DMF (0.5 mL) at 0°C. The reaction was stirred at 50°C for 1 hour. An additional solution of NBS (390 mg, 0.0022 mmol) in DMF (0.5 mL) was added to the reaction at 0°C, and the reaction was stirred at 50°C for another 1 hour. LCMS showed complete reaction of the starting material with the presence of the desired product. The reaction was diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by normal phase column chromatography (silica, ethyl acetate:petroleum ether = 0-30%) to afford compound 1 (814 mg, 0.0025 mol, 83.3% yield).

[0615] 1H NMR: 400MHz, DMSO-d6δ8.55(s,1H),8.20(s,1H),4.57(s,2H),1.44(s,9H).MS(ESI)m / z=329.0[M+H] +

[0616] Step 2: Compound 1 (300 mg, 0.911 mmol), K3PO4 (387 mg, 1.82 mmol), and compound 2 (146 mg, 1.09 mmol) were dissolved in 10 mL of dioxane:water (5:1). Pd(dppf)Cl2 (66.7 mg, 0.0911 mmol) was added, and the reaction was stirred at 100°C under a nitrogen atmosphere (15 psi) for 12 hours. LCMS and TLC (petroleum ether:ethyl acetate = 3:1, Rf(P1) = 0.30) showed complete reaction of the starting materials and formation of the product. The reaction solution was filtered through celite, and the filtrate was collected and concentrated under reduced pressure. The crude product was isolated and purified by normal phase column chromatography (silica, ethyl acetate:petroleum ether = 0-25%) to afford compound 3 (244 mg, 0.883 mmol, 96.8% yield).

[0617] 1 H NMR: 400MHz, DMSO-d6δ8.47(s,1H),8.12(s,1H),7.07(dd,J=17.6,11.2Hz,1H),6. 18(dd,J=17.6,2.0Hz,1H),5.42(dd,J=11.2,2.0Hz,1H),4.58(s,2H),1.43(s,9H).

[0618] Step 3: To a solution of compound 3 (40.0 mg, 0.145 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL), and the reaction was stirred at 20°C for 3 hours. LCMS indicated complete reaction of the starting material and product formation was observed. The reaction solution was concentrated under reduced pressure to afford the crude product, compound 4 (31.0 mg, crude). The product was a yellow oil and was used directly in the next reaction.

[0619] Step 4: Compound 4 (31.0 mg, 0.141 mmol), DIEA (72.8 mg, 0.563 mmol), and compound 5 (28.9 mg, 0.141 mmol) were dissolved in tetrahydrofuran (3 mL). T4P (203 mg, 0.282 mmol) was added at 0°C, and the reaction was stirred at 20°C for 12 hours. LCMS showed complete reaction of the starting materials and the product was detected. The mixture was concentrated under reduced pressure and subjected to prep-HPLC (Gemini column, mobile phase: acetonitrile / water (0.1% FA), gradient: 40-70%) to afford compound BR-040742 (32.4 mg, 99.4% purity, 0.0791 mmol, 56.1% yield).

[0620] 1 H NMR: 400MHz, DMSO-d6δ8.80(d,J=7.6Hz,1H),8.44(s,1H),8.06(s,1H),7.45(d,J=8.8Hz,2H),7.33(d,J=8.4Hz,2H),7.13–7.01(m,1H),6.16( dd,J=17.6,2.4Hz,1H),5.40(dd,J=11.2,2.0Hz,1H),4.96(p,J=7.2Hz,1H),4.61–4.50(m,2H),1.38(d,J=7.2Hz,3H).MS(ESI)m / z=408.1[M+H] +

[0621] Example 92 Synthesis of Compound BR-040769

[0622] Step 1: Compound 3 (80.0 mg, 0.289 mmol) obtained in Example 91 was dissolved in methanol (6 mL). Palladium on carbon (30.8 mg, 0.289 mmol) was added and the reaction mixture was stirred at 20°C under a hydrogen atmosphere (15 Psi) for 2 hours. LCMS indicated complete reaction of the starting material and product was monitored. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to afford compound 1 (79.0 mg, crude).

[0623] 1 H NMR: 400MHz, DMSO-d6δ8.37(s,1H),8.07(s,1H),4.56(s,2H),2.87(q,J=7.6Hz,2H),1.43(s,9H),1.20(t,J=7.6Hz,3H).

[0624] Step 2: To a solution of compound 1 (79.0 mg, 0.284 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL) at 0°C. The reaction was stirred at 20°C for 12 hours. LCMS indicated complete reaction of the starting material and the presence of product. The reaction solution was concentrated under reduced pressure to afford the crude product, compound 2 (60.0 mg). The product was a yellow oil and was used directly in the next reaction.

[0625] Step 3: Compound 2 (60.0 mg, 0.270 mmol), DIEA (139 mg, 1.08 mmol) and compound 4

[0626] (55.4 mg, 0.270 mmol) was dissolved in tetrahydrofuran (4 mL), and T4P (389 mg, 0.540 mmol, 50 wt.% in EtOAC) was added at 0°C. The reaction was stirred at 20°C for 12 hours. LCMS analysis showed complete reaction of the starting material and product formation was observed. The mixture was concentrated under reduced pressure and subjected to prep-HPLC (Gemini column, mobile phase: acetonitrile / water (0.1% FA), gradient: 30-70%) to afford compound BR-040769 (85.69 mg, 99.9% purity, 0.209 mmol, 77.4% yield).

[0627] 1 H NMR: 400MHz, DMSO-d6δ8.80(d,J=7.6Hz,1H),8.35(s,1H),8.00(s,1H),7.45(d,J=8.8Hz,2H),7.33(d,J=8.4Hz,2H),4.96(p, J=6.8Hz,1H),4.59–4.47(m,2H),2.86(q,J=7.6Hz,2H),1.38(d,J=7.2Hz,3H),1.19(t,J=7.6Hz,3H).MS(ESI)m / z=410.1[M+H] +

[0628] Example 93 Synthesis of Compound BR-040820

[0629] Step 1: Compound 1 (200 mg, 0.607 mmol) from Example 91, K 3 PO 4 (258 mg, 1.22 mmol), cesium fluoride (92.3 mg, 0.607 mmol), and compound 1 (62.6 mg, 0.729 mmol) were dissolved in dioxane (8 mL). Pd(PPh 3 ) 4 (70.2 mg, 0.0607 mmol) was added, and the reaction mixture was stirred at 80° C. under a nitrogen atmosphere for 4 hours. LCMS indicated the formation of the product. The reaction mixture was concentrated under reduced pressure, and the crude product was isolated and purified by column chromatography (silica, ethyl acetate:petroleum ether = 0-40%) and prep-HPLC (column type: Gemini, mobile phase: acetonitrile / water (0.1% FA), gradient: 30-70%) to obtain compound 2 (20.0 mg, 0.0620 mmol, 10.2% yield). LCMS: MS(ESI)m / z=291.1[M+H] +

[0630] Step 2: To a solution of compound 2 (15.0 mg, 0.0517 mmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (1.5 mL), and the reaction was stirred at 20°C for 4 hours. LCMS showed complete reaction of the starting material and product formation was observed. The reaction solution was concentrated under reduced pressure to give the crude product, compound 3 (12.0 mg, crude). The product was a yellow oil and was used directly in the next reaction.

[0631] Step 3: Compound 3 (12.0 mg, 0.0512 mmol), DIEA (26.5 mg, 0.204 mmol), and compound 4 (10.5 mg, 0.0512 mmol) were dissolved in tetrahydrofuran (2 mL). T4P (73.8 mg, 0.102 mmol) was added at 0°C, and the reaction was stirred at 20°C for 4 hours. LCMS analysis indicated complete reaction of the starting materials and formation of the product. The mixture was concentrated under reduced pressure and subjected to prep-HPLC (Gemini column, mobile phase: acetonitrile / water (0.1% FA), gradient: 30-70%) to afford compound BR-040820 (14.36 mg, 98.1% purity, 0.0334 mmol, 65.2% yield).

[0632] 1H NMR: 400MHz, DMSO-d6δ8.79(d,J=7.6Hz,1H),8.26(s,1H),7.97(s,1H),7.45(d,J=8.8Hz,2H),7.33(d,J=8.0Hz,2H),4. 97(p,J=7.2Hz,1H),4.61–4.44(m,2H),2.46(s,1H),1.39(d,J=7.2Hz,3H),0.99–0.85(m,4H).MS(ESI)m / z=422.0[M+H] +

[0633] Example 94 Synthesis of Compound BR-040844

[0634] Step 1: Compound 7 (1.09 g, 4.12 mmol) from Example 90 and NBS (1.46 g, 8.24 mmol) were dissolved in DMF (11 mL). The mixture was stirred at 20°C for 2 hours. LCMS analysis showed that the starting materials were consumed, with approximately 93% of the desired product produced. The reaction solution was concentrated under reduced pressure to obtain a crude product. This crude product was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0-25%) to afford compound 2 (1.51 g, 90% purity, 97.5% yield) as a white solid.

[0635] 1 H NMR: CDCl3δ7.41(s,1H),4.48(s,2H),2.60(s,3H),1.50(s,9H).MS(ESI)m / z=342.90[M+H] +

[0636] Step 2: To a solution of compound 2 (200 mg, 0.582 mmol), compound 3 (109 mg, 0.874 mmol), and potassium phosphate (371 mg, 1.74 mmol) in dioxane / water (4:1, 5 mL) was added Pd(PPh3)4 (67.3 mg, 0.0582 mmol). The mixture was stirred at 100°C under a nitrogen atmosphere for 12 hours. LCMS analysis showed that the starting materials were consumed and the desired product was produced. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0-48%) to obtain compound 4 (51.0 mg, 0.183 mmol, 31.4% yield) as a yellow oil.

[0637] 1H NMR: CDCl3δ7.39(s,1H),4.48(s,2H),2.65(s,6H),1.50(s,9H).MS(ESI)m / z=279.05[M+H] +

[0638] Step 3: To a solution of compound 4 (41.0 mg, 0.147 mmol) in DCM (2 mL) was added TFA (1 mL) at 0°C, and the mixture was stirred at 20°C for 2 hours. LCMS analysis showed that the starting material was consumed and the desired product was produced. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was used in the next step without purification. Compound 6 (32.6 mg, crude) was obtained as a yellow oil.

[0639] Step 4: To a solution of compound 6 (32.6 mg, crude), compound 8 (30.1 mg, 0.146 mmol), and DIEA (94.8 mg, 0.733 mmol) in tetrahydrofuran (5 mL) at 0°C was added T4P (211 mg, 50 wt.% in ethyl acetate). The mixture was stirred at 20°C for 12 hours. LCMS analysis showed that the starting material was consumed and the desired product was produced. The mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (mobile phase: methanol / dichloromethane = 0-3%) to afford BR-040844 (58.3 mg, 0.142 mmol, 99.77% purity, 96.8% yield) as a white solid.

[0640] 1 H NMR: DMSO-d6δ8.78(d,J=8.0Hz,1H),7.96(s,1H),7.45(d,J=8.8Hz,2H),7.33(d,J=8.0Hz,2H),4.96(p,J= 7.2Hz,1H),4.57–4.46(m,2H),2.45(s,3H),2.42(s,3H),1.38(d,J=7.2Hz,3H).MS(ESI)m / z=410.05[M+H] +

[0641] Example 95 Synthesis of Compound BR-040845

[0642] Step 1: To a solution of compound 1 (300 mg, 2.01 mmol) and potassium carbonate (555 mg, 4.02 mmol) in DMF (10 mL) at 0°C was added compound 2 (470 mg, 2.41 mmol). The mixture was stirred at 20°C for 4 hours. LCMS analysis showed that the starting materials were consumed and the desired product was produced. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0-30%) to obtain compound 3 (320 mg, 1.15 mmol, 57.4% yield) as a colorless solid. MS (ESI) m / z = 208.0 [M-55] +

[0643] Step 2: To a solution of compound 3 (320 mg, 1.21 mmol) in DCM (10 mL) was added TFA (3 mL), and the mixture was stirred at 200°C for 3 hours. LCMS analysis showed that the starting material was consumed and the desired product was produced. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was used directly in the next step without purification. Compound 4 (350 mg, crude) was obtained as a white solid. MS (ESI) m / z = 208.1 [M+1] +

[0644] Step 3: To a solution of compound 4 (100 mg, crude), compound 5 (90.9 mg, 0.482 mmol), and DIEA (249 mg, 1.93 mmol) in tetrahydrofuran (5 mL) at 0°C was added T4P (695 mg, 50 wt.% in ethyl acetate). The mixture was stirred at 20°C for 12 hours. LCMS analysis showed complete consumption of the starting material, with approximately 80% of the desired product produced. The mixture was concentrated under reduced pressure to obtain a crude product. This crude product was purified by prep-HPLC (mobile phase: ACN-H2O (0.1% FA), gradient: 45-90%) to afford BR-040845 (96.15 mg, 0.243 mmol, 50.4% yield) as a white solid.

[0645] 1 H NMR: DMSO-d6δ8.78(d,J=7.6Hz,1H),7.87(s,1H),7.39(m,5H),6.37(d,J=2.4Hz,1H),4.96(p, J=6.8Hz,1H),4.59–4.43(m,2H),2.39(s,3H),1.39(d,J=7.2Hz,3H).MS(ESI)m / z=395.1[M+H] +

[0646] Test Example 1: Determination of compound activity using human GPR139 FLIPR Assay

[0647] CHO K1 cells were seeded at a density of 100,000 cells in a 10 cm culture dish and 10% FBS in F-12 (Gibco) was added in a 37 ° C incubator overnight. On the day of transfection, 1 μg of plasmid DNA of GPR139 WT was transfected into the cells by TransIT2020 (Mirus Bio). After 24 hours, the cells were trypsinized and seeded at a density of 15,000 cells per well in a black-edged, transparent-bottom 384-well plate (Greiner Bio-one). On the day of the assay, the growth medium was removed and the cells were loaded with 20 μL / well of 1x Fluo-4 direct calcium dye (prepared in HBSS buffer) (Invitrogen) and incubated in the dark at 37 ° C for 1 hour. FLIPR (Molecular Devices) was programmed to take 10 readings (1 reading per second), initially as a baseline before adding 10 μl of 3x JNJ-63533054 solution (prepared in HBSS buffer containing 0.1% BSA). Fluorescence intensity was recorded within 2 minutes after adding the drug for agonist activity detection. Different concentrations of the test compound were used, with JNJ-63533054 as the standard molecule, and its E max The value was defined as 100%, and the data were analyzed by nonlinear regression using GraphPad Prism 8.0. The activity results of some compounds (EC 50 and Emax %) are shown in Tables 3A and 3B, respectively. EC 50 <50nM:++++; 50nM≤EC 50 <100nM:++++; 100nM≤EC 50 <300nM:+++; 300nM ≤EC 50 <500nM:++; 500nM≤EC 50 :+E max (Maximal effect) refers to the maximum biological effect or response intensity produced by a test compound under given experimental conditions.

[0648] Test Example 2: NFAT-Luc assay for compound activity

[0649] 293T-GPR139-NFAT reporter gene stable cell line was seeded at 40,000 cells per well in a 96-well, white-walled, clear-bottomed cell culture plate using DMEM medium supplemented with 10% FBS and cultured overnight in a 37°C, 5% CO2 incubator. The next day, the test compound was diluted in a 3-fold series (30 μM, 10 μM, 3.3 μM, 1.1 μM, 0.37 μM, 0.12 μM, 0.04 μM, 0.014 μM) using DMEM medium supplemented with FBS. The overnight cultured cell plate was removed from the incubator, the original medium in the plate was discarded, and the prepared DMEM medium containing the test compound at various concentrations was added. The cells were then incubated in a 37°C, 5% CO2 incubator for 6 hours. After completion of the incubation, the cell culture plate and luciferase assay reagent (Promega Steady-Glo Luciferase Assay System) were allowed to equilibrate at room temperature for 30 minutes. To a 96-well plate, 100 μL of the equilibrated detection reagent was added and incubated at room temperature for 10 minutes. Fluorescence was measured using a full-function microplate reader (BioTek synergyNeo2), with TAK-041 used as the standard molecule, and its Emax value was defined as 100%. Data were analyzed using the Graphpad prim 8.0 nonlinear regression algorithm, and the EC values ​​of some compounds were determined using NFAT-Luc. 50 and E max The results are shown in Tables 4A and 4B, respectively. EC 50 <1 μM: +++++; 1 μM ≤ EC 50 <10μM:++++; 10μM≤EC 50 <20 μM: +++; 20 μM ≤ EC 50 <30 μM: ++; 30 μM ≤ EC 50 :+E max (Maximal effect) refers to the maximum biological effect or response produced by a test compound under given experimental conditions.

[0650] The technical solution of the present invention is not limited to the above-mentioned specific embodiments. Any technical variations made according to the technical solution of the present invention fall within the protection scope of the present invention.

Claims

1. A compound as shown in formula I, or a pharmaceutically acceptable salt thereof wherein Q1 is selected from N or CR5 and Q2 is selected from N, NR5 or CR5, wherein R1 and R5 are each independently selected from H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl; or two adjacent R5 or R5 and R1 together with the atoms to which they are attached form a C4-10 cycloalkenyl, a 4-10 membered heterocycloalkenyl, or a 5-10 membered heteroaryl; wherein the -O-C1- wherein R is selected from -OH, halogen, or C1-3 alkyl; R2 is each independently selected from H, deuterium, halogen, C1-5 alkyl optionally substituted by one or more halogens, or -O-C1-5 alkyl optionally substituted by one or more halogens; R3 is selected from deuterium, C1-6 alkyl, which is optionally substituted with one or more groups selected from the following: deuterium, -OH, halogen, oxo, -O-glucuronide, -NH2, or -NHCH2COOH; R4 is selected from H, deuterium, -OH or -O-glucuronide; and wherein m is an integer selected from 0 to 2, n is an integer selected from 0 to 5, and Indicates a double bond or a single bond; Preferably, the compound or a pharmaceutically acceptable salt thereof is substantially enantiomerically pure.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein represents a double bond; and wherein Q1 and Q2 are each independently selected from N or CR5, provided that Q1 and Q2 are not N at the same time, wherein R1 and R5 are each independently selected from H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl; or two R5 on adjacent carbons or R5 and R1 together with the carbons to which they are attached form a C4-10 cycloalkenyl or a 4-10 membered heterocycloalkenyl; wherein the -O -C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C4-10 cycloalkenyl, or 4-10 membered heterocycloalkenyl is optionally substituted with one or more groups selected from the group consisting of deuterium, oxo, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, or -C(O)R9, wherein R9 is selected from -OH, halogen, or C1-3 alkyl; R2 is each independently selected from H, deuterium, halogen, C1-5 alkyl optionally substituted by one or more halogens, or -O-C1-5 alkyl optionally substituted by one or more halogens; R3 is selected from deuterium, C1-6 alkyl, which is optionally substituted with one or more groups selected from the following: deuterium, -OH, halogen, oxo, -O-glucuronide, -NH2, or -NHCH2COOH; R4 is selected from H, deuterium, -OH or -O-glucuronide; and wherein m is an integer selected from 0 to 2, n is an integer selected from 0 to 5, Preferably, the compound or a pharmaceutically acceptable salt thereof is substantially enantiomerically pure.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 and R5 are each independently selected from H, deuterium, halogen, -OH, -O-C1-5 alkyl, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, phenyl, C3-6 cycloalkyl, C4-6 cycloalkenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, or 4-6 membered heterocycloalkenyl, or two adjacent R5 or R5 and R1 together with the atoms to which they are attached form a C4-6 cycloalkenyl, a 4-6 membered heterocycloalkenyl, or a 5-6 membered heteroaryl; wherein wherein the -O-C1-5 alkyl, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, phenyl, C3-6 cycloalkyl, C4-6 cycloalkenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, or 5-6 membered heteroaryl is optionally substituted by one or more groups selected from the following: deuterium, -F, -Cl, -Br, -OH, -O-C1-3 alkyl, C1-3 alkyl, C2-4 alkenyl, or C2-4 alkynyl; and / or wherein R2 is independently selected from H, deuterium, -F, -Cl, -Br, a perhalogen-substituted C1-3 alkyl group or a perhalogen-substituted -O-C1-3 alkyl group, preferably a perhalogen-substituted methyl group or a perhalogen-substituted methoxy group, further preferably -CF3 or -OCF3, more preferably -OCF3; and / or wherein R3 is selected from deuterium, C1-3 alkyl, which is optionally substituted by one or more groups selected from the following: deuterium, -OH, halogen, oxo or -NH2; and / or wherein R4 is selected from H or deuterium; and / or wherein m is 0 or 1, and / or n is 0, 1 or 2.

4. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R1 and R5 are each independently selected from H, deuterium, halogen, -OH, -O-C1-5 alkyl, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, phenyl, C3-6 cycloalkyl, C4-6 cycloalkenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, or 4-6 membered heterocycloalkenyl, or two R5 on adjacent carbons or R5 and R1 together with the carbons to which they are attached together form a C4-6 cycloalkenyl or a 4-6 membered heterocyclic ring. wherein the -O-C1-5 alkyl, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, phenyl, C3-6 cycloalkyl, C4-6 cycloalkenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C4-6 cycloalkenyl or 4-6 membered heterocycloalkenyl is optionally substituted with one or more groups selected from the group consisting of deuterium, -F, -Cl, -Br, -OH, -O-C1-3 alkyl, or C1-3 alkyl; and / or wherein R2 is independently selected from H, deuterium, -F, -Cl, -Br, a perhalogen-substituted C1-3 alkyl group or a perhalogen-substituted -O-C1-3 alkyl group, preferably a perhalogen-substituted methyl group or a perhalogen-substituted methoxy group, further preferably -CF3 or -OCF3, more preferably -OCF3; and / or wherein R3 is selected from deuterium, C1-3 alkyl, which is optionally substituted by one or more groups selected from the following: deuterium, -OH, halogen, oxo or -NH2; and / or wherein R4 is selected from H or deuterium; and / or wherein m is 0 or 1, and / or n is 0, 1 or 2.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 and R5 are each independently selected from H, deuterium, -F, -Cl, -Br, and -O-C1-3 alkyl optionally substituted with one or more deuterium, -F, -Cl, Br, C1-3 alkyl or -O-C1-3 alkyl, C1-3 alkyl, propenyl, allyl, phenyl, C3-5 cycloalkyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, cyclopentenyl, cyclohexenyl, 3,6-dihydro-2H-pyranyl, or 2,5-dihydrofuranyl, or two adjacent R5 or R5 and R1 together with the atoms to which they are attached form a C5-6 cycloalkenyl, a 5-6 membered heterocycloalkenyl, or a 5-6 membered heteroaryl optionally substituted with one or more deuterium, -F, -Cl, Br, C1-3 alkyl, C2-4 alkenyl or -O-C1-3 alkyl.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 and R5 are each independently selected from H, deuterium, -F, -Cl, -Br, and -O-C1-3 alkyl, C1-3 alkyl, propenyl, allyl, phenyl, optionally substituted with one or more deuterium, -F, -Cl, Br, C1-3 alkyl or -O-C1-3 alkyl. Or two adjacent R5 or R5 and R1 together with the atoms to which they are respectively connected form a cyclopentenyl, cyclopentadienyl, cyclohexenyl, 1,4-cyclohexadienyl, tetrahydropyridinyl, dihydropyridinyl, pyrrolinyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2,5-dihydrofuranyl, 1H-imidazolyl, 1H-pyrrolyl group which is optionally substituted with one or more deuterium, -F, -Cl, Br, C1-3 alkyl, C2-4 alkenyl or -O-C1-3 alkyl group.

7. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R1 and R5 are each independently selected from H, deuterium, -F, -Cl, -Br, and -O-C1-3 alkyl optionally substituted with one or more deuterium, -F, -Cl, Br, C1-3 alkyl or -O-C1-3 alkyl, C1-3 alkyl, propenyl, allyl, phenyl, C3-5 cycloalkyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, cyclopentenyl, cyclohexenyl, 3,6-dihydro-2H-pyranyl, or 2,5-dihydrofuranyl, or two R5 on adjacent carbons or R5 and R1 together with the carbon to which they are each attached form a C5-6 cycloalkenyl or 5-6 membered heterocycloalkenyl optionally substituted with one or more deuterium, -F, -Cl, Br, C1-3 alkyl or -O-C1-3 alkyl.

8. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R1 and R5 are each independently selected from H, deuterium, -F, -Cl, -Br, and -O-C1-3 alkyl, C1-3 alkyl, propenyl, allyl, phenyl, optionally substituted with one or more deuterium, -F, -Cl, Br, C1-3 alkyl or -O-C1-3 alkyl. Or two R5 on adjacent carbons or R5 and R1 together with the carbon to which they are respectively connected form a cyclopentenyl, cyclopentadienyl, cyclohexenyl, 1,4-cyclohexadienyl, tetrahydropyridinyl, dihydropyridinyl, pyrrolinyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2,5-dihydrofuranyl group optionally substituted with one or more deuterium, -F, -Cl, Br, C1-3 alkyl or -O-C1-3 alkyl.

9. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R3 is selected from methyl and R4 is selected from H.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 and R5 are each independently selected from isopropyl, phenyl, cyclopropyl, propenyl or phenyl groups optionally substituted with one or more deuterium, -F, -Cl, Br, C1-3 alkyl or -O-C1-3 alkyl. Or two adjacent R5 or R5 and R1 together with the atoms to which they are respectively attached form a cyclopentenyl group optionally substituted by one or more deuterium, -F, -Cl, Br, C1-3 alkyl or -O-C1-3 alkyl.

11. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R1 and R5 are each independently selected from isopropyl, phenyl, cyclopropyl, or Or two R5 on adjacent carbons or R5 and R1 together with the carbons to which they are respectively attached form a cyclopentenyl group optionally substituted with one or more deuterium, -F, -Cl, Br, C1-3 alkyl or -O-C1-3 alkyl.

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The compound has a structure as shown in any one of formula (I-1) to formula (I-5): wherein R1, R2, R5, Q1, Q2 and n are as defined in claim 1, Q4 is selected from N or CR 10 , R 10 is selected from H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, or -C(O)R9, wherein R9 is selected from -OH, halogen or C1-3 alkyl, and q is an integer from 0 to 2, when q is 2, R 10 Can be the same or different.

13. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein The compound has a structure as shown in any one of formula (I-1) to formula (I-4): wherein R1, R2, R5, Q1, Q2 and n are as defined in claim 2, and wherein in formula (I-1) Represents a double bond.

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The compound has a structure as shown in formula (I-2i): wherein R1 is selected from H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl; wherein said -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl is optionally substituted with one or more groups selected from deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; R2 is selected from H, deuterium, halogen, C1-5 alkyl optionally substituted by one or more halogens, or -O-C1-5 alkyl optionally substituted by one or more halogens; Preferably, R1 is selected from the group consisting of: Deuterium, halogen (preferably Br), linear or branched C1-3 alkyl, -O-C1-3 alkyl, cis or trans propenyl wherein R6 is selected from deuterium, halogen (e.g., F, Cl, Br), -OH, C1-3 alkyl, -O-C1-3 alkyl, and o is 0, 1 or 2, and when o is 2, R6 may be the same or different; Q3 is selected from O, S, -CH2- or wherein R7 is selected from H, deuterium or C1-3 alkyl, preferably H and methyl, and R2 is selected from H, deuterium, -F, -Cl, -Br, perhalogen-substituted C1-3 alkyl or perhalogen-substituted -O-C1-3 alkyl, preferably perhalogen-substituted methyl or perhalogen-substituted methoxy, also preferably -CF3 or -OCF3, more preferably -OCF3.

15. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: Deuterium, Br, methyl, ethyl, propyl, isopropyl, -O-CH3, wherein each X is independently selected from F, Cl, Br or I.

16. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein The compound has a structure as shown in formula (I-2i): wherein R1 is selected from H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl; wherein said -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl is optionally substituted with one or more groups selected from deuterium, halogen, -OH, -O-C1-10 alkyl, or C1-10 alkyl; R2 is selected from H, deuterium, halogen, C1-5 alkyl optionally substituted by one or more halogens, or -O-C1-5 alkyl optionally substituted by one or more halogens; Preferably, R1 is selected from the group consisting of: Deuterium, halogen (preferably Br), linear or branched C1-3 alkyl, -O-C1-3 alkyl, cis or trans propenyl wherein R6 is selected from deuterium, halogen (e.g., F, Cl, Br), -OH, -O-C1-3 alkyl, and o is 0, 1 or 2, and when o is 2, R6 may be the same or different; Q3 is selected from O, S, -CH2- or wherein R7 is selected from H, deuterium or C1-3 alkyl, preferably H and methyl, and R2 is selected from H, deuterium, -F, -Cl, -Br, perhalogen-substituted C1-3 alkyl or perhalogen-substituted -O-C1-3 alkyl, preferably perhalogen-substituted methyl or perhalogen-substituted methoxy, also preferably -CF3 or -OCF3, more preferably -OCF3.

17. The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: Deuterium, Br, methyl, ethyl, propyl, isopropyl, -O-CH3, wherein each X is independently selected from F, Cl, Br or I.

18. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein The compound has a structure as shown in formula (I-2ii): Wherein Q3 is selected from O, S, -CH2- or And wherein R7 is selected from H, deuterium or C1-3 alkyl, preferably H and methyl, R8 is selected from H, deuterium, halogen, oxo, -OH, -O-C1-3 alkyl or C1-3 alkyl, and wherein R2 is selected from H, deuterium, -F, -Cl, -Br, perhalogen-substituted C1-3 alkyl or perhalogen-substituted -O-C1-3 alkyl, preferably perhalogen-substituted methyl or perhalogen-substituted methoxy, also preferably -CF3 or -OCF3, more preferably -OCF3.

19. The compound according to claim 18 or a pharmaceutically acceptable salt thereof, wherein The group in formula (I-2ii) Having a structure selected from the following:

20. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The compound has a structure as shown in formula (I-3i): wherein R1 is selected from H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl; wherein said -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl is optionally substituted with one or more groups selected from deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C1-10 alkenyl, or C2-10 alkynyl; R2 is selected from H, deuterium, halogen, C1-5 alkyl optionally substituted by one or more halogens, or -O-C1-5 alkyl optionally substituted by one or more halogens; Preferably, R1 is selected from the group consisting of: Deuterium, halogen (preferably Br), linear or branched C1-3 alkyl, -O-C1-3 alkyl, cis or trans propenyl wherein R6 is selected from deuterium, halogen (e.g., F, Cl, Br), -OH, C1-3 alkyl, -O-C1-3 alkyl, and o is 0, 1 or 2, and when o is 2, R6 may be the same or different; Q3 is selected from O, S, -CH2- or wherein R7 is selected from H, deuterium or C1-3 alkyl, preferably H and methyl, and R2 is selected from H, deuterium, -F, -Cl, -Br, perhalogen-substituted C1-3 alkyl or perhalogen-substituted -O-C1-3 alkyl, preferably perhalogen-substituted methyl or perhalogen-substituted methoxy, also preferably -CF3 or -OCF3, more preferably -OCF3.

21. The compound according to claim 20 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: Deuterium, Br, methyl, ethyl, propyl, isopropyl, -O-CH3, wherein each X is independently selected from F, Cl, Br or I.

22. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein The compound has a structure as shown in formula (I-3i): wherein R1 is selected from H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl; wherein said -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl is optionally substituted with one or more groups selected from deuterium, halogen, -OH, -O-C1-10 alkyl, or C1-10 alkyl; R2 is selected from H, deuterium, halogen, C1-5 alkyl optionally substituted by one or more halogens, or -O-C1-5 alkyl optionally substituted by one or more halogens; Preferably, R1 is selected from the group consisting of: Deuterium, halogen (preferably Br), linear or branched C1-3 alkyl, -O-C1-3 alkyl, cis or trans propenyl wherein R6 is selected from deuterium, halogen (e.g., F, Cl, Br), -OH, -O-C1-3 alkyl, and o is 0, 1 or 2, and when o is 2, R6 may be the same or different; Q3 is selected from O, S, -CH2- or wherein R7 is selected from H, deuterium or C1-3 alkyl, preferably H and methyl, and R2 is selected from H, deuterium, -F, -Cl, -Br, perhalogen-substituted C1-3 alkyl or perhalogen-substituted -O-C1-3 alkyl, preferably perhalogen-substituted methyl or perhalogen-substituted methoxy, also preferably -CF3 or -OCF3, more preferably -OCF3.

23. A compound according to claim 22 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: Deuterium, Br, methyl, ethyl, propyl, isopropyl, -O-CH3, wherein each X is independently selected from F, Cl, Br or I.

24. A compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein The compound has a structure as shown in formula (I-3ii): Wherein Q3 is selected from O, S, -CH2- or And wherein R7 is selected from H, deuterium or C1-3 alkyl, preferably H and methyl, R8 is selected from H, deuterium, halogen, oxo, -OH, -O-C1-3 alkyl or C1-3 alkyl, and wherein R2 is selected from H, deuterium, -F, -Cl, -Br, perhalogen-substituted C1-3 alkyl or perhalogen-substituted -O-C1-3 alkyl, preferably perhalogen-substituted methyl or perhalogen-substituted methoxy, also preferably -CF3 or -OCF3, more preferably -OCF3.

25. The compound according to claim 24 or a pharmaceutically acceptable salt thereof, wherein The group in formula (I-3ii) Having a structure selected from the following:

26. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The compound has a structure as shown in formula (I-4i): wherein R1 is selected from H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl; wherein said -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl is optionally substituted with one or more groups selected from deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; R2 is selected from H, deuterium, halogen, C1-5 alkyl optionally substituted by one or more halogens, or -O-C1-5 alkyl optionally substituted by one or more halogens; Preferably, R1 is selected from the group consisting of: Halogen (preferably Br), linear or branched C1-3 alkyl, -O-C1-3 alkyl, cis or trans propenyl wherein R6 is selected from halogen (e.g., F, Cl, Br), -OH, C1-3 alkyl, -O-C1-3 alkyl, and o is 0, 1 or 2, and when o is 2, R6 may be the same or different; Q3 is selected from O, S, -CH2- or wherein R7 is selected from H or C1-3 alkyl, preferably H and methyl, and R2 is selected from H, -F, -Cl, -Br, perhalogen-substituted C1-3 alkyl or perhalogen-substituted -O-C1-3 alkyl, preferably perhalogen-substituted methyl or perhalogen-substituted methoxy, also preferably -CF3 or -OCF3, more preferably -OCF3.

27. The compound according to claim 26 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: Br, methyl, ethyl, propyl, isopropyl, -O-CH3, wherein each X is independently selected from F, Cl, Br or I.

28. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein The compound has a structure as shown in formula (I-4i): wherein R1 is selected from H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl; wherein said -O-C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl is optionally substituted with one or more groups selected from deuterium, halogen, -OH, -O-C1-10 alkyl, or C1-10 alkyl; R2 is selected from H, deuterium, halogen, C1-5 alkyl optionally substituted by one or more halogens, or -O-C1-5 alkyl optionally substituted by one or more halogens; Preferably, R1 is selected from the group consisting of: Halogen (preferably Br), linear or branched C1-3 alkyl, -O-C1-3 alkyl, cis or trans propenyl Wherein R6 is selected from halogen (e.g., F, Cl, Br), -OH, -O-C1-3 alkyl, and o is 0, 1 or 2, when o is 2, R6 may be the same or different; Q3 is selected from O, S, -CH2- or wherein R7 is selected from H or C1-3 alkyl, preferably H and methyl, and R2 is selected from H, -F, -Cl, -Br, perhalogen-substituted C1-3 alkyl or perhalogen-substituted -O-C1-3 alkyl, preferably perhalogen-substituted methyl or perhalogen-substituted methoxy, also preferably -CF3 or -OCF3, more preferably -OCF3.

29. The compound according to claim 28 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: Br, methyl, ethyl, propyl, isopropyl, -O-CH3, wherein each X is independently selected from F, Cl, Br or I.

30. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The compound has a structure as shown in formula (I-5i): Where R 10 Each is independently selected from -H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-5 alkenyl, or -C(O)R9, wherein R9 is selected from -OH, halogen or C1-3 alkyl, preferably R 10 Each is independently selected from -H, C1-3 alkyl, and C2-3 alkenyl.

31. A compound according to claim 30 or a pharmaceutically acceptable salt thereof, wherein The group in formula (I-5i) Having a structure selected from the following:

32. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The compound has a structure as shown in formula (I-5ii): Where R 10 Each is independently selected from -H, deuterium, halogen, -OH, -O-C1-10 alkyl, C1-10 alkyl, C2-5 alkenyl, or -C(O)R9, wherein R9 is selected from -OH, halogen or C1-3 alkyl, preferably R 10 Each is independently selected from -H, C1-3 alkyl, and C2-3 alkenyl.

33. A compound according to claim 32 or a pharmaceutically acceptable salt thereof, wherein The group in formula (I-5ii) Having a structure selected from the following:

34. The compound of claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof:

35. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

36. The pharmaceutical composition of claim 35, for use in treating a disease, disorder or condition associated with GPR139 selected from schizophrenia, Alzheimer's disease, Parkinson's disease, autism spectrum disorder, sleep disorder, cognitive impairment, depression, obsessive-compulsive disorder, anxiety, attention deficit hyperactivity disorder, post-traumatic stress disorder, bipolar disorder, eating disorder, substance use disorder, substance abuse, drug addiction, epilepsy, pain, fibromyalgia.

37. The pharmaceutical composition of claim 35, further comprising one or more other active ingredients selected from the group consisting of an antidepressant, an antipsychotic, an anxiolytic, a sedative, a hypnotic, or a tranquilizer.

38. Use of a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease, disorder or condition associated with GPR139.

39. The use of claim 38, wherein the disease, disorder or condition associated with GPR139 is selected from schizophrenia, Alzheimer's disease, Parkinson's disease, autism spectrum disorder, sleep disorder, cognitive impairment, depression, obsessive-compulsive disorder, anxiety disorder, attention deficit hyperactivity disorder, post-traumatic stress disorder, bipolar disorder, eating disorder, substance use disorder, substance abuse, drug addiction, epilepsy, pain, fibromyalgia.

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